Transformation of follicular lymphoma – Why does it happen and can it be prevented?

Best Practice & Research Clinical Haematology 31 (2018) 49e56

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Transformation of follicular lymphoma e Why does it happen and can it be prevented? Brian K. Link University of Iowa College of Medicine, Department of Internal Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 September 2017 Accepted 23 October 2017

Follicular lymphoma is a clinical disease with a multitude of presentations and behaviors. Although infrequent, transformation of follicular lymphoma to a more aggressive behaving subtype e prototypically diffuse large B-cell lymphoma e confers a substantially adverse prognosis. There is no consensus for optimal management after transformation is recognized. Historically considered a distinct clinical event, this review highlights the multiple subclinical transformational events that either variably or cumulatively result in clinical recognition of transformed follicular lymphoma. Known and suspected events include genetic and epigenetic perturbations, metabolomic changes, and alterations in the microenvironment. This diverse spectrum of pathways leads to heterogeneous clinical presentations and outcomes of transformed follicular lymphoma. Current options for prevention of transformation are limited to known strategies of managing follicular lymphoma before the transformation is recognized. Although most retrospectively analyzed studies suggest an association of lower transformation rates with early systemic therapy, specific components of therapy such as anti-CD20 antibodies, anthracyclines, or purine analogues are less strongly associated with “preventative’ value. Thus, the goal of preventing transformation is of limited value among all factors that go into decisions on early management of follicular lymphoma. Future opportunities to prevent clinical evidence of transformation will benefit from early detection of markers of subclinical transformation and development of therapies to specifically target the biology implied by those markers. © 2017 Published by Elsevier Ltd.

Keywords: Follicular lymphoma Transformed lymphoma Follicular transformation Review

1. Transformation of follicular lymphoma 1.1. Why is it of interest and what is the scope of the problem? Follicular lymphoma (FL) is a disease commonly characterized as incurable, though relatively slow in pace of growth with a median life expectancy of 15e20 years [1], and systemically treatable with expectations of somewhat extended response at the cost of limited toxicity [2]. As patients assimilate and adjust to the horror of incurable cancer, the lymphoma care team often prioritizes education to provide some comfort e especially since systemic therapy may not be indicated early after diagnosis. Somewhere in the educational effort, following “indolent”, “low grade” “responsive to therapy” “long remissions” “gentle treatments” and “many years”, the conversation gets around to “transformation” much like a depiction of rainbow-

