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Outcomes for patients with myeloid blast phase chronic myeloid leukemia (CML-MBP) are dismal, and no preferred chemotherapy regimen has been identified. Recent studies have suggested a higher response rate with administration of timed-sequenced regimens (TSR) (purine analog, high-dose cytarabine, anthracycline) in high-risk acute myeloid leukemia patients. We retrospectively evaluated outcomes of newly diagnosed CML-MBP patients consecutively treated at our institution with a TSR or standard-dose cytarabine and an anthracycline ("7 + 3") combined with a tyrosine-kinase inhibitor (TKI) between 2011 and 2023. Endpoints of interest included hematologic response, clinically significant cytogenetic response (CSCR) defined as achieving at least a minor cytogenetic response (Ph + metaphases 0%-≤65%) after induction therapy, event-free survival (EFS), and overall survival (OS). A total of 18 patients with CML-MBP were included of whom 9 (50%) received a TSR and 9 (50%) received "7 + 3". Hematologic response (55.6% vs. 55.6%) and CSCR (25% vs. 37.5%) were similar between TSR- and "7 + 3" treated patients. Twelve patients (66.7%) experienced at least one grade ≥ 3 non-hematologic, end-organ toxicity with 33.3% and 11.1% of TSR- and 7 + 3-treated patients, respectively, experiencing at least two. Our data suggests that intensification of upfront chemotherapy does not appear to improve treatment outcomes in CML-MBP patients however, further studies are warranted to confirm these findings involving a larger cohort.

INTRODUCTION: Blastoid variant-mantle cell lymphoma (BV-MCL) represents an aggressive subset of patients with no established standard of care treatment approach. METHODS: We performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV-MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Brutons Tyrosine-kinase (BTKi)-based therapies for upfront management. RESULTS: The complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two-year overall survival (OS) was low at 62.5% (95% CI, 34.7%-81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53-wild type (p = 0.031), intermediate- versus high-risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027). DISCUSSION: Treatment outcomes with chemo-immunotherapy in BV-MCL patients are poor, especially among TP53-mutated patients. Recent findings describing positive outcomes with novel BTKi-based therapies are encouraging and should be considered in this high-risk population.

There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

The introduction of posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy-based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

The role of eculizumab in treating Shiga-toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) patients with neurological involvement remains unclear. We describe two distinctly different STEC-HUS patients with neurologic involvement successfully managed with eculizumab, and perform a literature review of all published cases. Both patients had complete resolution of neurological symptoms after initiation of eculizumab. Eighty patients with STEC-HUS treated with eculizumab were identified in the literature, 68.7% had complete resolution of neurological symptoms. Based on our experience and literature review, three prevailing themes were noted: 1) Early eculizumab administration optimized neurological outcomes, 2) Symptom resolution may not be immediate, neurological symptoms may initially worsen before improvement, and 3) Plasma exchange yielded no benefit. Early administration of eculizumab may reverse neurotoxicity in patients with STEC-HUS.

Effective cellular therapy using CD19 chimeric antigen receptor T-cells for the treatment of advanced B-cell malignancies raises the question of whether the administration of adoptive cellular therapy (ACT) posttransplant could reduce relapse and improve survival. Moreover, several early phase clinical studies have shown the potential beneficial effects of administration of tumor-associated antigen-specific T-cells and natural killer cells posttransplant for high-risk patients, aiming to decrease relapse and possibly improve survival. In this article, we present an in-depth review of ACT after transplantation, which has the potential to significantly improve the efficacy of this procedure and revolutionize this field.

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR] = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) during, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.

Pretransplant conditioning with Fludarabine (Flu)-Busulfan (Bu) is safe, but clofarabine (Clo) has improved antileukemic activity. Hypothesis: Flu+Clo-Bu (FCB) yields superior progression-free survival (PFS) after allogeneic transplantation. We randomized 250 AML/MDS patients aged 3-70, Karnofsky Score ≥80, with matched donors, to FCB (n = 120) or Flu-Bu (n = 130), stratifying complete remission (CR) vs. No CR, (NCR). HCT-CI scores varied, from 0 to 10. All evaluable patients engrafted. Median follow-up was 66 months (interquartile range: 58-80). Three-year relapse incidence (RI), 25% with FCB, vs. 39% with Flu-Bu (p = 0.018), offset by higher non-relapse mortality, 22.6% (95%CI: 16-30.2%) vs. 12.3% (95%CI: 6.5-19%). Three-year PFS was 52% (95%CI: 44-62%) (FCB), vs. 48% (95%CI: 41-58%) (Flu-Bu). FCB benefited CR patients less, NCR patients age ≤ 60 had 3-year 34% RI (95%CI: 19-49%) (FCB) vs. 56% (95%CI: 38-70%) after Flu-Bu (p = 0.037). NCR patients >60 years had 3-year RI 10.0% (FCB), vs. 56.0%, after Flu-Bu (p = 0.003). Bayesian regression analysis including treatment-covariate interactions showed FCB superiority in NCR patients with low HCT-CI (0-2). Serious adverse event profiles were similar for the regimens. Conditioning with FCB did not improve PFS overall, but improved disease control in NCR patients, mandating confirmatory trials. Remission status and HCT-CI should be considered when using FCB.

