Master Class on Aplastic Anemia

Case Discussion: Aplastic Anaemia

Tamil Nadu Haemato-Oncology Team

30 Jun-2021

Chepsy C Philip MD ( CMC Ludhiana) , DM ( CMC Vellore)

Senior Consultant & Program Director, R A C T H A M
EHA certified in Hematology ( Europe)
IACA Fellow in Blood & Marrow Transplantation (FHCRC)
Disclaimer: The views, opinions, ideas, etc. expressed therein are solely those of the author. Novartis does not certify the accuracy, completeness, currency of any

information and shall not be responsible or in anyway liable for any errors, omissions or inaccuracies in such information. Novartis is not liable to you in any manner

whatsoever for any decision made or action or non-action taken by you in reliance upon the information provided. Novartis does not recommend the use of its

products in unapproved indications and recommends to refer to complete prescribing information prior to using any of the Novartis products.

For the use of a registered medical practitioner or a hospital or a laboratory.

This information is issued as a scientific service to medical professionals by:
Novartis Healthcare Private Limited,
Inspire BKC, 7th Floor
Bandra Kurla Complex,
Bandra (East), Mumbai - 400051
India

www.novartisoncology.com
 Case: History & Examination

• Increased gum bleeding when brushing her teeth in the morning

Relevant history
• For the past 4 weeks, she has had difficulty climbing the stairs in her
home
• Presyncopal episode 1 week previously

• Obesity, GERD and hyperlipidaemia

• Family history was positive for hypertension, diabetes, and heart
Past & Family History
disease.
• There was no history of inherited or acquired hematologic disorders or
cancer

51 year old female

• Pulse – 128 BPM
Physical Examination • Weight – 70kg, Height-1.5m
• Petechial rashes over the trunk and lower extremities
In routine clinical practice:
• What are the usual cases of pancytopenia you encounter in your
practice
• How do you approach pancytopenia
• How frequently do you encounter the cases of aplastic anemia?
• What are the presenting features of aplastic anemia?
• What is approach to establish diagnosis
 Global distribution of aplastic
anaemia
• Incidence in Western countries is approximately two cases per 1 million people/year1,2

• In East Asia, the incidence is 2–3 times higher than in Western countries3

• In India, the incidence is estimated to be 6.8 per million population4

• It affects both sexes

• It can affect any age

• Aplastic anaemia can be either inherited, or acquired5

1. Montané E et al. Haematologica 2008;93:518; 2. Hamerschlak N et al. Sao Paulo Med J 2005;123:101; 3. Issaragrisil S et al. Blood 2006;107:1299; 4. Malhotra P. Journal of public health. 2015. 38(2).
223-228 5. Killick SB et al. Br J Haematol 2016;172:187–207
Aplastic anemia: Clinical Presentation
• It affects both sexes1 Children
Majority are diagnosed <16 years of age1
• Although aplastic anemia may occur in all age groups, there is
a biphasic age distribution, with peaks in 2 age groups 1:
>25%: genetic origin1
• Between 10 and 25 years of age
• In individuals older than 60 years 90% disease-free survival after allogeneic
stem cell transplantation3

• Aplastic anaemia is associated with premature mortality3

Adults

• Aplastic anaemia can be either inherited, or acquired4 Peaks: 10–25 years and >60 years2

Adult manifestation of genetic aplastic

anaemia is uncommon3

Transplant-related mortality in older patients

(>40 years) is nearly 50%4

1. Young NS et al. Curr Opin Hematol 2008;15:162. 2. Young NS, Maciejewski J. N Eng J Med. 1997;336:1365; 3. Dokal I, Vulliamy T. Blood Rev. 2008;22:141. 4. Giammarco M et al. Blood
2018.131(17).1989-1992
Acquired Aplastic Anemia: Other
Associations
Factor Notes

• Exact mechanisms are unclear1

• Chloramphenicol1
• Penicillamine1
Medical drugs Anticonvulsants (eg, phenytoin, carbamazepine)2
•
• Antithyroid drugs (eg, carbimazole, thiouracil)2
• Chemotherapy/radiotherapy for cancer treatment 2

Industrial chemicals • Benzene1

• Pesticides1

• The relationship between pregnancy and aplastic anemia is unclear;

Pregnancy however, spontaneous hematologic improvements after (induced) abortion or delivery
has been reported3

Autoimmune • T-cell–mediated autoimmune destruction of bone marrow

• Cause of T-cell activation is unclear, but may be associated with polymorphisms in
destruction cytokine genes associated with an increased immune response 4