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colored fish, crabs, coral and sea turtles as occupants of the reef gets around to sharks. Along with early treatment failure following immunochemotherapy [3e6], transformation to high grade lymphoma e prototypically diffuse large B-cell lymphoma e represents the greatest fear for patients, their loved ones, and medical teams as the anticipated long journey with FL is commenced. Several recent reports of large cohorts of varying origin and methodology have provided a fairly consistent depiction of the frequency and implications of follicular lymphoma transformation (tFL) [6e17]. In the setting of immunotherapy and chemotherapy treatment options, the risk of transformation to DLBCL is 2e3% per year for FL patients for at least the first 10 years after which the data become less reliable though some series hint at lower rates farther out from diagnosis [14]. Outcomes following transformation are unfortunate and inferior to those of patient with FL who do not experience transformation but are no longer recognized as universally catastrophic as they had been in the twentieth century with median survival after transformation in most series between 4 and 5 years [7,9,13,15,16]. Survival is reported to be better for patients with lower FLIPI [18] scores, those previously anthracycline naïve, and for patients who transform later following FL diagnosis as opposed to transformation within the first 18 months [7,12,13]. Management strategies following recognition of transformation are numerous and without much consensus or consistent success [9,12,13,15,16]. Given the generally poor outcomes and unsatisfactory understanding of optimal management after transformation is clinically recognized, seeking better understanding of cause and potential prevention of clinically apparent transformation of follicular lymphoma is warranted. Two central tenets of this review will be heightened appreciation of the diversity of tFL and of the complex dynamics of preclinical transformation events. 2. Why does transformation happen? 2.1. Transformed follicular lymphoma is a heterogeneous disease with heterogeneous origins (Table 1) A simple definition for transformed follicular lymphoma is without universal consensus. The gold standard for diagnosing transformation in FL is generally recognized as biopsies demonstrating: a) FL grade 1, 2, or 3a and b) at a distant place or time histological demonstration of an increase in the proportion of large centroblasts infiltrating lymph nodes leading to effacement of the follicular architecture [19]. Strictly speaking these histologies should be confirmed to be clonally related. This gold standard is often adapted loosely in clinical series and in clinical practice. Such biopsies may be sequential, and some investigators historically restricted the definition of tFL to those scenarios where such biopsies were separated by at least 6 months [10,20,21]. Some newer published series of tFL, however, evaluated patients with concurrent identification of follicular lymphoma and diffuse large B-cell Lymphoma (DLBCL) either in a single biopsy [16] (alternatively referred to by others as composite lymphoma) [22,23] or in multiple synchronous biopsies (alternatively referred to as discordant lymphoma) [23,24]. Furthermore, some investigators accept a clinical definition of transformation in patients for whom no biopsy demonstrating DLBCL is available. Clinical criteria proposed by Al-Tourah et al. including a sudden rise in LDH, rapid discordant localized nodal growth, new B symptoms, hypercalcemia, or new extranodal sites of disease are the most often cited for inclusion in tFL series [8]. FDG-PET scans are also advocated by some as adjuvant determinants of transformation, with standardized uptake values between 10 and 17 proposed as a surrogate for pathological evidence of transformation [25e27]. Given recent advances in the appreciation of multiple pathways by which transformation can emerge from subclinical genetic alterations to the full blown clinical manifestations, this review will adapt an inclusive attitude when considering tFL and will endeavor to point out examples with a marginal or conditional definition for tFl when relevant. Histologic diversity of follicular lymphoma upon transformation is evident with the most common histology being DLBCL [8,19] followed by the entity previously categorized as Burkitt-like lymphoma, subsequently as B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma, and most recently as high grade B cell lymphoma NOS [28e30]. Uncommonly, histologic and immunophenotypic characteristics of tFL overlap with acute lymphoblastic leukemia/lymphoma or other blastoid histologies [31,32]. Even the DLBCL histologies can be diverse with 80% marking as germinal b-cell like origin, yet 16% marking as activated b-cell like origin [33], and MYC rearrangement or overexpression is seen in nearly half of biopsies [34]. Clinical diversity of FL upon transformation is evident by timing of the recognition of transformation. Some authors recognize transformation at the time of lymphoma diagnosis when both DLBCL and FL histologies are found at initial evaluation. In the largest reported series of these “de novo transformed” patients, the National LymphoCare Study (NLCS) demonstrated probability of survival with de novo transformation was favorable when compared to patients with a more traditionally defined sequential transformation and not clearly different than FL patients in whom no transforming event was identified [16]. In another series, patients with recognized transformation within 18 months of FL diagnosis had a distinctly adverse 5 year survival rate relative to those with later transformation (66% vs 22%) [13]. Additionally, some patients are immunochemotherapy naïve at clinical transformation, some are simply chemotherapy naïve, and others have variable prior exposure to anthracyclines, alkylating agents or purine analogues [7,8,11,13,14,16,17]. Genetic diversity of tFL is profound with studies suggesting the transforming biology cannot be accounted for by disruptions of a unifying pathway. Early studies implicated acquisition of mutations in p53 [35,36] or p16 [37] in paired biopsy samples and at least altered gene expression if not frank mutation in MYC in many cases [38,39]. More recently, eloquent dissection of abnormalities in MLL2, EZH2, and CREBBP are suggestive of epigenetic (chromatin regulating) drivers of transformation in some patients [40e42], while alterations in MYC or CDKN2A/B in other patient samples implicate

