Allogeneic Transplantation for Follicular Lymphoma: Does One Size Fit All?

Transcription

1 Clinical Review Allogeneic Transplantation for Follicular Lymphoma: Does One Size Fit All? Mehdi Hamadani and Mary M. Horowitz Medical College of Wisconsin; and Center for International Blood and Marrow Transplant Research, Milwaukee, WI ASSOCIATED CONTENT See accompanying commentaries on pages 808 and 810 Abstract Follicular lymphoma (FL) exhibits striking biologic and clinical heterogeneity. Patients with newly diagnosed asymptomatic or low-bulk disease may be observed or managed with immunotherapies alone. Chemoimmunotherapy is considered a standard treatment for patients with advanced, symptomatic disease. In patients with FL who achieve at least a partial remission after first-line chemoimmunotherapy, autologous (auto-) hematopoietic cell transplantation (HCT) consolidation is not recommended; however, most patients with FL experience disease relapse after frontline therapies, with the experience of therapy failure within 2 years of first-line treatments predicting poor survival. Despite remarkable efficacy, even in patients who experience failure with other therapies, auto-hct and allogeneic (allo-) HCT remain underutilized in relapsed/refractory FL, even among healthy and younger patients. Early use of auto-hct consolidation should be considered a standard therapy option for high-risk patients who experience early failure of chemoimmunotherapy (, 2 years). For patients with FL who experience failure of frontline therapies late (. 2 years), deferring auto-hct until later in the disease course is reasonable. Allo-HCT is best reserved for medically fit individuals with heavily pretreated disease, persistent marrow involvement, refractory, but low-bulk, disease, and in those who experience a failure to mobilize stem cells for auto-hct. Allo-HCT is also a reasonable option for patients with FL who experience failure with a prior autograft; lower-intensity conditioning regimens and HLA-matched related donors are preferred in that setting. Future research should focus on the eradication of minimal residual disease before HCT and the prevention of disease relapse after HCT by integrating novel targeted agents into pre-hct and post-hct regimens. DOI: INTRODUCTION Follicular lymphoma (FL) accounts for 22% of non-hodgkin lymphoma (NHL) patient-cases in the Western hemisphere. 1 Median age at diagnosis is 60 years, with a slight female preponderance. The disease course in FL is one of remissions and relapses, followed not infrequently by the development of chemotherapy-refractory status or transformation into a more aggressive histology. A subset of patients with FL exhibits an aggressive clinical course from diagnosis, with an approximate 15% mortality at 2 years as a result of progressive or transformed disease. 2 The addition of rituximab to frontline chemotherapies has represented a paradigm shift in FL management, with a consistent benefit for progression-free survival (PFS) and overall survival (OS) demonstrated across different trials 3,4 ; however, disease relapse remains frequent. Patient-specific, disease risk stratified management strategies for relapsed FL are not well defined. Such clinical models as the FL International Prognostic Index are powerful prognostic 798 Volume 13 / Issue 12 / December 2017 n Journal of Oncology Practice Copyright 2017 by American Society of Clinical Oncology

2 Allogeneic HCT for Follicular Lymphoma tools, 5,6 but they are not useful in directing individualized therapies for patients with relapsed/refractory disease. Hematopoietic cell transplantation (HCT), both autologous (auto-) and allogeneic (allo-), has long been used as salvage therapy. In recent years, a better understanding of the molecular biology of the disease has led to the introduction of many other agents for the treatment of FL, including novel monoclonal antibodies and myriad targeted therapies for example, drug antibody conjugates, immunomodulatory agents, phosphoinositide-3 kinase inhibitors, checkpoint inhibitors, Bcl-2 inhibitors, etc. This ever-expanding therapeutic arsenal challenges the role of HCT in general, and allo-hct in particular, for the treatment of advanced FL. 7 Randomized trials that compare contemporary treatments with HCT are lacking, which has led to controversy regarding the role and timing of HCT in patients with FL. In this review, we aim to define the current role of allo-hct in the modern management of FL; however, to do so, one must also understand the current role of auto-hct, which we review first. ARE DOSE INTENSITY AND AUTOLOGOUS