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Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances
HEMONC 178 17 June 2017 Hematol Oncol Stem Cell Ther (2017) xxx, xxx– xxx
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Available at www.sciencedirect.com
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journal homepage: www.elsevier.com/locate/hemonc
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Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances
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Narendranath Epperla a, Mehdi Hamadani a,b,*
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a b
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA Center for International Blood and Marrow Transplant Research, Milwaukee, WI 53226, USA
Received 6 January 2017; accepted 28 February 2017
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KEYWORDS Allo-HCT; Auto-HCT; Diffuse large B-cell lymphoma; Follicular lymphoma
Abstract Non-Hodgkin’s lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with diverse biologic, histologic, and clinical features. With a better understanding of the molecular pathogenesis, recently there have been major advances in the treatment of NHLs including addition of novel monoclonal antibodies, targeted therapies, and immune activators to the therapy armamentarium. Despite these remarkable developments, autologous hematopoietic cell transplantation (auto-HCT) remains not only a standard-of-care curative option for aggressive NHL but also an important therapeutic option for indolent NHL. In NHL, for patients with high-risk features, including those heavily pretreated or with refractory disease or those experiencing failure after an auto-HCT, allogeneic HCT (allo-HCT) remains the only curative option. In this review, we briefly discuss the role of transplantation in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In DLBCL patients, we discuss the role of HCT in clinically and biologically defined ultra-high-risk disease. In FL patients, auto-HCT is best reserved for relapsed chemosensitive patients after two to three lines of prior chemoimmunotherapies, who are not candidates for allo-HCT, either because of donor unavailability, associated comorbidities, or patient preference. Reduced-intensity conditioning allo-HCT offers the curative option for patients with relapsed/refractory FL. Although the emergence of targeted, biologic, and immunological therapies is welcoming, it is currently unclear how these new therapies might enhance or replace allo-HCT. Until we have further definitive data, allo-HCT remains the only curative option. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
* Corresponding author at: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226, USA. E-mail address: [email protected] (M. Hamadani). http://dx.doi.org/10.1016/j.hemonc.2017.05.004 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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N. Epperla, M. Hamadani troversial. Several randomized studies evaluating the role of upfront auto-HCT consolidation in DLBCL in the prerituximab era reported conflicting results [18–21]. A meta-analysis of these pre-rituximab era trials, however, did not show the superiority of auto-HCT consolidation compared with the standard chemotherapy alone [22]. Therefore, auto-HCT was not adopted as standard therapy in the frontline setting for high-risk DLBCL in CR1. In the rituximab era, provocative findings of the Southwest Oncology Group S9704 [23] study reignited the discussion of upfront auto-HCT in DLBCL by showing a possible overall survival (OS) benefit in an unplanned/post hoc analysis for the high-risk IPI subgroup. However, DLBCL comprised only 60% of S9704 study population and not all DLBCL patients received rituximab-containing frontline therapies [23]. Of note, two recent randomized trials restricted to IPI defined intermediate–high or high-risk DLBCL, treated uniformly with rituximab-based therapies, did not show any benefit with upfront auto-HCT consolidation [24,25]. Based on these data, upfront auto-HCT in high-risk DLBCL in CR1, as defined by clinical prognostic markers, cannot be considered a standard option. Whether upfront auto-HCT can improve outcomes of biologically defined poor-risk DLBCL (e.g., DHL or DEL) is not known. Limited retrospective data suggest that upfront auto-HCT consolidation in DHL can provide durable disease control [11]. While outcomes of DHL when treated with RCHOP like therapies are poor [14], those achieving CR1 with more intensive frontline therapies can experience durable disease control with or without auto-HCT consolidation [26]. Considering the relative rarity of DHL, a randomized trial evaluating the role of auto-HCT in this setting is unlikely. Upfront auto-HCT should be strongly considered in DHL patients receiving R-CHOP as first-line treatment or those not achieving CR1 with more intensive induction therapies. Large registry studies are urgently needed to further define the role of upfront auto-HCT in DHL and DEL.
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Auto-HCT in relapsed/refractory DLBCL
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The landmark PARMA study firmly established auto-HCT consolidation as standard-of-care in relapsed/chemosensitive DLBCL, by demonstrating a survival benefit over salvage chemotherapy alone [27]. The CORAL study, while reaffirming the role of auto-HCT in relapsed DLBCL in the rituximab era, also hinted at the futility of this approach in patients experiencing early failure of rituximab-based therapies [28]. At the Center for International Blood and Marrow Transplant Research (CIBMTR), we evaluated the role of auto-HCT in relapsed DLBCL in the rituximab era, relative to the timing of chemoimmunotherapy failure and noted that DLBCL with early rituximab failure had a higher risk of disease relapse in the 1st year after transplantation. However, beyond that point no survival difference was noted [29]. Thus, auto-HCT remains the standard of care for chemosensitive relapsed/refractory DLBCL.
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Upfront transplantation (in first complete remission)
Relapsed DLBCL unlikely to benefit from auto-HCT
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Auto-HCT consolidation in DLBCL patients achieving first complete remission (CR1) after frontline therapies is con-
Prognostic markers able to identify relapsed/refractory DLBCL patients unlikely to benefit from auto-HCT are
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Introduction
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Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders with diverse biologic, histologic, and clinical features. Over the past decade, a better understanding of the molecular pathogenesis has led to major advances in the treatment of NHL, including the addition of monoclonal antibodies and other novel agents such as B-cell receptor signaling inhibitors, immunomodulatory agents, check-point inhibitors, and proteasome inhibitors. Despite these remarkable developments, autologous hematopoietic cell transplantation (auto-HCT) remains not only a standard-of-care option for relapsed aggressive NHL but also an important therapeutic option for indolent NHL. In NHL, for patients with highrisk features, including heavily pretreated or refractory disease or those experiencing failure after an auto-HCT, allogeneic HCT (allo-HCT) remains the only curative option. In this review, we discuss the current role of HCT in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), relative to the novel prognostic tools available in the clinic.
