NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY

Chronic Myeloid Leukemia, Version 2.2024

Neil P. Shah, MD, PhD1,*; Ravi Bhatia, MD2,*; Jessica K. Altman, MD3; Maria Amaya, MD, PhD4; Kebede H. Begna, MD5;
Ellin Berman, MD6; Onyee Chan, MD7; Joan Clements8; Robert H. Collins Jr, MD9; Peter T. Curtin, MD10;
Daniel J. DeAngelo, MD, PhD11; Michael Drazer, MD12; Lori Maness, MD13; Leland Metheny, MD14;
Sanjay Mohan, MD, MSCI15; Joseph O. Moore, MD16; Vivian Oehler, MD17; Keith Pratz, MD18;
Iskra Pusic, MD, MSCI19; Michal G. Rose, MD20; William Shomali, MD21; B. Douglas Smith, MD22; Michael Styler, MD23;
Moshe Talpaz, MD24; Tiffany N. Tanaka, MD25; Srinivas Tantravahi, MBBS26; James Thompson, MD, MS27;
Steven Tsai, MD28; Jennifer Vaughn, MD, MSPH29; Jeanna Welborn, MD30; David T. Yang, MD31;
Hema Sundar, PhD32; and Kristina Gregory, RN, MSN32

ABSTRACT NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform
Chronic myeloid leukemia (CML) is defined by the presence of NCCN consensus that the intervention is appropriate.
Philadelphia chromosome resulting from a reciprocal translocation be- Category 2A: Based upon lower-level evidence, there is uniform
tween chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fu- NCCN consensus that the intervention is appropriate.
sion gene. CML occurs in 3 different phases (chronic, accelerated, and Category 2B: Based upon lower-level evidence, there is
blast phase) and is usually diagnosed in the chronic phase in devel- NCCN consensus that the intervention is appropriate.
oped countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effec-
Category 3: Based upon any level of evidence, there is major
tive treatment option for patients with chronic phase–CML. The primary NCCN disagreement that the intervention is appropriate.
goal of TKI therapy in patients with chronic phase–CML is to prevent
disease progression to accelerated phase–CML or blast phase–CML. All recommendations are category 2A unless otherwise noted.
Discontinuation of TKI therapy with careful monitoring is feasible in se-
lected patients. This manuscript discusses the recommendations out- Clinical trials: NCCN believes that the best management of
lined in the NCCN Guidelines for the diagnosis and management of any patient with cancer is in a clinical trial. Participation in
patients with chronic phase–CML. clinical trials is especially encouraged.

J Natl Compr Canc Netw 2024;22(1):e240007

doi:10.6004/jnccn.2024.0007
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) are a statement of evidence and consensus of the
authors regarding their views of currently accepted approaches
to treatment. Any clinician seeking to apply or consult the NCCN
Guidelines is expected to use independent medical judgment in
the context of individual clinical circumstances to determine any
patient’s care or treatment. The National Comprehensive Cancer
Network® (NCCN®) makes no representations or warranties of
1
UCSF Helen Diller Family Comprehensive Cancer Center; 2O’Neal any kind regarding their content, use, or application and disclaims
Comprehensive Cancer Center at UAB; 3Robert H. Lurie Comprehensive Cancer any responsibility for their application or use in any way.
Center of Northwestern University; 4University of Colorado Cancer Center;
5
Mayo Clinic Comprehensive Cancer Center; 6Memorial Sloan Kettering Cancer The complete NCCN Guidelines for Chronic Myeloid Leuke-
Center; 7Moffitt Cancer Center; 8CML Buster Foundation; 9UT Southwestern mia are not printed in this issue of JNCCN but can be ac-
Simmons Comprehensive Cancer Center; 10City of Hope National Medical cessed online at NCCN.org.
Center; 11Dana-Farber/Brigham and Women’s Cancer Center; 12The UChicago
Medicine Comprehensive Cancer Center; 13Fred and Pamela Buffett Cancer
© 2024, National Comprehensive Cancer Network® (NCCN®).
Center; 14Case Comprehensive Cancer Center University Hospitals Seidman
All rights reserved. The NCCN Guidelines and the illustrations
Cancer Center and Cleveland Clinic Taussig Cancer Institute; 15Vanderbilt-
herein may not be reproduced in any form without the express
Ingram Cancer Center; 16Duke Cancer Institute; 17Fred Hutchinson Cancer
written permission of NCCN.
Center; 18Abramson Cancer Center at the University of Pennsylvania; 19Siteman
Cancer Center at Barnes-Jewish Hospital and Washington University School of Disclosures for the NCCN Chronic Myeloid Leukemia
Panel
Medicine; 20Yale Cancer Center/Smilow Cancer Hospital; 21Stanford Cancer
Institute; 22The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; At the beginning of each NCCN Guidelines Panel meeting, panel
23
Fox Chase Cancer Center; 24University of Michigan Rogel Cancer Center; members review all potential conflicts of interest. NCCN, in
25
UC San Diego Moores Cancer Center; 26Huntsman Cancer Institute at the keeping with its commitment to public transparency, publishes
University of Utah; 27Roswell Park Comprehensive Cancer Center; these disclosures for panel members, staff, and NCCN itself.
28
UCLA Jonsson Comprehensive Cancer Center; 29The Ohio State University
Individual disclosures for the NCCN Chronic Myeloid Leukemia
Comprehensive Cancer Center - James Cancer Hospital and Solove Research
Panel members can be found on page 69. (The most recent ver-
Institute; 30UC Davis Comprehensive Cancer Center; 31University of Wisconsin
sion of these guidelines and accompanying disclosures are avail-
Carbone Cancer Center; and 32National Comprehensive Cancer Network.
able at NCCN.org.)
*Discussion Writing Committee Member. The complete and most recent version of these guidelines is
available free of charge at NCCN.org.
Supplementary material is published online at https://doi.org/10.6004/jnccn.2024.0007

JNCCN.org | Volume 22 Issue 1 | February 2024 43

 NCCN GUIDELINES® Chronic Myeloid Leukemia, Version 2.2024

Overview usually produced in the setting of Ph-positive acute lym-

Chronic myeloid leukemia (CML) accounts for 15% of adult phoblastic leukemia, and p230 is associated with enhanced
leukemias. The median age of disease onset is 67 years; neutrophil differentiation. Atypical BCR::ABL1 transcripts
however, CML occurs in all age groups (SEER statistics). (eg, e13a3, e14a3, e6a2) have also been detected in about
In 2023, an estimated 8,930 people will be diagnosed 1%–2% of patients with CML. The proportion of different
with CML in the United States, and 1,310 people will die BCR::ABL1 transcripts and the impact of BCR::ABL1 tran-
of the disease.1 script type on response to tyrosine kinase inhibitor (TKI)
CML is defined by the presence of the Philadelphia therapy are discussed in the section “BCR::ABL1 Transcript
chromosome (Ph) in a patient with a myeloproliferative Variants in CML” (page 46).
neoplasm. Ph results from a reciprocal translocation be- CML occurs in 3 different phases (chronic, accelerated,
tween chromosomes 9 and 22 [t9;22] that gives rise to a and blast phase) and is usually diagnosed in the chronic
BCR::ABL1 fusion gene.2 In most patients, the chromo- phase in developed countries. Untreated chronic phase
somal breakpoints are located in intron 13 or 14 of the CML (CP-CML) will eventually progress to accelerated
BCR gene on chromosome 22 (major breakpoint cluster phase CML (AP-CML) or blast phase CML (BP-CML) in 3
region; M-BCR). In the ABL1 gene they are located be- to 5 years on average.5 Progression to AP-CML and BP-
tween the 2 alternative ABL1 exons Ib and Ia, or between CML bridges a continuum of clinical features (ie, fever, bone
ABL1 exons 1 and 2.3,4 Irrespective of the precise ABL1 pain, spleen size), cytogenetic changes, and blast count.
breakpoint, splicing almost invariably fuses ABL1 exon 2 Gene expression profiling has shown a close correlation of
with BCR exons 13 or 14, resulting in e13a2 and e14a2 gene expression between AP-CML and BP-CML indicating
transcripts that code for a protein, p210, with deregulated that the bulk of the genetic changes in progression occur
tyrosine kinase activity, which causes CML. in the transition from CP-CML to AP-CML.6 The activation
Unusual BCR::ABL1 transcripts, e1a2 encoding for p190 of the beta-catenin signaling pathway in CML granulocyte-
(involving the minor breakpoint cluster region; m-BCR), or macrophage progenitors (which enhances the self-renewal
e19a2 encoding for p230 (involving the micro breakpoint activity and leukemic potential of these cells) may be a key
cluster region; m-BCR), are found infrequently.3,4 p190 is pathobiologic event in the evolution to BP-CML.7

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The NCCN Clinical Practice Guidelines in Oncology genes can be used to confirm the diagnosis of CML. Inter-
(NCCN Guidelines) for CML discuss the clinical manage- phase FISH is performed on peripheral blood but can be
ment of CML in all 3 phases (chronic, accelerated, or blast associated with a false-positive rate of 1%–5% depending
phase). Evaluation for diseases other than CML as outlined on the specific probe used in the assay.13 Hypermetaphase
in the NCCN Guidelines for Myeloproliferative Neoplasms FISH is more sensitive and can analyze up to 500 meta-
is recommended for all patients with BCR::ABL1-negative phases at a time, but it is applicable only to dividing cells
myeloproliferative neoplasm. in the bone marrow.14 Double-fusion FISH is associated
with low false-positive rates and can detect all variant
Diagnosis and Workup translocations of the Ph-chromosome.15
Initial evaluation should consist of a history and physical Quantitative RT-PCR (qPCR) should be done at ini-
examination, including palpation of the spleen, complete tial workup to establish the presence of quantifiable
blood count with differential, chemistry profile, and hepa- BCR::ABL1 mRNA transcripts. qPCR, usually done on pe-
titis B panel. Bone marrow aspirate and biopsy for mor- ripheral blood, is the most sensitive assay available for
phologic and cytogenetic evaluation and quantitative the measurement of BCR::ABL1 mRNA and it can detect
reverse transcription polymerase chain reaction (RT-PCR) one CML cell in a background of $100,000 normal cells.
to establish the presence of quantifiable BCR::ABL1 mRNA qPCR results can be expressed in various ways, such as
transcripts at baseline are recommended to confirm the the ratio of BCR::ABL1 transcript numbers to the number
diagnosis of CML (See page CML-1). of control gene transcripts.16 An International Scale (IS)
Bone marrow cytogenetics with a minimum of 20 has been established to standardize molecular monitor-
metaphases is useful to detect additional chromosomal ing with qPCR across different laboratories with the use
abnormalities (ACAs) in Ph-positive cells, also known as of 1 of 3 control genes (BCR, ABL1, or GUSB) and a qPCR
clonal cytogenetic evolution (discussed in next section).8–12 assay with a sensitivity of at least 4-log reduction from the
If bone marrow evaluation is not feasible, fluorescence in standardized baseline.17 IS has become the gold standard
situ hybridization (FISH) on the bone marrow or a periph- of expressing qPCR values. More details on monitoring
eral blood specimen with dual probes for BCR and ABL1 with qPCR using the IS are provided in a later section.

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Qualitative RT-PCR for detecting atypical BCR::ABL1 tran- shown a trend toward better survival outcomes with
scripts should be considered if there is discordance be- e14a2 transcript,24,25 in other studies the type of tran-
tween FISH and qPCR results. See the section on script did not have any significant impact on long-term
“BCR::ABL1 Transcript Variants in CML” (next section). survival outcomes.23,26,29
BCR::ABL1 transcripts in the peripheral blood at very Limited available data from studies that evaluated
low levels (1–10 of 108 peripheral blood leukocytes) can the impact of BCR::ABL1 transcript variants on response
be detected in approximately 30% of individuals without to second-generation (2G) TKI therapy suggest that nilo-
CML, and the incidence of this increases with age. The tinib may be associated with inferior molecular response
risk of developing CML for these individuals is extremely rates in patients with e13a2 as well as e14a2 transcripts
low, and neither continued monitoring nor therapy is compared with imatinib 800 mg or dasatinib.24,30 The re-
indicated.18,19 sults of another study indicate that the difference in the
amplification characteristics between the e13a2 and
BCR::ABL1 Transcript Variants in CML e14a2 transcripts can affect the measurement of residual
e13a2 and e14a2 transcripts (both encoding for p210) disease, thus emphasizing the need to consider sequen-
were the most common BCR::ABL1 transcript variants tial measurement of minimal residual disease in addition
identified in about 39% and 62% of patients, respectively; to the achievement of response milestones at specific
e13a2 was more frequent in males and the proportion timepoints.31
decreased with age in both sexes.20,21 Unusual or atypical The presence of e1a2 transcript (encoding for p190)
transcripts were identified in about 2% of patients, with is associated with a higher risk of disease progression, in-
e1a2, e19a2, e13a3, and e14a3 being the most frequently ferior cytogenetic and molecular responses to TKI ther-
identified transcripts.20 The incidence of these atypical apy, and the presence of frequent mutations in epigenetic
transcripts was higher in females and the proportion de- modifiers genes.32–38 In a multivariate analysis, the e1a2
creased with age in both genders. The presence of e14a2 transcript was also identified as an independent predictor
at baseline was associated with higher molecular re- of inferior survival outcomes.34 It is important to be aware
sponse rates to imatinib.22–28 Although some studies have that these data refer to the presence of dominant e1a2

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transcript, not to the presence of low-level e1a2 transcripts of “major route” ACAs in Ph-positive cells (trisomy 8, iso-
in patients with dominant e13a2 or e14a2 transcripts. The chromosome 17q, second Ph, trisomy 19, and chromo-
presence of e19a2 transcript (encoding for p230) is asso- some 3 abnormalities) at diagnosis may have a negative
ciated with lower rates of cytogenetic and molecular prognostic impact on survival and disease progression to
response to TKIs and inferior survival outcomes, despite accelerated or blast phase.49–52 However, in another anal-
previous reports of an indolent disease course in the ysis that evaluated the outcomes of patients with CP-
pre-TKI era.35,36,39 Referral to centers with expertise in CML (with or without ACAs) treated with TKI therapy in
the management of CML is recommended. prospective studies, the presence of ACAs in Ph-positive
Qualitative RT-PCR, nested RT-PCR, or Sanger se- cells at the time of diagnosis was not associated with
quencing are useful for identifying atypical BCR::ABL1 worse prognosis.53 Survival outcomes were not signifi-
transcripts.40,41 qPCR using log-reduction from standard- cantly different among patients with ACAs in Ph-positive
ized baseline can be used to monitor e1a2 transcripts, cells based on TKI therapy (imatinib vs 2G TKIs) or imati-
and monitoring e19a2 transcripts is usually performed nib dose (400 vs 800 mg). It remains uncertain if 2G TKIs
using qualitative RT-PCR or nested RT-PCR. However, or high-dose imatinib would be more beneficial for pa-
there are no standardized qPCR assays for monitoring tients with ACAs in Ph-positive cells. Patients with ACAs
molecular response to TKI therapy in patients with atypi- in Ph-positive cells at diagnosis should be monitored
cal BCR::ABL1 transcripts.42,43 The utility of multiplex carefully for evidence of resistance to TKI therapy, and
PCR assays and patient-specific genomic DNA quantita- follow-up metaphase karyotype analysis should be per-
tive PCR assays for monitoring atypical BCR::ABL1 tran- formed if resistance is evident.
scripts has been demonstrated in some reports.44–48 Clonal cytogenetic evolution in Ph-negative cells has
also been reported in a small subset of patients treated
Clonal Cytogenetic Evolution with TKI therapy.54–65 The most common abnormalities
The prognostic significance of ACAs in Ph-positive cells include trisomy 8 and loss of the Y chromosome. Previous
is related to the specific chromosomal abnormality and work suggested that the overall prognosis of Ph-negative
other features of the accelerated phase.8–12 The presence clonal evolution is good and depends on response to

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imatinib therapy.58 However, the presence of chromo- clinical trials. Higher age, higher peripheral blasts, bigger
some abnormalities other than loss of the Y chromosome spleen, and low platelet counts were significantly associ-
has been associated with decreased survival in patients ated with increased probabilities of dying of CML. Pa-
with CP-CML treated with various TKIs, suggesting that tients in the intermediate- and the high-risk groups had
closer follow-up is indicated.66 Progression to myelodys- significantly higher probabilities of dying of CML than
plastic syndromes and acute myeloid leukemia have those in the low-risk group, and the probabilities were
been reported in patients with monosomy 7 (del 7q).67–69 also significantly different between the intermediate- and
high-risk groups. Unlike other scoring systems, the ELTS
score is focused on CML-specific overall survival (OS).
Additional Evaluation This is important, because many patients with CML die
CP-CML: Risk Stratification of non-CML causes, reflecting the efficacy of TKI therapy.
Sokal and Hasford (Euro) scoring systems have been used Determination of risk score using either the Sokal or
for the risk stratification of patients into 3 risk groups (low, Euro or ELTS scoring systems before start of TKI therapy is
intermediate, and high) in clinical trials evaluating TKIs.70,71 recommended for patients diagnosed with CP-CML.70–72
The Sokal score is based on the patient’s age, spleen size on
clinical examination, platelet count, and percentage of Myeloid Mutational Analysis
blasts in the peripheral blood.70 The Euro score includes eo- Mutations in epigenetic modifier genes (eg, ASXL1,
sinophils and basophils in the peripheral blood in addition IKZF1, BCOR, TET1/2, IDH1/2, DNMT3A/3B, EZH2) have
to the same clinical variables used in the Sokal score.71 been described in patients with CML, and the presence
The European Treatment and Outcome Study long- of epigenetic gene mutations at diagnosis has also been
term survival (ELTS) score is based on the same variables associated with lower rates of molecular/cytogenetic re-
as the Sokol score and provides the most useful predictor sponses and lower rates of progression-free survival
of CML-related death in patients treated with first-line (PFS)/event-free survival (EFS).73–87
imatinib.72 The ELTS score has been validated in a cohort Mutations in the ASXL1 gene are the most com-
of 1,120 patients with CP-CML treated with imatinib in 6 monly described secondary alterations in patients with

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CP-CML and are an independent predictor of inferior Next-generation sequencing (NGS) allows for the
molecular/cytogenetic responses and EFS rates after TKI detection of low-level BCR::ABL1 kinase domain muta-
therapy (including 2G-TKI therapy).86,87 In an analysis of tions and mutations in genes other than BCR::ABL1
222 patients with CP-CML (prospectively enrolled in the that may confer resistance to TKIs or portend disease
CML-V study), an ASXL1 mutation was detected in 20 progression.89,90 In a prospective, multicenter study
patients at the time of diagnosis. All patients had re- (NEXT-in-CML) that assessed the feasibility of NGS to
ceived nilotinib-based TKI therapy. The probability of detect low-level mutations in 236 consecutive patients
experiencing major molecular response (MMR) or better with CML and an inadequate response to TKI therapy,
at 12 months was significantly lower for patients with an NGS was more effective than conventional Sanger se-
ASXL1 mutation (55%; P5.0036) compared with 85% for quencing in the detection of low-level mutations.90
patients with no mutations and 82% for patients with Prospective monitoring of mutation kinetics demon-
other non-ASXL1 mutations.87 However, in another study strated that TKI-resistant low-level mutations are invari-
of 124 patients with newly diagnosed CP-CML, mutations ably selected if the patients are not switched to another
in epigenetic modifier genes (including ASXL1 mutation) TKI or if they are switched to an inappropriate TKI or
were predictive of response rates only in patients treated TKI dose.90 NGS with myeloid mutation panel should be
with imatinib but did not have any impact on the out- considered for patients with no identifiable BCR::ABL1
comes in patients treated with 2G TKIs.81 mutations.
IKZF1 exon deletions and mutations in ASXL1, RUNX1, Testing for BCR::ABL1–independent mutations using
and BCOR genes were the most frequently described NGS with myeloid mutation panel may be useful for pa-
secondary alterations in advanced phase–CML, while tients with CP-CML who do not experience optimal re-
IDH1/2 mutations were detected at a markedly lower sponse milestones due to the presence of cytopenias, for
frequency.74,79,82,84,85 IKZF1, RUNX1, and DNMT3A alter- those patients with TKI-resistant disease and for patients
ations were identified as important markers of disease with advanced phase–CML.80,83 However, there are very
progression to advanced phase–CML and risk of relapse limited data on the impact of BCR::ABL1–independent
after discontinuation of TKI.73,75,79,88 mutations in patients with newly diagnosed CP-CML.

