A multicenter, phase I study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation
CTLA-4 blockade augments the graft-vs-tumor effect in relapsed hematologic malignancies (HMs) after allogeneic hematopoietic cell transplantation (alloHCT). PD-1/PDL-1 interactions also contribute to functional T cell impairment, but retrospective studies of anti-PD-1 therapy following alloHCT reported substantial toxicity from GVHD. Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed HMs after alloHCT (ClinicalTrials.gov, NCT01822509). The primary objectives in this phase I multicenter, investigator-initiated study were to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1 mg/kg cohort, with planned de-escalation based on toxicity to a 0.5 mg/kg cohort. Twenty-eight patients were treated (n=19 myeloid, n=9 lymphoid). Median age was 57 (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of six patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year PFS and OS were 23% and 56%, respectively. In this first prospective clinical trial of an anti-PD-1 antibody for post-alloHCT relapse, GVHD and irAEs occurred, requiring dose de-escalation, with only modest anti-tumor activity. Further studies of anti-PD-1 therapy post alloHCT may require specific toxicity mitigation strategies.
Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT
JAMA oncology. 2019
Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naive high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naive FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.
PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL
Blood advances. 2019;3(3):360-369
This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.
Lower GVHD and relapse risk in PTCy-based Haploidentical vs Matched Sibling Donor RIC Transplant for Hodgkin Lymphoma
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Classical Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of two reduced-intensity conditioning (RIC) HCT platforms in cHL: T cell-replete related donor haploidentical (haplo) HCT with post-transplantation cyclophosphamide (PTCy)-based approach versus MSD/calcineurin inhibitor (CNI)-based approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008-2016, using either haplo-PTCy (n=139) or MSD/CNI-based (n=457) approach. Overall survival (OS) was the primary endpoint. Secondary endpoints included acute (a) and (c) graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no significant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR]=1.07; 95%CI=0.79-1.45; p=0.66) or PFS (HR=0.86; 95%CI=0.68-1.10; p=0.22). Haplo/PTCy was associated with a significantly higher risk of grade 2-4 aGVHD (odds ratio [OR]=1.73, 95%CI=1.16-2.59, p=0.007), but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts (OR=0.61, 95%CI=0.29-1.27, p=0.19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR=0.45, 95%CI=0.32-0.64, p<0.001), and a significant reduction in relapse risk (HR=0.74, 95%CI=0.56-0.97, p=0.03). There was a statistically non-significant trend towards higher NRM with haplo/PTCy approach (HR=1.65, 95%CI=0.99-2.77, p=0.06). Haplo/PTCy-based approaches are associated with lower incidence of cGVHD and relapse, with PFS and OS outcomes comparable to MSD/CNI-based approaches. There was a leaning towards higher NRM with haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable to MSD/CNI-based allo-HCT.
Adult patients who underwent a first RIC allo-HCT for classical Hodgkin lymphoma between 2008-2016 (n=596)
T cell-replete related donor haploidentical HCT with post-transplantation cyclophosphamide (Haplo/PTCy) (n=139)
Matched Sibling Donor with calcineurin inhibitor (MSD/CNI) (n=457)
On multivariate analysis, there was no significant difference between Haplo/PTCy and MSD/CNI-based approaches in terms of overall survival or progression-free survival. Haplo/PTCy was associated with a significantly higher risk of grade 2-4 aGVHD, but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts. The haplo/PTCy platform provided a significant reduction in cGVHD risk, and a significant reduction in relapse. There was a statistically non-significant trend towards higher NRM with haplo/PTCy approach.
Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation
Journal of hematology & oncology. 2018;11(1):87
BACKGROUND Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied. METHODS We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m(2) subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m(2) intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS). RESULTS With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease. CONCLUSION Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen. TRIAL REGISTRATION ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.
Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis
Blood advances. 2018;2(8):933-940
The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.
Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation
Journal of Clinical Oncology. 2017;35(1):24-31
Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.
Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma
Biology of Blood & Marrow Transplantation. 2017
Double-hit lymphomas (DHL) and double-expressor lymphomas (DEL) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). 78 patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and FISH were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared to patients without DEL (PFS 30% v 39%, p=0.24; OS 31% v 49%, p=0.17) or between patients with DHL compared to patients without DHL (PFS 40% v 34%, p=0.62; OS 50% v 38%, p=0.46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, though limited sample size may have limited our ability to detect significant differences. In our cohort, alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.
Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis
Journal of Clinical Oncology. 2016;34(26):3141-9
PURPOSE Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry. MATERIALS AND METHODS We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis. RESULTS Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34). CONCLUSION Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD. Copyright © 2016 by American Society of Clinical Oncology.
Next-generation sequencing-based detection of circulating tumour DNA After allogeneic stem cell transplantation for lymphoma
British Journal of Haematology. 2016;175(5):841-850
Next-generation sequencing (NGS)-based circulating tumour DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ctDNA was associated with outcome after allogeneic haematopoietic stem cell transplantation (HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced-intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre-specified time points before and after HSCT and were assayed for ctDNA by sequencing of the immunoglobulin or T-cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ctDNA prior to progression at a median of 3.7 months prior to relapse/progression. Patients with detectable ctDNA 3 months after HSCT had inferior progression-free survival (PFS) (2-year PFS 58% vs. 84% in ctDNA-negative patients, P = 0.033). In multivariate models, detectable ctDNA was associated with increased risk of progression/death (Hazard ratio 3.9, P = 0.003) and increased risk of relapse/progression (Hazard ratio 10.8, P = 0.0006). Detectable ctDNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS-based minimal residual disease monitoring in lymphoma patients after HSCT. Copyright © 2016 John Wiley & Sons Ltd.