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Diffuse large B-cell lymphoma
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DLBCL is the most common type of NHL. Like International Prognostic Index (IPI) [1], newer clinical prognostic models, such as Revised-IPI [2] or NCCN-IPI [3], can risk-stratify patients based on simple clinical parameters. In addition to these clinical prognostic models, a greater understanding of lymphomagenesis in DLBCL has allowed us to predict patient-specific outcomes based on biological predictors such as cell-of-origin (defined by gene expression profiling or immunohistochemistry) [4,5], and translocation and/or overexpression of the MYC and BCL-2 or BCL-6 oncogenes [6], potentially ushering in the era of precision medicine in NHL treatment. Rearrangement of the MYC proto-oncogene is seen in 12– 15% of DLBCL [7,8]. The concurrent rearrangement of MYC plus BCL2 and/or BCL6 genes leads to a clinically resistant form of lymphoma termed double-hit lymphoma (DHL). DHL comprises 5–7% of newly diagnosed DLBCL and carries a dismal prognosis with standard therapies [9–11]. The recently described double-expresser lymphoma (DEL) is DLBCL with overexpression of both the MYC and BCL2 (cutoff of 40% and >50%, respectively) proteins by immunohistochemistry and accounts for 21–34% of patients newly diagnosed with DLBCL [12,13]. Similar to DHL, patients with DEL also have poor outcomes after R-CHOP therapy, independent of DHL or cell-oforigin status [9,14–16]. DLBCL cases with dual DHL/DEL have grim prognosis [17]. The challenge in the year 2017 and beyond is to incorporate these biological prognostic markers in the decision-making algorithms of HCT.
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Role of auto-HCT in DLBCL
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HCT in DLBCL and FL
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urgently needed to investigate alternative therapies. In the recently reported REgistry of diFfuse large B-cell lymphoma with prImary treatmeNt failurE (REFINE) analysis, the presence of at least two out of three risk factors—(a) primary progressive disease, (b) MYC rearrangement, and (c) intermediate-high/high NCCN-IPI—in relapsed/refractory DLBCL predicted a 2-year OS of only 13% after a subsequent auto-HCT [30]. This simple-to-use prognostic score can be utilized as a benchmark tool to investigate novel therapeutic approaches in this ultra-high-risk DLBCL subgroup. The data for auto-HCT in relapsed/refractory DHL/DEL are sparse. This question was addressed in a recent multicenter retrospective study, limited to relapsed/chemosensitive DLBCL patients (non-DHL/DEL = 58, DEL = 47, DHL = 12) who underwent auto-HCT [17]. This study suggested that perhaps a subset of chemosensitive DEL (without DHL status) can experience durable disease control with auto-HCT (4-year progression-free survival [PFS] of 48%), but outcomes of chemosensitive DHL (or concurrent DHL/DEL) patients remained dismal, underscoring the need for alternative consolidation modalities of this subgroup.
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Bottom line
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Auto-HCT remains the standard of care for chemosensitive relapsed/refractory DLBCL patients. For the REFINEdefined ultra-high-risk patients or relapsed DHL patients, alternative consolidation modalities are urgently needed.
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Role of allo-HCT in DLBCL Approximately 30–40% of DLBCL cases will experience relapse/progression after auto-HCT. In addition, auto-HCT is not appropriate for patients with refractory disease. For such patients, allo-HCT might be curative option. Table 1 summarizes recent studies of allo-HCT involving DLBCL patients (n 40). These studies, in general, show that reduced-intensity conditioning (RIC) allo-HCT can provide durable disease control (OS, 45–50%; PFS, 35–45%) in patients with relapsed/refractory DLBCL [31–34]. CIBMTR data show no clear benefit of myeloablative conditioning (MAC) over RIC allo-HCT in either chemosensitive [35] or refractory patients [36].
Identifying DLBCL patients likely to benefit from allo-HCT after prior autografting Easy-to-use prognostic models able to predict allo-HCT outcomes in DLBCL relapsing after a prior auto-HCT could be clinically useful. Unlike auto-HCT, pre allo-HCT positron emission tomography scans have not consistently been shown to predict transplantation outcomes [37]. CIBMTR recently reported a prognostic model that based on three prognostic variables (Karnofsky Performance Status < 80, chemoresistant disease at allo-HCT, and <1 year between auto-HCT and allo-HCT) was able to define four different risk groups: low, intermediate, high and very-high with 3year OS probabilities of 43%, 39%, 19%, and 11% respectively [38]. This model can be used to identify patients unlikely to
3 benefit from allo-HCT, or those where relapse prevention strategies postallografting should be evaluated. The role of allo-HCT in relapsed/refractory DHL/DEL warrants investigation. In a recent retrospective analysis of DLBCL patients undergoing allo-HCT, interestingly, neither DHL nor DEL seemed to impact outcomes (PFS, OS, nonrelapse mortality, and relapse), suggesting that allo-HCT may potentially abrogate the negative prognostic impact of this high-risk subset of DLBCL patients [17].
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There is no clear benefit of MAC over RIC allo-HCT in patients with DLBCL. CIBMTR risk score can be used to identify patients likely to benefit from allo-HCT, after failing a prior autograft. Allo-HCT also seems to have a role in biologically high-risk patients (DHL and DEL) but needs further validation.
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Follicular lymphoma
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FL is a common indolent NHL, with disease course highlighted by frequent relapses and eventual evolution to refractory disease.