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Additionally, BCR::ABL1–independent gene mutations have The selection of first-line TKI therapy (bosutinib, da-
also been frequently described in Ph-negative clones.91 The satinib, imatinib, or nilotinib) in a given patient should
impact of mutations is also variable depending on whether be based on the risk score, toxicity profile, patient’s age,
they occur in Ph-positive or Ph-negative clones. ability to tolerate therapy, and the presence of comorbid
Myeloid mutational analysis using NGS can be consid- conditions (see page CML-2). Allogeneic hematopoietic
ered for patients with CP-CML and advanced phase–CML cell transplantation (HCT) is no longer recommended as
at diagnosis. This is a category 2B recommendation for pa- a first-line treatment of patients with CP-CML.
tients with newly diagnosed CP-CML.

Clinical Considerations for the Selection of

Management of CP-CML First-Line Therapy
Primary Treatment Risk Stratification
Long-term efficacy data from randomized phase III studies Imatinib (400 mg daily) and 2G TKIs (bosutinib [400 mg
for first-line TKI therapy in patients with newly diagnosed daily], dasatinib [100 mg once daily], and nilotinib [300 mg
CP-CML are summarized in Table S1 in the Supplemen- twice daily]) are all appropriate options for first-line
tary material (available online with this article).92–96 In TKI therapy for patients with CP-CML across all risk
summary, (1) all TKIs recommended are highly effective in scores.92–96
newly diagnosed CP-CML, with long-term OS expected to The generic version of innovator drug (imatinib) has
be similar to that of aged-matched controls; (2) 2G TKIs, been shown to be noninferior to innovator drug (imatinib)
compared with imatinib, generally result in faster cytoge- in terms of efficacy with an acceptable toxicity profile.97–99
netic and molecular responses, with less progression to ad- A US FDA-approved generic version is an appropriate
vanced phase–CML; and (3) as of yet, in randomized substitute for an innovator drug (imatinib).100 Innova-
clinical trials, there are no significant differences in OS in tor and generic drugs approved by the regulatory au-
patients who start imatinib versus a 2G TKI (dasatinib, thorities based on pharmacokinetic equivalence can
nilotinib, and bosutinib). be used interchangeably.

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Data from randomized phase III studies that have (see Supplementary Table S3), which may facilitate
evaluated high-dose imatinib as first-line therapy for CP- subsequent discontinuation of TKI therapy in selected
CML suggest that imatinib 800 mg was not associated with patients.93,94,96
lower rates of disease progression than imatinib 400 mg, Therefore, 2G TKIs may be preferred over imatinib
despite improved early responses (see Supplementary for younger patients, particularly females since the
Table S2).101–103 Imatinib 800 mg was also associated with achievement of a deep and rapid molecular response
higher rates of dose interruption, reduction, or discon- may allow for eventual safe interruption of TKI therapy
tinuation due to grade 3 or 4 adverse events in all of for fertility purposes. Imatinib may be preferred for
the studies. However, patients who could tolerate the older patients with comorbidities, especially cardio-
higher dose of imatinib achieved higher response rates vascular comorbidities.
than those receiving standard-dose imatinib.104 Imatinib
800 mg is not recommended as initial therapy, given the Toxicity Profile
data showing superior efficacy of 2G TKIs in newly diag- All the TKIs are generally well tolerated. Since bosuti-
nosed CP-CML. nib, dasatinib, and nilotinib have very good efficacy in
Disease progression is more frequent in patients with the upfront setting, differences in their potential toxic-
intermediate- or high-risk score, and prevention of disease ity profiles may inform the selection of a specific TKI
progression to AP-CML or BP-CML is the primary goal of as initial therapy. Adverse events of first-line TKI therapy
TKI therapy in patients with CP-CML. 2G TKIs are associ- in patients with CP-CML reported in phase III random-
ated with a lower risk of disease progression than imatinib ized studies are discussed below and are summarized in
and are preferred for patients with an intermediate- or Supplementary Table S4.
high-risk Sokal or Euro score. 2G TKIs also result in quicker Nilotinib or bosutinib may be preferred for patients
molecular responses and higher rates of MMR (#0.1% with a history of lung disease or deemed to be at risk for
BCR::ABL1 IS) and deep molecular response (DMR) (MR4.0 developing pleural effusions. Dasatinib or bosutinib may
[#0.01% BCR::ABL1 IS] or MR4.5 [#0.0032% BCR::ABL1 be preferred in patients with a history of arrhythmias,
IS]) in patients with CP-CML across all risk scores cardiovascular disease, pancreatitis, or hyperglycemia.

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Bosutinib quality of life in patients who take imatinib.111 Hypophos-

In the BFORE study, diarrhea, increased alanine amino- phatemia and decrease in bone mineral density have
transferase, and aspartate aminotransferase were more been noted in a small group of patients, suggesting that
common with bosutinib, whereas muscle spasms and pe- monitoring bone health should be considered for pa-
ripheral edema were more common with imatinib.94,95 tients taking imatinib.112,113 Skin hypopigmentation has
Grade 3–4 thrombocytopenia was higher with bosutinib also been reported as a side effect of imatinib and is re-
and grade 3–4 neutropenia was higher with imatinib. versible on discontinuation or dose reduction.114,115 Re-
Grade 3–4 anemia was similar in both groups. Discontinu- versible renal dysfunction with prolonged use of imatinib
ation of therapy due to drug-related adverse events oc- has also been reported.116
curred in 14% of patients in the bosutinib group compared
with 11% in the imatinib group. Increased alanine amino- Nilotinib
transferase (5%) and increased aspartate aminotransferase In the ENESTnd study, rates of nonhematologic adverse
(2%) were the most common adverse events leading to events such as nausea, diarrhea, vomiting, muscle spasm,
discontinuation of bosutinib. However, there were no and peripheral edema of any grade were higher for pa-
hepatotoxicity-related fatalities during the study. tients receiving imatinib. Conversely, rash and headache
were more common with nilotinib.96 Grade 3 or 4 neutro-
Dasatinib penia was more frequently observed in the imatinib
In the DASISION study, the incidences of grade 3–4 he- group, whereas thrombocytopenia and anemia were sim-
matologic toxicities (anemia, neutropenia, and thrombo- ilar in both groups. Electrolyte abnormalities and eleva-
cytopenia) were higher for dasatinib than imatinib.93 tions in lipase, glucose, and bilirubin were more frequent
Nonhematologic adverse events such as muscle spasms, with nilotinib than with imatinib. Patients with a previ-
peripheral edema, and hypophosphatemia were more ous history of pancreatitis may be at greater risk of ele-
frequent with imatinib. Discontinuation of therapy be- vated serum lipase. The overall incidences of adverse
cause of drug-related adverse events occurred in 16% events leading to discontinuation of therapy were com-
and 7% of patients in the dasatinib and imatinib arms, parable in the nilotinib 300 mg twice-daily and imatinib
respectively. Dasatinib is associated with significant but arms (12% and 14%, respectively) and slightly higher in
reversible inhibition of platelet aggregation that may con- the nilotinib 400 mg twice-daily arm (20%).
tribute to bleeding in some patients, especially if accom- Nilotinib labeling contains a black box warning re-
panied by thrombocytopenia.105 garding the risk of QT interval prolongation, and sudden
Pleural effusion was also more common with dasati- cardiac death has been reported in patients receiving ni-
nib (28% in the DASISION study compared with ,1% lotinib.110 QT interval prolongation could be managed
with imatinib and 33% in a dose optimization study) and with dose reduction. Electrolyte abnormalities should be
age has been identified as a significant risk factor for the corrected before starting treatment with nilotinib, and
development of pleural effusion.106 The occurrence of electrolytes should be monitored periodically. Drugs that
pleural effusion is significantly reduced with dasatinib prolong QT interval should be avoided. Electrocardio-
100 mg once daily compared with 70 mg twice daily. Pa- gram should be obtained to monitor the QT interval at
tients with prior cardiac history, with hypertension, and baseline, 7 days after initiation of nilotinib, and periodi-
receiving dasatinib 70 mg twice daily are at increased risk cally thereafter, as well as after any dose adjustments.
of developing pleural effusions.107 Close monitoring and Nilotinib is associated with an increased risk of ische-
timely intervention are necessary for patients at risk for mic heart disease, ischemic cerebrovascular disease and
developing pleural effusions. peripheral arterial occlusive disease.96 The 10-year follow-
Largely reversible pulmonary arterial hypertension has up data from ENESTnd study showed a higher rate of
been reported as a rare but serious side effect of dasati- cardiovascular events with nilotinib (17% and 24%, re-
nib.108–110 In the DASISION study, pulmonary hypertension spectively for nilotinib 300 mg twice daily and nilotinib
was reported in 5% of patients treated with dasatinib com- 400 mg twice daily) versus imatinib (4%).96 Evaluation for
pared with ,1% of patients treated with imatinib.93 Evalua- pre-existing cardiovascular risk factors before starting
tion for signs and symptoms of underlying cardiopulmonary treatment with nilotinib and close monitoring for any car-
disease before starting and during treatment with dasatinib diovascular events during treatment with nilotinib is rec-
is recommended. If pulmonary arterial hypertension is con- ommended for all patients. Patients with cardiovascular
firmed, dasatinib must be permanently discontinued. risk factors should be referred to a cardiologist.

Imatinib Monitoring Response to TKI Therapy

Chronic fatigue (often correlated with musculoskeletal Response to TKI therapy is determined by the measure-
pain and muscular cramps) is a major factor in reducing ment of hematologic (normalization of peripheral blood

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Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

counts), cytogenetic (decrease in the number of Ph-positive the IS by applying a laboratory-specific conversion
metaphases using bone marrow cytogenetics), and molecu- factor.17,127
lar assessments (decrease in the amount of BCR::ABL1
chimeric mRNA using qPCR). The criteria for hemato- Recommendations for Monitoring Response to
logic, cytogenetic, and molecular response are summa- TKI Therapy
rized in CML-D (page 46). qPCR (IS) is the preferred method to monitor response to
Conventional bone marrow cytogenetics is the stan- TKI therapy. qPCR assays with a sensitivity of $4.5-log
dard method for monitoring cytogenetic responses, and reduction from the standardized baseline are recom-
many clinical trial response analyses have been based mended to measure BCR::ABL1 transcripts (See CML-E,
on conventional bone marrow cytogenetics. With the ad- page 47). In patients with prolonged myelosuppression
vent of qPCR, bone marrow cytogenetic analyses to as- who may not be in complete hematologic response (CHR)
sess response are rarely performed. If conventional bone due to persistent cytopenias or an unexplained drop in
marrow cytogenetics yield no analyzable metaphases, blood counts during therapy, bone marrow cytogenetics is
cytogenetic response can be evaluated by FISH, prefera- indicated to confirm response to TKI therapy and exclude
bly with a dual color probe to minimize false-positive other pathology, such as myelodysplastic syndrome or the
rates. FISH and cytogenetic results are correlated, but presence of chromosomal abnormalities other than Ph.
are not superimposable.117–119 Although some investiga- Given the risk for transient myelosuppression that can oc-
tors have reported that interphase FISH can be used to cur during early disease responses, TKI therapy should not
monitor complete cytogenetic response (CCyR), inade- be held while bone marrow evaluation is pending.
quate response to TKI therapy has not been defined on Monitoring with qPCR (IS) every 3 months is recom-
the basis of FISH analysis.120,121 The panel feels that FISH mended for all patients after initiating TKI therapy, in-
has been inadequately studied for monitoring response cluding those who meet response milestones at 3, 6, and
to TKI therapy and is not generally recommended for 12 months (#10% BCR::ABL1 IS at 3 and 6 months, #1%
monitoring response if conventional cytogenetics or qPCR BCR::ABL1 IS at 12 months, and #0.1% BCR::ABL1 IS at
are available. .12 months). After CCyR (#1% BCR::ABL1 IS) has been
qPCR is the only tool capable of monitoring responses achieved, molecular monitoring is recommended every
after the patient has experienced CCyR, since BCR::ABL1 3 months for 2 years and every 3 to 6 months thereafter.
transcripts typically remain detectable after CCyR is Frequent molecular monitoring with qPCR (IS) can
achieved. A major advantage of qPCR is the strong corre- help to identify nonadherence to TKI therapy early in the
lation between the results obtained from the peripheral treatment course.128 Since adherence to TKI therapy is
blood and the bone marrow, allowing for molecular associated with better clinical outcomes, frequent molec-
monitoring without bone marrow aspirations.122,123 ular monitoring is essential if there are concerns about
the patient's adherence to TKI therapy. In patients with
Standardization of Molecular Monitoring Using the IS deeper molecular responses (MMR and better) and who
In the IS, the standardized baseline (defined as the aver- are adherent with TKI therapy, the frequency of molecu-
age expression of BCR::ABL1 transcripts in 30 patients lar monitoring can be reduced, though the optimal fre-
with untreated CML enrolled in the IRIS trial) is set to quency is unknown. Molecular monitoring of response
100%. Molecular response is expressed as log-reduction to TKI therapy more frequently than every 3 months is
from 100%. For example, a 2-log reduction or greater not presently recommended.
(#1% BCR::ABL1 IS; MR2.0) generally correlates with
CCyR and a $3-log reduction (#0.1% BCR::ABL1 IS) is re- Prognostic Significance of Cytogenetic and
ferred to as MMR or MR3.0.17,124,125 Molecular Response
DMR is defined by the assay's level of sensitivity Early molecular response (EMR; #10% BCR::ABL1 IS at 3
(#0.01% BCR::ABL1 [IS], MR4.0; #0.0032% BCR::ABL1 and 6 months) after first-line TKI therapy has emerged as
[IS], MR4.5).126 The sensitivity of a qPCR assay depends an effective prognosticator of favorable long-term PFS
not only on the performance of the assay, but also on the and OS (see Supplementary Table S5).93,96,103,129 Some re-
quality of a given sample. ports suggest that EMR at 3 months has a superior prog-
As such, the term complete molecular response to nostic value and supports early intervention strategies
denote undetectable BCR::ABL1 transcripts (a negative based on the BCR::ABL1 transcript level at 3 months.130,131
qPCR test) should be abandoned, as it may refer to very However, other studies yielded partially conflicting re-
different levels of response, dependent on the quality of sults regarding the predictive value of BCR::ABL1 tran-
the sample and sensitivity of the test. Laboratories can scripts at 3 months.132 From a practical perspective, it is
use their individual assays, but the BCR::ABL1 transcripts important to consider these data points within the clini-
obtained in a given laboratory should be converted to cal context. For instance, if BCR::ABL1 transcript level is