Multiple myeloma (MM) is a plasma cell malignancy that affects an increasing number of patients worldwide. Despite all the efforts to understand its pathogenesis and develop new treatment modalities, MM remains an incurable disease. Novel immunotherapies, such as CAR T cell therapy (CAR) and bispecific T cell engagers (BiTE), are intensively targeting different surface antigens, such as BMCA, SLAMF7 (CS1), GPRC5D, FCRH5 or CD38. However, stem cell transplantation is still indispensable in transplant-eligible patients. Studies suggest that the early use of immunotherapy may improve outcomes significantly. In this review, we summarize the currently available clinical literature on CAR and BiTE in MM. Furthermore, we will compare these two T cell-based immunotherapies and discuss potential therapeutic approaches to promote development of new clinical trials, using T cell-based immunotherapies, even as bridging therapies to a transplant.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.

The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) performed has increased substantially in recent years. Previous single-center studies using in silico algorithms to quantitively measure HLA disparity have shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT. In this study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLAMatchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients. We analyzed data from 1287 patients who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myelogenous leukemia, or myelodysplastic syndrome between 2013 and 2017, as entered in the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total class I and II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets. In the study cohort, ME scores derived from total HLA class I or class II loci or individual HLA loci were not associated with overall survival, disease-free survival, nonrelapse mortality, relapse, acute GVHD, or chronic GVHD (P < .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.75 to 0.91; P < .0001) and platelet engraftment (HR, 0.80; 95% CI, 0.72 to 0.88; P < .0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR, 0.82; 95% CI, 0.73 to 0.92; P = .001) and slower platelet engraftment (HR, 0.76; 95% CI, 0.70 to 0.84; P < .0001). Additional analyses suggested that this effect is attributable to a match versus a mismatch in the graft-versus-host direction and not to ME load, as a dose effect was not identified. These findings contradict those of previous relatively small studies reporting an association between ME load, as quantified by HLAMatchmaker, and haplo-HSCT outcomes. This study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, and other molecular mismatch algorithms in haplo-HSCT settings should be tested.

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR score (CF-iKIR) was associated with improved progression-free survival (adjusted hazard ratio [HR], 0.71; P = .029) and overall survival (OS) (HR, 0.66; P = .016), while none of the other models predicted for survival in these patients. Moreover, using exploratory classification and regression tree analysis, we found that donor age 58 years was associated with the worst OS. In the rest of our cohort (80%), cytomegalovirus-reactive recipients with a donor

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. Alloreactivity after HSCT is known to be mediated by adaptive immune cells expressing rearranging receptors. Recent studies demonstrated that the innate immune system could likewise sense the non-self signals and subsequently enhance the alloimmune response. We recently demonstrated that the donor/recipient mismatch of signal regulatory protein α (SIRPα), an immunoglobulin receptor exclusively expressed on innate cells, is associated with a higher risk of cGVHD and relapse protection in a cohort of acute myeloid leukemia patients who underwent allo-HSCT. Whether these effects also occur in other hematologic malignancies remains unclear. In the present study, we compared outcomes by SIRPα match status in a cohort of 310 patients who received allo-HSCT from an HLA matched-related donor for the treatment of lymphoid malignancies. Multivariable analysis showed that SIRPα mismatch was associated with a significantly higher rate of cGVHD (hazard ratio [HR] 1.8, P= .002), cGVHD requiring systemic immunosuppressive therapy (HR 1.9, P= .005), a lower rate of disease progression (HR 0.5, P= .003) and improved progression-free survival (HR 0.5, P= .001). Notably, the effects of SIRPα mismatch were observed only in the patients who achieved >95% of donor T-cell chimerism. The mismatch in SIRPα is associated with favorable relapse protection and concurrently increased risk of cGVHD in patients who undergo allo-HSCT for lymphoid malignancies, and the optimal donor could be selected based on the finding of the study to mitigate the risk of GVHD and relapse.

In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105-1 × 108 cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).