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Role of auto-HCT in FL
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Upfront transplant (in CR1)
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The role of upfront auto-HCT consolidation was evaluated for FL patients in CR1 in an effort to improve outcomes. Three randomized studies (German Low-Grade Lymphoma Study Group [GLSG], Groupe d’Etude des Lymphomes de ´mies et Autres l’Adulte, and Groupe Ouest-Est des Leuce Maladies du Sang [GOELAMS]) conducted in the prerituximab era for advanced stage FL patients in CR1 compared consolidation strategy with auto-HCT or interferon maintenance [39–41]. While a PFS benefit was noted in GLSG and GOELAMS trials [39,41], none of these studies reported an OS benefit with auto-HCT consolidation. Moreover, there was a significantly increased risk of secondary malignancies (such as myelodysplastic syndrome and acute myeloid leukemia) in the auto-HCT consolidation arm. A major limitation of these three trials is that they were conducted in the pre-rituximab era, and hence their applicability and relevance are questioned in current practice. The only randomized study addressing this question in the rituximab era also showed results in line with the pre-rituximab era by demonstrating an improved PFS but not OS, along with a trend toward more second malignancies with upfront auto-HCT [42]. Routine use of auto-HCT for FL in CR1 is not recommended.
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Auto-HCT in relapsed/refractory FL
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Although FL patients generally respond to initial therapy, disease relapse remains common. The CUP trial conducted in the pre-rituximab era compared salvage chemotherapy alone with chemotherapy followed by either purged or unpurged auto-HCT consolidation, in relapsed/chemosensi-
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N. Epperla, M. Hamadani Table 1
Studies reporting the outcomes of allogeneic HCT for DLBCL (>40 patients).
Author or registry (y)
N
Prior auto-HCT
Median age (range)
Conditioning regimen
NRM/TRM (y)
Relapse (y)
PFS (y)
OS (y)
Thomson et al [32] Sirvent et al [33] CIBMTR [66] van Kampen et al [34]
48 68 79a 101
69% 79% 0% 100%
46 48 46 46
32% 23% 43% 28%
(4) (1) (3) (3)
33% 41% 33% 30%
47% 44% 24% 42%
48% 49% 26% 54%
Rigacci et al [67]
165
100%
43 (16–65)
19–32% (2)
NR
32% (2)
39% (2)
CIBMTR [35]
396
32%
54 (18–66)
36–56% (5)
26–40% (5)
15–25% (5)
18–26% (5)
CIBMTR [36]
533b
25%
CIBMTR [38]
503
100%
46 (19–66) 53 (20–70) 52 (19–72)
RIC (100%) RIC (100%) MAC (100%) MAC (37%) RIC (63%) MAC (30%) RIC (70%) MAC (42%) RIC (58%) MAC (58%) RIC (42%) MAC (25%) RIC (75%)
53% (3) 42% (3) 31% (5)
28% (3) 35% (3) 40% (5)
19% (3) 23% (3) 29% (5)
19% (3) 28% (3) 34% (5)
(23–64) (17–66) (21–59) (18–66)
(4) (2) (3) (3)
(4) (2) (3) (3)
(4) (2) (3) (3)
Note. CIBMTR = Center for International Blood and Marrow Transplant Research; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HCT = hematopoietic cell transplantation; MAC = myeloablative conditioning; NR = not reported; NRM = nonrelapse mortality; OS = overall survival; PFS = progression-free survival; RIC = reduced intensity conditioning; TRM = treatment-related mortality. a Analysis restricted to patients undergoing myeloablative allo-HCT as first transplant. b Included 85% DLBCL and 15% FL Grade 3; all patients had chemo-resistant disease pretransplant.
261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286
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tive FL. This trial was closed prematurely due to poor accrual, but despite the small number of patients enrolled (n = 89), it showed a significant PFS and OS benefit in favor of auto-HCT [43]. However, the current clinical relevance of this trial is questionable, because it was conducted before the advent of contemporary chemoimmunotherapies. To investigate whether auto-HCT offered any benefit over chemotherapy alone in the rituximab era, a post hoc analysis of patients enrolled in two consecutive French studies (Groupe d’Etude des Lymphomes Folliculaires [GELF]) was performed. In this analysis, in patients who received rituximab-based salvage therapies, auto-HCT was not associated with statistically significant OS benefit when compared with patients receiving salvage chemoimmunotherapy alone [44]. Of note, patients in GELF studies did not receive rituximab-based frontline therapies. In the combined St. Bart/Dana-Farber retrospective study of relapsed FL patients (again primarily from the prerituximab era), prolonged remissions were noted after auto-HCT, but this benefit was restricted mostly to patients in second CR [45]. However, a large set of registry data (European Society for Blood and Marrow Transplantation and CIBMTR) did not show a clear plateau in relapse rates postautografting in FL [46–49]. In addition, the risk of second malignancies after auto-HCT (5–15%) has historically dampened the enthusiasm for this modality [45,46].
Role of allo-HCT in relapsed/refractory FL Allo-HCT is a potentially curative option for FL. A CIBMTR study that compared auto-HCT with allo-HCT in the prerituximab era showed significantly reduced risk of relapse after allo-HCT with clear plateaus in relapse curves [60]. Subsequently, several small prospective and large registry studies have looked at the role of allo-HCT in relapsed/
refractory FL and are summarized in Table 2. These studies show that while transplant-related mortality with RIC alloHCT ranged from 8% to 17% at 1 year, PFS has been in the 51–83% range [32,48–58].