TRANSPLANTATION CURATIVE FOR FL? Unlike aggressive NHL and Hodgkin lymphoma, 8,9 the curative potential of high-dose therapy (HDT) and auto-hct in FL is intensely debated. Historically, auto-hct in the treatment of FL was evaluated in two distinct clinical settings: as upfront consolidation after first-line therapies, and in patients with previously treated relapsed/refractory disease. Three randomized studies from the prerituximab era and one randomized trial from the rituximab era 13 evaluated the role of upfront auto-hct consolidation versus observation or interferon maintenance in patients with advanced stage FL who were in remission after first-line therapies. Despite a consistent PFS benefit, which suggests some disease control effect of dose intensification, none of these studies observed an OS benefit with auto-hct consolidation. Moreover, a significantly increased risk of second malignancies, including myelodysplastic syndromes and acute myeloid leukemia, in the auto-hct arm of some of these studies 11,14 generated near universal consensus against upfront HDT consolidation in patients with FL. 15 Auto-HCT for relapsed FL in the current era of escalating health care costs and strained resources remains underutilized, likelybecausethedataaremoremixedintherelapseand progression setting. The European CUP trial conducted in the prerituximab era compared salvage chemotherapy alone with chemotherapy followed by either purged or unpurged auto-hct consolidation in patients with relapsed/ chemosensitive FL. 16 This trial closed early because of poor accrual, but, notwithstanding the small number of patients who were randomly assigned (n 5 89), it demonstrated a statistically significant PFS and OS benefit that favored HDT 16 ; however, the clinical relevance of this result is uncertain because it was conducted before the advent of modern chemoimmunotherapies. To investigate whether auto-hct offers any benefit over salvage chemotherapy alone in the rituximab era, the Groupe d Etude des Lymphomes Folliculaires performed a post hoc analysis of patients who were enrolled in two consecutive studies. 17 In this analysis, among patients with FL who received rituximab-containing salvage therapies, there was no PFS or OS benefit with auto-hct compared with salvage chemoimmunotherapy alone, although the sample size was small. 17 Of note, none of the patients in the studies by the Groupe d Etude des Lymphomes Folliculaires received rituximab-based frontline therapies, which led again to uncertainty about the benefit of auto-hct in patients who experienced relapse after current frontline therapies. Retrospective data from several other groups, some that include patients who received frontline rituximab, suggest that prolonged remissions after auto-hct, although possible, are restricted mostly to the subset of patients with FL who underwent transplantation in second complete remission All of these studies and others confirmed that HDT with auto- HCT can be performed with low procedure-related morbidity and mortality with current nonrelapse mortality (NRM) rates at approximately 5%. 19,21 On the basis of mostly prerituximab-era data that show greater benefit of auto-hct earlier in the disease course, it is common practice in many centers to limit auto-hct use to patients who have received two to three or fewer prior lines of therapy 7 ; however, in the rituximab era, data from the Center for International Blood and Marrow Transplant Research (CIBMTR) show that lines of prior therapy alone are not the main determinant of auto-hct outcomes, 21,22 which underscores the need to identify disease risk and biology-driven patient selection approaches for HCT in the modern era. The National LymphoCare Study (NLCS) recently reported that patients with FL who experience relapse within 2 years of starting first-line chemoimmunotherapy represent a biologically high-risk cohort with an extremely poor prognosis. 23 On the basis of these observations, CIBMTR and NLCS recently investigated the role of auto-hct in patients with FL who Copyright 2017 by American Society of Clinical Oncology Volume 13 / Issue 12 / December 2017 n jop.ascopubs.org 799