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Table 1 Diversity in transformed follicular lymphoma. Category

Variable

Frequency

reference

Histology

DLBCL Germinal b-cell like cell of origin Activated b-cell like cell of origin MYC rearranged or overexpressed High Grade B cell Lymphoma NOS Blastoid variant Recognition of FL and aggressive histology synchronous composite discordant sequential <18 months from FL diagnosis >18 months from FL diagnosis Therapy prior to transformation None Immunotherapy only Anthracycline naive Mutations in p53 Mutations in p16 Epigenetic drivers (MLL2, EZH2, and CREBBP) Cell cycle regulators (MYC, CDKN2A/B) Mitochondrial activity (peptide deformylase) CD4þ localization of cells within vs between follicles PD1þ T-cells

80% 80% 16% 50% 14% 1%

[8,19] [33] [33] [34] [19,28] [31,32]

10% NR NR 90% NR NR

[16]

Clinical

Genetic

Metabolomic Tumor Microenvironment

[13,16]

[9,12,13,16] 20e32% 20e30% 65e75% NR NR NR NR NR NR NR

[35,36] [37] [40e42] [41e43] [45e47] [62] [63]

regulators of proliferation and cell-cycle control [41e43]. Amplification of REL, BCL6, and BCL2 are other changes associated with transformation [44]. Metabolomic diversity is also hypothesized in tFL and other MYC edriven lymphomas, highlighted by investigations into the mitochondrial activity required to sustain tFL through the enzyme peptide deformylase (PDF) [42,45e47]. Though the pathway is under more careful study, it is included here because of the anti-lymphoma potential demonstrated by the PDF inhibitor actinonin [46,48]. The root of such diversity in tFL is likely found in the prevailing model of transformation. Follicular lymphoma is recognized to be a clinical disease emergent from a proliferation of clonal lymphocytes composed of innumerable subclones [49]. The subclonal genetic landscape indicates most subclones arise from distinct genetic events e usually from early FL “stem cells” e in a divergent rather than linear or sequential pattern, such that few perturbations are common to all subclones [50]. The preponderance of modern studies in tFL conclude that subclones dominant in biopsies demonstrating histological transformation acquired key genetic drivers of transformation early in the stem cell evolutionary process, and were genetically unique from the subclones dominant in the diagnostic FL histology [41,42,49,51]. Dynamic modeling demonstrated that the transformation-specific subclones rapidly attained clonal dominance in the transformed biopsy samples [50]. With multiple potential driver pathways and multiple early FL subclones on which to build, diversity of clinical, pathologic and genetic presentations is inevitable, without even accounting for variables in the host. Although articulate research has demonstrated convincingly that genetic alterations in the transformation of FL are phylogenetically early events, and at least in some cases already exist at the time of clinical FL diagnosis [50,52], there is no clear understanding of what causes those alterations or which of the alterations are necessary or sufficient to lead to clinically relevant transformed lymphoma behavior. Later discussion in this review will focus on the potential for prevention of tFL and for clinicians those opportunities will generally begin at a patient level once FL has been diagnosed. Thus, two key questions are how early can the markers suggestive of transformed biology be detected, and once detected; can clinical intervention impact emergence potential of the transformed subclone? In the absence of obvious target-specific therapy options, instinctive oncologist behavior might motivate the use of more aggressive cytotoxic chemotherapy combinations if subclones predictive of transformed behavior were identified prior to clinical transformed disease in an effort to “eradicate” the offending subclone. Alternatively, immunologist instincts might motivate minimal cytotoxic therapies in an effort to avoid disruption to any subclone control via the innate immune system or even to consider immune enhancing therapies including checkpoint inhibitors with direct or indirect T/NK cell augmentation [53,54]. Studies in emergence of secondary myeloid malignancies following chemotherapy suggest similar models of pre-existing subclones with malignant potential that emerge following cytotoxic chemotherapy [55,56]. Geneticist instincts might motivate any number of behaviors ranging from use of epigenetic modifiers such as histone de-acetylators [57] in an effort to prevent further evolution along the transformed pathway, to strict avoidance of therapies with further mutagenic potential. Although the role of host factors such as the tumor microenvironment are generally felt to be important in the biology of FL as assessed by gene expression [58], immunohistochemical methods relying on protein expression of tumor infiltrating immune cells have not yielded unifying results [59e61] and as a result the role of the tumor microenvironment in tFL is not as

