Follicular Lymphoma Current Management and Novel

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Nathan H. Fowler
Editor

Follicular Lymphoma
Current Management and Novel Approaches
Editor
Nathan H. Fowler
Department of Lymphoma/Myeloma
The University of Texas MD Anderson Cancer Center
Houston, TX
USA

ISBN 978-3-030-26210-5    ISBN 978-3-030-26211-2 (eBook)

https://doi.org/10.1007/978-3-030-26211-2

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Preface

Few things strike fear into the clinician and patient as the word “cancer.” Despite
decades of research and countless dollars, the majority of cancers remain incurable,
and therapy carries a high cost, both financially and on patients’ short- and long-­
term quality of life. With the exception of very early-stage malignancies, most can-
cers carry a high risk of relapse following frontline treatment. Side effects occur
often, can be severe, and are unpredictable. Fortunately, due to technical advances,
emerging science, and a fundamental shift in new drug development, we are wit-
nessing dramatic improvements in life expectancy and treatment tolerability across
a spectrum of malignancies.
For years, follicular lymphoma has remained a disease with more questions than
answers. The natural history can be highly variable, and clinical information at
diagnosis only occasionally predicts a patient’s long-term outcome. Some patients
achieve spontaneous remission in the absence of therapy, while others transform or
fail high-dose chemotherapy in short order. Historically, attempts to biologically
define these dramatically different patient groups have been largely unsuccessful.
Although the cell of origin and the hallmark mutation have been well described,
very few targeted therapeutics existed. Finally, traditional chemotherapy approaches
are associated with high response rates, yet nearly all patients still relapse. The rea-
son behind many of these observations was largely unknown.
Fortunately, the last several years have been marked by a significant improve-
ment in the understanding of the pathogenesis and biology underlying follicular
lymphoma. Research into the role of the immune microenvironment have helped
teams develop innovative approaches to treat follicular lymphoma. The work on key
cellular pathways, novel cellular antigens, and unique genomic drivers has led to the
identification of several potential therapeutic targets resulting in an explosion of
active drugs and dramatically improved out-comes.
In this textbook, we will review the pathogenesis and molecular drivers of fol-
licular lymphoma. We will also cover the history and activity of traditional thera-
peutic strategies and discuss many exciting advances which have recently become
available for patients. In each section, the authors will also discuss the future

v
vi Preface

t­herapeutic role of key molecular pathways, targeted agents, immunotherapeutics,

and next-generation radiotherapy approaches.
As our understanding of lymphoma continues to evolve, I am confident that we
will soon discover the answers to key questions surrounding follicular lymphoma.
But most importantly, ongoing and future work will lead to even better options for
clinicians – eventually leading to curative, less toxic options for all patients.
Finally, whether clinician, scientist, patient, or caregiver, our time in this life is
short. Never underestimate the power of small acts of kindness.

Houston, TX, USA  Nathan H. Fowler

Contents

Part I Biology and Pathogenesis of Follicular Lymphoma

  1 Follicular Lymphoma: Epidemiology, Pathogenesis

and Initiating Events��������������������������������������������������������������������������������    3
Zi Yun Ng, Connull Leslie, and Chan Yoon Cheah
  2 Pathologic Features, Grading, and Variants
of Follicular Lymphoma��������������������������������������������������������������������������   23
Ali Sakhdari and Roberto N. Miranda
  3 Genomic Drivers in Follicular Lymphoma��������������������������������������������   47
Saber Tadros and Michael R. Green
  4 The Microenvironment in Follicular Lymphoma ��������������������������������   65
Nahum Puebla-Osorio, Paolo Strati, and Sattva S. Neelapu
  5 Prognostic Factors in Follicular Lymphoma ����������������������������������������   83
Anna Johnston and Judith Trotman