3 Hamadani and Horowitz experience the early failure of chemoimmunotherapies. A preliminary report of this analysis demonstrated that the early application of auto-hct that is, within 1 year of experiencing early failure in patients with NLCS-defined highrisk FL was associated with an OS benefit compared with similar patients who did not undergo auto-hct (5-year OS 73% v 60%; P 5.02). 24 This important contribution from CIBMTR/NLCS, we hope, will inform clinical practice about the optimal timing of auto-hct in patients with high-risk FL. In our practice (Fig 1), we now consider auto-hct as a standard therapy if first relapse/progression occurs within 2 years of initial chemoimmunotherapy. For patients who experience later failures, auto-hct may be deferred until later in the disease course; however, the fact that the large set of registry data from the European Group for Blood and Marrow Transplantation (EBMT) and CIBMTR does not show a clear plateau in relapse risk after auto-hct in FL 21,22,25,26 has prompted many investigators to pursue other therapies with curative potential. ALLO-HCT AND CURE THROUGH GRAFT-VERSUS- MALIGNANCY EFFECTS Adoptive immunotherapy in the form of allo-hct is potentially curative for patients with FL. The eradication of advanced hematologic malignancies via potent graft-versus-malignancy (GVM) effects exerted by donor effector cells is well known. 27 The substantially lower risk of relapse in patients with FL who develop graft-versus-host disease (GVHD), 28 and durable FL undergoing first-line CIT PR or CR after first-line CIT Refractory disease (< PR) after first-line CIT HCT consolidation not recommended Relapse/progression Refractory disease or relapse/progression within 2 years of starting first-line CIT Relapse/progression within 2 years of starting first-line CIT Auto-HCT preferred if CR/PR obtained with salvage therapy (fit pts up to age years) Consider allo-hct for refractory pts or those requiring > 2-3 salvage therapies to obtain remission Observe without HCT consolidation in pts responding to second-line therapies Pts in second or subsequent relapse/progression Auto-HCT favored in: Older pts (age years) With medical comorbidities 2-3 prior therapy lines PET-negative remission No marrow involvement Allo-HCT considered for: Ideally age years Few or no comorbidities Available matched donor Heavily pretreated disease Chemorefractory relapse Marrow involvement Failed stem cell mobilization Relapse after prior auto-hct Fig 1. A suggested algorithm for deciding between autologous and allogeneic transplantation for relapsed/refractory follicular lymphoma patients. allo-hct, allogeneic hematopoietic cell transplantation; auto-hct, autologous hematopoietic cell transplantation; CIT, chemoimmunotherapy; CR, complete remission; FL, follicular lymphoma; HCT, hematopoietic cell transplantation; PET, positron emission tomography; PR, partial remission; pts, patients. 800 Volume 13 / Issue 12 / December 2017 n Journal of Oncology Practice Copyright 2017 by American Society of Clinical Oncology

4 Allogeneic HCT for Follicular Lymphoma remissions reported in a subset of chemotherapy-unresponsive patients, 29 are indicative of the clinically relevant GVM effects in FL. Unlike auto-hct where the risk of relapse persists for many years perhaps indefinitely after therapy, registry data from CIBMTR and EBMT 26,30 clearly demonstrate that a plateau in relapse risk occurs 2 to 3 years after allografting for FL, which indicates that a substantial proportion of these patients can be cured with allo-hct. Table 1 summarizes the prospective single-arm studies that have evaluated the role of allo-hct in relapsed/refractory FL employing reduced-intensity conditioning platforms. Reduced-intensity conditioning, which does not deliver the dose intensification that is necessary for the efficacy of auto- HCT, provides disease control while facilitating donor cell engraftment, which allows for the subsequent eradication of disease via the effects of GVM. It is an important HCT innovation that has allowed allo-hct to be performed more safely in older and sicker patients. 37 The studies listed in Table 1, in general, demonstrate that 55% to 70% of patients with FL who undergo allo-hct are alive and disease free 3 to 5 years after transplantation and that disease relapse becomes a rare event approximately 2 years after allografting; however, although the rates of relapse after allo-hct in FL are impressively low (15% to 20%), this degree of disease control is accompanied by considerable procedure-related rates of morbidity (acute GVHD rates of approximately 25% to 35%, and chronic GVHD rates of 50% to 55%) and mortality (approximately 15% to 20%). The median age at diagnosis of FL ($ 60 years) and the high frequency of medical comorbidities at that age means that most patients with FL are not candidates for allo-hct, even with reduced-intensity conditioning. Even among potential candidates, the relatively high NRM rate after allo-hct has fueled a decades-old debate regarding the superiority or lack thereof of allo-hct over auto-hct, especially when used as the first transplantation approach. ALLOGENEIC VERSUS AUTOLOGOUS HCT IN FL A commonly encountered question in the clinic is whether to offer auto-hct or allo-hct the latter with reducedintensity conditioning to patients with FL who experienced relapse after multiple lines of prior therapies. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0202 trial was launched to address this question prospectively by assigning patients with relapsed/refractory FL to auto-hct versus reduced-intensity conditioning allo-hct using the biologic assignment donor versus no donor principle (Table 2). Unfortunately, this trial, although asking a highly relevant clinical question, was closed early as a result of poor accrual. 38 Among the 30 patients who were enrolled in the BMT CTN 0202 study, 3-year OS was 73% in the 22 patients who underwent auto-hct versus 100% in the eight patients who underwent allo-hct; corresponding 3-year PFS rates were 63% and 86%, respectively. A later single-arm phase II trial that included 65 patients who were treated with the same allo-hct approach as in BMT CTN 0701 confirmed the excellent results with allo-hct, with 3-year PFS and OS rates of 71% and 82%, respectively. 36 Because no randomized data Table 1. Results of Prospective, Single-Arm, Phase II Trials Evaluating Allogeneic Hematopoietic Cell Transplantation in Patients With Follicular Lymphoma First Author No. of Patients Age (range) Conditioning Regimen NRM, % EFS/PFS, % OS, % Comment Khouri 31, (33-68) FCR 6 ATG 15 (5 years) 72 (11 years) 78 (11 years) Grades 2-4 acute GVHD in 11%; all had chemosensitive disease Thomson (26-65) FMC 15 (4 years) 76 (4 years) 76 (4 years) Grades 2-4 acute GVHD in 13%; 9% with refractory disease Piñana (34-62) FM (4 years) 54 (4 years) Grades 2-4 acute GVHD in 47%; included 46% with prior auto-hct Shea (39-68) FC 9 (3 years) 75 (3 years) 81 (3 years) All were sibling donors and none had prior auto-hct Laport (29-74) FCR (3 years) 82 (3 years) Grades 2-4 acute GVHD in 27% Abbreviations: ATG, antithymocyte globulin; auto-hct, autologous hematopoietic cell transplantation; EFS, event-free survival; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; FM, fludarabine, melphalan; FMC, fludarabine, melphalan, alemtuzumab; GVHD, graft-versushost disease; NRM, nonrelapse mortality; OS, overall survival; PFS, progression-free survival. Copyright 2017 by American Society of Clinical Oncology Volume 13 / Issue 12 / December 2017 n jop.ascopubs.org 801

5 Hamadani and Horowitz Table 2. Studies Comparing Autologous With Allogeneic Transplantation in Follicular Lymphoma First Author No. (auto v allo) Design NRM (auto v allo), % Relapse rate (auto v allo), % PFS (auto v allo), % OS (auto v allo), % Comment Tomblyn v 8 Prospective 22 v 0* (3 years) 15 v 14 (3 years) 63 v 86 (3 years) 73 v 100 (3 years) Premature closure because of slow accrual Van Besien v 176 Registry 8 v 30 (5 years) 58 v 21 (5 years) 55 v 51 (5 years) Prerituximab-era study Robinson v 149 Registry 3 v 15 (1 year) 47 v 20 (5 years) 48 v 57 (5 years) 72 v 67 (5 years) Not restricted to rituximab era Limited to RIC allo-hct Klyuchnikov v 268 Registry 5 v 26 (5 years) 54 v 20 (5 years) 51 v 58 (5 years) 74 v 66 (5 years) Limited to grade 1 or 2 FL, rituximab era, and RIC allo-hct Klyuchnikov v 61 Registry 4 v 27 (5 years) 61 v 20 (5 years) 36 v 51 (5 years) 59 v 54 (5 years) Limited to grade 3 FL, rituximab era, and RIC allo-hct Abbreviations: allo-hct, allogeneic hematopoietic cell transplantation; auto-hct, autologous hematopoietic cell transplantation; FL, follicular lymphoma; NRM, nonrelapse mortality; OS, overall survival; PFS, progression-free survival; RIC, reduced-intensity conditioning. *NRM data should be interpreted with caution because of the small sample size of this clinical trial. Only unpurged auto-hct data shown. in the rituximab era are available by which to guide the selection of auto-hct versus allo-hct in patients with FL, this decision is largely guided by large registry studies that have addressed this question (Table 2). CIBMTR conducted the only registry study that compared auto-hct with allo-hct plus reduced-intensity conditioning in patients with grade 1 or 2 FL who received rituximab-based therapies before undergoing transplantation. 