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well studied. Gene expression findings in FL patients developing tFL within 3 years or not were non-specifically suggestive of over-expression of immune-related genes while IHC findings included localization of CD4þ T cells within rather than between follicles more commonly in those patients with early tFL [62]. PD-1þ T cells have been associated with reduced risk of transformation [63]. A recent study from Norway evaluated paired biopsies from diagnosis and transformation in a cohort of 45 patients with tFL and compared findings with diagnostic biopsies from a matched cohort of patients with FL who's disease had not clinically transformed. In the tFL biopsies, PAX5þ tumor cells increased and CD3þT cells decreased compared to baseline samples. CD4þ, CD8þ, and CD57þ T cells also decreased. Higher total area scores of FOXP3þ T reg cells and intrafollicular CD4þ and CD57þ T cells at diagnosis were associated with higher risk of transformation and shorter time to transformation [64]. While in aggregate these findings lead credence to the likelihood that the immunologic milieu of the tumor microenvironment may play a role in development and emergence of tFL, improved methodology and more studies including larger numbers of patients with tFL will be needed to develop confidence-inspiring models. With a multitude of early sequential changes in the genetics, epigenetics, metabolomics, and the microenvironment implicated in the transformation of FL, it seems clear that current clinical and histological definitions of transformation along with diagnostic methodologies are inadequate for identifying the problem leading to undesirable outcomes for patients. A heightened recognition of the existence of diverse sub-clinical populations of lymphoma cells in various stages of transforming biology coupled with tools to detect those populations will be critical to development of strategies of more effective treatment or prevention. The accumulated genetic aberrancies associated with transformed biology make these subclinical populations good candidates for detection through assays of circulating tumor DNA (ctDNA) [65e67]. Plasma assays of ctDNA can provide information on total circulating clonal heterogeneity and assess molecular changes over time, whereas tissue biopsies are difficult to obtain serially and are subject to sample site specific biases. Assays of ctDNA utilizing rearranged VDJ sequences have already demonstrated utility in early detection of recurrent DLBCL [68,69]. Applications of ctDNA to monitoring follicular and other indolent lymphomas are under development [70].

3. Can transformation of follicular lymphoma be prevented? Many of the greatest successes in reduction of malignancy-related mortality in the previous century have been the result of prevention rather than successful therapies e cervical carcinoma and colon cancer with screening for precancerous lesions, lung cancer with avoidance of causative behavior and further anticipated reductions in cervical carcinoma, head and neck cancers and hepatoma with ongoing oncogenic viral management strategies [71e73]. Notably, these successes are seen in malignancies relatively resistant to systemic therapies as is tFL, although unlike tFL these successes are seen in malignancies with a high incidence. Given the generally poor outcomes of tFL and the unsatisfactory understanding of optimal management once clinically apparent, a strategy of prevention is appealing. Several series published to date provide the opportunity to examine if therapies currently employed give clues regarding a preventative strategy (Table 2). Very few of the series are prospective clinical trials, with the majority being retrospectively analyzed cohorts after either prospective or retrospective assembly, making uncontrolled or unmeasured variables hard to account for though many employ statistical efforts to aid as much as possible. The first obvious question is whether systemic therapy at time of FL diagnosis “prevents” or is at least associated with reduced risk of subsequent clinically evident transformation. This question is relevant because to initiate systemic therapy or not is often a fundamental decision addressed by patients and their providers with the decision based upon many factors. Two large prospectively assembled and retrospectively analyzed observational studies totalling over 3200 patients with Fl newly diagnosed after the availability of anti-CD20 antibody therapy both observed statistically reduced rates of tFL over time in