1. Young NS. Hematology Am Soc Hematol Educ Program 2006;72; 2. Marsh JCW et al. Br J Haematol 2009;147:43; 3. Oostercamp HM et al. Br J Haematol 1998;103:315; 4. Young NS & Maciejewski
J. N Eng J Med 1997;336:1365
 Aplastic anemia: Clinical
Presentation
• Aplastic anaemia can present abruptly Petechial rash
(onset over a few days) or over weeks
to months1
• Common presenting symptoms include:
• Symptoms of anemia2
• Fatigue, difficulty breathing on exertion1
• Skin or mucosal hemorrhage2
• Easy bruising1
• Petechiae (red or purple spots on the body)1
• Gingival bleeding (bleeding gums)1
• Epistaxis (nosebleeds)1
• Visual disturbance due to retinal
hemorrhage2
1. Brodsky RA & Jones RJ. Lancet 2005;365:1647; 2. Marsh JCW et al. Br J Haematol 2009;147:43; Image: http://commons.wikimedia.org/wiki/File:Petechial_rash.JPG (accessed October 2013)
 Case continued: Investigation
• Laboratory values include the following:

Laboratory test Patient’s result Reference range

Hemoglobin 6.8 g/dL 12–16 g/dL
White blood cell count 0.8  109/L 4.0–10 × 109/L
Absolute neutrophil count 0.3  109/L 1.4–7.5  109/L
Absolute reticulocyte count 7  109/L 20–80  109/L
51 year old
female Platelet count 7  109/L 150–450  109/L

• Bone Marrow Aspiration:

• 10% of bone marrow cellularity
• Bone marrow aspirate showed markedly reduced trilineage hematopoiesis with normal megakaryocyte
morphology, without dysplasia in any cell line
• Baseline chemistry panel including electrolytes, liver and renal function tests, and LDH were all normal
What additional investigations will you perform in your routine
practice?
Which are the usual confounders?
How do you approach a hypoplastic MDS?
 Diagnosis of aplastic anemia
Following investigations are required to confirm the diagnosis and exclude
Inherited Bone Marrow Failure Syndromes (IBMFS):
1. Full blood count and bone marrow examination
2. Reticulocyte count
3. Blood film examination
4. HbF%
5. Peripheral blood chromosomal breakage analysis: diepoxybutane test
6. Flow cytometry for GPI-anchored protein to detect PNH clones Emerging Tests:

7. Vitamin B12 and Folate levels 1. Peripheral blood leucocyte telomere

8. LFT length
9. Viral studies: HAV,HBV,HCV,EBV, CMV, HIV, Parvovirus B19 2. NGS
10. ANA & Anti-DS-DNA 3. SNP Array karyotyping
11. CXR & radiology
12. Abdominal USG and Echocardiogram
Killick SB et al. Br J Haematol 2016;172:187–207
 Diagnosis of aplastic anemia
• Idiopathic AA is a diagnosis of exclusion and no single test reliably
diagnoses idiopathic acquired AA

•All new patients presenting with acquired aplastic anaemia should be

assessed to:
• Confirm the diagnosis and exclude other causes of pancytopenia and hypocellular bone marrow

• Classify disease severity using the blood and bone marrow criteria

• Document the presence of associated paroxysmal nocturnal haemoglobinuria (PNH) and

cytogenetic clones

• Exclude late-onset inherited bone marrow failure syndromes

Killick SB et al. Br J Haematol 2016;172:187–207

AA is classified as very severe, severe and non-severe
(moderate)

Killick SB et al. Br J Haematol 2016;172:187–207

 Case continued: Diagnosis
All the tests for IBMFS are negative

Laboratory test Patient’s result

Hemoglobin 6.8 g/dL
White blood cell count 0.8  109/L
• Bone marrow cellularity < 25%
• ANC < 0.5 and >0.2  109/L
Absolute neutrophil count 0.3  109/L • Platelet count < 20  109/L
Absolute reticulocyte count 7  109/L • Reticulocyte count < 20  109/L
51 year old
female Platelet count 7  109/L

Acquired Severe Aplastic Anemia

 What treatment would you prescribe for this patient?