21 This analysis suggested that auto-hct and allo-hct, when applied as the first transplantation approach, provided comparable outcomes PFS and OS in relapsed/refractory FL; however, the risk of relapse was substantially lower and NRM was significantly higher after allo-hct. Of note, in this study, among patients with FL who survived disease free for 2 years after HCT, those who received allo-hct had a late survival benefit 21 ; however, this late benefit was negated by early NRM, and precisely identifying patients with FL, before undergoing HCT, who are unlikely to experience early NRM is currently not feasible. Patients with FL who experience relapse after an auto-hct can be treated with a variety of therapies. EBMT recently reported the outcomes of patients with FL who underwent reduced-intensity conditioning allo- HCT after experiencing an auto-hct failure (n 5 183). 39 The 5-year OS and PFS were 48% and 51%, respectively, and NRM was 27% at 2 years, which suggests that reduced-intensity allo-hct is an effective salvage strategy in patients with FL who experience disease recurrence after prior auto-hct. A one-size-fits-all approach is unlikely to be optimal in a complex clinical scenario, such as in the choice of HCT procedure for patients with FL. Investigating risk-adapted, individualized therapy approaches remains an unmet need for FL in the era of precision medicine. The combined CIBMTR/NLCS, 24 discussed previously, is a step in the right direction. Whether allo-hct offers any advantage over auto-hct in NLCS-defined high-risk FL is an important question that is being investigated in an ongoing CIBMTR study; however, comparable OS and PFS rates in the studies cited above suggest that allo-hct can be considered a reasonable alternative for patients who are candidates but who have a contraindication for auto-hct for example, heavy marrow involvement or an inability to mobilize an adequate autologous graft. It might also be considered an alternative for young patients without comorbidities with low predicted risk of NRM and for whom cure is important. DOES THE INTENSITY OF ALLOGENEIC HCT CONDITIONING MATTER? Owing to the advanced age of most patients with FL and the presence of potent GVM effects for this disease, reducedintensity conditioning regimens are now almost exclusively used for allo-hct. A CIBMTR study compared reducedintensity conditioning with myeloablative conditioning in patients with mostly chemosensitive, relapsed FL. 40 Whereas a modest increase in late relapse was noted with 802 Volume 13 / Issue 12 / December 2017 n Journal of Oncology Practice Copyright 2017 by American Society of Clinical Oncology

6 Allogeneic HCT for Follicular Lymphoma reduced-intensity conditioning, there was no significant difference in PFS and OS between the two conditioning intensities. 40 A second CIBMTR analysis that was limited to patients with aggressive NHL or grade 3 FL with chemotherapy-unresponsive disease also did not show any OS or PFS differences between myeloablative or reduced-intensity conditioning regimens. 29 It is unlikely that a prospective clinical trial will be performed to compare allo-hct conditioning regimen intensities in patients with FL. In the absence of robust data that prove otherwise, reduced-intensity conditioning regimens should be considered the standard of care for allo-hct in most patients with FL, especially for those with advanced age and/or medical comorbidities and in patients with chemotherapy-responsive disease. The addition of rituximab to reduced-intensity conditioning regimens has been shown in a recent CIBMTR study to improve PFS. 41 ALTERNATIVE DONOR TRANSPLANTATION IN FL In patients with FL being considered for allo-hct without an available HLA-identical sibling or unrelated donor, alternative donor sources are frequently considered. Current alternative donor options include mismatched unrelated donors (mmurds), umbilical cord blood (UCB) units, or related haploidentical donors. No large studies limited to patients with FL have compared these alternative donor sources against HLA-matched related or unrelated donors. A CIBMTR study reported comparable survival outcomes in patients with lymphoma who underwent matched unrelated donor, mmurd, or UCB allo-hct (3-year OS, 43% v 37% v 41%, respectively), but with significantly higher risk of NRM after mmurd. 