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minimally above the 10% cutoff (eg, 11%–15% at 3 months), available to show that a change of therapy would im-
it is reasonable to reassess at 6 months before considering prove survival, PFS, or EFS in this group of patients.146
major changes to the treatment strategy. However, the achievement of MMR (#0.1% BCR::ABL1
Some studies have suggested that the rate of decline IS) at 12 months is associated with a very low probability
in BCR::ABL1 transcripts correlates with longer-term of subsequent loss of response and a high likelihood of
response.133–135 Among patients with .10% BCR::ABL1 experiencing a subsequent DMR (MR4.0; #0.01%
IS after 3 months of treatment with imatinib, those with BCR::ABL1 IS), which may facilitate discontinuation of
a faster decline in BCR::ABL1 (BCR::ABL1 halving time TKI therapy.43,144 In view of the ongoing evolution of
,76 days) had a superior outcome compared with those treatment goals (OS vs treatment-free remission [TFR]),
with a slower decline (4-year PFS rate was 92% vs 63%, expert panels have emphasized the importance of joint
respectively).133 In the German CML IV study, lack of a decision-making between patient and provider, particu-
half-log reduction of BCR::ABL1 transcripts at 3 months larly in ambiguous situations.147
was associated with a higher risk of disease progression
on imatinib therapy.134 The results of the D-First study Response Milestones After First-Line TKI Therapy
also showed that in patients treated with dasatinib, The most important goals of TKI therapy are to prevent
BCR::ABL1 halving time of 14 days or less was a signifi- disease progression to AP-CML or BP-CML and to
cant predictor of MMR by 12 months and DMR (MR4.0; achieve either MR2.0 (#1% BCR::ABL1 IS, which corre-
#0.01% BCR::ABL1 IS) by 18 months.135 sponds to CCyR) or MMR (#0.1% BCR::ABL1 IS) within
Achievement of CCyR or #1% BCR::ABL1 IS within 12 months after first-line TKI therapy. The guidelines em-
12 months after first-line TKI therapy is an established phasize that achievement of response milestones must
prognostic indicator of long-term survival.136,137 In the IRIS be interpreted within the clinical context, before making
study, the estimated 6-year PFS rate was 97% for patients drastic changes to the treatment strategy, especially in
experiencing a CCyR at 6 months compared with 80% for ambiguous situations.
patients with no cytogenetic response at 6 months.136 In an The panel has included #10% BCR::ABL1 IS at 3 and
analysis of patients with newly diagnosed CP-CML treated 6 months after initiation of first-line TKI therapy as a re-
with imatinib or 2G TKIs, the 3-year EFS and OS rates sponse milestone, because the achievement of EMR after
were 98% and 99% for patients who experienced CCyR at first-line TKI therapy is an effective prognosticator of fa-
12 months compared with 67% and 94% in patients who vorable long-term PFS (see CML-3, page 48). Achieve-
did not experience a CCyR.137 ment of .0.1%–1% BCR::ABL1 IS (#1% BCR::ABL1 IS,
MMR (#0.1% BCR::ABL1 IS) as a predictor of PFS and which correlates with CCyR) is considered the optimal
OS has also been evaluated in several studies.122,138–144 In response milestone at 12 months if the goal of therapy in
all of these studies, the analyses were done for different an individual patient is long-term survival, whereas the
outcomes measures at multiple time points, but failed to achievement of MMR (#0.1% BCR::ABL1 IS) at 12 months
adjust for multiple comparisons, thereby reducing the va- should be considered as the optimal response milestone
lidity of the conclusions. The general conclusion from if the treatment goal in an individual patient is TFR. Pa-
these studies is that the achievement of MMR is associ- tients who experience these response milestones are con-
ated with durable long-term cytogenetic remission and sidered to have TKI-sensitive disease, and continuation
lower rate of disease progression, but MMR is not a signif- of the same dose of TKI and assessment of BCR::ABL1
icant predictor of superior OS in patients with a stable transcripts with qPCR (IS) every 3 months is recom-
CCyR. Importantly, with longer follow-up, CCyR becomes mended for this group of patients.
an ever-stronger indicator of MMR, reducing the added In patients with a .10% BCR::ABL1 IS at 3 months and
prognostic value of MMR. Although the CML IV study .1% BCR::ABL1 IS at 12 months, clinical judgment should
showed that MR4.5 (#0.0032% BCR::ABL1 IS) at 4 years be used, considering problems with adherence (which can
was associated with a significantly higher OS (indepen- be common given drug toxicity at the start of therapy), rate
dent of therapy) than MR2.0 (#1% BCR::ABL1 IS, which of decline in BCR::ABL1 (the faster, the better), and how far
corresponds to CCyR), this study demonstrated no signifi- from the cutoff the BCR::ABL1 value falls. Inability to reach
cant differences in OS in patients who experienced MMR #10% BCR::ABL1 IS at 3 months or #1% BCR::ABL1 IS at
(#0.1% BCR::ABL1 IS) and those who experienced MR2.0 12 months is associated with a higher risk for disease pro-
(#1% BCR::ABL1 IS).143 gression. Patients with .10% BCR::ABL1 at 3 months or
The absence of MMR in the presence of a CCyR is .1% BCR::ABL1 at 12 months can switch to alternate TKI
therefore not considered as an inadequate response to or continue the same dose of TKI (bosutinib, dasatinib, im-
treatment. Although some investigators have reported atinib, or nilotinib) for another 3 months. BCR::ABL1 muta-
that dose escalation of imatinib might benefit patients tional analysis and evaluation for allogeneic HCT should
in CCyR with no MMR,145 no randomized studies are be considered. Bone marrow cytogenetics should be

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Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

considered to assess for major cytogenetic response Ponatinib was initially approved as a treatment op-
(MCyR) at 3 months or CCyR at 12 months. tion for patients with a T315I mutation and/or for patients
In patients with .0.1%–1% BCR::ABL1 IS at 12 months, for whom no other TKI is indicated based on the results
shared decision-making is recommended depending on of the PACE trial.160 The recommended initial dose of po-
the goal of therapy in individual patients (longer-term sur- natinib was 45 mg once daily. The high-dose intensity of
vival vs TFR). As discussed previously, although not associ- ponatinib was associated with increased risk of arterial
ated with increased OS, MMR at 12 months is associated occlusive events (AOE) and the incidence of cardiovascu-
with a lower rate of disease progression and a higher likeli- lar adverse events was highest among patients with pre-
hood of achieving DMR, which is a prerequisite for TFR. existing cardiovascular risk factors.160,165–167 In the PACE
Switching to a 2G TKI from imatinib might be considered trial, serious AOE (cardiovascular, cerebrovascular, and
to increase the probability of achieving MMR (#0.1% peripheral vascular) and venous thromboembolic events
BCR::ABL1 IS) at 12 months. However, there is a possibility occurred in 31% and 6% of patients, respectively.160 Car-
that a switch may be associated with increased toxicity. diovascular, cerebrovascular, and peripheral AOEs were
Referral to specialized CML centers and/or enrollment reported in 16%, 13%, and 14% of patients, respectively.
in a clinical trial should be considered. In the OPTIC trial that evaluated the safety and effi-
Patients with .10% BCR::ABL1 IS at 6 and 12 months cacy of response-adjusted dosing regimens, patients
are considered to have TKI-resistant disease. Evaluation were randomized to ponatinib starting doses of 45 mg,
for allogeneic HCT (ie, a discussion with a transplant 30 mg, and 15 mg, with dose reduction to 15 mg with ex-
specialist, which might include HLA testing) is recom- perience of #1% BCR::ABL1 (IS) in the 45 mg and 30 mg
mended. Bone marrow cytogenetic analysis to assess cohorts.161 Ponatinib was effective at all 3 dose levels
ACAs should be considered. Alternative treatment op- (45 mg, 30 mg, and 15 mg) and the maximum benefit was
tions should be considered as described subsequently. observed with 45 mg. After a median follow-up of
32 months, BCR::ABL1 (IS) #1% at 12 months was achieved
Second-Line Therapy in 44% of patients in the 45 mg cohort compared with
Dose escalation of imatinib up to 800 mg daily has been 29% and 23% in the 30 mg and 15 mg cohorts, respec-
shown to overcome some cases of primary resistance and tively. After response-based dose reduction to 15 mg, re-
is particularly effective for cytogenetic relapse in patients sponses were maintained in 73% and 79% of patients in
who had experienced cytogenetic response with imatinib the 45 mg and 30 mg cohorts, respectively. The rate of any
400 mg daily, although the duration of responses has typi- AOE reported in the OPTIC trial (10% in the 45 mg cohort;
cally been short.148–151 However, it is unlikely to benefit 5% and 3% in the 30 mg and 15 mg cohorts, respectively)
patients who do not experience hematologic response or was lower than that reported for ponatinib 45 mg in the
those who never had a cytogenetic response with imatinib PACE trial. Based on the results of the OPTIC trial, the
400 mg daily. In patients with .10% BCR::ABL1 IS at FDA has approved a response-adjusted dosing regimen
3 months after imatinib 400 mg, switching to nilotinib or for ponatinib (starting dose of 45 mg once daily with a re-
dasatinib has been shown to result in higher rates of duction to 15 mg on achievement of BCR::ABL1 [IS] #1%)
MMR at 12 months than dose escalation of imatinib.152–154 for patients with CP-CML with resistance or intolerance
Although dose escalation of imatinib has been shown to to $2 prior kinase inhibitors.
be beneficial for patients in CCyR without MMR, no ran- Cardiovascular risk factors (eg, diabetes mellitus, hy-
domized studies have shown that a change of therapy pertension, hyperlipidemia, smoking, estrogen use) should
would improve PFS or EFS in this group of patients.145,146 be identified and controlled before starting ponatinib. Pa-
Dasatinib, nilotinib, and bosutinib, which are more tients should be monitored for high blood pressure, evi-
potent than imatinib in vitro and retain activity against dence of arterial occlusive or thromboembolic events, and
many of the imatinib-resistant BCR::ABL1 kinase domain reduced cardiac function.168 Ponatinib should be inter-
mutants except T315I, are effective treatment options for rupted or stopped immediately for vascular occlusion and
patients who are intolerant to imatinib or CP-CML that is for new or worsening heart failure. Patients with cardiovas-
resistant to imatinib.155–157 Bosutinib also has shown ac- cular risk factors should be referred to a cardiologist. Asci-
tivity in patients with CP-CML that is resistant to multiple minib is approved for patients with CP-CML having the
TKIs (imatinib, dasatinib, and nilotinib).158,159 Ponatinib T315I mutation and/or CP-CML with resistance or intoler-
and asciminib (specifically targeting the ABL myristoyl ance to $2 prior TKIs.
pocket inhibitor) are active against most of the resistant In the phase III randomized study (ASCEMBL), asci-
BCR::ABL1 kinase domain mutants including T315I.160–164 minib 40 mg twice daily achieved higher molecular re-
Long-term efficacy data from clinical trials on second- sponse rates (MMR, MR4.0, and MR4.5) than bosutinib
line and subsequent TKI therapy for CP-CML are summa- 500 mg once daily in patients with CP-CML previously
rized in Supplementary Table S6. treated with $2 prior TKIs. The incidence of adverse

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events leading to treatment discontinuation was also EMR (#10% BCR::ABL1 IS at 3 and 6 months) after
lower with asciminib (6% vs 21%).163,164 Gastrointestinal second-line TKI therapy with dasatinib or nilotinib has
toxicities (diarrhea, nausea, and vomiting) and biochemi- also been reported to be a prognosticator of OS and PFS
cal abnormalities (increased alanine aminotransferase and (see Supplementary Table S7).155,156 Patients who do not
aspartate aminotransferase levels) were notably higher experience cytogenetic or molecular responses at 3, 6, or
with bosutinib. AOEs were reported in 3% and 1% of pa- 12 months after second-line and subsequent TKI therapy
tients treated with asciminib and bosutinib, respectively. should be considered for alternative therapies or alloge-
Patients with a history of cardiovascular risk factors or car- neic HCT if deemed eligible.
diovascular signs and symptoms should be carefully moni- BCR::ABL1 kinase domain mutation analysis (see later
tored, and appropriate treatment should be started as section), evaluation of drug interactions, and compliance to
clinically indicated. The recommended initial dose of asci- therapy are recommended before the start of second-line
minib is 80 mg once daily or 40 mg twice daily in patients TKI therapy. As discussed earlier, myeloid mutational analy-
without a T315I mutation and 200 mg twice daily for pa- sis using NGS to identify BCR::ABL1–independent mutations
tients with a T315I mutation. In the phase I study, most may also be useful for patients with CP-CML who do not ex-
patients with a T315I mutation experiencing CCyR and perience optimal response milestones due to the presence
MMR had received .150 mg twice-daily asciminib.162 of cytopenias and for those with TKI resistant disease.
Omacetaxine is a treatment option for patients with
CP-CML resistant or intolerant to $2 TKIs including Drug Interactions
those with a T315I mutation.169,170 Omacetaxine resulted All TKIs are metabolized in the liver by cytochrome P450
in MCyR, CCyR, and MMR rates of 23%, 16%, and 17%, (CYP) enzymes, and concomitant use of drugs that in-
respectively. The T315I clone declined to below detection duce or inhibit CYP3A4 or CYP3A5 enzymes may alter
limits in 61% of patients with CP-CML resistant to prior the therapeutic effect of TKIs.172,173
TKI therapy and the T315I mutation (CML 202 study; Drugs that are CYP3A4 or CYP3A5 inducers may de-
n562).169 The median PFS was 8 months and the median crease the therapeutic plasma concentration of TKIs,
OS had not yet been reached. In the cohort of patients whereas CYP3A4 inhibitors and drugs that are metabo-
with CP-CML resistant or intolerant to $2 TKIs (CML 203 lized by the CYP3A4 or CYP3A5 enzyme might result in
study; n546), the MCyR and CCyR rates were 22% and increased plasma levels of TKIs. In addition, imatinib is
4%, respectively. The median PFS and OS were 7 months also a weak inhibitor of the CYP2D6 and CYP2C9 isoen-
and 30 months, respectively.170 The response rates and zymes and nilotinib is a competitive inhibitor of CYP2C8,
survival outcomes, however, were substantially lower CYP2C9, CYP2D6, and UGT1A1, potentially increasing
than those observed with ponatinib in the PACE trial. the plasma concentrations of drugs eliminated by these
Omacetaxine had an acceptable toxicity profile, and the enzymes. Asciminib is also a CYP2C9 inhibitor and con-
most common grade 3–4 adverse events were thrombo- comitant use of asciminib increases the plasma concen-
cytopenia (67%), neutropenia (47%), and anemia (37%). tration of other drugs that are CYP2C9 substrates.
Concomitant use of drugs metabolized by these
Clinical Considerations for the Selection of enzymes requires caution, and appropriate alternatives
Second-Line TKI Therapy should be explored to optimize treatment outcome. If
Switching to a 2G TKI (based on the BCR::ABL1 kinase coadministration cannot be avoided, dose modification
domain mutation status) is recommended for patients should be considered.
with disease that is resistant to imatinib 400 mg daily.
Patients with disease that is resistant to bosutinib, Adherence to Therapy
dasatinib, or nilotinib could be switched to an alternate Treatment interruptions and nonadherence to therapy
2G TKI. However, there is no clear evidence to support may lead to undesirable clinical outcomes.174–176 In the
that switching to alternate 2G TKI therapy would improve ADAGIO study, nonadherence to imatinib was associated
long-term clinical outcome for this group of patients.171 with poorer response. Patients with suboptimal response
Subsequent therapy with an alternate 2G TKI is ex- missed significantly more imatinib doses (23%) than did
pected to be effective only in patients with identifiable those with optimal response (7%).174 Adherence to imati-
BCR::ABL1 mutations that confer resistance to TKI nib therapy has been identified as the only independent
therapy. Ponatinib is the preferred treatment option predictor for achieving complete molecular response on
for patients with a T315I mutation in any phase. Pona- standard-dose imatinib.175 The 6-year probability of
tinib is also preferred for patients with no identifiable experiencing complete molecular response was signifi-
BCR::ABL1 mutations. Evaluation of allogeneic HCT or cantly higher for patients with .90% adherence rate
enrollment in a clinical trial should be considered for (44% compared with 0% for patients with #90% adher-
this group of patients. ence rate; P5.002).175 Poor adherence to imatinib therapy

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has also been identified as the most important factor con- to imatinib, dasatinib, nilotinib, and bosutinib.202,203 The
tributing to cytogenetic relapse and inadequate response T315A, F317L/I/V/C, and V299L mutants are resistant to
to imatinib.176 Patients with adherence of 85% or less had dasatinib and the E255K/V, F359V/C, and Y253H mutants
a higher probability of losing CCyR at 2 years than those are resistant to nilotinib.200,204–206 The G250E and V299L
with adherence of greater than 85% (27% and 2%, respec- mutants are resistant to bosutinib.158
tively). Poor adherence to therapy has also been reported Bosutinib and dasatinib have demonstrated activity
in patients receiving dasatinib and nilotinib following in- in patients with BCR::ABL1 mutants resistant to nilotinib
adequate response to imatinib.177,178 (Y253H, E255K/V, and F359C/I/V).158,206 Bosutinib has
Patient education on adherence to therapy and close minimal activity against the F317L mutation (which is re-
monitoring of each patient’s adherence is critical to achiev- sistant to dasatinib) and nilotinib may be preferred over
ing optimal responses. In a significant proportion of pa- bosutinib in patients with the F317L mutation.200,205,207
tients with TKI-induced toxicities, responses have been Ponatinib is active against BCR::ABL1 mutants resistant
observed with doses well below their determined maxi- to dasatinib or nilotinib, including E255V, Y253H, F359V,
mum tolerated doses.179 Short interruptions or dose reduc- and T315I.160 There are not enough data available regard-
tions, when medically necessary, may not have a negative ing the impact of mutations on the efficacy of asciminib
impact on disease control or other outcomes. because of the heterogeneity of reported mutations and
Adequate and appropriate management of side effects low patient numbers in the ASCEMBL trial.163 Patients
and scheduling appropriate follow-up visits to review side with detectable bosutinib-resistant BCR::ABL1 mutations
effects may be helpful to improve patient adherence to (T315I or V299L) were ineligible to participate in this
therapy.180 Switching to an alternate TKI because of in- trial.163 In addition to T315I, asciminib has been reported
tolerance is appropriate for patients with disease re- to be active against select BCR::ABL1 mutants resistant to
sponding to TKI therapy and it might be beneficial for bosutinib, dasatinib, or nilotinib (G250E, Y253H, E255V).
selected patients with acute grade 3–4 nonhematologic However, F359V/I/C mutations are insensitive to ascimi-
toxicities or in those with chronic, low-grade nonhema- nib.208 Although new myristoyl-pocket mutations have
tologic toxicities that are not manageable with adequate been detected during asciminib treatment, there is insuf-
supportive care measures.181,182 ficient data to determine their significance.
BCR::ABL1 compound mutations (variants containing
Resistance to TKI Therapy $2 mutations within the same BCR::ABL1 allele that pre-
Aberrant expressions of drug transporters183–185 and sumably arise sequentially) confer different levels of resis-
plasma protein binding of TKI186–188 could contribute to tance to TKI therapy, and compound mutants involving
primary resistance by altering the intracellular and plasma T315I confer the highest level of resistance to all TKIs, in-
concentration of TKI. cluding ponatinib.209,210 In another study that used NGS to
Pretreatment levels of organic cation transporter 1 detect low-level and BCR::ABL1 compound mutations in
(OCT1) have been reported as the most powerful predic- 267 patients with heavily pretreated CP-CML from the
tor of response to imatinib.189 Conversely, cellular uptake PACE trial, no compound mutation was identified that con-
of dasatinib or nilotinib seems to be independent of sistently conferred resistance to ponatinib, suggesting that
OCT1 expression, suggesting that patients with low OCT1 such compound mutations are uncommon following treat-
expression might have better outcomes with dasatinib or ment with bosutinib, dasatinib, or nilotinib for CP-CML.211
nilotinib than with imatinib.190–193 BCR::ABL135INS has been associated with resistance
Monitoring imatinib plasma levels may be useful in to imatinib.212,213 In one study, BCR::ABL135INS was de-
determining patient adherence to therapy. However, tected in 23% of patients (64 of the 284 patients; 45 patients
there are no data to support that change of therapy based with CP-CML).213 Among the 34 patients with CP-CML
on plasma imatinib levels will affect treatment outcomes, treated with imatinib, primary refractory disease, disease
and assays that measure plasma levels of imatinib are progression while on imatinib and disease progression
not widely available. after dose interruption were reported in 24% (n58),
32% (n511), and 12% (n54) of patients respectively.
BCR::ABL1 Kinase Domain Mutation Analysis BCR::ABL135INS was also associated with grade 3 or 4 he-
Point mutations in the BCR::ABL1 kinase domain are a matologic toxicity. This study, however, was not powered
frequent mechanism of secondary resistance to TKI ther- to determine the efficacy of 2G TKI against BCR-ABL135INS
apy and are associated with poor prognosis and a higher since very few patients with this mutation received either
risk of disease progression.194–199 E255K/V, F359C/V, Y253H, dasatinib or nilotinib.
and T315I mutants are most commonly associated with BCR::ABL1 kinase domain mutational analysis is
disease progression and relapse.200,201 Among the BCR::ABL1 helpful in the selection of subsequent TKI therapy for
kinase domain mutations, T315I confers complete resistance patients with inadequate initial response to first-line or

