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Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using (90)Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma
Mei, M., Palmer, J., Tsai, N. N., Simpson, J., O'Hearn, J., Stein, A., Forman, S., Spielberger, R., Cai, J. L., Htut, M., et al
Clinical lymphoma, myeloma & leukemia. 2023
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. (90)Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens. OBJECTIVES The purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL. STUDY DESIGN We conducted a phase II trial (NCT00577278) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received (111)In-Zevalin (5.0 mCi) on day -21 pre-HCT, followed by (90)Y-Zevalin (0.4 mCi/kg) on day -14. Fludarabine (25 mg/m(2) daily) was given from days -9 to -5 and melphalan (140 mg/m(2)) was administered on day -4. All patients received rituximab 250 mg/m2 on day +8 and an additional dose on either day +1 or -21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days -21 and -15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day -3, and stem cells were infused on day 0. RESULTS The 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day +100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS (P = .0013) and PFS (P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints. CONCLUSION Addition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.
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Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial
Herrera, A. F., Chen, L., Nieto, Y., Holmberg, L., Johnston, P., Mei, M., Popplewell, L., Armenian, S., Cao, T., Farol, L., et al
The Lancet. Haematology. 2022
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Editor's Choice
Abstract
BACKGROUND After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. METHODS We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. FINDINGS Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. INTERPRETATION Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. FUNDING Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.
PICO Summary
Population
Adults with high-risk relapsed or refractory Hodgkin lymphoma from five centres in the USA (n=59)
Intervention
Brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT
Comparison
None
Outcome
Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed.
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Anti-CD25 Radioimmunotherapy with BEAM Autologous Hematopoietic Cell Transplantation Conditioning in Hodgkin Lymphoma
Herrera, A. F., Palmer Ph, D. Jm, Adhikarla, V., Yamauchi, D. M., Poku, E. K., Bading, J., Yazaki, P., Dandapani, S., Mei, M. G., Chen, R. W., et al
Blood advances. 2021
Abstract
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL and we hypothesized that the addition of 90Y-antiCD25 (aTac) to BEAM AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled onto this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution and a third developed an unrelated catheter-associated bacteremia; therefore 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed and 0.6mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive > 2500cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with 3 or more risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL and we are further evaluating the efficacy of this approach in a phase 2 trial. The clinical trial was registered at clinicaltrials.gov (NCT01476839).
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Treatment of Allosensitized Patients Receiving Allogeneic Transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Zou, J., Aung, F. M., Rondon, G., Chen, J., Taniguchi, M., Otoukesh, S., Nademanee, A., et al
Blood advances. 2021
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Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat for patients with DSA at two institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSA (N=345). Majority of patients in the DSA group were females (83.8% vs. 37.1% in controls, p<0.001) and received stem cells from a child as donor (67.6% vs. 44.1%, p=0.002). Mean DSA level before and after desensitization was 10,198 and 5,937 MFI, respectively with mean differences of 4,030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA >20,000 MFI and with persistent C1q+ after desensitization had a significantly lower engraftment rate, resulted in a significantly higher non-relapse mortality (NRM) and worse overall survival (OS) than controls whereas graft outcome and survivals of patients with initial DSA <20,000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with plasma exchange, rituximab, IvIg and donor buffy coat is effective in promoting engraftment in patients with DSA up to 20,000 MFI.
PICO Summary
Population
Patients with donor specific antibodies (DSAs) from two US centres, receiving allogeneic transplantation (DSA group, n=37)
Intervention
Desensitisation protocol: alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat (n=37)
Comparison
Patients without DSAs undergoing haploidentical transplantation (Control, n=345)
Outcome
The majority of patients in the DSA group were female (83.8% vs 37.1% in controls,) and received stem cells from a child as the donor (67.6% vs 44.1%). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls.
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Iron Overload is Associated with Delayed Engraftment and Increased Non-Relapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation
Malki, M. M. A., Song, J. Y., Yang, D., Cao, T., Aldoss, I., Mokhtari, S., Dadwal, S., Marcucci, G., Karanes, C., Snyder, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The negative impact of Iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well-recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin level (SF) of 2000 ng/ml. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/ml was 26.1% (95%CI: 10.6%-44.7%) and 52.1% (95%CI: 40.1%-62.8%), respectively; HR=2.26 (95%CI: 1.28-4.00, P=0.005). Two-year non-relapse mortality rate was higher among patients with SF >2000 ng/ml (56.5%, 95%CI: 33.3%-74.4%) compared to SF ≤2000 ng/ml (30.1%, 95%CI: 20.0%-40.9%); HR=2.18, (95%CI: 1.10-4.31, P=0.025). Neutrophil engraftment at 42 days was 78.3% (95%CI: 53.5%-90.8%) in patients with SF >2000 ng/ml, versus 91.8% (95%CI: 82.1%-96.4%) in patients with SF ≤2000 ng/ml; HR=0.58 (95%CI: 0.35-0.96, P=0.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95%CI: 29.4%-70.8%) for SF>2000 ng/ml versus 80.8% (95%CI: 69.5%-88.3%) for SF ≤2000 ng/ml; HR=0.48 (95%CI: 0.23-0.98, P=0.044). In conclusion, IO defined by SF of 2000 ng/ml is a strong adverse prognostic factor for UCB-HCT and should be a considered when UCB is chosen as the graft source for patients without a fully matched donor.