Part II Current Therapy for Follicular Lymphoma

  6 Management of Localized Low-Grade Follicular Lymphoma������������ 103

Neil B. Desai and Sarah A. Milgrom
  7 Current Management and Novel Approaches
to the Management of Follicular Lymphoma���������������������������������������� 119
Jonathon B. Cohen and Brad S. Kahl
  8 Transformed Follicular Lymphoma ������������������������������������������������������ 135
Michael J. Leukam and Sonali M. Smith
  9 Cellular Therapy for Follicular Lymphoma������������������������������������������ 165
Ok-kyong Chaekal, Paolo Strati, and Koen van Besien

vii
viii Contents

Part III Emerging Therapy in Follicular Lymphoma

10 Antibody Therapy in Follicular Lymphoma����������������������������������������� 189

J. C. Villasboas and Grzegorz S. Nowakowski
11 Molecular Targeting in Follicular Lymphoma�������������������������������������� 207
Loretta J. Nastoupil
12 Targeting the Tumor Microenvironment ���������������������������������������������� 219
Paolo Strati, Nathan H. Fowler, and Eric Fountain
Index������������������������������������������������������������������������������������������������������������������ 233
Contributors

Ok-kyong Chaekal Department of Hematology/Oncology, Weill Cornell Medical

College/New York Presbyterian, New York, NY, USA
Chan Yoon Cheah Department of Haematology, Sir Charles Gairdner Hospital,
Nedlands, WA, Australia
Medical School, University of Western Australia, Crawley, WA, Australia
Jonathon B. Cohen Department of Hematology and Medical Oncology, Emory
University – Winship Cancer Institute, Atlanta, GA, USA
Neil B. Desai University of Texas Southwestern, Department of Radiation
Oncology, Dallas, TX, USA
Eric Fountain Division of Cancer Medicine, University of Texas, MD Anderson,
Houston, TX, USA
Nathan H. Fowler Department of Lymphoma/Myeloma, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Michael R. Green University of Texas MD Anderson Cancer Center, Department
of Lymphoma/Myeloma, Houston, TX, USA
Anna Johnston University of Tasmania and Department of Haematology, Royal
Hobart Hospital, Hobart, TAS, Australia
Brad S. Kahl Department of Internal Medicine, Division of Medical Oncology,
Washington University School of Medicine – Siteman Cancer Center, Washington
University, St. Louis, MO, USA
Connull Leslie Department of Anatomical Pathology, Pathwest QEII Medical
Centre, Nedlands, WA, Australia
School of Biomedical Sciences, University of Western Australia, Crawley, WA,
Australia

ix
x Contributors

Michael J. Leukam Department of Medicine, Section of Hematology and

Oncology, University of Chicago Medicine, Chicago, IL, USA
Sarah A. Milgrom MD Anderson Cancer Center, Department of Radiation
Oncology, Houston, TX, USA
Roberto N. Miranda The University of Texas MD Anderson Cancer Center,
Department of Hematopathology, Houston, TX, USA
Loretta J. Nastoupil UT MD Anderson Cancer Center, Department of Lymphoma/
Myeloma, Houston, TX, USA
Sattva S. Neelapu Department of Lymphoma and Myeloma, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Zi Yun Ng Department of Haematology, Sir Charles Gairdner Hospital, Nedlands,
WA, Australia
Grzegorz S. Nowakowski Department of Medicine, Division of Hematology,
Mayo Clinic, Rochester, MN, USA
Nahum Puebla-Osorio Department of Lymphoma and Myeloma, The University
of Texas MD Anderson Cancer Center, Houston, TX, USA
Ali Sakhdari The University of Texas MD Anderson Cancer Center, Department
of Hematopathology, Houston, TX, USA
University of Toronto, Toronto, ON, Canada
Sonali M. Smith Section of Hematology/Oncology, Lymphoma Program,
Department of Medicine, The University of Chicago, Chicago, IL, USA
Paolo Strati Department of Lymphoma and Myeloma, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Saber Tadros University of Texas MD Anderson Cancer Center, Department of
Lymphoma/Myeloma, Houston, TX, USA
Judith Trotman University of Sydney and Department of Haematology, Concord
Repatriation Hospital, Sydney, NSW, Australia
Koen van Besien Department of Hematology/Oncology, Weill Cornell Medical
College/New York Presbyterian, New York, NY, USA
J. C. Villasboas Department of Medicine, Division of Hematology, Mayo Clinic,
Rochester, MN, USA
 Part I
Biology and Pathogenesis of Follicular
Lymphoma
Chapter 1
Follicular Lymphoma: Epidemiology,
Pathogenesis and Initiating Events

Zi Yun Ng, Connull Leslie, and Chan Yoon Cheah

Epidemiology

Introduction

Follicular lymphoma (FL) is the second most common lymphoma in the United
States (US) and Western Europe and the most common indolent lymphoma [1]. FL
is a lymphoproliferative disorder of germinal centre B-cells with a median age of
diagnosis of 58 years [1]. It is commonly associated with the inappropriate activa-
tion of BCL2, a proto-oncogene which is most commonly activated through the
t(14; 18)(q32;q21) chromosomal translocation [2].