Table 2 Clinical strategies associated with risk of transformation (prevention). Therapy

Cohort summary

Associated effect on transformation rates

Initial therapy versus observation

>3500 FL pts prospectively collected and retrospectively analyzed 281 FL pts Retrospective series 463 pts prospectively randomized to rituximab versus observation >4000 FL pts retrospectively analyzed 1018 FL patients prospectively followed after choice of induction 286 FL pts retrospectively analyzed 463 pts prospectively randomized

Initial therapy favors protection from transformation [13,14,16]

Anthracycline as initial therapy Rituximab vs observation Rituximab maintenance

Observation favors protection from transformation Transformation events 11% observed versus 7% treated (p ¼ 0.19) after 4 years followup No protective effect seen with anthracycline use No protective effect seen with anthracycline use

Rituximab associated with lower transformation risk Transformation events 11% observed versus 7% treated (p ¼ 0.19) >3500 FL pts prospectively collected and retrospectively Maintenance rituximab associated with lower risk of analyzed transformation 1018 FL patients randomly assigned to maintenance rituximab Rituximab maintenance arm had fewer vs. observation after immunochemotherapy transformations (16 versus 24) 300 low burden FL patients assigned to rituximab maintenance 6 transformations in maintenance arm and 8 in vs retreatment at progression retreatment arm after 4.5 years followup

Reference

[17] [77] [7,11,13,16]

[13] [77] [13,16] [15] [78]

