Abstract

INTRODUCTION Disease relapse is the most common cause of therapy failure in non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM). Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI. METHODS In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression and progression-free survival (PFS). RESULTS At baseline the Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients had a higher HCT-CI. On multivariate analysis the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively. Relapse was the most common cause of death in both cohorts. CONCLUSIONS In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment modality for primary myelofibrosis (MF) and related myeloproliferative neoplasms. Older age at diagnosis and age-related comorbidities make most patients ineligible for alloHCT, given concerns for non-relapse mortality (NRM). Herein, we report the outcomes of 37 consecutive recipients of allogeneic HCT for MF performed at a single center between 2009 and 2018 with a standardized institutional protocol. Most patients received ruxolitinib prior to HCT (n=32), and those with splenomegaly >22 cm received pre-transplant splenic irradiation. Median age at HCT was 60 years (range, 40-74): 68% carried JAK2 driver mutation. All patients received fludarabine/busulfan-based conditioning: 22 patients (59%) received reduced intensity conditioning. All patients received peripheral blood grafts. Sixteen (43%) patients had matched sibling donor, and others had unrelated (n=20) or haploidentical-related donor (n=1). Sixty one percent had an HCT-CI score ≥3, 40% had KPS <90 and 24% had a high-risk DIPSS Plus score. With a median follow-up of 40.2 months (range, 16.9-115), the 3-year overall and relapse-free survival were 81.1% (95% Confidence Interval [95%CI], 64.4-90.5%) and 78.4% (95% CI, 61.4-88.5%), respectively. Only two patients relapsed/progressed after transplant. NRM at 2 years was 16.2% (95% CI, 6.5-29.9%). All patients engrafted. Sixteen patients were treated with ruxolitinib post-transplant for treatment of GVHD, graft rejection/relapse and persistent MF. These results suggest that pre-transplant ruxolitinib, fludarabine/busulfan-based conditioning and splenic management are keys to improved transplant outcomes in MF.

Abstract

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor (PI) that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 subjects to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of four doses, beginning days +60 through +90, to recipients of matched sibling donor (MRD, n=25) or unrelated donor (MUD, n=26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n=6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well-tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints and fatigue as the most common adverse events (>10%). In phase II (n=51), the cumulative incidence of cGVHD at 1-year was 36% (95%CI, 19-54) in MRD cohort, and 39% (95%CI, 21-56) in the MUD cohort. One-year cumulative incidence of non-relapse mortality (NRM) and relapse were 0% and 20% (95%CI, 8-36) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0-16) and 34% (17-52). The outcomes on the study were compared post-hoc with contemporaneous matched CIBMTR controls. This post-hoc analysis showed no significant improvement in cGVHD rates in both the MRD (HR 0.85, p=0.64) or MUD cohorts (HR 0.68, p=0.26) on the study compared to CIBMTR controls. B-cell activating factor (BAFF) plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD-free compared to those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation when compared to matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Abstract

Reduced-intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo-HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)-matched sibling or unrelated donor allo-HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0.01. There were no significant differences between regimens in risk for non-relapse mortality (NRM) (P = 0.54), relapse/progression (P = 0.02) or progression-free survival (PFS) (P = 0.14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo-HCT (HR = 0.28; 95% CI = 0.10-0.73; P = 0.009), but beyond 11 months post allo-HCT it was associated with a significantly higher risk of mortality, (HR = 2.46; 95% CI = 0.1.32-4.61; P = 0.005). Four-year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0.64), respectively. These data confirm the choice of RIC for allo-HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo-HCT (possibly due to late NRM events).

Abstract

For relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL) consolidation with autologous hematopoietic cell transplantation (auto-HCT) is a standard option. Since the approval of anti-CD19 CAR T-cells in 2017, the Center for International Blood and Marrow Transplant Research (CIBMTR) reported a 45% decrease in the number of auto-HCT for DLBCL in the U.S. in 2018. Using the CIBMTR database, we report outcomes for auto-HCT in relapsed chemosensitive DLBCL in a partial response (PR). 249 relapsed DLBCL patients undergoing auto-HCT from 2003-13 with a PET/CT+ PR prior to transplant were identified. The study cohort was divided into two groups: (a) early chemo-immunotherapy failure (ECF) defined as patients with primary refractory disease (PRefD) or relapse within 12 months of diagnosis, (b) late chemoimmunotherapy failure defined as patients relapsing ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. 182 patients had ECF and 67 were no ECF. ECF patients were younger (57 versus (vs) 63 years, p<0.01) and 79% of had PRefD. The adjusted 5-year probabilities for PFS and OS (ECF vs no ECF) was not different: 41% vs 41% (p=0.93) and 51% vs 63% (p=0.09), respectively. On multivariate analysis, ECF patients had increased risk of death (HR=1.61, 95%CI 1.05-2.46, p=0.03) but no increased risk in PFS or relapse. In conclusion, for relapsed, chemosensitive DLBCL patients with residual PET/CT+ disease prior to auto-HCT, the adjusted 5-year PFS (41%) was comparable irrespective of time to relapse. These data support ongoing application of auto-HCT in chemosensitive DLBCL.