In the coronavirus disease 19 (COVID-19) pandemic era, the number of haploidentical hematopoietic cell transplantations (HCTs) with peripheral blood (PB) grafts increased significantly compared with HCTs with bone marrow (BM) grafts, which may be associated with adverse outcomes. We compared outcomes of HCT in BM graft and PB graft recipients age ≥18 years with hematologic malignancies who underwent T cell- replete haploidentical HCT and received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Among the 264 patients, 180 (68%) received a BM graft and 84 (32%) received a PB graft. The median patient age was 50 years in both groups. The majority (n = 199; 75%) received reduced-intensity conditioning. The rate of acute leukemia or myelodysplastic syndrome was higher in the BM graft recipients compared with the PB graft recipients (85% [n = 152] versus 55% [n = 46]; P < .01). The median times to neutrophil and platelet engraftment and the incidence of grade II-IV and grade III-IV acute GVHD (aGVHD) were comparable in the 2 groups. Among the patients with grade II-IV aGVHD, the rate of steroid-refractory aGVHD was 9% (95% confidence interval [CI], 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) in the PB group (hazard ratio [HR], 3.7, 95% CI, 1.5 to 9.3; P = .006). At 1 year post-HCT, the rate of chronic GVHD (cGVHD) was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) in the PB group (HR, 3.0; 95% CI, 1.4-6.6; P = .005), and the rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively (HR, 5.6; 95% CI, 1.7 to 18; P = .004). The PB group had a significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, nonrelapse mortality, or survival. Our data suggest a benefit of the use of BM grafts over PB grafts for haplo-HCT.

Donor-specific anti-HLA antibodies (DSAs) 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 (PE), rituximab, intravenous γ globulin (IVIg) and an irradiated donor buffy coat for patients with DSAs at 2 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 DSAs (n = 345). The majority of patients in the DSA group were female (83.8% vs 37.1% in controls, P < .001) and received stem cells from a child as the donor (67.6% vs 44.1%, P = .002). 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. In conclusion, treatment with PE, rituximab, IVIg, and donor buffy coat is effective in promoting engraftment in patients with DSAs ≤20 000 MFI.

Recent compelling evidence showed that innate immune effector cells could recognize allogeneic grafts and prime an adaptive immune response. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on myeloid cells; the interaction between SIRPα and its ubiquitously expressed ligand CD47 elicits an inhibitory signal that suppresses macrophage phagocytic function. Additional studies showed that donor-recipient mismatch in SIRPα variants might activate monocytic allorecognition, possibly as the result of non-self SIRPα-CD47 interaction. However, the frequency of SIRPα variation and its role in hematopoietic stem cell transplantation (HSCT) remains unexplored. We studied 350 patients with acute myeloid leukemia/myelodysplastic syndrome who underwent HLA-matched related HSCT and found that SIRPα allelic mismatches were present in 39% of transplantation pairs. SIRPα variant mismatch was associated with a significantly higher rate of chronic graft-versus-host disease (GVHD; hazard ratio [HR], 1.5; P = .03), especially de novo chronic GVHD (HR, 2.0; P = .01), after adjusting for other predictors. Those with mismatched SIRPα had a lower relapse rate (HR, 0.6; P = .05) and significantly longer relapse-free survival (RFS; HR, 0.6; P = .04). Notably, the effect of SIRPα variant mismatch on relapse protection was most pronounced early after HSCT and in patients who were not in remission at HSCT (cumulative incidence, 73% vs 54%; HR, 0.5; P = .01). These findings show that SIRPα variant mismatch is associated with HSCT outcomes, possibly owing to innate allorecognition. SIRPα variant matching could provide valuable information for donor selection and risk stratification in HSCT.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

BackgroundThe association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.MethodsThis study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.ResultsThe median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.ConclusionsPatients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.

Compared with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the Disease Risk Index (DRI) in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/intermediate-risk DRI cohort, RIC was associated with lower nonrelapse mortality (NRM) (hazard ratio [HR], .74; 95% confidence interval [CI], .62 to .88; P < .001) but significantly greater relapse risk (HR, 1.54; 95% CI, 1.35 to 1.76; P < .001) and thus inferior disease-free survival (DFS) (HR, 1.19; 95% CI, 1.07 to 1.33; P = .001). In the high/very high-risk DRI cohort, RIC was associated with marginally lower NRM (HR, .83; 95% CI, .68 to 1.00; P = .051) and significantly higher relapse risk (HR, 1.23; 95% CI, 1.08 to 1.41; P = .002), leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for patients with AML/MDS with low/intermediate-risk DRI, but with a similar benefit as RIC in high/very high-risk DRI. Novel MAC regimens with less toxicity could benefit all patients, but more potent antineoplastic approaches are needed for the high/very-high risk DRI group.

BACKGROUND: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. METHODS: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. RESULTS: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). CONCLUSIONS: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.

Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor-β (TGF-β) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF-β signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF-derived fibroblast cell lines and transforming growth factor-β receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2.

Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.

We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.