All others contributed equally to this work

Z. Y. Ng
Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
e-mail: [email protected]
C. Leslie
Department of Anatomical Pathology, Pathwest QEII Medical Centre,
Nedlands, WA, Australia
School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
e-mail: [email protected]
C. Y. Cheah (*)
Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
Medical School, University of Western Australia, Crawley, WA, Australia
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 3

N. H. Fowler (ed.), Follicular Lymphoma,
https://doi.org/10.1007/978-3-030-26211-2_1
4 Z. Y. Ng et al.

General Trend of Incidence

In the United States, Teras et al. analysed data from the Surveillance, Epidemiology,
and End Results (SEER) registries to provide estimates of the total numbers of US
lymphoid neoplasm cases by subtype as well as a detailed evaluation of incidence
and survival statistics. The US age-adjusted incidence rate from 2011 to 2012 for
FL was 3.4 per 100,000 population. In this study, while most lymphoid malignan-
cies showed excess risk for males, this was not seen for FL which had an incidence
rate ratio (IRR) for gender of 1.18 [3]. Similarly, in the United Kingdom from 2004
to 2014, FL had a higher age-standardised sex rate ratio of 0.93 ([95% CI 0.89–
0.98], P = 0.006), meaning there were marginally more females than males diag-
nosed with FL [4].
From 1992 to 2001, the incidence of FL showed a non-significant rise of 1.8%
per year among the elderly [5]. However, the incidence for both genders declined
from 2001 to 2012. For males with FL, the annual percentage change in incidence
dropped from 4.7% in 2001–2004 to −2.2% in 2004–2012. For females, the annual
percentage change declined from 3.4% to −0.8% (2001–2004) and then a further
−3.6% from 2007 to 2012. It is hypothesised that the decline in incidence rates is
due to declining smoking rates over this period. Gender and race did not signifi-
cantly influence 2-, 5-, and 10-year survival rates [3].

International Variation

Multiple epidemiological studies have shown that FL has higher incidence in

Caucasian populations compared to African or Asian [2, 5, 6]. Analysis of 19 case-­
control studies by the InterLymph Consortium showed that magnitudes of associa-
tions with FL according to region (Europe, North America and Australia) were
mostly consistent [1]. A study of non-Hodgkin lymphoma (NHL) from 1988 to
1990 showed FL comprised a greater proportion of NHL diagnoses in North
America, London and Cape Town (28%–32%) relative to other sites like Hong
Kong (8%), Sweden (11%) or France (17%) [7]. Similarly, a study of 4056 cases of
NHL at 13 major medical centres in Thailand from 2007 to 2014 found only 5.6%
of these cases to be FL [8].
When looking at a migrant population in England from 2001 to 2007, rates of
FL were lowest among Chinese and individuals of African descent, intermediate
among South Asians and highest among Caucasians. There was little difference
between Afro-Caribbeans and Africans, with incidence rates around 60% lower
than that of Caucasians. Between the South Asian groups, Pakistanis showed the
highest rates, followed by Indians and Bangladeshis (IRRs of 1.11, 0.68 and 0.54,
respectively) [9]. FL is less common in India compared to Europe or America; for
example, a study from Mumbai showed that FL accounted for only 12.6% of 2773
NHL cases [10].
1 Follicular Lymphoma: Epidemiology, Pathogenesis and Initiating Events 5

Interestingly, investigating incidence of FL in Americans of Asian descent,

Clarke et al. found the incidence was significantly lower in foreign-born Asian-­
Americans compared to American-born (IRR 0.57 [95% CI 0.44–0.73]), suggesting
a role for environmental factors in the pathogenesis of FL [11]. Supporting this, the
risk of FL seems to be lower in first-generation Asian-born Japanese and Chinese
migrants compared to their descendants [12].