Auto-HCT vs. allo-HCT in relapsed/refractory FL The data discussed above have fueled the decades-old quest of defining the superiority of auto-HCT versus allo-HCT over each other. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0202 trial tried to answer this question by comparing auto-HCT with RIC allo-HCT in a randomized fashion in FL. Unfortunately, the trial was closed early due to poor accrual (N for auto-HCT = 22 and N for alloHCT = 8) [59]. For the 30 patients enrolled in the BMT CTN 0202 study, the 3-year OS was 73% with auto-HCT versus 100% following allo-HCT, and 3-year PFS was 63% in the auto-HCT group versus 86% in the allo-HCT cohort. Because there are no randomized data in the rituximab era, CIBMTR analyzed the auto-HCT versus RIC allo-HCT in FL treated in the rituximab era. This updated study suggested that autoHCT and allo-HCT, when applied as the first transplantation approach, provided comparable outcomes in FL; however, the risk of relapse was substantially lower, and nonrelapse mortality significantly higher after allo-HCT. In long-term disease-free survivors (>2 years), allo-HCT was associated with a survival benefit [48,49].
High-risk FL: What are the options? Choosing auto-HCT vs. allo-HCT in relapsed FL remains controversial and largely a factor of treating physician and transplant center preferences. Based on mostly pre-
Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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HCT in DLBCL and FL Table 2
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Studies evaluating allogeneic HCT in relapsed/refractory FL (>30 patients).
Author/registry (y)
N
Conditioning regimen
Median age (range)
TRM/NRM (y)
Relapse (y)
PFS/EFS (y)
OS (y)
Rezvani et al [50] CIBMTR [51] Pinana et al [52] Thomson et al [68] Shea et al [57] Khouri et al [53] Evens et al [56] Robinson et al [54] CIBMTR [48] Yano et al [55] CIBMTR [49] BMT CTN [58]
46 208 37 82 44a 47 48 149 268 46 70 62
RIC MAC (58%) RIC (42%) RIC RIC RIC RIC NR RIC RIC RIC RIC RIC
54 44 50 45 53 53 50 51 52 48 53 55
42% (3) 23% (1) 37% (4) 15% (4) 9 15% (8) 24% (3) 22% (3) 26% (5) 23% (5) 27% (5) 13 (3)
14% (3) 8–17% (3) 8% (4) 26% (4) NR 4% (8) 16% (3) 20% (5) 20% (5) 15% (5) 20% (5) 16 (3)
43% (3) 55–67% (3) 57% (4) 76% (4) 75 83% (8) NR 57% (5) 68% (5) 75% (5) 51% (5) 71 (3)
52% (3) 62–71% (3) 57% (4) 76% (4) 81 85% (8) 61% (3) 67% (5) 66% (5) 81% (5) 54% (5) 82 (3)
(33–66) (27–70) 51 (27–700 (34–62) (26–65) (39–68) (33–68) (27–64) (33–66) (27–74) (34–66) (36–64) (29–74)
Note. BMT CTN = Blood and Marrow Transplant Clinical Trials Network; CIBMTR = Center for International Blood and Marrow Transplant Research; EFS = event-free survival; FL = follicular lymphoma; HCT = hematopoietic cell transplantation; MAC = myeloablative conditioning; NR = not reported; NRM = nonrelapse mortality; OS = overall survival; PFS = progression-free survival; RIC = reduced intensity conditioning; TRM = treatment-related mortality. a Of the 44 evaluable patients, there were only 16 FL patients.
Conclusion
Fig. 1 Overall survival by lines of chemotherapy prior to autologous hematopoietic cell transplantation.
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rituximab era data showing greater benefit of auto-HCT early in the disease course, it is common practice in many centers to limit auto-HCT use in patients who have received two to three prior lines of therapy [45,60]. However, rituximab-era unpublished data from the CIBMTR show that lines of prior therapies might not be predictive of auto-HCT outcomes (unpublished data; Fig. 1). Perhaps in the rituximab era, investigation of auto-HCT consolidation in biologically high-risk cohort of FL cases must be performed. The National LymphoCare Study (NLCS) recently reported that early failure of first-line chemoimmunotherapies (<2 years) identified a biologically high-risk subset of FL patients with an extremely poor prognosis [61]. An ongoing collaborative study between CIBMTR and NLCS is investigating the role of auto-HCT in FL patients experiencing early failure of chemoimmunotherapies. Results from that study will hopefully clarify the role of auto-HCT in this high-risk group of patients.
Although rapid strides have been made in the treatment of NHL largely due to the better understanding of the molecular pathogenesis, there are still areas that need further investigation. Studies should be performed to identify high-risk FL patients who are likely to benefit from early application of auto-HCT and hopefully the ongoing NLCS/ CIBMTR study will inform this question. Effective salvage therapies, especially for REFINE ultra-high-risk DLBCL, are an unmet medical need. These patients should be ideally enrolled into clinical trials with experimental therapies such as the use of chimeric antigen receptor T cells as standalone therapy [62] or in the setting of auto-HCT [63] or allo-HCT [64]. Efforts need to be focused on evaluating novel post-HCT consolidation or maintenance strategies, possibly with agents not used in induction chemoimmunotherapies. Currently, there are several ongoing trials in the post-auto-HCT setting evaluating the combination of bortezomib and vorinostat (NCT00992446), everolimus and rituximab (NCT01665768), lenalidomide (NCT01241734), pembrolizumab (NCT02362997), and ibrutinib (BMT CTN/Alliance trial, which will be opened soon). Consolidation and/or maintenance with monoclonal antibodies (to cite a few anti-CD 79b [Polatuzumab vedotin], anti-CD19 [MEDI 551], and anti-CD20 [Obinutuzumab]), programmed death-ligand 1 (MPDL3280A), Bcl-2 inhibitors (ABT-199), and aurora A kinase inhibitors (Alisertib) in the post-auto-HCT setting seem to be a potential area of further investigation [65]. Although the emergence of targeted, biologic, and immunological therapies is exciting, it is currently unclear how these new therapies might enhance or replace HCT. Until we have further definitive data, allo-HCT remains the only curative option.
Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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Conflicts of interest
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The authors have no conflicts of interest to declare.
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journal homepage: www.elsevier.com/locate/hemonc
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Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances
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Narendranath Epperla a, Mehdi Hamadani a,b,*
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a b
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA Center for International Blood and Marrow Transplant Research, Milwaukee, WI 53226, USA
Received 6 January 2017; accepted 28 February 2017
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KEYWORDS Allo-HCT; Auto-HCT; Diffuse large B-cell lymphoma; Follicular lymphoma
Abstract Non-Hodgkin’s lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with diverse biologic, histologic, and clinical features. With a better understanding of the molecular pathogenesis, recently there have been major advances in the treatment of NHLs including addition of novel monoclonal antibodies, targeted therapies, and immune activators to the therapy armamentarium. Despite these remarkable developments, autologous hematopoietic cell transplantation (auto-HCT) remains not only a standard-of-care curative option for aggressive NHL but also an important therapeutic option for indolent NHL. In NHL, for patients with high-risk features, including those heavily pretreated or with refractory disease or those experiencing failure after an auto-HCT, allogeneic HCT (allo-HCT) remains the only curative option. In this review, we briefly discuss the role of transplantation in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In DLBCL patients, we discuss the role of HCT in clinically and biologically defined ultra-high-risk disease. In FL patients, auto-HCT is best reserved for relapsed chemosensitive patients after two to three lines of prior chemoimmunotherapies, who are not candidates for allo-HCT, either because of donor unavailability, associated comorbidities, or patient preference. Reduced-intensity conditioning allo-HCT offers the curative option for patients with relapsed/refractory FL. Although the emergence of targeted, biologic, and immunological therapies is welcoming, it is currently unclear how these new therapies might enhance or replace allo-HCT. Until we have further definitive data, allo-HCT remains the only curative option. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
* Corresponding author at: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226, USA. E-mail address: [email protected] (M. Hamadani). http://dx.doi.org/10.1016/j.hemonc.2017.05.004 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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N. Epperla, M. Hamadani troversial. Several randomized studies evaluating the role of upfront auto-HCT consolidation in DLBCL in the prerituximab era reported conflicting results [18–21]. A meta-analysis of these pre-rituximab era trials, however, did not show the superiority of auto-HCT consolidation compared with the standard chemotherapy alone [22]. Therefore, auto-HCT was not adopted as standard therapy in the frontline setting for high-risk DLBCL in CR1. In the rituximab era, provocative findings of the Southwest Oncology Group S9704 [23] study reignited the discussion of upfront auto-HCT in DLBCL by showing a possible overall survival (OS) benefit in an unplanned/post hoc analysis for the high-risk IPI subgroup. However, DLBCL comprised only 60% of S9704 study population and not all DLBCL patients received rituximab-containing frontline therapies [23]. Of note, two recent randomized trials restricted to IPI defined intermediate–high or high-risk DLBCL, treated uniformly with rituximab-based therapies, did not show any benefit with upfront auto-HCT consolidation [24,25]. Based on these data, upfront auto-HCT in high-risk DLBCL in CR1, as defined by clinical prognostic markers, cannot be considered a standard option. Whether upfront auto-HCT can improve outcomes of biologically defined poor-risk DLBCL (e.g., DHL or DEL) is not known. Limited retrospective data suggest that upfront auto-HCT consolidation in DHL can provide durable disease control [11]. While outcomes of DHL when treated with RCHOP like therapies are poor [14], those achieving CR1 with more intensive frontline therapies can experience durable disease control with or without auto-HCT consolidation [26]. Considering the relative rarity of DHL, a randomized trial evaluating the role of auto-HCT in this setting is unlikely. Upfront auto-HCT should be strongly considered in DHL patients receiving R-CHOP as first-line treatment or those not achieving CR1 with more intensive induction therapies. Large registry studies are urgently needed to further define the role of upfront auto-HCT in DHL and DEL.
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Auto-HCT in relapsed/refractory DLBCL
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The landmark PARMA study firmly established auto-HCT consolidation as standard-of-care in relapsed/chemosensitive DLBCL, by demonstrating a survival benefit over salvage chemotherapy alone [27]. The CORAL study, while reaffirming the role of auto-HCT in relapsed DLBCL in the rituximab era, also hinted at the futility of this approach in patients experiencing early failure of rituximab-based therapies [28]. At the Center for International Blood and Marrow Transplant Research (CIBMTR), we evaluated the role of auto-HCT in relapsed DLBCL in the rituximab era, relative to the timing of chemoimmunotherapy failure and noted that DLBCL with early rituximab failure had a higher risk of disease relapse in the 1st year after transplantation. However, beyond that point no survival difference was noted [29]. Thus, auto-HCT remains the standard of care for chemosensitive relapsed/refractory DLBCL.
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Upfront transplantation (in first complete remission)
Relapsed DLBCL unlikely to benefit from auto-HCT
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Auto-HCT consolidation in DLBCL patients achieving first complete remission (CR1) after frontline therapies is con-
Prognostic markers able to identify relapsed/refractory DLBCL patients unlikely to benefit from auto-HCT are
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Introduction
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Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders with diverse biologic, histologic, and clinical features. Over the past decade, a better understanding of the molecular pathogenesis has led to major advances in the treatment of NHL, including the addition of monoclonal antibodies and other novel agents such as B-cell receptor signaling inhibitors, immunomodulatory agents, check-point inhibitors, and proteasome inhibitors. Despite these remarkable developments, autologous hematopoietic cell transplantation (auto-HCT) remains not only a standard-of-care option for relapsed aggressive NHL but also an important therapeutic option for indolent NHL. In NHL, for patients with highrisk features, including heavily pretreated or refractory disease or those experiencing failure after an auto-HCT, allogeneic HCT (allo-HCT) remains the only curative option. In this review, we discuss the current role of HCT in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), relative to the novel prognostic tools available in the clinic.