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second-line TKI therapy.214 The guidelines recommend ($MR4.0; #0.01% BCR::ABL1 IS) for 2 or more years has
BCR::ABL1 kinase domain mutational analysis for pa- been evaluated in several clinical studies.220–234 Longer-
tients who do not achieve response milestones, for those term follow-up data from the TKI discontinuation trials are
with any sign of loss of response (hematologic or cytoge- summarized in Supplementary Table S8.
netic relapse), and if there is a 1-log increase in BCR::ABL1 The results of the RE-STIM study showed the safety
level with loss of MMR. of a second TKI discontinuation after a first unsuccessful
BCR::ABL1 kinase domain mutational analysis pro- attempt.235 The rate of molecular relapse after the first TKI
vides additional guidance for selecting subsequent TKI discontinuation attempt was the only factor significantly
therapy only in patients with identifiable mutations. associated with outcome. The TFR rate 24 months after
Treatment options based on BCR::ABL1 kinase domain the second TKI discontinuation was higher for patients
mutation status are outlined on CML-5 (page 49). In pa- who remained in DMR within the first 3 months after the
tients with no identifiable mutations, the selection of first TKI discontinuation (72% vs 32% for other patients).
subsequent TKI therapy should be based on the patient’s Approximately 40%–60% of patients who discontinue
age, ability to tolerate therapy, presence of comorbid TKI therapy after achieving DMR experience recurrence
conditions, and toxicity profile of the TKI. within 12 months of treatment cessation, in some cases
as early as 1 month after discontinuation of TKI therapy.
Rising BCR::ABL1 Transcripts Several factors may help predict the risk of recurrence af-
Rising BCR::ABL1 transcripts are associated with an in- ter TKI discontinuation (a higher Sokal risk score, female
creased likelihood of detecting BCR::ABL1 kinase domain gender, lower natural killer cell counts, suboptimal re-
mutations and cytogenetic relapse.215–219 In patients who had sponse or resistance to imatinib, duration of TKI therapy,
experienced very low levels of BCR::ABL1 transcripts, emer- and DMR before TKI discontinuation). However, only the
gence of BCR::ABL1 kinase domain mutations was more fre- duration of TKI therapy and DMR before discontinuation
quent in those who had a .2-fold increase in BCR::ABL1 of TKI therapy have been associated with TFR with a
transcripts compared with those with stable or decreasing high level of consistency.220,225,229,230
BCR::ABL1 transcripts.215 A serial rise has been reported to be In the EURO-SKI study, duration of treatment with ima-
more reliable than a single $2-fold increase in BCR::ABL1 tinib ($6 years) and duration of DMR (MR4.0 for 3 years)
transcripts.216,217 Among patients in CCyR with a $0.5-log were significantly associated with MMR maintenance at
increase in BCR::ABL1 transcripts on at least 2 occasions, the 6 months after discontinuation of imatinib and lack of
highest risk of disease progression was associated with loss MR4.0 at 36 months after discontinuation of TKI therapy
of MMR and .1-log increase in BCR::ABL1 transcripts.217 was highly predictive of subsequent loss of MMR.229,236 A
Rising transcript levels should prompt an investigation rapid initial decline in BCR::ABL1 transcripts after initiation
of treatment adherence and reassessment of coadminis- of first-line TKI therapy has also been shown to be an inde-
tered medications. The precise increase in BCR::ABL1 tran- pendent predictor of TFR eligibility and sustained TFR.237
scripts that warrants a mutation analysis depends on the Resumption of TKI therapy immediately after recur-
performance characteristics of the qPCR assay.219 Some rence results in the achievement of DMR in almost all pa-
laboratories have advocated a 2- to 3-fold range,141,218,219 tients. In the STIM study, molecular relapse (trigger to
while others have taken a more conservative approach resume TKI therapy) was defined as positivity for
(5- to 10-fold).217 Obviously, some common sense must BCR::ABL1 transcripts by qPCR confirmed by a 1-log in-
prevail, since the amount of change in absolute terms de- crease in BCR::ABL1 transcripts between 2 successive as-
pends on the level of molecular response. For example, a sessments or loss of MMR at one point.220,221 The results
finding of any BCR::ABL1 after achieving a DMR (MR4.5; of the A-STIM study showed that loss of MMR (#0.1%
#0.0032% BCR::ABL1 IS) is an infinite increase in BCR::ABL1 BCR::ABL1 IS) could be used as a practical criterion for
transcripts. However, a change in BCR::ABL1 transcripts from restarting TKI therapy. The estimated probability of MMR
a barely detectable level to MR4.5 is clearly different from a loss was 35% at 12 months and 36% at 24 months after
5-fold increase in BCR::ABL1 transcripts after achieving MMR. discontinuation of imatinib.223
Currently there are no specific guidelines for chang- TKI withdrawal syndrome (aggravation or new devel-
ing therapy only based on rising BCR::ABL1 levels as de- opment of musculoskeletal pain and/or pruritus after dis-
tected by qPCR, and it should be done only in the continuation of TKI therapy) has been reported during the
context of a clinical trial. TFR period in some TKI discontinuation studies.225,230,232,233
The occurrence of imatinib withdrawal syndrome was
Discontinuation of TKI Therapy associated with a lower rate of molecular relapse in the
The feasibility of discontinuation of TKI therapy (dasatinib, KID study.225
imatinib, or nilotinib) with close monitoring in carefully se- The feasibility of TFR after discontinuation of TKIs
lected patients who have exerienced and maintained DMR other than dasatinib, imatinib, or nilotinib has not yet

58 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 22 Issue 1 | February 2024
Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

been evaluated in clinical studies. In the EURO-SKI study from selected studies are outlined in Supplementary Ta-
that evaluated TFR after discontinuation of any first-line ble S9 and Supplementary Table S10.
TKI therapy (imatinib, dasatinib, or nilotinib) in eligible
patients, the type of first-line TKI therapy did not signifi- Bosutinib
cantly affect molecular relapse-free survival.229 Therefore, The recommended starting dose of bosutinib is 400 mg
it is reasonable to assume that the likelihood of TFR after daily for patients with newly diagnosed CP-CML (which
discontinuation would be similar irrespective of TKI in is better tolerated than the 500 mg daily dose that was
patients who have experienced and maintained DMR used in the initial randomized phase III trial) and 500 mg
(MR4.0; #0.01% BCR::ABL1 IS) for 2 or more years. once daily for intolerant or resistant CP-CML.
Clinical studies that have evaluated the safety and ef- In patients with newly diagnosed CP-CML, recommen-
ficacy of discontinuation of TKI have used strict eligibility dations from an expert panel suggest initiating bosutinib at
criteria and have mandated more frequent molecular 200 to 300 mg once daily (with dose escalation as clinically
monitoring than typically recommended for patients on indicated) in most patients and initiation at 400 mg daily is
TKI therapy. Access to a reliable qPCR (IS) with a sensitiv- recommended only for patients with high-risk disease.238
ity of detection of at least MR4.5 (BCR::ABL1 #0.0032% The results of a retrospective analysis suggest that dose re-
IS) and the availability of test results within 2 weeks is duction of bosutinib to 300 mg or 400 mg results in better
one of the key requirements to monitor patients after dis- tolerability and improved efficacy in patients with CP-CML
continuation of TKI therapy and ascertain their safety. resistant imatinib, dasatinib and/or nilotinib.239
Based on available evidence from clinical studies
that have evaluated the feasibility of TFR, the panel mem- Dasatinib
bers feel that discontinuation of TKI therapy (with close The recommended starting dose of dasatinib is 100 mg
monitoring) is feasible in carefully selected, consenting once daily for patients with CP-CML.
patients (in early CP-CML) who have achieved and main- Long-term follow-up of a single-arm study (81 evalu-
tained a DMR ($MR4.0) for 2 or more years. The panel able patients) suggests that dasatinib 50 mg once daily may
acknowledges that more frequent molecular monitoring have similar efficacy in patients with low- or intermediate-
is essential following discontinuation of TKI therapy for risk CP-CML.240,241 Dasatinib 20 mg once daily has also
the early identification of loss of MMR. Frequency of mo- been shown to be an appropriate starting dose for patients
lecular monitoring has varied substantially among differ- 65 years and over with newly diagnosed CP-CML.242,243 In-
ent studies, and the optimal frequency of molecular termittent dosing (on/off treatment with a drug holiday) or
monitoring in patients with a loss of MMR after dis- dose reduction to 50 mg once daily has also been shown to
continuation of TKI therapy has not been established. be effective as second-line and subsequent therapy in pa-
The criteria for the selection of patients suitable for tients with CP-CML resistant/intolerant to imatinib.244–247
discontinuation of TKI therapy and recommendations for Dasatinib at 50 mg (20 mg with careful monitoring in
molecular monitoring in TFR phase are outlined on CML- selected patients) should be considered for patients with
F (page 50). The panel emphasizes that discontinuation of clinically significant intolerance to dasatinib 100 mg once
TKI therapy outside of a clinical trial should be considered daily to avoid serious adverse events (eg, pleural effusion,
only if all the criteria included on the list are met. myelosuppression), necessitating the discontinuation of
dasatinib.
Dose Modifications of TKI Therapy
Limited available evidence (mostly from nonrandomized Imatinib
studies and retrospective analysis) suggests that initiation of The recommended starting dose of imatinib is 400 mg
TKIs (bosutinib, dasatinib, nilotinib) at lower doses and/or once daily for patients with CP-CML.
de-escalation for all TKIs (with close monitoring) in patients In a phase II study that evaluated imatinib 400 mg in
who achieve optimal responses are appropriate strategies 481 patients with newly diagnosed CML, dose reduction
for the prevention and management of treatment-related was required in 46% of patients due to intolerance and ex-
adverse events and to avoid long-term toxicities. However, cessive dose reductions to less than 300 mg was associated
except for ponatinib (OPTIC trial), the minimum effective with inferior response rates and survival outcomes.248
dose or optimal de-escalation of TKI has not yet been estab-
lished in prospective phase III randomized clinical trials. Nilotinib
The recommended starting dose of nilotinib is 300 mg
Initiation of TKIs at Lower Dose twice daily for patients with newly diagnosed CP-CML and
Low-dose TKIs for first-line or dose modifications for in- 400 mg twice daily for resistant or intolerant CP-CML.
tolerance or resistance have been evaluated mostly in In a retrospective analysis of 70 patients with newly
nonrandomized studies and retrospective analyses. Data diagnosed CP-CML, early dose reduction of nilotinib to

JNCCN.org | Volume 22 Issue 1 | February 2024 59

 NCCN GUIDELINES® Chronic Myeloid Leukemia, Version 2.2024

less than 600 mg/day resulted in a lower rate of adverse reduced dose nilotinib (once daily) in patients experiencing
events and better therapeutic efficacy.249 One-year MMR MMR on standard-dose nilotinib (twice daily).
and overall MR4.5 rates were 90% and 60%, respectively
for the 10 patients treated with 600 mg/day of nilotinib Management of CML During Pregnancy and
throughout the study, with no disease progression to ad- Breastfeeding
vanced phase. The median age of disease onset is 65 years, but CML oc-
The ENESTswift study showed that switching to nilo- curs in all age groups. The EUTOS population-based reg-
tinib 300 mg twice daily (which is lower than the recom- istry has reported that approximately 37% of patients are
mended dose of 400 mg daily in the second-line setting) of reproductive age at diagnosis.260 Clinical care teams
was effective and well-tolerated in most patients with should be prepared to address issues relating to fertility
CP-CML with intolerance to imatinib or dasatinib in the and pregnancy as well as counsel these patients about
first-line setting.250 the potential risks and benefits of treatment discontinua-
tion and possible resumption of TKI therapy should CML
Ponatinib recur during pregnancy.
The recommended initial dose of ponatinib is 45 mg
once daily. TKI Therapy and Conception
In the OPTIC trial, the optimal benefit was observed TKI therapy appears to affect some male hormones at
with 45 mg once daily for all patients including those least transiently, but it does not appear to have a deleteri-
with the T315I mutation. Ponatinib at lower dose levels ous effect on male fertility. Furthermore, the miscarriage
(30 mg once daily and 15 mg once daily) resulted in clini- or fetal abnormality rate is not elevated in female part-
cal benefit in patients without the T315I mutation (see ners of males on TKI therapy.261–265
Supplementary Table S6). These data support initiation TKI therapy during pregnancy has been associated
of ponatinib at 45 mg once daily for patients with the with both a higher rate of miscarriage and fetal abnor-
T315I mutation followed by dose reduction to 15 mg malities.266–271 In one report on the outcome of pregnan-
once daily on achievement of BCR::ABL1 (IS) #1%.161 cies in 180 patients exposed to imatinib during pregnancy,
The results of a retrospective analysis showed that 50% of pregnancies with known outcome were normal
ponatinib 15 mg daily was associated with a lower inci- and 10% of pregnancies with known outcome had fetal ab-
dence of drug-related adverse events with no impact on normalities.266 Eighteen pregnancies ended in spontane-
efficacy.251 ous abortion. In another report on the outcomes of
pregnancy and conception during treatment with dasati-
nib, among 46 patients treated with dasatinib, 15 patients
De-escalation or Intermittent Dosing of TKI (33%) delivered a normal infant.267 Elective or spontaneous
TKI de-escalation has been shown to be feasible in pa- abortions were reported in 18 (39%) and 8 patients (17%),
tients, primarily those without prior TKI resistance, who respectively, and 5 patients (11%) had an abnormal preg-
had received TKI therapy for 2 or more years with dura- nancy. Fetal abnormalities were reported in 7 cases.
ble MMR or DMR for 12 or more months.252–259 Among 33 patients who conceived with males who had re-
Data from selected clinical trials that have evaluated ceived treatment with dasatinib, 30 (91%) delivered infants
this approach are summarized in Supplementary Table S11. who were normal at birth. In a report of 16 pregnancy
The phase II INTERIM study first established that in- cases among patients assigned female at birth treated with
termittent dosing of imatinib is feasible in patients 65 years bosutinib noted 6 live births, 4 abortions, and 6 unknown
and over in stable MMR or MR4, after 2 or more years outcomes.272
of treatment.252 The interim analysis of the phase III Although there is a paucity of data regarding the out-
OPTkIMA study demonstrated that this approach is also come of pregnancy in patients receiving bosutinib, ponati-
feasible for patients treated with dasatinib or nilotinib.259 nib, or asciminib at conception, all TKIs also must be
OPTkIMA is an ongoing study that is evaluating the poten- considered unsafe for use during pregnancy. Conception
tial de-escalation of all TKIs after achieving a stable DMR. while on active TKI therapy is strongly discouraged due to
The DESTINY trial showed the feasibility of de-escalating the risk of fetal abnormalities. Close monitoring and
TKIs (imatinib, dasatinib, or nilotinib) to half the standard prompt consideration of holding TKI therapy (if pregnancy
dose for 12 months (imatinib 200 mg once daily; dasatinib occurs while on TKI therapy) should be considered.
50 mg once daily, or nilotinib 200 mg twice daily) in patients Depending on other factors such as age, a natural preg-
achieving MMR or MR4 followed by discontinuation for nancy may occur months after stopping TKI therapy.273,274
24 months (with frequent monitoring).255,256 A prolonged washout period before pregnancy should be
The NILO-RED study (published only as an abstract) considered, although there are no data regarding how long
demonstrated the feasibility of maintenance therapy with a patient should be off TKI therapy before trying to become