Genetic Factors

The InterLymph Consortium which comprised of 19 case-control studies (3530

cases and 22,639 controls) in Europe, North America and Australia showed that a
family history of non-Hodgkin lymphoma in a first-degree relative confers approxi-
mately double the population background risk of FL [1]. The risk was 3.6 times
higher in participants with first-degree male relatives with multiple myeloma com-
pared to the general population. Interestingly, this was not evident if there was a
first-degree female relative with myeloma. First-degree relatives with leukaemia or
Hodgkin lymphoma did not seem to confer an increased risk of FL [1]. Analysis of
4455 individuals in the Swedish Family-Cancer Database found that a parental
history of FL was associated with a significantly increased risk of FL (standardised
incidence ratio of 6.1), while an affected sibling conferred a 2.3 times risk [13].
There have been an increasing number of genome-wide association studies
(GWAS) identifying single-nucleotide polymorphisms (SNPs) associated with risk
of developing FL (detailed in Table 1.1).
Certain polymorphisms of the DNA repair gene XRCC3 may increase the risk of
developing FL, especially in current smokers [20].

Environmental Factors

The aforementioned migrant studies provide some evidence that environmental fac-
tors play a role in the pathogenesis of FL [12]. Attempts to study environmental risk
factors in epidemiological studies are greatly hampered by unavoidable confound-
ers and bias. As a result, drawing firm conclusions regarding the relative contribu-
tion of specific environmental risk factors is challenging, as data from studies are
often conflicting.
A number of studies have examined the association between occupation and risk
of FL. A reduced risk of FL was found in bakers and millers (OR 0.51 [95% CI
0.28–0.93]) and university or higher education teachers (OR 0.58 [95% CI 0.41–
0.83]) [1]. However, a separate meta-analysis showed an increased risk for NHL in
teachers at all levels [21]. A small prospective study in Germany which included 92
FL patients showed significant FL risk increases for occupational groups like medi-
cal, dental and veterinary workers (OR 3.1 [95% CI 1.4–6.8]); sales workers (OR
6 Z. Y. Ng et al.

Table 1.1 Genome-wide association studies with the relevant SNPs identified to be associated
with FL
Genome-wide association Single-nucleotide polymorphisms (SNPs) identified to be associated
studies (GWAS) with FL
Conde et al. [14] rs10484561
rs7755224
SNPs in the psoriasis susceptibility region 1 (PSORS1)
Smedby et al. [15] rs10484561 – also associated with risk of diffuse large B-cell
lymphoma (DLBCL)
rs2647012
Skibola et al. [16] rs6457327 – region of strongest association near PSORS1 locus
Vijai et al. [17] rs4530903
rs9268853
rs2647046
rs2621416
Skibola et al. [18] rs9275517a – no longer associated when its high linkage
disequilibrium with rs2647012 was accounted for
rs3117222a – correlated with increased levels of HLA-DPB1,
suggesting its expression regulation as a possible disease mechanism
Skibola et al. [19] rs17203612
rs3130437
rs4938573b near CXCR5
rs4937362b near ETS1
rs6444305b in LPP
rs17749561b near BCL2
rs13254990b near PVT1
Inversely associated with FL
a

SNPs in non-HLA loci

b

2.8 [95% CI 1.3–5.9]); machinery fitters (OR 3.4 [95% CI 1.5–7.8]); and electrical
fitters (OR 3.5 [95% CI 1.5–8.4]) [22]. Risk of FL certainly significantly increased
with exposure to chemical solvents such as benzene, toluene, xylene and styrene
(OR 1.7 [95% CI 1.2–2.5] P = 4 × 10−7) [23]. Spray painters and those working with
paint solvents had increased risk of FL (OR 2.66 [95% CI 1.36–5.24]) [1, 24, 25].
Medical doctors who had worked more than 10 years had a significantly elevated
risk (OR 2.06 [95% CI 1.08–3.92]) based on 38 cases vs. 13 controls [1]. Employment
in other occupations was not associated with risk of FL, including working/living on
a farm [1]. The t(14;18) translocation which occurs in up to 70–90% of FL was
found to be associated with certain agricultural pesticides in two studies [26, 27]. A
different study found that occupational exposure to pesticides would increase
BCL2-IGH prevalence together with the frequency of BCL2-IGH-bearing cells
especially during periods of high pesticide use [28]. It should be noted that this
translocation can be detected in healthy individuals or patients with other cancers.
There were also modestly increased risks of FL related to residential proximity to a
petroleum refinery (OR 1.3) or a primary metal industry (OR 1.2) [29].
Unlike other lymphomas, studies suggest that autoimmune diseases are not gen-
erally associated with an increased risk of FL with the exception of Sjögren’s
1 Follicular Lymphoma: Epidemiology, Pathogenesis and Initiating Events 7