42 Recent registry data from EBMT 43 and CIBMTR 44,45 also suggest comparable outcomes between conventional donor sources and haploidentical related donor allo-hct using posttransplant cyclophosphamide for GVHD prevention. A subgroup analysis of patients with FL who were included in the CIBMTR study 45 displayed 3-year OS after haploidentical and HLA-identical sibling donor HCT of 66% versus 64%, respectively; however, this subgroup analysis was based on only 28 patients with FL who underwent haploidentical HCT. Of importance, the aforementioned registry studies often had short follow-up and limited power to detect small survival differences between standard and alternative donor sources. Considering the paucity of published data, enrolling patients with FL without an available matched adult donor in the ongoing BMT CTN 1101 study comparing UCB with haploidentical transplantation or the CIBMTR phase II study of mmurds should be strongly considered. DECIDING BETWEEN AUTO-HCT AND ALLO-HCT IN THE CLINIC: OUR APPROACH Figure 1 depicts the algorithm by which we select auto-hct or allo-hct in patients with relapsed/refractory FL. Whereas we acknowledge the limitations of HDT in relapsed FL, it is also prudent to highlight that approximately one third of carefully selected patients with chemosensitive FL experience durable responses after auto-hct (30% to 40% PFS at 10 years) 21,25 ; however, we must also critically examine the outcomes of FL with modern non-hct approaches. Despite significant progress with novel agents, cure remains elusive, the duration of disease control is modest at best for example, median PFS is approximately 12 months with idelalisib in FL with early failure of chemoimmunothrapy, 46 and 12 to 24 months with lenalidomide alone or in combination with rituximab 47 and therapy-related rates of morbidity and mortality in some studies rival rates observed with allo-hct. 48,49 Moreover, the cost of these often-continuous therapies with novel agents strains a now-fragile US health care system. With the realities of the current era in mind, we must strive to reassess and repurpose old tools, especially auto-hct, to fit the needs of modern times. Despite its low NRM, auto-hct remains an underutilized modality for FL (Fig 2), with only approximately 150 to 200 patients with FL undergoing this procedure in the United States every year. These figures reflect a striking clinical disconnect between the efficacy of auto-hct in the rituximab era 5-year PFS, 41%; 10-year PFS, 30%; and 5-year NRM, 5% in the CIBMTR report 21 and No. of Patients Year of Transplant Fig 2. Number of autologous transplantations performed per year in the United States (2006 to 2015 Center for International Blood and Marrow Transplant Research data). Copyright 2017 by American Society of Clinical Oncology Volume 13 / Issue 12 / December 2017 n jop.ascopubs.org 803

7 Hamadani and Horowitz its (relatively) low cost versus the modest activity and not insignificant toxicities and price tag of novel non-hct approaches. The recommendations in the sections below reflect, in part, the authors opinion taking into account practical considerations discussed above and, in part, the data generated by carefully conducted analyses of HCT outcomes in patients with FL by our group at CIBMTR and those reported by EBMT over several decades. In patients with FL who have achieved complete or partial remission after first-line chemoimmunotherapy, routine use of upfront auto-hct consolidation is not recommended. In this setting, maintenance rituximab, observation, or enrollment in available trials should be considered. FL with early failure of chemoimmunotherapy that is, disease relapse or progression within 2 years of starting frontline rituximab-containing chemoimmunotherapies has a poor prognosis. In terms of durability of disease control, our limited experience with novel agents in such high-risk patients is disappointing. 46 If such high-risk patients demonstrate evidence of chemosensitive disease after salvage therapy, early consideration of auto-hct consolidation within 1 year of first relapse/progression is considered a standard therapy option. In patients with relapse/ refractory FL who experience failure of frontline therapies late (. 2 years from the start of first-line treatments), it is our institutional practice to offer auto-hct later in the disease course, generally after two to three lines of therapy. In patients with refractory disease and those with persistent bone marrow involvement after salvage therapy, alternative consolidation modalities should be pursued. Patient age, per se, is not a contraindication for HCT. Second cancers after auto-hct are cited as an argument against this option; however, mounting data utilizing whole-exome sequencing techniques show that preexisting clonal hematopoiesis of indeterminate potential (CHIP) in patients with lymphoma before HCT is a major risk factor for post auto-hct second cancers. 50 In fact, pre-hct factors and exposure to multiple prior chemotherapies might be major determinants of new cancers after HDT, rather than HCT itself. 