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Diffuse large B-cell lymphoma
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DLBCL is the most common type of NHL. Like International Prognostic Index (IPI) [1], newer clinical prognostic models, such as Revised-IPI [2] or NCCN-IPI [3], can risk-stratify patients based on simple clinical parameters. In addition to these clinical prognostic models, a greater understanding of lymphomagenesis in DLBCL has allowed us to predict patient-specific outcomes based on biological predictors such as cell-of-origin (defined by gene expression profiling or immunohistochemistry) [4,5], and translocation and/or overexpression of the MYC and BCL-2 or BCL-6 oncogenes [6], potentially ushering in the era of precision medicine in NHL treatment. Rearrangement of the MYC proto-oncogene is seen in 12– 15% of DLBCL [7,8]. The concurrent rearrangement of MYC plus BCL2 and/or BCL6 genes leads to a clinically resistant form of lymphoma termed double-hit lymphoma (DHL). DHL comprises 5–7% of newly diagnosed DLBCL and carries a dismal prognosis with standard therapies [9–11]. The recently described double-expresser lymphoma (DEL) is DLBCL with overexpression of both the MYC and BCL2 (cutoff of 40% and >50%, respectively) proteins by immunohistochemistry and accounts for 21–34% of patients newly diagnosed with DLBCL [12,13]. Similar to DHL, patients with DEL also have poor outcomes after R-CHOP therapy, independent of DHL or cell-oforigin status [9,14–16]. DLBCL cases with dual DHL/DEL have grim prognosis [17]. The challenge in the year 2017 and beyond is to incorporate these biological prognostic markers in the decision-making algorithms of HCT.
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urgently needed to investigate alternative therapies. In the recently reported REgistry of diFfuse large B-cell lymphoma with prImary treatmeNt failurE (REFINE) analysis, the presence of at least two out of three risk factors—(a) primary progressive disease, (b) MYC rearrangement, and (c) intermediate-high/high NCCN-IPI—in relapsed/refractory DLBCL predicted a 2-year OS of only 13% after a subsequent auto-HCT [30]. This simple-to-use prognostic score can be utilized as a benchmark tool to investigate novel therapeutic approaches in this ultra-high-risk DLBCL subgroup. The data for auto-HCT in relapsed/refractory DHL/DEL are sparse. This question was addressed in a recent multicenter retrospective study, limited to relapsed/chemosensitive DLBCL patients (non-DHL/DEL = 58, DEL = 47, DHL = 12) who underwent auto-HCT [17]. This study suggested that perhaps a subset of chemosensitive DEL (without DHL status) can experience durable disease control with auto-HCT (4-year progression-free survival [PFS] of 48%), but outcomes of chemosensitive DHL (or concurrent DHL/DEL) patients remained dismal, underscoring the need for alternative consolidation modalities of this subgroup.
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Auto-HCT remains the standard of care for chemosensitive relapsed/refractory DLBCL patients. For the REFINEdefined ultra-high-risk patients or relapsed DHL patients, alternative consolidation modalities are urgently needed.
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Role of allo-HCT in DLBCL Approximately 30–40% of DLBCL cases will experience relapse/progression after auto-HCT. In addition, auto-HCT is not appropriate for patients with refractory disease. For such patients, allo-HCT might be curative option. Table 1 summarizes recent studies of allo-HCT involving DLBCL patients (n 40). These studies, in general, show that reduced-intensity conditioning (RIC) allo-HCT can provide durable disease control (OS, 45–50%; PFS, 35–45%) in patients with relapsed/refractory DLBCL [31–34]. CIBMTR data show no clear benefit of myeloablative conditioning (MAC) over RIC allo-HCT in either chemosensitive [35] or refractory patients [36].
Identifying DLBCL patients likely to benefit from allo-HCT after prior autografting Easy-to-use prognostic models able to predict allo-HCT outcomes in DLBCL relapsing after a prior auto-HCT could be clinically useful. Unlike auto-HCT, pre allo-HCT positron emission tomography scans have not consistently been shown to predict transplantation outcomes [37]. CIBMTR recently reported a prognostic model that based on three prognostic variables (Karnofsky Performance Status < 80, chemoresistant disease at allo-HCT, and <1 year between auto-HCT and allo-HCT) was able to define four different risk groups: low, intermediate, high and very-high with 3year OS probabilities of 43%, 39%, 19%, and 11% respectively [38]. This model can be used to identify patients unlikely to
3 benefit from allo-HCT, or those where relapse prevention strategies postallografting should be evaluated. The role of allo-HCT in relapsed/refractory DHL/DEL warrants investigation. In a recent retrospective analysis of DLBCL patients undergoing allo-HCT, interestingly, neither DHL nor DEL seemed to impact outcomes (PFS, OS, nonrelapse mortality, and relapse), suggesting that allo-HCT may potentially abrogate the negative prognostic impact of this high-risk subset of DLBCL patients [17].
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There is no clear benefit of MAC over RIC allo-HCT in patients with DLBCL. CIBMTR risk score can be used to identify patients likely to benefit from allo-HCT, after failing a prior autograft. Allo-HCT also seems to have a role in biologically high-risk patients (DHL and DEL) but needs further validation.
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Follicular lymphoma
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FL is a common indolent NHL, with disease course highlighted by frequent relapses and eventual evolution to refractory disease.