The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). Amplification of CKS1B is frequently associated with the deletion of the CDKN2C gene at chromosome region 1p32 (1p-), which is also associated with inferior outcomes. In this retrospective study, we evaluated the outcomes of patients with 1q+ and/or 1p- after high-dose therapy and autologous hematopoietic cell transplantation (auto-HCT). From January 2006 to December 2015, 1491 newly diagnosed patients with MM underwent upfront high-dose therapy and auto-HCT at our institution. Of those, 899 had the fluorescent in situ hybridization (FISH) data available. FISH was performed at diagnosis and before the start of induction in 686 (76%) patients and after the initiation of induction therapy in 213 (24%) patients. We identified 100 patients with 1q+ and/or 1p- by FISH from the cohort of 899 patients. A control group (n = 287) with diploid cytogenetics and normal FISH panel was selected from the same cohort. From the above 2 cohorts, using a propensity score matched analysis, we identified matched controls for 85 of the 100 patients with 1q+/1p-. Patients were matched for age at auto-HCT, sex, International Staging System stage, induction regimen, creatinine level, disease status at auto-HCT, conditioning regimen, and maintenance therapy. Sixty-seven (79%), 4 (5%), and 14 (16%) patients had 1q+, 1p-, or both 1q+ and 1p-, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the 1q+/1p- and the control group. The median follow-up time for all patients was 29.2 months (range, 0.29 to 84.96). The cumulative incidence of 100-day nonrelapse mortality was 1.2% and 0% for the 1q+/1p- and the control group, respectively. Forty-two patients (50%) in the 1q+/1p- group achieved complete response compared with 40 patients (47%) in the control group. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 41% and 79% for the 1q+/1p- group and 56% and 86% for the control group. Patients in the 1q+/1p- group were at significantly increased risk of progression or death compared to the control group (hazard ratio [HR], 2.21; confidence interval [CI], 1.18 to 4.16; P = .014). No significant association between OS in the 2 groups was observed. The outcome of the 1q+/1p- alone (with no additional high-risk cytogenetics) and the propensity score matched control groups was also compared. Median PFS for the 1q+/1p- alone subgroup was 26.6 months, compared with 38.8 months for the control group (HR, 1.9; CI, 0.9 to 4.08; P = .09). The median OS had not been reached for the 1q+/1p- alone subgroup and was 81.1 months for the control group (HR, 1.25; CI, 0.3 to 4.6; P= .73). 1q+/1p- abnormalities with amplification of CKS1B and deletion ofCDKN2Cgenes were associated with shorter PFS compared with a propensity score matched group of patients with diploid cytogenetics and normal a FISH panel. The outcomes of 1q+/1p- patients with MM have improved with the use of more effective induction, conditioning, and maintenance therapy compared with historical controls, but we still need more effective therapeutic approaches to fully overcome the negative impact of 1q+/1p-.

Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.

[This corrects the article DOI: 10.18632/oncotarget.16602.].

BackgroundPatients with spondyloarthritis with radiographic sacroiliitis are traditionally classified according to the modified New York (mNY) criteria as ankylosing spondylitis (AS) and more recently according to the Assessment of SpondyloArthritis international Society (ASAS) criteria as radiographic axial spondyloarthritis (r-axSpA).ObjectiveTo investigate the agreement between the mNY criteria for AS and the ASAS criteria for r-axSpA and reasons for disagreement.MethodsPatients with back pain ≥3 months diagnosed as axSpA with radiographic sacroiliitis (mNY radiographic criterion) were selected from eight cohorts (ASAS, Esperanza, GESPIC, OASIS, Reuma.pt, SCQM, SPACE, UCSF). Subsequently, we calculated the percentage of patients who fulfilled the ASAS r-axSpA criteria within the group of patients who fulfilled the mNY criteria and vice versa in six cohorts with complete information.ResultsOf the 3882 patients fulfilling the mNY criteria, 93% also fulfilled the ASAS r-axSpA criteria. Inversely, of the 3434 patients fulfilling the ASAS r-axSpA criteria, 96% also fulfilled the mNY criteria. The main cause for discrepancy between the two criteria sets was the reported age at onset of back pain.ConclusionAlmost all patients with axSpA with radiographic sacroiliitis fulfil both ASAS and mNY criteria, which supports the interchangeable use of the terms AS and r-axSpA.

In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell-replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; P = .007) and relapse was higher (HR, 1.51; 44% vs 33%; P = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; P = .83) and relapse (HR, 1.32; 42% vs 31%; P = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; P = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.

Although bortezomib and rituximab have synergistic activity in patients with lymphoma and both can attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem cell transplantation (alloSCT). In this phase I/II trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 to 1.3 mg/m2 per dose) was administered i.v. on days -13, -6, -1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results with an historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and matched unrelated donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m2. The weighted cumulative incidences of grades II to IV and III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival was not reached in patients age ≤ 50 years and with a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤ 50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.