60 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 22 Issue 1 | February 2024
Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

pregnant. There are no published guidelines regarding the regarding how best to monitor CML during pregnancy,
optimal depth of molecular response that is considered nor how best to manage progressive disease should it
“safe” to stop TKI therapy before attempting pregnancy.275 occur during pregnancy. Referral to a CML specialty
Discontinuation of TKI therapy because of preg- center and consultation with a high-risk obstetrician is
nancy in patients assigned female at birth who were not recommended.
in DMR (#0.01% BCR::ABL1 IS) has only been reported
in a small series of patients.273,274,276,277 In one series,
among 10 patients who stopped imatinib because of preg- Treatment During Pregnancy
nancy after a median of 8 months of therapy, 5 of the 9 pa- Most of the literature regarding treatment during preg-
tients who had experienced a CHR lost the response after nancy consists of case reports. TKI therapy, particularly
stopping therapy, and 6 had an increase in Ph-positive during the first trimester, should be avoided because of
metaphases.273 At 18 months after resuming therapy, all teratogenic risk. If TKI therapy is considered during preg-
9 patients had achieved a CHR but only 3 females experi- nancy, the potential benefit for the mother and the po-
enced a CCyR and none had experienced an MMR. In an- tential risk to the fetus of continuing TKI therapy versus
other series that reported the outcomes for 7 patients who the risk of treatment interruption leading to the loss of
were not in DMR at the time imatinib was stopped be- optimal disease response must be carefully evaluated on
cause of pregnancy, 3 were in an MMR.274 All 7 patients an individual basis.
had disease relapse. The 3 who had an MMR at the time Leukapheresis can be used for a rising white blood
imatinib was stopped could regain the same response cell count and/or platelet count, although there are no
once the drug was restarted, whereas the remaining 4 data that recommend at what level leukapheresis and/or
patients did not. platelet pheresis should be initiated.278–281 Low-dose aspi-
rin or low-molecular-weight heparin can be considered
Planning a Pregnancy for patients with thrombocytosis.282,283
In patients assigned male at birth, the general recom- The panel also recommends against the use of
mendation is that TKI therapy need not be discontinued hydroxyurea during pregnancy, especially in the first
if a pregnancy is planned. However, experience is limited. trimester.284–286 If treatment is needed during preg-
Sperm banking can also be performed before starting nancy, it is preferable to initiate treatment with inter-
TKI therapy, but no data are available regarding quality feron alfa-2a.287 Most data using interferons during
of sperm in males with untreated CML. pregnancy have been reported in patients with essential
In patients assigned female at birth, due to the risk thrombocythemia.288,289 If introduced earlier, interferons
of miscarriage and fetal abnormalities during pregnancy, can preserve molecular remission after discontinuation
TKI therapy should be stopped prior to natural concep- of TKI.290,291 Peginterferon alfa-2a is the only interferon
tion and patients should remain off therapy during available for clinical use in the United States.
pregnancy.266–268 Monthly monitoring of complete blood count with
Fertility preservation should be discussed with all pa- differential and frequent monitoring with qPCR (every
tients of childbearing age before starting TKI therapy. Re- 1–3 months) would be helpful to guide the timing for ini-
ferral to an in vitro fertilization center is recommended tiation of TKI therapy, although specific thresholds for
in coordination with the patient’s obstetrician. TKI treatment reinitiation have not been defined.
should be stopped prior to attempting oocyte retrieval,
but the optimal timing of discontinuation is unknown.
No data are available to recommend how long a patient Breastfeeding
should be off therapy before oocyte retrieval, although TKI therapy can be restarted after delivery. However,
usually at least 1 month off therapy is recommended. In patients on TKI therapy should be advised not to
addition to the high incidence of disease recurrence off breastfeed, as TKIs pass into human breast milk.292–295
TKI therapy, patients should also be made aware of the Breastfeeding without TKI therapy may be safe with mo-
significant obstacles related to in vitro fertilization (eg, lecular monitoring, preferably in those patients with
lack of access to centers that perform the procedure, high CML who have durable DMR. It may be acceptable to
costs associated with drugs, surgical procedures, and avoid TKIs for the short period of the first 2 to 5 days
embryo/oocyte storage that may not be covered by in- after labor to give the child colostrum.295,296
surance, variable access to surrogate programs, the need Close molecular monitoring is recommended for fe-
to take family medical leave from work to attend in vitro males who extend the treatment-free period for breast-
fertilization appointments). feeding. If the loss of MMR after treatment cessation is
Before attempting pregnancy, patients and their confirmed, breastfeeding needs to be terminated and
partners should be counseled that no guidelines exist TKI should be restarted.295

JNCCN.org | Volume 22 Issue 1 | February 2024 61

 NCCN GUIDELINES® Chronic Myeloid Leukemia, Version 2.2024

References
1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA 24. Jain P, Kantarjian H, Patel KP, et al. Impact of BCR-ABL transcript type
Cancer J Clin 2023;73:17–48. on outcome in patients with chronic-phase CML treated with tyro-
2. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid sine kinase inhibitors. Blood 2016;127:1269–1275.
leukemia. N Engl J Med 1999;341:164–172. 25. Castagnetti F, Gugliotta G, Breccia M, et al. The BCR-ABL1 transcript
3. Melo JV. The diversity of BCR-ABL fusion proteins and their relationship type influences response and outcome in Philadelphia chromosome-
to leukemia phenotype. Blood 1996;88:2375–2384. positive chronic myeloid leukemia patients treated frontline with imati-
4. Melo JV. BCR-ABL gene variants. Baillieres Clin Haematol 1997;10: nib. Am J Hematol 2017;92:797–805.
203–222. 26. Pagnano KB, Miranda EC, Delamain MT, et al. Influence of BCR-ABL
5. Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340: transcript type on outcome in patients with chronic-phase chronic mye-
1330–1340. loid leukemia treated with imatinib. Clin Lymphoma Myeloma Leuk
6. Radich JP, Dai H, Mao M, et al. Gene expression changes associated 2017;17:728–733.
with progression and response in chronic myeloid leukemia. Proc Natl 27. Lee SE, Choi SY, Kim SH, et al. Baseline BCR-ABL1 transcript type of
Acad Sci USA 2006;103:2794–2799. e13a2 and large spleen size are predictors of poor long-term outcomes
7. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage pro- in chronic phase chronic myeloid leukemia patients who failed to
genitors as candidate leukemic stem cells in blast-crisis CML. N Engl J achieve an early molecular response after 3 months of imatinib therapy.
Med 2004;351:657–667. Leuk Lymphoma 2018;59:105–113.
8. Cortes JE, Talpaz M, Giles F, et al. Prognostic significance of cytoge- 28. Ercaliskan A, Eskazan AE. The impact of BCR-ABL1 transcript type
netic clonal evolution in patients with chronic myelogenous leukemia on on tyrosine kinase inhibitor responses and outcomes in patients with
imatinib mesylate therapy. Blood 2003;101:3794–3800. chronic myeloid leukemia. Cancer 2018;124:3806–3818.
9. O’Dwyer ME, Mauro MJ, Blasdel C, et al. Clonal evolution and lack of 29. Pfirrmann M, Evtimova D, Saussele S, et al. No influence of BCR-ABL1
cytogenetic response are adverse prognostic factors for hematologic transcript types e13a2 and e14a2 on long-term survival: results in 1494
relapse of chronic phase CML patients treated with imatinib mesy- patients with chronic myeloid leukemia treated with imatinib. J Cancer
late. Blood 2004;103:451–455. Res Clin Oncol 2017;143:843–850.
10. Wang W, Cortes JE, Lin P, et al. Clinical and prognostic significance of 30. Genthon A, Nicolini FE, Huguet F, et al. Influence of major BCR-ABL1
3q26.2 and other chromosome 3 abnormalities in CML in the era of transcript subtype on outcome in patients with chronic myeloid leuke-
tyrosine kinase inhibitors. Blood 2015;126:1699–1706. mia in chronic phase treated frontline with nilotinib. Oncotarget 2020;
11. Wang W, Tang G, Cortes JE, et al. Chromosomal rearrangement in- 11:2560–2570.
volving 11q23 locus in chronic myelogenous leukemia: a rare phe- 31. Salmon M, White HE, Zizkova H, et al. Impact of BCR:ABL1 transcript
nomenon frequently associated with disease progression and poor type on RT-qPCR amplification performance and molecular response to
prognosis. J Hematol Oncol 2015;8:32. therapy. Leukemia 2022;36:1879–1886.
12. Wang W, Cortes JE, Tang G, et al. Risk stratification of chromosomal 32. Verma D, Kantarjian HM, Jones D, et al. Chronic myeloid leukemia
abnormalities in chronic myelogenous leukemia in the era of tyrosine (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and
kinase inhibitor therapy. Blood 2016;127:2742–2750.
prognostic significance. Blood 2009;114:2232–2235.
13. Douet-Guilbert N, Morel F, Le Charpentier T, et al. Interphase FISH for
33. Arun AK, Senthamizhselvi A, Mani S, et al. Frequency of rare BCR-ABL1
follow-up of Philadelphia chromosome-positive chronic myeloid leuke-
fusion transcripts in chronic myeloid leukemia patients. Int J Lab Hema-
mia treatment. Anticancer Res 2004;24:2535–2539.
tol 2017;39:235–242.
14. Seong DC, Kantarjian HM, Ro JY, et al. Hypermetaphase fluorescence
34. Gong Z, Medeiros LJ, Cortes JE, et al. Clinical and prognostic signifi-
in situ hybridization for quantitative monitoring of Philadelphia chromo-
some-positive cells in patients with chronic myelogenous leukemia dur- cance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leuke-
ing treatment. Blood 1995;86:2343–2349. mia. Blood Cancer J 2017;7:e583.
15. Dewald GW, Wyatt WA, Juneau AL, et al. Highly sensitive fluorescence 35. Qin YZ, Jiang Q, Jiang H, et al. Prevalence and outcomes of uncommon
in situ hybridization method to detect double BCR/ABL fusion and mon- BCR-ABL1 fusion transcripts in patients with chronic myeloid leukaemia:
itor response to therapy in chronic myeloid leukemia. Blood 1998;91: data from a single centre. Br J Haematol 2018;182:693–700.
3357–3365. 36. Xue M, Wang Q, Huo L, et al. Clinical characteristics and prognostic
16. Kantarjian HM, Talpaz M, Cortes J, et al. Quantitative polymerase chain significance of chronic myeloid leukemia with rare BCR-ABL1 tran-
reaction monitoring of BCR-ABL during therapy with imatinib mesylate scripts. Leuk Lymphoma 2019;60:3051–3057.
(STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Clin 37. Adnan-Awad S, Kim D, Hohtari H, et al. Characterization of p190-Bcr-Abl
Cancer Res 2003;9:160–166. chronic myeloid leukemia reveals specific signaling pathways and
17. Hughes T, Deininger MW, Hochhaus A, et al. Monitoring CML patients therapeutic targets. Leukemia 2021;35:1964–1975.
responding to treatment with tyrosine kinase inhibitors: review and rec- 38. Abdelmagid MG, Litzow MR, McCullough KB, et al. Chronic phase CML
ommendations for harmonizing current methodology for detecting with sole P190 (e1a2) BCR:ABL1: long-term outcome among ten
BCR-ABL transcripts and kinase domain mutations and for expressing consecutive cases. Blood Cancer J 2022;12:103.
results. Blood 2006;108:28–37.
39. Verstovsek S, Lin H, Kantarjian H, et al. Neutrophilic-chronic myeloid
18. Biernaux C, Loos M, Sels A, et al. Detection of major BCR-ABL gene ex- leukemia: low levels of p230 BCR/ABL mRNA and undetectable
pression at a very low level in blood cells of some healthy individuals. BCR/ABL protein may predict an indolent course. Cancer 2002;94:
Blood 1995;86:3118–3122.
2416–2425.
19. Bose S, Deininger MW, Gora-Tybor J, et al. The presence of typical and
40. Langabeer SE, McCarron SL, Kelly J, et al. Chronic myeloid leukemia
atypical BCR-ABL fusion genes in leukocytes of normal individuals: bio-
with e19a2 BCR-ABL1 transcripts and marked thrombocytosis: the role
logic significance and implications for the assessment of minimal resid-
of molecular monitoring. Case Rep Hematol 2012;2012:458716.
ual disease. Blood 1998;92:3362–3367.
41. Crampe M, Haslam K, Kelly J, et al. Characterization of a novel variant
20. Baccarani M, Castagnetti F, Gugliotta G, et al. The proportion of differ-
ent BCR-ABL1 transcript types in chronic myeloid leukemia. An interna- BCR-ABL1 fusion transcript in a patient with chronic myeloid leukemia:
tional overview. Leukemia 2019;33:1173–1183. implications for molecular monitoring. Hematol Oncol Stem Cell Ther
2017;10:85–88.
21. Ghalesardi OK, Khosravi A, Azizi E, et al. The prognostic importance of
BCR-ABL transcripts in chronic myeloid leukemia: a systematic review 42. Langabeer SE. Standardized molecular monitoring for variant BCR-ABL1
and meta-analysis. Leuk Res 2021;101:106512. transcripts in chronic myeloid leukemia. Arch Pathol Lab Med 2015;
139:969.
22. Lucas CM, Harris RJ, Giannoudis A, et al. Chronic myeloid leukemia pa-
tients with the e13a2 BCR-ABL fusion transcript have inferior responses 43. Shanmuganathan N, Hughes TP. Molecular monitoring in CML: how
to imatinib compared to patients with the e14a2 transcript. Haemato- deep? How often? How should it influence therapy? Hematology Am
logica 2009;94:1362–1367. Soc Hematol Educ Program 2018;2018:168–176.
23. Hanfstein B, Lauseker M, Hehlmann R, et al. Distinct characteristics of 44. Burmeister T, Reinhardt R. A multiplex PCR for improved detection
e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under of typical and atypical BCR-ABL fusion transcripts. Leuk Res 2008;32:
first-line therapy with imatinib. Haematologica 2014;99:1441–1447. 579–585.

62 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 22 Issue 1 | February 2024
Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

45. Bennour A, Ouahchi I, Moez M, et al. Comprehensive analysis of BCR/ 64. Ni H, Sun X, Xu Y, et al. Clinical implications of clonal chromosomal ab-
ABL variants in chronic myeloid leukemia patients using multiplex RT- normalities in Philadelphia negative cells in CML patients after treated
PCR. Clin Lab 2012;58:433–439. with tyrosine kinase inhibitors. Cancer Genet 2019;238:44–49.
46. Mir R, Ahmad I, Javid J, et al. Simple multiplex RT-PCR for identifying 65. Sheng G, Xue M, Wang Q, et al. Occurrence of chromosomal abnor-
common fusion BCR-ABL transcript types and evaluation of molecular malities in Philadelphia chromosome-negative metaphases in patients
response of the a2b2 and a2b3 transcripts to Imatinib resistance in with chronic-phase chronic myeloid leukemia undergoing TKI treat-
north Indian chronic myeloid leukemia patients. Indian J Cancer 2015; ments. Leuk Lymphoma 2019;60:3503–3511.
52:314–318. 66. Issa GC, Kantarjian HM, Gonzalez GN, et al. Clonal chromosomal
47. Pagani IS, Dang P, Saunders VA, et al. Clinical utility of genomic DNA abnormalities appearing in Philadelphia chromosome-negative
Q-PCR for the monitoring of a patient with atypical e19a2 BCR-ABL1 metaphases during CML treatment. Blood 2017;130:2084–2091.
transcripts in chronic myeloid leukemia. Leuk Lymphoma 2020;61: 67. Karimata K, Masuko M, Ushiki T, et al. Myelodysplastic syndrome with
2527–2529. Ph negative monosomy 7 chromosome following transient bone marrow
48. Petiti J, Lo Iacono M, Dragani M, et al. Novel multiplex droplet digital dysplasia during imatinib treatment for chronic myeloid leukemia. Intern
PCR assays to monitor minimal residual disease in chronic myeloid leu- Med 2011;50:481–485.
kemia patients showing atypical BCR-ABL1 transcripts. J Clin Med 68. Navarro JT, Feliu E, Grau J, et al. Monosomy 7 with severe myelodys-
2020;9:1457. plasia developing during imatinib treatment of Philadelphia-positive
49. Verma D, Kantarjian H, Shan J, et al. Survival outcomes for clonal evolu- chronic myeloid leukemia: two cases with a different outcome. Am J
tion in chronic myeloid leukemia patients on second generation tyrosine Hematol 2007;82:849–851.
kinase inhibitor therapy. Cancer 2010;116:2673–2681. 69. Bidet A, Dulucq S, Smol T, et al. Poor prognosis of chromosome 7
50. Fabarius A, Kalmanti L, Dietz CT, et al. Impact of unbalanced minor clonal aberrations in Philadelphia-negative metaphases and relevance
route versus major route karyotypes at diagnosis on prognosis of CML. of potential underlying myelodysplastic features in chronic myeloid leu-
Ann Hematol 2015;94:2015–2024. kemia. Haematologica 2019;104:1150–1155.
51. Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytoge- 70. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in
netic aberrations at diagnosis on prognosis of CML: long-term observa- “good-risk” chronic granulocytic leukemia. Blood 1984;63:789–799.
tion of 1151 patients from the randomized CML Study IV. Blood 2011; 71. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for
118:6760–6768. survival of patients with chronic myeloid leukemia treated with inter-
52. Hehlmann R, Voskanyan A, Lauseker M, et al. High-risk additional chro- feron alfa. J Natl Cancer Inst 1998;90:850–858.
mosomal abnormalities at low blast counts herald death by CML. Leuke- 72. Pfirrmann M, Baccarani M, Saussele S, et al. Prognosis of long-term
mia 2020;34:2074–2086. survival considering disease-specific death in patients with chronic
53. Alhuraiji A, Kantarjian H, Boddu P, et al. Prognostic significance of addi- myeloid leukemia. Leukemia 2016;30:48–56.
tional chromosomal abnormalities at the time of diagnosis in patients 73. Grossmann V, Kohlmann A, Zenger M, et al. A deep-sequencing study
with chronic myeloid leukemia treated with frontline tyrosine kinase in- of chronic myeloid leukemia patients in blast crisis (BC-CML) detects
hibitors. Am J Hematol 2018;93:84–90. mutations in 76.9% of cases. Leukemia 2011;25:557–560.
54. Bumm T, M€ uller C, Al-Ali HK, et al. Emergence of clonal cytogenetic ab- 74. Makishima H, Jankowska AM, McDevitt MA, et al. CBL, CBLB, TET2,
normalities in Ph- cells in some CML patients in cytogenetic remission ASXL1, and IDH1/2 mutations and additional chromosomal aberrations
to imatinib but restoration of polyclonal hematopoiesis in the majority. constitute molecular events in chronic myelogenous leukemia. Blood
Blood 2003;101:1941–1949. 2011;117:e198–206.
55. Feldman E, Najfeld V, Schuster M, et al. The emergence of Ph-, trisomy 75. Kim T, Tyndel MS, Zhang Z, et al. Exome sequencing reveals DNMT3A
-81 cells in patients with chronic myeloid leukemia treated with imatinib and ASXL1 variants associate with progression of chronic myeloid leuke-
mesylate. Exp Hematol 2003;31:702–707. mia after tyrosine kinase inhibitor therapy. Leuk Res 2017;59:142–148.
56. Medina J, Kantarjian H, Talpaz M, et al. Chromosomal abnormalities in 76. Kim T, Tyndel MS, Kim HJ, et al. Spectrum of somatic mutation dynam-
Philadelphia chromosome-negative metaphases appearing during imati- ics in chronic myeloid leukemia following tyrosine kinase inhibitor ther-
nib mesylate therapy in patients with Philadelphia chromosome-positive apy. Blood 2017;129:38–47.
chronic myelogenous leukemia in chronic phase. Cancer 2003;98: 77. Mologni L, Piazza R, Khandelwal P, et al. Somatic mutations identified
1905–1911. at diagnosis by exome sequencing can predict response to imatinib in
57. Terre C, Eclache V, Rousselot P, et al. Report of 34 patients with clonal chronic phase chronic myeloid leukemia (CML) patients. Am J Hematol
chromosomal abnormalities in Philadelphia-negative cells during imati- 2017;92:E623–625.
nib treatment of Philadelphia-positive chronic myeloid leukemia. Leuke- 78. Togasaki E, Takeda J, Yoshida K, et al. Frequent somatic mutations in
mia 2004;18:1340–1346. epigenetic regulators in newly diagnosed chronic myeloid leukemia.
58. Deininger MW, Cortes J, Paquette R, et al. The prognosis for patients Blood Cancer J 2017;7:e559.
with chronic myeloid leukemia who have clonal cytogenetic abnor- 79. Branford S, Wang P, Yeung DT, et al. Integrative genomic analysis re-
malities in Philadelphia chromosome-negative cells. Cancer 2007; veals cancer-associated mutations at diagnosis of CML in patients with
110:1509–1519. high-risk disease. Blood 2018;132:948–961.
59. Jabbour E, Kantarjian HM, Abruzzo LV, et al. Chromosomal abnormali- 80. Erbilgin Y, Eskazan AE, Hatirnaz Ng O, € et al. Deep sequencing of BCR-
ties in Philadelphia chromosome negative metaphases appearing dur- ABL1 kinase domain mutations in chronic myeloid leukemia patients
ing imatinib mesylate therapy in patients with newly diagnosed chronic with resistance to tyrosine kinase inhibitors. Leuk Lymphoma 2019;60:
myeloid leukemia in chronic phase. Blood 2007;110:2991–2995. 200–207.
60. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces com- 81. Nteliopoulos G, Bazeos A, Claudiani S, et al. Somatic variants in epige-
plete remissions and prolonged survival in elderly Philadelphia chromo- netic modifiers can predict failure of response to imatinib but not to
some-positive patients with acute lymphoblastic leukemia without second-generation tyrosine kinase inhibitors. Haematologica 2019;104:
additional chemotherapy: results of the Gruppo Italiano Malattie Emato- 2400–2409.
logiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007;109: 82. Adnan Awad S, Kankainen M, Ojala T, et al. Mutation accumulation in
3676–3678. cancer genes relates to nonoptimal outcome in chronic myeloid leuke-
61. Fabarius A, Haferlach C, M€ uller MC, et al. Dynamics of cytogenetic mia. Blood Adv 2020;4:546–559.
aberrations in Philadelphia chromosome positive and negative hemato- 83. Wu W, Xu N, Zhou X, et al. Integrative genomic analysis reveals cancer-
poiesis during dasatinib therapy of chronic myeloid leukemia patients associated gene mutations in chronic myeloid leukemia patients with re-
after imatinib failure. Haematologica 2007;92:834–837. sistance or intolerance to tyrosine kinase inhibitor. Onco Targets Ther
62. Baldazzi C, Luatti S, Marzocchi G, et al. Emergence of clonal chromo- 2020;13:8581–8591.
somal abnormalities in Philadelphia negative hematopoiesis in chronic 84. Adnan Awad S, Dufva O, Ianevski A, et al. RUNX1 mutations in
myeloid leukemia patients treated with nilotinib after failure of imatinib blast-phase chronic myeloid leukemia associate with distinct pheno-
therapy. Leuk Res 2009;33:e218–220. types, transcriptional profiles, and drug responses. Leukemia 2021;
63. Wang H, Jin J, Wang Y, et al. Clonal chromosomal abnormalities in 35:1087–1099.
Philadelphia-negative cells in chronic myeloid leukemia patients 85. Ochi Y, Yoshida K, Huang YJ, et al. Clonal evolution and clinical implica-
treated with nilotinib used in first-line therapy. Ann Hematol 2013; tions of genetic abnormalities in blastic transformation of chronic mye-
92:1625–1632. loid leukaemia. Nat Commun 2021;12:2833.