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Role of auto-HCT in FL
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Upfront transplant (in CR1)
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The role of upfront auto-HCT consolidation was evaluated for FL patients in CR1 in an effort to improve outcomes. Three randomized studies (German Low-Grade Lymphoma Study Group [GLSG], Groupe d’Etude des Lymphomes de ´mies et Autres l’Adulte, and Groupe Ouest-Est des Leuce Maladies du Sang [GOELAMS]) conducted in the prerituximab era for advanced stage FL patients in CR1 compared consolidation strategy with auto-HCT or interferon maintenance [39–41]. While a PFS benefit was noted in GLSG and GOELAMS trials [39,41], none of these studies reported an OS benefit with auto-HCT consolidation. Moreover, there was a significantly increased risk of secondary malignancies (such as myelodysplastic syndrome and acute myeloid leukemia) in the auto-HCT consolidation arm. A major limitation of these three trials is that they were conducted in the pre-rituximab era, and hence their applicability and relevance are questioned in current practice. The only randomized study addressing this question in the rituximab era also showed results in line with the pre-rituximab era by demonstrating an improved PFS but not OS, along with a trend toward more second malignancies with upfront auto-HCT [42]. Routine use of auto-HCT for FL in CR1 is not recommended.
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Although FL patients generally respond to initial therapy, disease relapse remains common. The CUP trial conducted in the pre-rituximab era compared salvage chemotherapy alone with chemotherapy followed by either purged or unpurged auto-HCT consolidation, in relapsed/chemosensi-
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N. Epperla, M. Hamadani Table 1
Studies reporting the outcomes of allogeneic HCT for DLBCL (>40 patients).
Author or registry (y)
N
Prior auto-HCT
Median age (range)
Conditioning regimen
NRM/TRM (y)
Relapse (y)
PFS (y)
OS (y)
Thomson et al [32] Sirvent et al [33] CIBMTR [66] van Kampen et al [34]
48 68 79a 101
69% 79% 0% 100%
46 48 46 46
32% 23% 43% 28%
(4) (1) (3) (3)
33% 41% 33% 30%
47% 44% 24% 42%
48% 49% 26% 54%
Rigacci et al [67]
165
100%
43 (16–65)
19–32% (2)
NR
32% (2)
39% (2)
CIBMTR [35]
396
32%
54 (18–66)
36–56% (5)
26–40% (5)
15–25% (5)
18–26% (5)
CIBMTR [36]
533b
25%
CIBMTR [38]
503
100%
46 (19–66) 53 (20–70) 52 (19–72)
RIC (100%) RIC (100%) MAC (100%) MAC (37%) RIC (63%) MAC (30%) RIC (70%) MAC (42%) RIC (58%) MAC (58%) RIC (42%) MAC (25%) RIC (75%)
53% (3) 42% (3) 31% (5)
28% (3) 35% (3) 40% (5)
19% (3) 23% (3) 29% (5)
19% (3) 28% (3) 34% (5)
(23–64) (17–66) (21–59) (18–66)
(4) (2) (3) (3)
(4) (2) (3) (3)
(4) (2) (3) (3)
Note. CIBMTR = Center for International Blood and Marrow Transplant Research; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HCT = hematopoietic cell transplantation; MAC = myeloablative conditioning; NR = not reported; NRM = nonrelapse mortality; OS = overall survival; PFS = progression-free survival; RIC = reduced intensity conditioning; TRM = treatment-related mortality. a Analysis restricted to patients undergoing myeloablative allo-HCT as first transplant. b Included 85% DLBCL and 15% FL Grade 3; all patients had chemo-resistant disease pretransplant.
261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286
287
288 289 290 291 292 293
tive FL. This trial was closed prematurely due to poor accrual, but despite the small number of patients enrolled (n = 89), it showed a significant PFS and OS benefit in favor of auto-HCT [43]. However, the current clinical relevance of this trial is questionable, because it was conducted before the advent of contemporary chemoimmunotherapies. To investigate whether auto-HCT offered any benefit over chemotherapy alone in the rituximab era, a post hoc analysis of patients enrolled in two consecutive French studies (Groupe d’Etude des Lymphomes Folliculaires [GELF]) was performed. In this analysis, in patients who received rituximab-based salvage therapies, auto-HCT was not associated with statistically significant OS benefit when compared with patients receiving salvage chemoimmunotherapy alone [44]. Of note, patients in GELF studies did not receive rituximab-based frontline therapies. In the combined St. Bart/Dana-Farber retrospective study of relapsed FL patients (again primarily from the prerituximab era), prolonged remissions were noted after auto-HCT, but this benefit was restricted mostly to patients in second CR [45]. However, a large set of registry data (European Society for Blood and Marrow Transplantation and CIBMTR) did not show a clear plateau in relapse rates postautografting in FL [46–49]. In addition, the risk of second malignancies after auto-HCT (5–15%) has historically dampened the enthusiasm for this modality [45,46].
Role of allo-HCT in relapsed/refractory FL Allo-HCT is a potentially curative option for FL. A CIBMTR study that compared auto-HCT with allo-HCT in the prerituximab era showed significantly reduced risk of relapse after allo-HCT with clear plateaus in relapse curves [60]. Subsequently, several small prospective and large registry studies have looked at the role of allo-HCT in relapsed/
refractory FL and are summarized in Table 2. These studies show that while transplant-related mortality with RIC alloHCT ranged from 8% to 17% at 1 year, PFS has been in the 51–83% range [32,48–58].