Abstract

Patients with classic Hodgkin lymphoma (cHL) who relapse after autologous hematopoietic cell transplantation (auto-HCT) historically have had poor outcomes. We hypothesized that, post-auto-HCT relapse, overall survival (PR-OS) has improved in recent years as a result of more widespread use of novel therapies and allogeneic HCT (allo-HCT). We conducted a retrospective study in 4 US academic centers, evaluating 215 patients who underwent auto-HCT from 2005 to 2016 and relapsed thereafter. Patients were divided into 2 cohorts based on timing of auto-HCT, 2005 through 2010 (cohort 1; n = 118) and 2011 to 2016 (cohort 2; n = 97), to compare differences in clinical outcomes. The median age and disease status at auto-HCT were similar in cohorts 1 and 2. The proportions of patients who received brentuximab vedotin (Bv; 55% vs 69%; P = .07), checkpoint inhibitors (CPIs; 3% vs 36%; P ≤ .001), and allogeneic-HCT (22% vs 35%, P = .03) were significantly different between cohorts 1 and 2, respectively. At the 5-year follow-up after auto relapse, 32% and 50% of patients were alive in cohorts 1 and 2, respectively (P = .01). In multivariate analysis for PR-OS, cohort 1 vs 2 (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.14-4.60; P = .01), age at auto-HCT (HR, 1.48; 95% CI, 1.18-1.87; P ≤ .001), and time to relapse from auto-HCT (HR, 0.59; 95% CI, 0.47-74; P ≤ .0001), retained independent prognostic significance for PR-OS. Our study supports the hypothesis that survival of cHL patients after auto-HCT failure has significantly improved in recent years, most likely because of incorporation of novel therapies and more widespread use of allo-HCT.

Abstract

BACKGROUND Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL. METHODS Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). RESULTS The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. CONCLUSION In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.

Abstract

BACKGROUND Reduced-intensity conditioning (RIC) regimens are frequently used for allogeneic hematopoietic cell transplantation (allo-HCT) in diffuse large B-cell lymphoma (DLBCL). However, the RIC regimen with the best risk/benefit profile for allo-HCT in DLBCL is not known. This is particularly important, as patients with DLBCL undergoing allo-HCT in the future would be enriched for those whose lymphoma has failed chimeric antigen receptor T-cell (CAR-T) therapy or other novel immunotherapies, with potentially more advanced disease and suboptimal performance scores. Using the CIBMTR database, we report the outcomes of the three most commonly used allo-HCT RIC regimens in DLBCL. METHODS 562 adult DLBCL patients in the CIBMTR registry undergoing allo-HCT using matched related or unrelated donors, between 2008-2016 were included in the analysis. Patients received one of the three RIC regimens: fludarabine/i.v. busulfan (~6•4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m(2)) (Flu/Mel140) or BCNU/etoposide/cytarabine/melphalan (BEAM). FINDINGS The study cohort was divided into three groups: Flu/Bu (n=151), Flu/Mel140 (n=296) and BEAM (n=115). Relative to Flu/Bu, the Flu/Mel140 (HR=2.33, 95%CI=1.42-3.82; p=0.001) and BEAM (HR=2.54, 95%CI=1.34-4.80; p=0.004) regimens were associated with a higher non-relapse mortality (NRM) risk. Although the risk of relapse with Flu/Mel140 was lower compared to Flu/Bu (HR=0.70, 95%CI=0.52-0.95; p=0.02), this did not translate in an improvement in progression-free (HR=1.04) or overall survival (HR=1.30). There was a significantly higher risk of grade 3-4 acute graft-versus-host disease with BEAM (HR=2.19, 95%CI=1.10-4.35; p=0.03) compared to Flu/Bu. In the chemosensitive subset, multivariate analysis showed a significantly higher mortality risk with Flu/Mel140 (HR=1.48, 95%CI=1.07-2.04, p=0.02) relative to Flu/Bu conditioning. CONCLUSIONS In the largest analysis comparing the impact of various RIC conditioning regimens on the survival of DLBCL patients undergoing allo-HCT, our results suggest that Flu/Bu is a better RIC choice in less fit or heavily pretreated patients due to lowest NRM risk.