A. hsATG + Cys A

B. hsATG + CysA + Eltrombopag

C. HMSCT
• Preference of ATG??
• Long term responders in your practice??
• CSA tapering strategy
• CSA dependent resposne
 Treatment options of Severe Aplastic
Anemia
SAA Patient

HSCT key features:

Potential curative treament1
HSCT
Almost 90% disease-free survival after allogeneic
stem cell transplantation2
Advantages: Marked reduction in risk of relapse
and late clonal disorder when compared to IST1
Predictors of outcome: 1500 patients EBMT2
• Matched sibling donor
• Age of less than 16 years best outcomes
• Early transplant (time from diagnosis to
transplant of less than 83 days)
• Non-radiation conditioning regimen
Strong age effect on survival2

1. DeZern A E et al. Expert Rev Hematol. 2011 April ; 4(2): 221–230, 2. Bacigalupo A. Blood 2017. 129(11):1428-1436
 Treatment options of Severe Aplastic
Anemia
SAA Patient

IST with ATG+CsA

HSCT IST with ATG + CsA key features:
Haematological recover in 50-70% of
cases1,2
Age is an important predictor of the
outcome1,2

Non- eligible
The rates of secondary malignancy
and clonal evolution was higher with
HSCT
IST compared to HSCT

Strong age effect on survival (IST including Salvage

SCT)2
1. DeZern A E et al. Expert Rev Hematol. 2011 April ; 4(2): 221–230, 2. Bacigalupo A. Blood 2017. 129(11):1428-1436
 Treatment options of Severe Aplastic
Anemia
SAA Patient

HSCT Unmet need with IST with ATG+CsA

Majority of the hematologic responses observed following initial ATG+CsA are

partial, with only a few patients achieving a complete response (˜10%)

About 1/3rd to 1/4th will not respond

IST with Approximately 30-40% responders relapse

Non- eligible ATG+CsA
HSCT Approximately 40% of unresponsive patients will die within 5 years of diagnosis

1. DeZern A E et al. Expert Rev Hematol. 2011 April ; 4(2): 221–230, 2. Bacigalupo A. Blood 2017. 129(11):1428-1436; Scheinberg P & Young NS. Blood 2012;120:1185–1196; 2.Olnes MJ,
Scheinberg P,. N Eng J Med, 2012; 367(1):11-9; 3. Maciejewski JP, Kim S, et al. Am J Hematol; 65(2):123-31; 4. Rosenfeld S, Follmann D, et al . JAMA; 289(9):1130-5
 Treatment options of Severe Aplastic
Anemia
SAA Patient

Failure to respond to IST reflect residual Eltrombopag stimulation of stem cells may
HSCT stem cell numbers increase probability of hematopoietic recovery

Unmet
need IST
Non- eligible ATG+CsA
HSCT

Adapted from Young NS et al. Hematology Am Soc Hematol Educ Program 2013;76–81
Addition of eltrombopag increased Hematopoiesis

Townsley DM et al. Blood 2015;126:LBA-2, oral presentation at ASH 2015

 Treatment options of Severe Aplastic
Anemia
SAA Patient

IST plus Eltrombopag as first line

therapy improved outcomes in SAA:
HSCT Overall haematological response was 94%
at 6 months

Complete response was seen in 58%

(compared to 10% with IST historical
cohort)

Unmet Robust response was observed (age ≥12

need IST years):
Non- eligible 1. Eltrombopag initiated with dose of
ATG+CsA 150 mg for 6 months
HSCT 2. Initiated on day 1 along with ATG+CsA
3. CsA continued for upto 24 months to
avoid relapse

Overall survival was 99% at 2 years

Townsley DM et al. Blood 2015;126:LBA-2, oral presentation at ASH 2015

 NIH study: Eltrombopag added to IST improves hematologic response(Townsley
publication)

Historical IST hematologic response at 6 months: OR ~60–70%; CR (robust cell count recovery) ~10%2,3
Addition of eltrombopag to IST showed robust improvement in blood cell counts indicated by
higher rate of complete response (48% & 58% at 3 & 6 months) when started
simultaneously with ATG & Cys A from day 1 compared to 10% in IST alone
Note: Complete Response shows higher robustness of recovery in cell counts compared to partial response
1. Townsley DM et al. N Engl J Med 2017;376:1540–1550 2. Scheinberg P et al. Haematologica 2009;94:348–354; 3. Scheinberg P et al. N Engl J Med 2011;365:430–438
 NIH study: Eltrombopag added to IST and transfusion independence (Townsley
publication)
Median days for transfusion independence

RBC transfusion independence 39

Platelet transfusion independence 32

0 5 10 15 20 25 30 35 40 45

Townsley DM et al. Blood 2015;126:LBA-2, oral presentation at ASH 2015

 Case continued: Management
Acquired Severe Aplastic Anemia
Treatment Dose recommended Dose calculation
h-ATG IV 40mg/kg/day 40X70= 2800mg/day
Tab Cyclosporine 3mg/kg BD 3X70= 210mg BD
51 year old
female – 70 kg Tab Eltrombopag 150mg OD 150mg OD