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Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial
Aldoss, I., La Rosa, C., Baden, L. R., Longmate, J., Ariza-Heredia, E. J., Rida, W. N., Lingaraju, C. R., Zhou, Q., Martinez, J., Kaltcheva, T., et al
Annals of internal medicine. 2020
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Editor's Choice
Abstract
Background: Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT). Objective: To determine the safety and efficacy of Triplex. Design: First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933). Setting: 3 U.S. HCT centers. Participants: 102 CMV-seropositive HCT recipients at high risk for CMV reactivation. Intervention: Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens. Measurements: The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection. Results: A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients. Limitation: The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial. Conclusion: No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia. Primary Funding Source: National Cancer Institute and Helocyte.
PICO Summary
Population
CMV-seropositive HCT recipients at high risk for CMV reactivation (n=102)
Intervention
Intramuscular injections of Triplex CMV vaccine (n=51)
Comparison
Placebo (n=51)
Outcome
Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.
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Long-term outcome of allogeneic hematopoietic stem cell transplantation from unrelated donor using tacrolimus/sirolimus-based GVHD prophylaxis: impact of HLA mismatch
Al Malki, M. M., Gendzekhadze, K., Yang, D., Mokhtari, S., Parker, P., Karanes, C., Palmer, J., Snyder, D., Forman, S. J., Nademanee, A., et al
Transplantation. 2019
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Abstract
BACKGROUND While Tacrolimus/Sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor (URD) HCT (2005 - 2013) with T/S-based GvHD prophylaxis. RESULTS With a median follow-up of 6.2 years (range=2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95%CI: 43.0-52.0) and 43.6% (95%CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of non relapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% vs. 50.7% at 5 years, p=0.034), primarily due to greater risk of NRM (33.5% vs. 21.7%, p=0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% vs. 12.8%, p=0.022) and infection (33.0% vs. 18.1%, p<0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (HR= 2.21, 95%CI: 1.16-4.23; p<0.01) and mMUD (HR=1.55, 95%CI:.1.15-2.08; p=0.004) were independent predictive factors for OS. CONCLUSIONS T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.
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Protective effect of HLA-DPB1 mismatch remains valid in reduced-intensity conditioning unrelated donor hematopoietic cell transplantation
Malki, M. M. A., Gendzekhadze, K., Stiller, T., Mokhtari, S., Karanes, C., Parker, P., Snyder, D., Forman, S. J., Nakamura, R., Nademanee, A.
Bone marrow transplantation. 2019
Abstract
A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.
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Provisional Title: Safety Analysis of Brentuximab Vedotin From the Phase 3 AETHERA Trial in Hodgkin Lymphoma in the Posttransplant Consolidation Setting
Nademanee, A., Sureda, A., Stiff, P., Holowiecki, J., Abidi, M., Hunder, N. N., Pecsok, M., Uttarwar, M., Purevjal, I., Sweetenham, J.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
The phase 3 AETHERA trial demonstrated brentuximab vedotin's (BV) efficacy as consolidation therapy in patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression following autologous hematopoietic stem cell transplant (auto-HSCT; hazard ratio [HR]=0.57; P<0.001). The objective of this analysis is to provide further detail on the most common and clinically important treatment-emergent adverse events (TEAEs) in the AETHERA BV arm including their occurrence and management. AEs of clinical importance occurring in patients who participated in AETHERA (BV + best supportive care [BSC], n=165; placebo + BSC, n=164) were evaluated for time to onset, manageability through dose modification, and resolution. As previously reported, peripheral neuropathy (PN; 67%), infections (60%), and neutropenia (35%) were the most common BV-associated TEAEs. Neutropenia was managed with dose delays and granulocyte colony-stimulating factor; no dose reductions or discontinuations were required. The majority (57%) of PN cases were managed with dose delays and reductions. The median time to PN onset was 13.7 (range, 0.1-47.4) weeks. After end of treatment, PN continued to resolve; symptom resolution was similar to that in the placebo arm at 3 years, demonstrating reversibility. BV had no significant impact on preexisting PN. Patients with PN-related dose modifications had progression-free survival (PFS) comparable to patients without. Other less common but serious AEs, including pulmonary toxicities, hepatotoxicity, and cardiotoxicity, were rare in both arms and managed with BV dose modifications or discontinuations. Secondary malignancies were rare and reported in patients with comorbidities or other risk factors. Consolidation therapy with BV for patients with HL at high risk of relapse after auto-HSCT is associated with sustained PFS. The most common AEs in the BV arm were manageable and reversible. Awareness of these AEs and management approaches will enable healthcare providers and patients to plan the safest and most effective treatment plan.
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Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma
Herrera, A. F., Palmer, J., Martin, P., Armenian, S., Tsai, N. C., Kennedy, N., Sahebi, F., Cao, T., Budde, L. E., Mei, M., et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;29(3):724-730
Abstract
BACKGROUND We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. PATIENTS AND METHODS Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. RESULTS Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. CONCLUSIONS Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).