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patients who had received initial therapy compared to those who deferred initial systemic therapy, with hazard ratios of approximately 0.6 after adjusting for other known risk factors [13,16]. This is consistent with a previous report of higher transformation rates following expectant observation in 325 FL patients diagnosed in the 20th century [14]. Two other observational series looking at the question demonstrated only non-significant trends toward protection with systemic therapy [7,8]. There are notably few prospective randomized trials of systemic therapy versus observation in newly diagnosed FL [74e76] and most don't report on subsequent tFL as an outcome, though a recent study from UK prospectively randomizing 463 patients with low risk FL to observation versus rituximab monotherapy reported 33 clinically apparent transformation events with a non-significant trend toward protection in the treated population (11% obs vs. 7% treated p ¼ 0.19) after just 4 years median followup [77]. In total, the preponderance of accumulated published data, though not conclusive, support the notion that early therapy reduces, though certainly doesn't effectively prevent risk of subsequent clinically apparent transformation. The next logical question is amongst the systemic therapies available, is there a drug or class of drugs, or maybe even a measure of therapy intensity, that is more effective than the others in preventing clinically apparent tFL. Two commonly studied therapy subsets in the above reports are the anthracyclines and anti CD20 antibodies. Anthracycline use as initial therapy had inconsistent association with transformation in the two larger and several smaller assembled cohorts. Authors from the University of Iowa/Mayo Clinic series and other series described no correlation between anthracycline treatment and rate of transformation, while the NLCS group showed lower rates of transformation when any anthracycline-containing regimen was compared to regimens void of anthracycline, but not when R-CHOP was compared specifically to R-COP [7,11,13,16]. Just one study described lower rates of subsequent clinically apparent tFL when anthracycline-based therapy was initiated compared to purine-based therapy [8]. The best opportunity to evaluate the role of early anthracycline use in prevention of subsequent clinically apparent transformation comes from the PRIMA (Rituximab Maintenance for 2 Years in Patients With High Tumor Burden Follicular Lymphoma Responding to Rituximab Plus Chemotherapy) trial. This prospective clinical trial with predetermined eligibility criteria and enrollment procedures ensures a relatively homogenous patient population with standardized baseline clinical assessments to minimize missing data. Initial management is relatively consistent (defined in this case as immunochemotherapy) allowing for comparison within the subtly different immunochemotherapy choices, such as anthracycline or not. The randomized variable of maintenance rituximab versus observation after response offers a unique opportunity to explore the role of this management option on incidence or outcome of subsequent transformation. With 40 histologically documented transformations among over 1000 FL patients initially treated with a variety of non-randomized immunochemotherapy regimens, no association was seen between use of anthracycline and subsequent transformation [15]. Several larger studies make at least an indirect argument for rituximab influencing transformation rates. In the Iowa/Mayo report initial therapy with rituximab monotherapy was associated with lower rates of transformation than initial observation, while both the NLCS report and PRIMA analysis e again with the strongest control on variables e suggest lower rates of transformation when rituximab maintenance is employed after initial remission induction [13,15,16]. As described earlier, the only prospective randomized study of rituximab as monotherapy versus observation in newly diagnosed FL showed only a non-significant trend toward protection in the treated population after a brief 4-year median followup [77]. In the US cooperative group RESORT (Rituximab Extended Schedule Or Re-Treatment) randomized trial in low burden FL, 300 subjects responding to induction rituximab were randomized 1:1 to receive maintenance rituximab until relapse or rituximab upon retreatment for relapse only. Patients assigned to maintenance received substantially more rituximab, but again with only 14 transformation (6 in maintenance arm and 8 in retreatment arm) events after a median followup of 4.5 years, no conclusions can be made [78]. Among 111 previously treated FL patients who received radioimmunotherapy in the form of 90Yittrium ibritumomab tiuxetan, a remarkable fraction e 29% - experienced histological transformation with a median follow-up of just under 5 years. Notably, 12 of 25 patients that had received prior therapy with the purine analogue fludarabine experienced transformation [79]. Acknowledging the hazards of drawing conclusions from a single small study composed of multiply treated FL patients (a population who's transformation incidence is not well characterized), this report coupled with the previously mentioned series in which purine analogues were associated with higher transformation events than anthracyclines at least somewhat weakens enthusiasm for considering either radioimmunotherapy or purine analogues as protective.

4. Summary on clinical prevention strategies How do we combine state of the art understanding of genetic and other possible pre-clinical events in the dynamic process of FL transformation with emerging potential therapies to prevent transformation of FL?. Option A is to nonspecifically suppress the FL stem cell pool to mathematically minimize the odds of a FL stem cell acquiring the necessary transformed biology. Option B is to identify very early pre-clinical transformed events e perhaps through monitoring of ctDNA and target the threatening subclone e ideally utilizing precision therapy if the biology of the subclone is understood well enough in the context of a broad array of potential therapies. Further down the road is the loftier goal of understanding FL stem cell biology and unlocking the biology of self-replication as is happening with the chronic myelogenous leukemia stem cell [80]. While waiting for scientists to unravel the puzzles needed to pursue option B, clinicians are currently limited to considering option A. Although probably effective in reducing transformation, the infrequency of transformation and outcomes following

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therapy naïve transformations limit the motivation to invoke this strategy in all patients with FL, though it could be a deciding factor in patients who meet criteria for high risk. Conflict of interest In the past 2 years I have served on compensated DSMBs for AbbVie and Gilead, I am a consultant for Genentech and Celgene, and receive research support from Seattle Genetics. Funding This work was supported in part by grant no P50CA97274 from the National Institutes of Health, Bethesda MD, USA. Practice points     

Transformed follicular lymphomas (FL) are genetically distinct from the diagnostic FL. Multiple genetic, epigenetic, and metabolomic factors drive transformation. Transformed FL presents with diverse clinical backgrounds and features. Systemic therapy early in FL is associated with mildy reduced transformation rates. No specific component of systemic therapy is recognized as clearly preventative.

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