Treatment Day 1 Day 2 Day 3 Day 4 Day 5

h-ATG IV infusion 2800mg/day 2800 mg/day 2800 mg/day 2800 mg/day Stop
Tab Cyclosporine 200mg BD 200mg BD 200mg BD 200mg BD 200mg BD
Tab Eltrombopag 150mg OD 150mg OD 150mg OD 150mg OD 150mg OD

Supportive therapy:
RBC transfusion
Platelet transfusion to achieve platelet count >20X109/L prior to ATG therapy

Eltrombopag 150 mg OD continued for 6 months and stopped

CsA 200mg BD continued for 6 months
What is the importance of cyclosporine continuation?
Relapse With Eltrombopag Added to IST – Importance of CsA
continuation
• 25/78 (32%) responding patients relapsed after 6 months during the study:
• Following CsA discontinuation at 6 months, 19/35 (54%)
• Following continuation of low dose CsA beyond 6 months, 6/43 (14%)
Time to Relapsea
1.0

0.8

0.6 CsA discontinued at 6 months

Probability

18 months relapse free

0.4
probability (RFP) in patients
CsA discontinued at 24 months
0.2
who achieved CR in cohort 3
0.0
0 200 400 600 800
was 83.1%
Days
No. at risk:
CsA discontinued 92 35 17 16 16
CsA continued 92 43 24 11 1

• Blood counts were rescued in most patients (23/25 [92%]) by reinstitution of CsA alone (13/25 [52%]) or with addition of
eltrombopag (10/25 [40%])
CsA, cyclosporine
a
Relapse is defined as declining blood counts that warranted the reintroduction of full-dose CsA
Townsley DM et al. N Engl J Med. 2017;376:1540-1550.
 Case continued: Management Follow
up
• Patient achieved transfusion independence by 1 month
Patient’s result 3 Patient’s result 6
Laboratory test months
months
Hemoglobin 10.2 g/dL 11.4

White blood cell count 4.3  109/L 5.8 109/L No cytogenetic abnormality
detected at 6 months, 1 and 2
Absolute neutrophil count 1.3  109/L 1.6 109/L years
Platelet count 150  109/L 220 109/L

• CsA 150mg/ day (2mg/kg/day – 2X70=140mg) continued after 6 months to 2 years

• There was improvement in fatigue and overall QOL of patient
Summary
• Continued supportive care is essential for patients with AA

• It is important to achieve robust haematological response (complete response) among patients with SAA to
improve long term outcomes like overall survival

• Combination of immunosuppressive therapy with thrombopoietin receptor agonists represents first-line

treatment option for patients with SAA non-eligible for transplant which is now approved
in India

• The addition of Eltrombopag on Day 1 (for 6 months) to IST (h-ATG Days 1-4 +therapeutic dose of CsA for
6 months) is associated with a better response at Month 6:
• Overall Response – 94%, Complete response – 56%

• The overall safety profile of eltrombopag at doses up to 150 mg daily is still consistent with the expected
safety profile for subjects with SAA and the established safety profile of eltrombopag in the approved chronic
ITP, HCV and refractory SAA indications.
Thank You
Reserved Slides
NIH study: Frequency of clonal evolution on eltrombopag + IST was similar to historical
experience with standard IST
Age Time to MDS/AML somatic
Response Cytogenetics BM dysplasia Outcome
(years) evolution gene mutations (VAF)

Cytogenetics
68 CR 3 months 46, XX, del(13)(q12q22)[cp3]/46,XX[17] No none detected
normalized

39 CR 30 months 48,XX +6 +15 [2]/46,XX[18] No Stable DNMT3A (3%)

AML/HSCT, death
64 PR 3 months 45,XX,t(3;3)(q21;q26),-7[3]/ 46, XX[17] Yes none detected
(RTEL1)

PR/ ASXL1 (24%)

72 30 months 45, XY,-7[20] Yes Stable
Relapse RUNX1 (12%)

CR/
48 6 months 46,XX,del (7)(p13p15)[3]/46,XX[19] No HSCT DNMT3A (15%)
Relapse

61 PR 6 months 45,XX,-7[7]/46,XX[16] Yes Proceeding to HSCT none detected

HSCT
16 NR 3 months 45,XY,-7[6]/46,XY[14] No none detected
(RTEL1)

Clonal evolution occurred in 7/92 patients (8%)

AML, acute myeloid leukemia; BM, bone marrow; VAF, variant allele frequency
Dumitriu B et al. Blood 2015;125:706–709; Townsley DM et al. Blood 2015;126:LBA-2, oral presentation at ASH 2015