Auto-HCT vs. allo-HCT in relapsed/refractory FL The data discussed above have fueled the decades-old quest of defining the superiority of auto-HCT versus allo-HCT over each other. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0202 trial tried to answer this question by comparing auto-HCT with RIC allo-HCT in a randomized fashion in FL. Unfortunately, the trial was closed early due to poor accrual (N for auto-HCT = 22 and N for alloHCT = 8) [59]. For the 30 patients enrolled in the BMT CTN 0202 study, the 3-year OS was 73% with auto-HCT versus 100% following allo-HCT, and 3-year PFS was 63% in the auto-HCT group versus 86% in the allo-HCT cohort. Because there are no randomized data in the rituximab era, CIBMTR analyzed the auto-HCT versus RIC allo-HCT in FL treated in the rituximab era. This updated study suggested that autoHCT and allo-HCT, when applied as the first transplantation approach, provided comparable outcomes in FL; however, the risk of relapse was substantially lower, and nonrelapse mortality significantly higher after allo-HCT. In long-term disease-free survivors (>2 years), allo-HCT was associated with a survival benefit [48,49].
High-risk FL: What are the options? Choosing auto-HCT vs. allo-HCT in relapsed FL remains controversial and largely a factor of treating physician and transplant center preferences. Based on mostly pre-
Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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Studies evaluating allogeneic HCT in relapsed/refractory FL (>30 patients).
Author/registry (y)
N
Conditioning regimen
Median age (range)
TRM/NRM (y)
Relapse (y)
PFS/EFS (y)
OS (y)
Rezvani et al [50] CIBMTR [51] Pinana et al [52] Thomson et al [68] Shea et al [57] Khouri et al [53] Evens et al [56] Robinson et al [54] CIBMTR [48] Yano et al [55] CIBMTR [49] BMT CTN [58]
46 208 37 82 44a 47 48 149 268 46 70 62
RIC MAC (58%) RIC (42%) RIC RIC RIC RIC NR RIC RIC RIC RIC RIC
54 44 50 45 53 53 50 51 52 48 53 55
42% (3) 23% (1) 37% (4) 15% (4) 9 15% (8) 24% (3) 22% (3) 26% (5) 23% (5) 27% (5) 13 (3)
14% (3) 8–17% (3) 8% (4) 26% (4) NR 4% (8) 16% (3) 20% (5) 20% (5) 15% (5) 20% (5) 16 (3)
43% (3) 55–67% (3) 57% (4) 76% (4) 75 83% (8) NR 57% (5) 68% (5) 75% (5) 51% (5) 71 (3)
52% (3) 62–71% (3) 57% (4) 76% (4) 81 85% (8) 61% (3) 67% (5) 66% (5) 81% (5) 54% (5) 82 (3)
(33–66) (27–70) 51 (27–700 (34–62) (26–65) (39–68) (33–68) (27–64) (33–66) (27–74) (34–66) (36–64) (29–74)
Note. BMT CTN = Blood and Marrow Transplant Clinical Trials Network; CIBMTR = Center for International Blood and Marrow Transplant Research; EFS = event-free survival; FL = follicular lymphoma; HCT = hematopoietic cell transplantation; MAC = myeloablative conditioning; NR = not reported; NRM = nonrelapse mortality; OS = overall survival; PFS = progression-free survival; RIC = reduced intensity conditioning; TRM = treatment-related mortality. a Of the 44 evaluable patients, there were only 16 FL patients.
Conclusion
Fig. 1 Overall survival by lines of chemotherapy prior to autologous hematopoietic cell transplantation.
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rituximab era data showing greater benefit of auto-HCT early in the disease course, it is common practice in many centers to limit auto-HCT use in patients who have received two to three prior lines of therapy [45,60]. However, rituximab-era unpublished data from the CIBMTR show that lines of prior therapies might not be predictive of auto-HCT outcomes (unpublished data; Fig. 1). Perhaps in the rituximab era, investigation of auto-HCT consolidation in biologically high-risk cohort of FL cases must be performed. The National LymphoCare Study (NLCS) recently reported that early failure of first-line chemoimmunotherapies (<2 years) identified a biologically high-risk subset of FL patients with an extremely poor prognosis [61]. An ongoing collaborative study between CIBMTR and NLCS is investigating the role of auto-HCT in FL patients experiencing early failure of chemoimmunotherapies. Results from that study will hopefully clarify the role of auto-HCT in this high-risk group of patients.
Although rapid strides have been made in the treatment of NHL largely due to the better understanding of the molecular pathogenesis, there are still areas that need further investigation. Studies should be performed to identify high-risk FL patients who are likely to benefit from early application of auto-HCT and hopefully the ongoing NLCS/ CIBMTR study will inform this question. Effective salvage therapies, especially for REFINE ultra-high-risk DLBCL, are an unmet medical need. These patients should be ideally enrolled into clinical trials with experimental therapies such as the use of chimeric antigen receptor T cells as standalone therapy [62] or in the setting of auto-HCT [63] or allo-HCT [64]. Efforts need to be focused on evaluating novel post-HCT consolidation or maintenance strategies, possibly with agents not used in induction chemoimmunotherapies. Currently, there are several ongoing trials in the post-auto-HCT setting evaluating the combination of bortezomib and vorinostat (NCT00992446), everolimus and rituximab (NCT01665768), lenalidomide (NCT01241734), pembrolizumab (NCT02362997), and ibrutinib (BMT CTN/Alliance trial, which will be opened soon). Consolidation and/or maintenance with monoclonal antibodies (to cite a few anti-CD 79b [Polatuzumab vedotin], anti-CD19 [MEDI 551], and anti-CD20 [Obinutuzumab]), programmed death-ligand 1 (MPDL3280A), Bcl-2 inhibitors (ABT-199), and aurora A kinase inhibitors (Alisertib) in the post-auto-HCT setting seem to be a potential area of further investigation [65]. Although the emergence of targeted, biologic, and immunological therapies is exciting, it is currently unclear how these new therapies might enhance or replace HCT. Until we have further definitive data, allo-HCT remains the only curative option.
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The authors have no conflicts of interest to declare.
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Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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Please cite this article in press as: Epperla N, Hamadani M, Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.004
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