s­ yndrome (OR 3.37 [95% CI 1.23–9.19], P = 0.024) [1]. Rather, atopic diseases
(with the possible exception of eczema) were associated with a lower risk of FL [1,
30]. Females with allergic rhinitis (OR 0.70 [95% CI 0.56–0.88], P = 0.002) and
food allergy (OR 0.74 [95% CI 0.63–0.86], P < 0.001) had lower risk of FL, but this
was not apparent in males. Risk for combined and individual atopic/allergic disor-
ders showed greater reduction in Australia compared to Europe or North America
[1]. A 22% lower risk of FL was noted if there was a history of a blood transfusion –
with reductions in risk most notable if the transfusion was received after 55 years of
age and within 40 years of FL diagnosis [1]. Smaller studies examining the impact
of prior blood transfusion have suggested either no association [31] or increased
risk [32, 33]. Interestingly, although acquired immunosuppression from human
immunodeficiency virus (HIV) or organ transplants confer increased risk of lym-
phoid malignancies such as plasmablastic lymphoma, Epstein-Barr virus (EBV)-
driven lymphomas and primary central nervous system (CNS) lymphoma, no
increase in FL incidence has been described, suggesting a different mechanism of
lymphomagenesis [34, 35].
A population-based case-control study of in-person interviews of 1593 NHL
individuals from 1988 to 1995 showed that non-steroidal anti-inflammatory drug
use, treatment of type 2 diabetes mellitus with oral hypoglycaemics, a history of
hepatitis and three or more lifetime bee stings were inversely associated with FL. On
the other hand, a history of heart disease and beta-blocker use were positively asso-
ciated with FL risk. It is suggested that these conditions exert an immunomodula-
tory effect that influences the development of FL [36]. In the InterLymph study,
positive hepatitis C virus serology was not linked with FL risk (OR 1.28 [95% CI
0.64–2.57]) [1]. Polio vaccination was associated with decreased risk, while influ-
enza vaccination was the opposite; however, the knowledge between vaccinations
and FL risk is incomplete [37].
Earlier studies indicated an increased risk of FL for current smokers compared to
non-smokers [38, 39], particularly in those with more than a 36-pack-year history
[40]. This effect was found in females but not males, for reasons that are unclear [1,
41, 42]. A modest risk of FL among women who ever smoked cigarettes was limited
to current smokers, along with a significant positive trend for total duration of smok-
ing. Additionally, duration, rather than frequency of cigarette smoking, appeared
more important in the trend in pack-years of smoking in women [1]. The association
between smoking and FL is biologically plausible given the increased risk of
t(14;18) in heavy smokers [43]. However, two prospective studies showed contrary
results, suggesting a lower risk of FL with current/former smokers with one show-
ing a hazard ratio of 0.62 [95% CI 0.45–0.85] [44] and another observing a relative
risk of 0.67 [95% CI 0.52–0.86] [45].
There is some suggestion that a diet high in vitamin D [2, 46] and linoleic acid (a
polyunsaturated fatty acid) was associated with a lower risk of FL [2]. Men with a
dietary pattern high in “fat and meat” (highest quartile vs. lowest) had an increased
risk of FL (HR 5.16 [95% CI 1.33–20.0]) [47]. A few studies found that a diet high
in vegetables and fruit was associated with a decreased risk of FL [47, 48]. An
inverse relationship between FL risk and antioxidants like vitamin C, lutein +