Abstract

Importance: Hematopoietic cell transplantation (HCT) is a therapeutic strategy in the management of several hematological cancers. Limited data exist on the incidence and predictors of 30-day readmission after HCT. Objective: To measure the incidence of and risk factors associated with 30-day readmission following HCT in the United States. Design, Setting, and Participants: This cohort study examined patient data from the US population-based Nationwide Readmissions Database. All adults (age ≥18 years) who underwent autologous (auto-) or allogenic (allo-) HCT in US hospitals between January 1, 2012, and November 30, 2014, were included. The analysis was performed from June 2018 to February 2019. Main Outcomes and Measures: The main outcome was 30-day readmission rates for auto-HCT and allo-HCT. Factors associated with readmission, including baseline demographic characteristics and disease- and hospital-related characteristics (including annual case volume), were measured. Results: A total of 28356 index admissions for auto-HCT in 244 centers (191 low-volume, 38 medium-volume, and 15 high-volume centers) and 17217 index admissions for allo-HCT in 211 centers (161 low-volume, 37 medium-volume, and 13 high-volume centers) were identified during the study period. The overall 30-day readmission rates were 11.6% for auto-HCT and 24.4% for allo-HCT. The odds of readmission were significantly higher in low-volume hospitals compared with high-volume hospitals (adjusted odds ratio [aOR], 1.69; 95% CI, 1.08-2.64 for auto-HCT and aOR, 1.41; 95% CI, 1.09-1.82 for allo-HCT) but comparable to medium-volume hospitals (aOR, 1.06; 95% CI, 0.62-1.83 for auto-HCT and aOR, 1.19; 95% CI, 0.90-1.57 for allo-HCT). Other factors associated with readmission for auto-HCT included younger age (aOR for age ≥50 vs <49 years, 0.82; 95% CI, 0.68-0.98), female sex (aOR, 1.21; 95% CI, 1.06-1.36), disease type (aOR for other vs myeloma, 1.37; 95% CI, 1.06-1.77), and Elixhauser comorbidity index score (aOR for ≥20 vs 0, 1.5; 95% CI, 1.17-1.93). For allo-HCT, factors associated with readmission included disease type (aOR for acute lymphoblastic leukemia vs acute myelogenous leukemia, 1.30; 95% CI, 1.04-1.62), insurance (aOR for Medicare vs private, 1.18; 95% CI, 1.02-1.36), and Elixhauser comorbidity index score (aOR for 1-9 vs 0, 1.2; 95% CI, 1.04-1.39). Infections, neutropenic fever, and gastrointestinal symptoms were the most common reasons for readmission for both types of HCT. Conclusions and Relevance: This study found substantial rates of readmission for both types of HCT and an inverse association between hospital HCT volume and 30-day readmission. These results may provide guidance when developing quality indicators and policies penalizing hospitals for HCT readmission.

Abstract

Engraftment syndrome (ES), a complication of autologous hematopoietic cell transplantation (auto-HCT), can occur around the time of neutrophil recovery. We sought to identify the incidence of ES in light chain (AL) amyloidosis patients undergoing auto-HCT at our centre by evaluating 72 consecutive amyloidosis patients transplanted between 1999 and 2017. To assess trends in ES over time, patients were divided into two Eras (Era 1 = 1999-2008 and Era 2 = 2009-2017) based on year of auto-HCT. Twenty-two (31%) patients developed ES; three (16%) and 19 (36%) in Era 1 and 2, respectively (p = .1). Three (16%) and 51 (96%) patients in Era 1 and 2 received chemotherapy before auto-HCT (p = <.001). The most common symptoms observed with ES in addition to fever was diarrhoea (73%), rash (68%), weight gain (56%) and non-cardiogenic pulmonary oedema (23%). Day 100 post-auto-HCT haematological response (19.5% vs. 14%, p = .7) or post-transplant best organ response (23% vs. 36%, p = .2) were not significantly different in patients who did not or did develop ES, respectively. In this single centre series, we define the incidence and characteristics of ES in AL amyloidosis patients undergoing auto-HCT.