JNCCN.org | Volume 22 Issue 1 | February 2024 63

 NCCN GUIDELINES® Chronic Myeloid Leukemia, Version 2.2024

86. Bidikian A, Kantarjian H, Jabbour E, et al. Prognostic impact of ASXL1 107. Porkka K, Khoury HJ, Paquette RL, et al. Dasatinib 100 mg once daily
mutations in chronic phase chronic myeloid leukemia. Blood Cancer J minimizes the occurrence of pleural effusion in patients with chronic my-
2022;12:144. eloid leukemia in chronic phase and efficacy is unaffected in patients
87. Sch€onfeld L, Rinke J, Hinze A, et al. ASXL1 mutations predict inferior who develop pleural effusion. Cancer 2010;116:377–386.
molecular response to nilotinib treatment in chronic myeloid leukemia. 108. Montani D, Bergot E, G€ unther S, et al. Pulmonary arterial hypertension
Leukemia 2022;36:2242–2249. in patients treated by dasatinib. Circulation 2012;125:2128–2137.
88. Adnan Awad S, Br€ uck O, Shanmuganathan N, et al. Epigenetic modifier 109. Orlandi EM, Rocca B, Pazzano AS, et al. Reversible pulmonary arterial
gene mutations in chronic myeloid leukemia (CML) at diagnosis are as- hypertension likely related to long-term, low-dose dasatinib treatment
sociated with risk of relapse upon treatment discontinuation. Blood for chronic myeloid leukaemia. Leuk Res 2012;36:e4–6.
Cancer J 2022;12:69. 110. Cirmi S, El Abd A, Letinier L, et al. Cardiovascular toxicity of tyrosine
89. Kizilors A, Crisa E, Lea N, et al. Effect of low-level BCR-ABL1 kinase kinase inhibitors used in chronic myeloid leukemia: an analysis of the
domain mutations identified by next-generation sequencing in FDA Adverse Event Reporting System Database (FAERS). Cancers
patients with chronic myeloid leukaemia: a population-based study. (Basel) 2020;12:826.
Lancet Haematol 2019;6:e276–284. 111. Efficace F, Baccarani M, Breccia M, et al. Chronic fatigue is the most im-
90. Soverini S, Bavaro L, De Benedittis C, et al. Prospective assessment of portant factor limiting health-related quality of life of chronic myeloid
NGS-detectable mutations in CML patients with nonoptimal response: leukemia patients treated with imatinib. Leukemia 2013;27:1511–1519.
the NEXT-in-CML study. Blood 2020;135:534–541. 112. Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral
91. Schmidt M, Rinke J, Sch€ afer V, et al. Molecular-defined clonal evolution metabolism in patients receiving imatinib mesylate. N Engl J Med
in patients with chronic myeloid leukemia independent of the BCR-ABL 2006;354:2006–2013.
status. Leukemia 2014;28:2292–2299. 113. Berman E, Girotra M, Cheng C, et al. Effect of long term imatinib on
92. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imati- bone in adults with chronic myelogenous leukemia and gastrointestinal
nib treatment of chronic myeloid leukemia. N Engl J Med 2017;376: stromal tumors. Leuk Res 2013;37:790–794.
917–927.
114. Tsao AS, Kantarjian HM, Cortes JE, et al. Imatinib mesylate causes
93. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results hypopigmentation in the skin. Cancer 2003;98:2483–2487.
of DASISION: the dasatinib versus imatinib study in treatment-naive
115. Aleem A. Hypopigmentation of the skin due to imatinib mesylate in
chronic myeloid leukemia patients trial. J Clin Oncol 2016;34:
patients with chronic myeloid leukemia. Hematol Oncol Stem Cell
2333–2340.
Ther 2009;2:358–361.
94. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus
116. Sakurai M, Kikuchi T, Karigane D, et al. Renal dysfunction and anemia
imatinib for newly diagnosed chronic myeloid leukemia: results from the
associated with long-term imatinib treatment in patients with chronic
randomized BFORE trial. J Clin Oncol 2018;36:231–237.
myelogenous leukemia. Int J Hematol 2019;109:292–298.
95. Br€ummendorf TH, Cortes JE, Milojkovic D, et al. Bosutinib versus imati-
117. Reinhold U, Hennig E, Leiblein S, et al. FISH for BCR-ABL on inter-
nib for newly diagnosed chronic phase chronic myeloid leukemia: final
phases of peripheral blood neutrophils but not of unselected white cells
results from the BFORE trial. Leukemia 2022;36:1825–1833.
correlates with bone marrow cytogenetics in CML patients treated with
96. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with imatinib. Leukemia 2003;17:1925–1929.
frontline nilotinib versus imatinib in newly diagnosed chronic myeloid
leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia 2021; 118. Fugazza G, Miglino M, Bruzzone R, et al. Cytogenetic and fluorescence
35:440–453. in situ hybridization monitoring in Ph1 chronic myeloid leukemia pa-
tients treated with imatinib mesylate. J Exp Clin Cancer Res 2004;23:
97. Gemelli M, Elli EM, Elena C, et al. Use of generic imatinib as first-line 295–299.
treatment in patients with chronic myeloid leukemia (CML): the GIMS
(Glivec to Imatinib Switch) study. Blood Res 2020;55:139–145. 119. Landstrom AP, Ketterling RP, Knudson RA, et al. Utility of peripheral
blood dual color, double fusion fluorescent in situ hybridization for
98. Scalzulli E, Colafigli G, Latagliata R, et al. Switch from branded to BCR/ABL fusion to assess cytogenetic remission status in chronic mye-
generic imatinib: impact on molecular responses and safety in loid leukemia. Leuk Lymphoma 2006;47:2055–2061.
chronic-phase chronic myeloid leukemia patients. Ann Hematol
2020;99:2773–2777. 120. Testoni N, Marzocchi G, Luatti S, et al. Chronic myeloid leukemia: a pro-
spective comparison of interphase fluorescence in situ hybridization and
99. Erçalışkan A, Seyhan Erdo gan D, Eşkazan AE. Current evidence on the chromosome banding analysis for the definition of complete cytoge-
efficacy and safety of generic imatinib in CML and the impact of
netic response: a study of the GIMEMA CML WP. Blood 2009;114:
generics on health care costs. Blood Adv 2021;5:3344–3353.
4939–4943.
100. Kantarjian HM, Paul S, Thakkar J, et al. The influence of drug prices,
121. Lima L, Bernal-Mizrachi L, Saxe D, et al. Peripheral blood monitoring of
new availability of inexpensive generic imatinib, new approvals, and
chronic myeloid leukemia during treatment with imatinib, second-line
post-marketing research on the treatment of chronic myeloid leukaemia
agents, and beyond. Cancer 2011;117:1245–1252.
in the USA. Lancet Haematol 2022;9:e854–861.
122. Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic signifi-
101. Baccarani M, Druker BJ, Branford S, et al. Long-term response to imati-
cance of early molecular response to imatinib in newly diagnosed
nib is not affected by the initial dose in patients with Philadelphia chro-
chronic myeloid leukemia: an analysis from the International Random-
mosome-positive chronic myeloid leukemia in chronic phase: final
ized Study of Interferon and STI571 (IRIS). Blood 2010;116:3758–3765.
update from the Tyrosine Kinase Inhibitor Optimization and Selectivity
(TOPS) study. Int J Hematol 2014;99:616–624. 123. Akard LP, Cortes JE, Albitar M, et al. Correlations between cytogenetic
and molecular monitoring among patients with newly diagnosed
102. Deininger MW, Kopecky KJ, Radich JP, et al. Imatinib 800 mg daily in-
duces deeper molecular responses than imatinib 400 mg daily: results chronic myeloid leukemia in chronic phase: post hoc analyses of the Ra-
of SWOG S0325, an intergroup randomized PHASE II trial in newly di- tionale and Insight for Gleevec High-Dose Therapy study. Arch Pathol
agnosed chronic phase chronic myeloid leukaemia. Br J Haematol Lab Med 2014;138:1186–1192.
2014;164:223–232. 124. Branford S, Cross NC, Hochhaus A, et al. Rationale for the recommen-
103. Hehlmann R, Lauseker M, Saussele S, et al. Assessment of imatinib as dations for harmonizing current methodology for detecting BCR-ABL
first-line treatment of chronic myeloid leukemia: 10-year survival results transcripts in patients with chronic myeloid leukaemia. Leukemia 2006;
of the randomized CML study IV and impact of non-CML determinants. 20:1925–1930.
Leukemia 2017;31:2398–2406. 125. Cross NC. Standardisation of molecular monitoring for chronic myeloid
104. Hoffmann VS, Hasford J, Deininger MW, et al. Systematic review and leukaemia. Best Pract Res Clin Haematol 2009;22:355–365.
meta-analysis of standard-dose imatinib vs. high-dose imatinib and sec- 126. Cross NC, White HE, M€ uller MC, et al. Standardized definitions of
ond generation tyrosine kinase inhibitors for chronic myeloid leukemia. molecular response in chronic myeloid leukemia. Leukemia 2012;26:
J Cancer Res Clin Oncol 2017;143:1311–1318. 2172–2175.
105. Quint as-Cardama A, Han X, Kantarjian HM, et al. Tyrosine kinase 127. Branford S, Fletcher L, Cross NC, et al. Desirable performance charac-
inhibitor-induced platelet dysfunction in patients with chronic myeloid teristics for BCR-ABL measurement on an international reporting scale
leukemia. Blood 2009;114:261–263. to allow consistent interpretation of individual patient response and
106. Hughes TP, Laneuville P, Rousselot P, et al. Incidence, outcomes, and comparison of response rates between clinical trials. Blood 2008;112:
risk factors of pleural effusion in patients receiving dasatinib therapy for 3330–3338.
Philadelphia chromosome-positive leukemia. Haematologica 2019;104: 128. Gu erin A, Chen L, Dea K, et al. Association between regular molecular
93–101. monitoring and tyrosine kinase inhibitor therapy adherence in chronic

64 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 22 Issue 1 | February 2024
Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

myelogenous leukemia in the chronic phase. Curr Med Res Opin 2014; 149. Marin D, Goldman JM, Olavarria E, et al. Transient benefit only from in-
30:1345–1352. creasing the imatinib dose in CML patients who do not achieve com-
129. Hanfstein B, M€ uller MC, Hehlmann R, et al. Early molecular and cyto- plete cytogenetic remissions on conventional doses. Blood 2003;102:
genetic response is predictive for long-term progression-free and 2702–2703; author reply 2703–2704.
overall survival in chronic myeloid leukemia (CML). Leukemia 2012; 150. Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose esca-
26:2096–2102. lation is associated with durable responses in patients with chronic mye-
130. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript loid leukemia after cytogenetic failure on standard-dose imatinib
levels at 3 months is the only requirement for predicting outcome for therapy. Blood 2009;113:2154–2160.
patients with chronic myeloid leukemia treated with tyrosine kinase in- 151. Kantarjian HM, Larson RA, Guilhot F, et al. Efficacy of imatinib dose es-
hibitors. J Clin Oncol 2012;30:232–238. calation in patients with chronic myeloid leukemia in chronic phase.
131. Neelakantan P, Gerrard G, Lucas C, et al. Combining BCR-ABL1 tran- Cancer 2009;115:551–560.
script levels at 3 and 6 months in chronic myeloid leukemia: implications 152. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imati-
for early intervention strategies. Blood 2013;121:2739–2742. nib in CML with early switch to nilotinib for failure to achieve time-
132. Nazha A, Kantarjian HM, Jain P, et al. Assessment at 6 months may be dependent molecular targets. Blood 2015;125:915–923.
warranted for patients with chronic myeloid leukemia with no major cy- 153. Cortes JE, De Souza CA, Ayala M, et al. Switching to nilotinib versus im-
togenetic response at 3 months. Haematologica 2013;98:1686–1688. atinib dose escalation in patients with chronic myeloid leukaemia in
133. Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with chronic phase with suboptimal response to imatinib (LASOR): a rando-
CML and .10% BCR-ABL1 after 3 months of imatinib depends on the mised, open-label trial. Lancet Haematol 2016;3:e581–591.
rate of BCR-ABL1 decline. Blood 2014;124:511–518.
154. Cortes JE, Jiang Q, Wang J, et al. Dasatinib vs. imatinib in patients with
134. Hanfstein B, Shlyakhto V, Lauseker M, et al. Velocity of early BCR-ABL chronic myeloid leukemia in chronic phase (CML-CP) who have not
transcript elimination as an optimized predictor of outcome in chronic achieved an optimal response to 3 months of imatinib therapy: the
myeloid leukemia (CML) patients in chronic phase on treatment with im- DASCERN randomized study. Leukemia 2020;34:2064–2073.
atinib. Leukemia 2014;28:1988–1992.
155. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or
135. Iriyama N, Fujisawa S, Yoshida C, et al. Shorter halving time of BCR- -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year fol-
ABL1 transcripts is a novel predictor for achievement of molecular re- low-up of study CA180-034. Am J Hematol 2016;91:869–874.
sponses in newly diagnosed chronic-phase chronic myeloid leukemia
treated with dasatinib: results of the D-first study of Kanto CML study 156. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant
group. Am J Hematol 2015;90:282–287. or imatinib-intolerant patients with chronic myeloid leukemia in chronic
phase: 48-month follow-up results of a phase II study. Leukemia 2013;
136. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients
27:107–112.
receiving imatinib for the first-line treatment of chronic myeloid leuke-
mia. Leukemia 2009;23:1054–1061. 157. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy
of second-line bosutinib for chronic phase chronic myeloid leukemia
137. Jabbour E, Kantarjian HM, O’Brien S, et al. The achievement of an early
over a five-year period: final results of a phase I/II study. Haematologica
complete cytogenetic response is a major determinant for outcome in
2018;103:1298–1307.
patients with early chronic phase chronic myeloid leukemia treated with
tyrosine kinase inhibitors. Blood 2011;118:4541–4546; quiz 4759. 158. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for
138. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients chronic phase chronic myeloid leukemia after failure of imatinib plus da-
receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; satinib and/or nilotinib. Am J Hematol 2016;91:1206–1214.
355:2408–2417. 159. Hochhaus A, Gambacorti-Passerini C, Abboud C, et al. Bosutinib for
139. Press RD, Galderisi C, Yang R, et al. A half-log increase in BCR-ABL pretreated patients with chronic phase chronic myeloid leukemia:
RNA predicts a higher risk of relapse in patients with chronic myeloid primary results of the phase 4 BYOND study. Leukemia 2020;34:
leukemia with an imatinib-induced complete cytogenetic response. Clin 2125–2137.
Cancer Res 2007;13:6136–6143. 160. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in
140. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly Philadelphia chromosome-positive leukemia: final 5-year results of the
diagnosed patients with chronic myeloid leukemia: incidence of sus- phase 2 PACE trial. Blood 2018;132:393–404.
tained responses in an intention-to-treat analysis. J Clin Oncol 2008; 161. Cortes JE, Apperley J, Lomaia E, et al. Ponatinib dose-ranging study in
26:3358–3363. chronic-phase chronic myeloid leukemia: a randomized, open-label
141. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria phase 2 clinical trial. Blood 2021;138:2042–2050.
for failure or suboptimal response reliably identify patients with CML in 162. Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid
early chronic phase treated with imatinib whose eventual outcome is leukemia after ABL kinase inhibitor failure. N Engl J Med 2019;381:
poor. Blood 2008;112:4437–4444. 2315–2326.
142. Jabbour E, Kantarjian HM, O’Brien S, et al. Front-line therapy with sec- 163. Rea D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, ran-
ond-generation tyrosine kinase inhibitors in patients with early chronic domized study of asciminib, a STAMP inhibitor, vs bosutinib in CML
phase chronic myeloid leukemia: what is the optimal response? J Clin after 2 or more prior TKIs. Blood 2021;138:2031–2041.
Oncol 2011;29:4260–4265.
164. Hochhaus A, R ea D, Boquimpani C, et al. Asciminib vs bosutinib in
143. Hehlmann R, M€ uller MC, Lauseker M, et al. Deep molecular re- chronic-phase chronic myeloid leukemia previously treated with at least
sponse is reached by the majority of patients treated with imatinib, two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL.
predicts survival, and is achieved more quickly by optimized high- Leukemia 2023;37:617–626.
dose imatinib: results from the randomized CML-study IV. J Clin
Oncol 2014;32:415–423. 165. Dorer DJ, Knickerbocker RK, Baccarani M, et al. Impact of dose intensity
of ponatinib on selected adverse events: multivariate analyses from a
144. Saussele S, Hehlmann R, Fabarius A, et al. Defining therapy goals for pooled population of clinical trial patients. Leuk Res 2016;48:84–91.
major molecular remission in chronic myeloid leukemia: results of the
randomized CML Study IV. Leukemia 2018;32:1222–1228. 166. Jain P, Kantarjian HM, Boddu PC, et al. Analysis of cardiovascular and
arteriothrombotic adverse events in chronic-phase CML patients after
145. Cervantes F, L opez-Garrido P, Montero MI, et al. Early intervention dur-
frontline TKIs. Blood Adv 2019;3:851–861.
ing imatinib therapy in patients with newly diagnosed chronic-phase
chronic myeloid leukemia: a study of the Spanish PETHEMA group. 167. Caocci G, Mulas O, Abruzzese E, et al. Arterial occlusive events in
Haematologica 2010;95:1317–1324. chronic myeloid leukemia patients treated with ponatinib in the real-life
practice are predicted by the Systematic Coronary Risk Evaluation
146. Kantarjian HM, Cortes J. Considerations in the management of
patients with Philadelphia chromosome-positive chronic myeloid (SCORE) chart. Hematol Oncol 2019;37:296–302.
leukemia receiving tyrosine kinase inhibitor therapy. J Clin Oncol 168. Casavecchia G, Galderisi M, Novo G, et al. Early diagnosis, clinical man-
2011;29:1512–1516. agement, and follow-up of cardiovascular events with ponatinib. Heart
147. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 Fail Rev 2020;25:447–456.
recommendations for treating chronic myeloid leukemia. Leukemia 169. Cortes JE, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous oma-
2020;34:966–984. cetaxine mepesuccinate after TKI failure in patients with chronic-phase
148. Kantarjian HM, Talpaz M, O’Brien S, et al. Dose escalation of imatinib CML with T315I mutation. Blood 2012;120:2573–2580.
mesylate can overcome resistance to standard-dose therapy in patients 170. Cortes JE, Digumarti R, Parikh PM, et al. Phase 2 study of subcutaneous
with chronic myelogenous leukemia. Blood 2003;101:473–475. omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia

JNCCN.org | Volume 22 Issue 1 | February 2024 65

 NCCN GUIDELINES® Chronic Myeloid Leukemia, Version 2.2024

patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hem- 193. White DL, Saunders VA, Dang P, et al. OCT-1-mediated influx is a key
atol 2013;88:350–354. determinant of the intracellular uptake of imatinib but not nilotinib
171. Garg RJ, Kantarjian HM, O’Brien S, et al. The use of nilotinib or dasati- (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity
nib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. to imatinib. Blood 2006;108:697–704.
Blood 2009;114:4361–4368. 194. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations
172. van Leeuwen RW, van Gelder T, Mathijssen RH, et al. Drug-drug inter- in patients with CML treated with imatinib is virtually always accom-
actions with tyrosine-kinase inhibitors: a clinical perspective. Lancet On- panied by clinical resistance, and mutations in the ATP phosphate-
col 2014;15:e315–326. binding loop (P-loop) are associated with a poor prognosis. Blood
173. Osorio S, Escudero-Vilaplana V, G omez-Centuri on I, et al. Drug-to-drug 2003;102:276–283.
interactions of tyrosine kinase inhibitors in chronic myeloid leukemia pa- 195. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic
tients. Is it a real problem? Ann Hematol 2018;97:2089–2098. phase chronic myeloid leukemia patients with up-front cytogenetic resis-
174. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and tance to imatinib are associated with a greater likelihood of progression
outcomes of nonadherence to imatinib therapy in patients with chronic to blast crisis and shorter survival: a study by the GIMEMA Working
myeloid leukemia: the ADAGIO study. Blood 2009;113:5401–5411. Party on Chronic Myeloid Leukemia. J Clin Oncol 2005;23:4100–4109.
175. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for 196. Nicolini FE, Corm S, L^ e QH, et al. Mutation status and clinical outcome
achieving molecular responses in patients with chronic myeloid leuke- of 89 imatinib mesylate-resistant chronic myelogenous leukemia pa-
mia who achieve complete cytogenetic responses on imatinib. J Clin tients: a retrospective analysis from the French intergroup of CML
Oncol 2010;28:2381–2388. (Fi(phi)-LMC GROUP). Leukemia 2006;20:1061–1066.
176. Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main 197. Soverini S, Colarossi S, Gnani A, et al. Contribution of ABL kinase do-
reason for loss of CCyR and imatinib failure for chronic myeloid leuke- main mutations to imatinib resistance in different subsets of Philadel-
mia patients on long-term therapy. Blood 2011;117:3733–3736. phia-positive patients: by the GIMEMA Working Party on Chronic
Myeloid Leukemia. Clin Cancer Res 2006;12:7374–7379.
177. Wu EQ, Guerin A, Yu AP, et al. Retrospective real-world comparison of
medical visits, costs, and adherence between nilotinib and dasatinib in 198. Khorashad JS, de Lavallade H, Apperley JF, et al. Finding of kinase do-
chronic myeloid leukemia. Curr Med Res Opin 2010;26:2861–2869. main mutations in patients with chronic phase chronic myeloid leukemia
responding to imatinib may identify those at high risk of disease pro-
178. Yood MU, Oliveria SA, Cziraky M, et al. Adherence to treatment with
gression. J Clin Oncol 2008;26:4806–4813.
second-line therapies, dasatinib and nilotinib, in patients with chronic
myeloid leukemia. Curr Med Res Opin 2012;28:213–219. 199. Soverini S, Gnani A, Colarossi S, et al. Philadelphia-positive patients
who already harbor imatinib-resistant BCR-ABL kinase domain muta-
179. Quint as-Cardama A, Cortes JE, Kantarjian HM. Practical management
tions have a higher likelihood of developing additional mutations asso-
of toxicities associated with tyrosine kinase inhibitors in chronic myeloid
leukemia. Clin Lymphoma Myeloma 2008;8(Suppl 3):S82–88. ciated with resistance to second- or third-line tyrosine kinase inhibitors.
Blood 2009;114:2168–2171.
180. Cornelison M, Jabbour EJ, Welch MA. Managing side effects of tyrosine
kinase inhibitor therapy to optimize adherence in patients with chronic 200. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mu-
myeloid leukemia: the role of the midlevel practitioner. J Support Oncol tations on response to nilotinib in patients with chronic myeloid leuke-
2012;10:14–24. mia in chronic phase. J Clin Oncol 2009;27:4204–4210.
181. Cortes JE, Lipton JH, Miller CB, et al. Evaluating the impact of a switch 201. Naqvi K, Cortes JE, Luthra R, et al. Characteristics and outcome of
to nilotinib on imatinib-related chronic low-grade adverse events in pa- chronic myeloid leukemia patients with E255K/V BCR-ABL kinase do-
tients with CML-CP: the ENRICH study. Clin Lymphoma Myeloma Leuk main mutations. Int J Hematol 2018;107:689–695.
2016;16:286–296. 202. Nicolini FE, Hayette S, Corm S, et al. Clinical outcome of 27 imatinib
182. Kim DW, Saussele S, Williams LA, et al. Outcomes of switching to dasa- mesylate-resistant chronic myelogenous leukemia patients harboring a
tinib after imatinib-related low-grade adverse events in patients with T315I BCR-ABL mutation. Haematologica 2007;92:1238–1241.
chronic myeloid leukemia in chronic phase: the DASPERSE study. Ann 203. Jabbour E, Kantarjian HM, Jones D, et al. Characteristics and outcomes
Hematol 2018;97:1357–1367. of patients with chronic myeloid leukemia and T315I mutation following
183. Thomas J, Wang L, Clark RE, et al. Active transport of imatinib into and failure of imatinib mesylate therapy. Blood 2008;112:53–55.
out of cells: implications for drug resistance. Blood 2004;104:3739–3745. 204. Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in Phila-
184. Mahon FX, Hayette S, Lagarde V, et al. Evidence that resistance to nilo- delphia-positive leukemia patients and the presence or the selection of
tinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Can- mutations at residues 315 and 317 in the BCR-ABL kinase domain.
cer Res 2008;68:9809–9816. Haematologica 2007;92:401–404.
185. Hegedus C, Ozvegy-Laczka C, Ap ati A, et al. Interaction of nilotinib, da- 205. Jabbour E, Kantarjian HM, Jones D, et al. Characteristics and outcome
satinib and bosutinib with ABCB1 and ABCG2: implications for altered of chronic myeloid leukemia patients with F317L BCR-ABL kinase do-
anti-cancer effects and pharmacological properties. Br J Pharmacol main mutation after therapy with tyrosine kinase inhibitors. Blood 2008;
2009;158:1153–1164. 112:4839–4842.
186. Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are as- 206. M€ uller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-
sociated with both cytogenetic and molecular responses to standard- phase chronic myeloid leukemia: analysis of responses according to pre-
dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496–3499. existing BCR-ABL mutations. Blood 2009;114:4944–4953.
187. Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its 207. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic
correlation with response and safety in chronic-phase chronic myeloid phase chronic myeloid leukemia after imatinib and dasatinib and/or ni-
leukemia: a subanalysis of the IRIS study. Blood 2008;111:4022–4028. lotinib therapy failure. Blood 2012;119:3403–3412.
188. Bouchet S, Titier K, Moore N, et al. Therapeutic drug monitoring of ima- 208. Eide CA, Zabriskie MS, Savage Stevens SL, et al. Combining the alloste-
tinib in chronic myeloid leukemia: experience from 1216 patients at a ric inhibitor asciminib with ponatinib suppresses emergence of and re-
centralized laboratory. Fundam Clin Pharmacol 2013;27:690–697. stores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell
189. White DL, Radich J, Soverini S, et al. Chronic phase chronic myeloid leu- 2019;36:431–443.e5.
kemia patients with low OCT-1 activity randomized to high-dose imatinib 209. Khorashad JS, Kelley TW, Szankasi P, et al. BCR-ABL1 compound muta-
achieve better responses and have lower failure rates than those ran- tions in tyrosine kinase inhibitor-resistant CML: frequency and clonal re-
domized to standard-dose imatinib. Haematologica 2012;97:907–914. lationships. Blood 2013;121:489–498.
190. Giannoudis A, Davies A, Lucas CM, et al. Effective dasatinib uptake 210. Zabriskie MS, Eide CA, Tantravahi SK, et al. BCR-ABL1 compound mu-
may occur without human organic cation transporter 1 (hOCT1): impli- tations combining key kinase domain positions confer clinical resistance
cations for the treatment of imatinib-resistant chronic myeloid leukemia. to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 2014;26:
Blood 2008;112:3348–3354. 428–442.
191. Hiwase DK, Saunders V, Hewett D, et al. Dasatinib cellular uptake and 211. Deininger MW, Hodgson JG, Shah NP, et al. Compound mutations in
efflux in chronic myeloid leukemia cells: therapeutic implications. Clin BCR-ABL1 are not major drivers of primary or secondary resistance to
Cancer Res 2008;14:3881–3888. ponatinib in CP-CML patients. Blood 2016;127:703–712.
192. Davies A, Jordanides NE, Giannoudis A, et al. Nilotinib concentration in 212. Laudadio J, Deininger MW, Mauro MJ, et al. An intron-derived inser-
cell lines and primary CD34(1) chronic myeloid leukemia cells is not tion/truncation mutation in the BCR-ABL kinase domain in chronic mye-
mediated by active uptake or efflux by major drug transporters. Leuke- loid leukemia patients undergoing kinase inhibitor therapy. J Mol Diagn
mia 2009;23:1999–2006. 2008;10:177–180.

66 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 22 Issue 1 | February 2024
Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

213. Berman E, Jhanwar S, Hedvat C, et al. Resistance to imatinib in patients 234. Gugliotta G, Castagnetti F, Breccia M, et al. Treatment-free remis-
with chronic myelogenous leukemia and the splice variant BCR- sion in chronic myeloid leukemia patients treated front-line with
ABL1(35INS). Leuk Res 2016;49:108–112. nilotinib: 10-year followup of the GIMEMA CML 0307 study.
214. Soverini S, Branford S, Nicolini FE, et al. Implications of BCR-ABL1 Haematologica 2022;107:2356–2364.
kinase domain-mediated resistance in chronic myeloid leukemia. 235. Legros L, Nicolini FE, Etienne G, et al. Second tyrosine kinase inhibitor
Leuk Res 2014;38:10–20. discontinuation attempt in patients with chronic myeloid leukemia.
215. Branford S, Rudzki Z, Parkinson I, et al. Real-time quantitative PCR anal- Cancer 2017;123:4403–4410.
ysis can be used as a primary screen to identify patients with CML 236. Richter J, L€
ubking A, S€oderlund S, et al. Molecular status 36 months after
treated with imatinib who have BCR-ABL kinase domain mutations. TKI discontinuation in CML is highly predictive for subsequent loss of
Blood 2004;104:2926–2932. MMR-final report from AFTER-SKI. Leukemia 2021;35:2416–2418.
216. Wang L, Knight K, Lucas C, et al. The role of serial BCR-ABL transcript 237. Shanmuganathan N, Pagani IS, Ross DM, et al. Early BCR-ABL1 kinetics
monitoring in predicting the emergence of BCR-ABL kinase mutations are predictive of subsequent achievement of treatment-free remission in
in imatinib-treated patients with chronic myeloid leukemia. Haematolog- chronic myeloid leukemia. Blood 2021;137:1196–1207.
ica 2006;91:235–239.
238. Cortes JE, Apperley JF, DeAngelo DJ, et al. Management of adverse
217. Kantarjian HM, Shan J, Jones D, et al. Significance of increasing levels events associated with bosutinib treatment of chronic-phase chronic
of minimal residual disease in patients with Philadelphia chromosome- myeloid leukemia: expert panel review. J Hematol Oncol 2018;11:143.
positive chronic myelogenous leukemia in complete cytogenetic re-
sponse. J Clin Oncol 2009;27:3659–3663. 239. Kota V, Br€ ummendorf TH, Gambacorti-Passerini C, et al. Efficacy and
safety following bosutinib dose reduction in patients with Philadelphia
218. Marin D, Khorashad JS, Foroni L, et al. Does a rise in the BCR-ABL1
chromosome–positive leukemias. Leuk Res 2021;111:106690.
transcript level identify chronic phase CML patients responding to imati-
nib who have a high risk of cytogenetic relapse? Br J Haematol 2009; 240. Naqvi K, Jabbour E, Skinner J, et al. Long-term follow-up of lower dose
145:373–375. dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-
219. Press RD, Willis SG, Laudadio J, et al. Determining the rise in BCR-ABL phase chronic myeloid leukemia. Cancer 2020;126:67–75.
RNA that optimally predicts a kinase domain mutation in patients with 241. Jabbour E, Sasaki K, Haddad FG, et al. Low-dose dasatinib 50 mg/day
chronic myeloid leukemia on imatinib. Blood 2009;114:2598–2605. versus standard-dose dasatinib 100 mg/day as frontline therapy in
220. Mahon FX, R ea D, Guilhot J, et al. Discontinuation of imatinib in pa- chronic myeloid leukemia in chronic phase: a propensity score analysis.
tients with chronic myeloid leukaemia who have maintained complete Am J Hematol 2022;97:1413–1418.
molecular remission for at least 2 years: the prospective, multicentre 242. Itamura H, Kubota Y, Shindo T, et al. Elderly patients with chronic mye-
Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029–1035. loid leukemia benefit from a dasatinib dose as low as 20 mg. Clin Lym-
221. Etienne G, Guilhot J, R ea D, et al. Long-term follow-up of the French phoma Myeloma Leuk 2017;17:370–374.
Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. 243. Murai K, Ureshino H, Kumagai T, et al. Low-dose dasatinib in older pa-
J Clin Oncol 2017;35:298–305. tients with chronic myeloid leukaemia in chronic phase (DAVLEC): a sin-
222. Thielen N, van der Holt B, Cornelissen JJ, et al. Imatinib discontinuation gle-arm, multicentre, phase 2 trial. Lancet Haematol 2021;8:e902–911.
in chronic phase myeloid leukaemia patients in sustained complete mo- 244. Visani G, Breccia M, Gozzini A, et al. Dasatinib, even at low doses, is an
lecular response: a randomised trial of the Dutch-Belgian Cooperative effective second-line therapy for chronic myeloid leukemia patients re-
Trial for Haemato-Oncology (HOVON). Eur J Cancer 2013;49:3242–3246. sistant or intolerant to imatinib. Results from a real life-based Italian mul-
223. Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Loss of major mo- ticenter retrospective study on 114 patients. Am J Hematol 2010;85:
lecular response as a trigger for restarting tyrosine kinase inhibitor ther- 960–963.
apy in patients with chronic-phase chronic myelogenous leukemia who 245. La Ros ee P, Martiat P, Leitner A, et al. Improved tolerability by a modi-
have stopped imatinib after durable undetectable disease. J Clin Oncol fied intermittent treatment schedule of dasatinib for patients with
2014;32:424–430. chronic myeloid leukemia resistant or intolerant to imatinib. Ann Hema-
224. Mori S, Vagge E, le Coutre P, et al. Age and dPCR can predict relapse tol 2013;92:1345–1350.
in CML patients who discontinued imatinib: the ISAV study. Am J 246. Hjorth-Hansen H, Stenke L, S€ oderlund S, et al. Dasatinib induces fast
Hematol 2015;90:910–914. and deep responses in newly diagnosed chronic myeloid leukaemia pa-
225. Lee SE, Choi SY, Song HY, et al. Imatinib withdrawal syndrome and lon- tients in chronic phase: clinical results from a randomised phase-2 study
ger duration of imatinib have a close association with a lower molecular (NordCML006). Eur J Haematol 2015;94:243–250.
relapse after treatment discontinuation: the KID study. Haematologica
247. Iriyama N, Ohashi K, Hashino S, et al. The efficacy of reduced-dose da-
2016;101:717–723.
satinib as a subsequent therapy in patients with chronic myeloid leuke-
226. Ross DM, Pagani IS, Shanmuganathan N, et al. Long-term treatment- mia in the chronic phase: the LD-CML study of the KANTO CML study
free remission of chronic myeloid leukemia with falling levels of residual group. Intern Med 2018;57:17–23.
leukemic cells. Leukemia 2018;32:2572–2579.
248. Ohnishi K, Nakaseko C, Takeuchi J, et al. Long-term outcome following
227. Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or niloti- imatinib therapy for chronic myelogenous leukemia, with assessment of
nib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI dosage and blood levels: the JALSG CML202 study. Cancer Sci 2012;
study. Blood 2017;129:846–854. 103:1071–1078.
228. Okada M, Imagawa J, Tanaka H, et al. Final 3-year results of the dasati- 249. Tokuhira M, Kimura Y, Sugimoto K, et al. Efficacy and safety of nilotinib
nib discontinuation trial in patients with chronic myeloid leukemia who
therapy in patients with newly diagnosed chronic myeloid leukemia in
received dasatinib as a second-line treatment. Clin Lymphoma Myeloma
the chronic phase. Med Oncol 2018;35:38.
Leuk 2018;18:353–360.e1.
250. Hiwase D, Tan P, D’Rozario J, et al. Efficacy and safety of nilotinib
229. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase
300 mg twice daily in patients with chronic myeloid leukemia in
inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespeci-
fied interim analysis of a prospective, multicentre, non-randomised, trial. chronic phase who are intolerant to prior tyrosine kinase inhibitors:
Lancet Oncol 2018;19:747–757. results from the Phase IIIb ENESTswift study. Leuk Res 2018;67:
109–115.
230. Shah NP, Garcıa-Guti errez V, Jimenez-Velasco A, et al. Dasatinib dis-
continuation in patients with chronic-phase chronic myeloid leukemia 251. Iurlo A, Cattaneo D, Malato A, et al. Low-dose ponatinib is a good op-
and stable deep molecular response: the DASFREE study. Leuk Lym- tion in chronic myeloid leukemia patients intolerant to previous TKIs.
phoma 2020;61:650–659. Am J Hematol 2020;95:E260–263.
231. Kimura S, Imagawa J, Murai K, et al. Treatment-free remission after first- 252. Russo D, Malagola M, Skert C, et al. Managing chronic myeloid leukae-
line dasatinib discontinuation in patients with chronic myeloid leukaemia mia in the elderly with intermittent imatinib treatment. Blood Cancer J
(first-line DADI trial): a single-arm, multicentre, phase 2 trial. Lancet Hae- 2015;5:e347.
matol 2020;7:e218–225. 253. Faber E, Divok a M, Skoumalov a I, et al. A lower dosage of imatinib is
232. Radich JP, Hochhaus A, Masszi T, et al. Treatment-free remission following sufficient to maintain undetectable disease in patients with chronic mye-
frontline nilotinib in patients with chronic phase chronic myeloid leukemia: loid leukemia with long-term low-grade toxicity of the treatment. Leuk
5-year update of the ENESTfreedom trial. Leukemia 2021;35:1344–1355. Lymphoma 2016;57:370–375.
233. Hughes TP, Clementino NCD, Fominykh M, et al. Long-term treatment- 254. Cervantes F, Correa JG, P erez I, et al. Imatinib dose reduction in
free remission in patients with chronic myeloid leukemia after second- patients with chronic myeloid leukemia in sustained deep molecular
line nilotinib: ENESTop 5-year update. Leukemia 2021;35:1631–1642. response. Ann Hematol 2017;96:81–85.