51 Evaluating patients for CHIP before deciding on auto-hct may be a reasonable approach. To date, the decision to proceed with allo-hct over auto- HCT remains largely a factor of transplant center preference. The choice of the first transplantation modality in the current era should take into account several practical considerations. The benefits of auto-hct include comparatively lower costs and disease control though not necessarily cure with relatively low morbidity and mortality. Early NRM and quality-of-life considerations secondary to GVHD and/or slow immune reconstitution/infections remain a limitation with allo-hct; however, CIBMTR data indicate that relapses 2 years after allo-hct are rare, 21,22 and patients who survive initial procedure-related toxicities enjoy a long-term survival benefit. We consider allo-hct in carefully selected, medically fit individuals with a suitable donor especially later in the disease course, after experiencing failure of at least anthracycline, bendamustine, and platinum-based therapies. Allo-HCT can also be considered in patients with relapsed disease with persistent bone marrow involvement, refractory, but low-bulk, disease, and those who experience a failure to mobilize stem cells for auto-hct. It is also a reasonable option for patients with FL who experience the failure of a prior autograft. 39 Of note, these data pertain to allografting from matched sibling or adult unrelated donors, which account for most of the currently available data. Whether these observations can be extrapolated to alternative donor UCB or haploidentical allo-hct warrants investigation. In conclusion, there seems to be a clear role for HCT in patients who experience the early failure of frontline chemoimmunotherapy and for patients who experience later initial failure and failure of subsequent lines of therapy. No predictive and validated molecular signature or biomarkers are available to guide the role and timing of HCT in FL, and this issue remains an area of active research. The m7 FL International Prognostic Index is a newer prognostic model that incorporates frequently mutated FL genes with clinical variables to predict failure-free survival, 52 but has not been validated to direct therapy choice. Most data suggest that auto-hct is the HCT approach of choice for most patients, but careful consideration of patient and disease factors may identify patients who are better served by allo-hct. Reliable identification of patients who are at increased risk of second cancers for example, those with CHIP after auto-hct may provide a subgroup better served by allo-hct as their first transplantation approach. Other criteria are poor graft mobilization, heavy marrow involvement, and recurrence after auto-hct. Until less toxic, curative therapies are available, clinical practice must increasingly integrate HCT into management algorithms not only as a modality that is capable of providing durable disease control, but also as an increasingly costfriendly therapeutic option. 804 Volume 13 / Issue 12 / December 2017 n Journal of Oncology Practice Copyright 2017 by American Society of Clinical Oncology

8 Allogeneic HCT for Follicular Lymphoma Acknowledgment Supported, in part, by the National Cancer Institute (NCI; Grant No. U24- CA076518), the National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Allergy and Infectious Diseases, and a cooperative agreement from NHLBI and NCI (Grant No. 5U10HL069294; to M.M.H.). Authors Disclosures of Potential Conflicts of Interest Disclosures provided by the authors are available with this article at jop.ascopubs.org. Author Contributions Conception and design: All authors Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors Corresponding author: Mehdi Hamadani, MD, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 9200 W Wisconsin Ave, Suite C5500, Milwaukee, WI 53226; mhamadani@ mcw.edu. References 1. 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10 Allogeneic HCT for Follicular Lymphoma AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Allogeneic Transplantation for Follicular Lymphoma: Does One Size Fit All? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO s conflict of interest policy, please refer to or ascopubs.org/jop/site/ifc/journal-policies.html. Mehdi Hamadani Honoraria: Celgene Consulting or Advisory Role: MedImmune, Celerant, Janssen Oncology Speakers Bureau: Sanofi, Genzyme Research Funding: Takeda Pharmaceuticals, Spectrum Pharmaceuticals Mary M. Horowitz Research Funding: Biovitrum, Otsuka, Novartis, Therakos, Telomere Diagnostics, Gamida Cell Copyright 2017 by American Society of Clinical Oncology Volume 13 / Issue 12 / December 2017 n jop.ascopubs.org