JNCCN.org | Volume 22 Issue 1 | February 2024 67

 NCCN GUIDELINES® Chronic Myeloid Leukemia, Version 2.2024

255. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine term disease control in chronic myeloid leukemia. Leuk Lymphoma
kinase inhibitor dose in patients with chronic myeloid leukaemia with 2019;60:1796–1802.
stable major molecular response (DESTINY): an interim analysis of a 277. Stella S, Tirr
o E, Massimino M, et al. Successful management of a preg-
non-randomised, phase 2 trial. Lancet Haematol 2017;4:e310–316. nant patient with chronic myeloid leukemia receiving standard dose im-
256. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine atinib. In Vivo 2019;33:1593–1598.
kinase inhibitor therapy before complete treatment discontinuation 278. Ali R, Ozkalemkaş F, Ozkocaman V, et al. Successful pregnancy and de-
in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, livery in a patient with chronic myelogenous leukemia (CML), and man-
phase 2 trial. Lancet Haematol 2019;6:e375–383. agement of CML with leukapheresis during pregnancy: a case report
257. Cayssials E, Torregrosa-Diaz J, Gallego-Hernanz P, et al. Low-dose tyro- and review of the literature. Jpn J Clin Oncol 2004;34:215–217.
sine kinase inhibitors before treatment discontinuation do not impair 279. Koh LP, Kanagalingam D. Pregnancies in patients with chronic myeloid
treatment-free remission in chronic myeloid leukemia patients: results of leukemia in the era of imatinib. Int J Hematol 2006;84:459–462.
a retrospective study. Cancer 2020;126:3438–3447.
280. Palani R, Milojkovic D, Apperley JF. Managing pregnancy in chronic my-
258. Claudiani S, Apperley JF, Szydlo R, et al. TKI dose reduction can effec- eloid leukaemia. Ann Hematol 2015;94(Suppl 2):S167–176.
tively maintain major molecular remission in patients with chronic mye-
281. Staley EM, Simmons SC, Feldman AZ, et al. Management of chronic
loid leukaemia. Br J Haematol 2021;193:346–355.
myeloid leukemia in the setting of pregnancy: when is leukocytapheresis
259. Malagola M, Iurlo A, Abruzzese E, et al. Molecular response and quality appropriate? A case report and review of the literature. Transfusion
of life in chronic myeloid leukemia patients treated with intermittent 2018;58:456–460.
TKIs: first interim analysis of OPTkIMA study. Cancer Med 2021;10:
282. James AH, Brancazio LR, Price T. Aspirin and reproductive outcomes.
1726–1737.
Obstet Gynecol Surv 2008;63:49–57.
260. Hoffmann VS, Baccarani M, Hasford J, et al. The EUTOS population-
283. Deruelle P, Coulon C. The use of low-molecular-weight heparins in preg-
based registry: incidence and clinical characteristics of 2904 CML pa-
nancy–how safe are they? Curr Opin Obstet Gynecol 2007;19:573–577.
tients in 20 European Countries. Leukemia 2015;29:1336–1343.
284. Baykal C, Zengin N, Coşkun F, et al. Use of hydroxyurea and alpha-
261. Ramasamy K, Hayden J, Lim Z, et al. Successful pregnancies involving
interferon in chronic myeloid leukemia during pregnancy: a case
men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol
report. Eur J Gynaecol Oncol 2000;21:89–90.
2007;137:374–375.
285. Thauvin-Robinet C, Maingueneau C, Robert E, et al. Exposure to hydroxy-
262. Breccia M, Cannella L, Montefusco E, et al. Male patients with chronic
urea during pregnancy: a case series. Leukemia 2001;15:1309–1311.
myeloid leukemia treated with imatinib involved in healthy pregnancies:
report of five cases. Leuk Res 2008;32:519–520. 286. Fadilah SA, Ahmad-Zailani H, Soon-Keng C, et al. Successful treatment
of chronic myeloid leukemia during pregnancy with hydroxyurea. Leuke-
263. Oweini H, Otrock ZK, Mahfouz RA, et al. Successful pregnancy involving
mia 2002;16:1202–1203.
a man with chronic myeloid leukemia on dasatinib. Arch Gynecol
Obstet 2011;283:133–134. 287. Balsat M, Etienne M, Elhamri M, et al. Successful pregnancies in pa-
tients with BCR-ABL-positive leukemias treated with interferon-alpha
264. Ghalaut VS, Prakash G, Bansal P, et al. Effect of imatinib on male
therapy during the tyrosine kinase inhibitors era. Eur J Haematol 2018;
reproductive hormones in BCR-ABL positive CML patients: a pre-
101:774–780.
liminary report. J Oncol Pharm Pract 2014;20:243–248.
288. Beauverd Y, Radia D, Cargo C, et al. Pegylated interferon alpha-2a for
265. Alizadeh H, Jaafar H, Rajnics P, et al. Outcome of pregnancy in chronic
essential thrombocythemia during pregnancy: outcome and safety. A
myeloid leukaemia patients treated with tyrosine kinase inhibitors: short
case series. Haematologica 2016;101:e182–184.
report from a single centre. Leuk Res 2015;39:47–51.
289. Schrickel L, Heidel FH, Sadjadian P, et al. Interferon alpha for essential
266. Pye SM, Cortes JE, Ault P, et al. The effects of imatinib on pregnancy
thrombocythemia during 34 high-risk pregnancies: outcome and safety.
outcome. Blood 2008;111:5505–5508.
J Cancer Res Clin Oncol 2021;147:1481–1491.
267. Cortes JE, Abruzzese E, Chelysheva E, et al. The impact of dasatinib on
290. Burchert A, M€ uller MC, Kostrewa P, et al. Sustained molecular response
pregnancy outcomes. Am J Hematol 2015;90:1111–1115.
with interferon alfa maintenance after induction therapy with imatinib
268. Barkoulas T, Hall PD. Experience with dasatinib and nilotinib use in plus interferon alfa in patients with chronic myeloid leukemia. J Clin On-
pregnancy. J Oncol Pharm Pract 2018;24:121–128. col 2010;28:1429–1435.
269. Salem W, Li K, Krapp C, et al. Imatinib treatments have long-term im- 291. Abruzzese E, Turkina AG, Apperley JF, et al. Pregnancy management in cml
pact on placentation and embryo survival. Sci Rep 2019;9:2535. patients: to treat or not to treat? Report of 224 outcomes of the European
270. Madabhavi I, Sarkar M, Modi M, et al. Pregnancy outcomes in chronic Leukemia Net (ELN) database. Blood 2019;134(Suppl 1):Abstract 632.
myeloid leukemia: a single center experience. J Glob Oncol 2019;5:1–11. 292. Russell MA, Carpenter MW, Akhtar M, et al. Imatinib mesylate and me-
271. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Pregnancy tabolite concentrations in maternal blood, umbilical cord blood, pla-
outcomes in patients treated with bosutinib. Int J Hematol Oncol centa and breast milk. J Perinatol 2007;27:241–243.
2020;9:IJH26. 293. Ali R, Ozkalemkas F, Kimya Y, et al. Imatinib use during pregnancy and
272. Assi R, Kantarjian HM, Keating M, et al. Management of chronic mye- breast feeding: a case report and review of the literature. Arch Gynecol
loid leukemia during pregnancy among patients treated with a tyrosine Obstet 2009;280:169–175.
kinase inhibitor: a single-center experience. Leuk Lymphoma 2021;62: 294. US National Institutes of Health. Drugs and lactation database
909–917. (LactMed). Accessed November 1, 2023. Available at: https://
273. Ault P, Kantarjian HM, O’Brien S, et al. Pregnancy among patients with www.ncbi.nlm.nih.gov/books/NBK501922/
chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006;24: 295. Chelysheva E, Aleshin S, Polushkina E, et al. Breastfeeding in patients
1204–1208. with chronic myeloid leukaemia: case series with measurements of drug
274. Kuwabara A, Babb A, Ibrahim A, et al. Poor outcome after reintroduc- concentrations in maternal milk and literature review. Mediterr J Hema-
tion of imatinib in patients with chronic myeloid leukemia who interrupt tol Infect Dis 2018;10:e2018027.
therapy on account of pregnancy without having achieved an optimal 296. Abruzzese E, Trawinska MM, Perrotti AP, et al. Tyrosine kinase inhibitors
response. Blood 2010;116:1014–1016. and pregnancy. Mediterr J Hematol Infect Dis 2014;6:e2014028.
275. Berman E. Family planning and pregnancy in patients with chronic mye- 297. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks
loid leukemia. Curr Hematol Malig Rep 2023;18:33–39. of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic
276. Lasica M, Willcox A, Burbury K, et al. The effect of tyrosine kinase inhibi- phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;
tor interruption and interferon use on pregnancy outcomes and long- 30:1044–1054.

68 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 22 Issue 1 | February 2024
Chronic Myeloid Leukemia, Version 2.2024 NCCN GUIDELINES®

Individual Disclosures for the NCCN Chronic Myeloid Leukemia Panel

Promotional Advisory
Clinical Research Support/Data Safety Scientific Advisory Boards, Consultant, or Boards, Consultant, or
Panel Member Monitoring Board Expert Witness Speakers Bureau Specialization

Jessica K. Altman, MD AbbVie, Inc.; ALX Oncology; Amgen Inc.; Aprea; Aptos; Astellas Pharma US, Inc.; BlueBird Bio; Curio; GlycoMimetics, Inc. Hematology/Hematology oncology
Astellas Pharma US, Inc.; BioSight; Bristol Myers Squibb; Daiichi- Sankyo Co.; Gilead Sciences, Inc.;
Cellectis; Fujifilm Corporation; Gilead Sciences, Inc.; Kura Oncology, Inc.; Kymera; Stemline; Syros
GlycoMimetics, Inc.; ImmunoGen, Inc.; Kartos; Kura Pharmaceuticals
Oncology, Inc.; MEI Pharma Inc.; Rafael; Telios

Maria Amaya, MD, PhD None None None Hematology/Hematology oncology

Kebede H. Begna, MD None Novartis Pharmaceuticals Corporation None Hematology/Hematology oncology

Ellin Berman, MD Novartis Pharmaceuticals Corporation None None Hematology/Hematology oncology;

Medical oncology; Internal
medicine

Ravi Bhatia, MD None None None Hematology/Hematology oncology

Onyee Chan, MD Cullinan Oncology; Jazz Pharmaceuticals Inc.; Magenta None Bristol Myers Squibb; Hematology/Hematology oncology
Therapeutics NeuroVascular Research &
Design; TF Health Co.

Joan Clements None Kaiser Permanente; Novartis Pharmaceuticals Novartis Pharmaceuticals Patient advocacy
Corporation; Pfizer Inc. Corporation

Robert H. Collins Jr, MD None Ro5 Inc. None Hematology/Hematology oncology

Peter T. Curtin, MD CRISPR Therapeutics None None Medical oncology; Hematology/

Hematology oncology;
Hematopoietic cell transplantation

Daniel J. DeAngelo, MD, PhD AbbVie, Inc.; Blueprint Medicines; Daiichi- Sankyo Co.; None None Hematology/Hematology oncology;
GlycoMimetics, Inc.; Jazz Pharmaceuticals Inc.; Kite Medical oncology
Pharma; Mt Sinai MPN Consortium; Novartis
Pharmaceuticals Corporation

Michael Drazer, MD None Argenx None Hematology/Hematology oncology

Lori Maness, MD None None None Hematology/Hematology oncology

Leland Metheny, MD Adienne; Pfizer Inc. Gamida; Incyte Corporation; Pfizer Inc./ None Hematology/Hematology oncology;
Hospira Inc. Internal medicine

Sanjay Mohan, MD, MSCI Ichnos; Incyte Corporation; Kartos; Karyopharm None None Hematology/Hematology oncology
Therapeutics; Taiho Pharmaceuticals Co., Ltd.

Joseph O. Moore, MD Pharmacyclics Pharmacyclics Janssen Pharmaceutica Medical oncology

Products, LP

Vivian Oehler, MD Actuate/Courante Oncology; Ascentage; Astex Novartis Pharmaceuticals Corporation None Hematology/Hematology oncology
Pharmaceuticals; Bristol Myers Squibb; Pfizer Inc.

Keith Pratz, MD AbbVie, Inc.; Astellas Pharma US, Inc.; Takeda AbbVie, Inc.; Astellas Pharma US, Inc.; None Medical oncology
Pharmaceuticals North America, Inc. AstraZeneca Pharmaceuticals LP; Bristol
Myers Squibb; Roche Laboratories, Inc.;
Servier

Iskra Pusic, MD, MSCI GSK; Incyte Corporation; Kadmon; SYNDAX Incyte Corporation; Syndax None Medical oncology

Michal G. Rose, MD None None None Medical oncology

Neil P. Shah, MD, PhD Aerovate Therapeutics; Bristol Myers Squibb; Taiho Aerovate Therapeutics None Hematology/Hematology oncology
Pharmaceuticals Co., Ltd.

William Shomali, MD Blueprint Medicines; Incyte Corporation Incyte Corporation None Hematology/Hematology oncology

B. Douglas Smith, MD None Bristol Myers Squibb; Novartis None Medical oncology; Internal
Pharmaceuticals Corporation; Pfizer Inc.; medicine
Servier

Michael Styler, MD Janssen Pharmaceutica Products, LP None None Hematology/Hematology oncology;

Medical oncology

Moshe Talpaz, MD None Bristol Myers Squibb; Novartis None Medical oncology
Pharmaceuticals Corporation; Sumitomo

Tiffany N. Tanaka, MD None None CTI BioPharma Corp.; Hematology/Hematology oncology

Gilead Sciences, Inc.

Srinivas Tantravahi, MBBS Karyopharm Therapeutics AbbVie, Inc.; CTI BioPharma Corp.; Guidant None Hematology/Hematology oncology
Corporation; Karyopharm Therapeutics;
MorphoSys AG; Novartis Pharmaceuticals
Corporation

James Thompson, MD, MS Bristol Myers Squibb; Novartis Pharmaceuticals None None Hematology/Hematology oncology
Corporation

Steven Tsai, MD None None None Hematology/Hematology oncology;

Hematopoietic cell transplantation

Jennifer Vaughn, MD, MSPH None None Cogent Pharmaceuticals; Hematology/Hematology oncology
Ionis

Jeanna Welborn, MD None None None Medical oncology

David T. Yang, MD None None None Pathology

The NCCN Guidelines Staff have no conflicts to disclose.

JNCCN.org | Volume 22 Issue 1 | February 2024 69