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We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.

Reduced-intensity conditioning (RIC) regimens developed to extend allogeneic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the two most commonly used RIC regimens, intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in myelodysplastic syndrome (MDS). Through CIBMTR, we identified 1045 MDS patients aged ≥ 60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using RIC. CIBMTR’s definition of RIC was used: a regimen that incorporated an intravenous busulfan total dose ≤ 7.2 mg/kg, or a low-dose melphalan total dose of ≤ 150 mg/m(2). The two groups, FluBu (n=697) and FluMel (n=448), were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44% (p≤0.0001). Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%, p≤0.0001). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, p=0.02, and 35% vs. 27% at 3 years, p=0.01). Overall survival (OS) was comparable at 1 year (63% vs. 61%, p=0.4) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%, p=0.03). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (P=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (P=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

Total body irradiation (TBI) has been included in standard conditioning for acute lymphoblastic leukemia (ALL) before hematopoietic cell transplantation (HCT). Non-TBI regimens have incorporated busulfan (Bu) to decrease toxicity. This retrospective study analyzed TBI and Bu on outcomes of ALL patients 18–60 years old, in first or second complete remission (CR), undergoing HLA-compatible sibling, related, or unrelated donor HCT, who reported to the Center for International Blood and Marrow Transplant Research from 2005 to 2014. TBI plus etoposide (25%) or cyclophosphamide (75%) was used in 819 patients, and intravenous Bu plus fludarabine (41%), clofarabine (30%), cyclophosphamide (15%), or melphalan (13%) was used in 299 patients. Bu-containing regimens were analyzed together, since no significant differences for patient outcomes were noted between them. Bu patients were older, with better performance status; took longer to achieve first CR and receive HCT; were treated more recently; and were more likely to receive peripheral blood grafts, antithymocyte globulin, or tyrosine kinase inhibitors. With median follow-up of 3.6 years for Bu and 5.3 years for TBI, adjusted 3-year outcomes showed treatment-related mortality Bu 19% versus TBI 25% (P =.04); relapse Bu 37% versus TBI 28% (P =.007); disease-free survival (DFS) Bu 45% versus TBI 48% (P =.35); and overall survival (OS) Bu 57% versus TBI 53% (P =.35). In multivariate analysis, Bu patients had higher risk of relapse (relative risk, 1.46; 95% confidence interval, 1.15 to 1.85; P =.002) compared with TBI patients. Despite the higher relapse, Bu-containing conditioning led to similar OS and DFS following HCT for ALL.

We compared postrelapse overall survival (OS) after autologous/allogeneic (auto/allo) versus tandem autologous (auto/auto) hematopoietic cell transplantation (HCT) in patients with multiple myeloma (MM). Postrelapse survival of patients receiving an auto/auto or auto/allo HCT for MM and prospectively reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2010 were analyzed. Relapse occurred in 404 patients (72.4%) in the auto/auto group and in 178 patients (67.4%) in the auto/allo group after a median follow-up of 8.5 years. Relapse occurred before 6 months after a second HCT in 46% of the auto/allo patients, compared with 26% of the auto/auto patients. The 6-year postrelapse survival was better in the auto/allo group compared with the auto/auto group (44% versus 35%; P = .05). Mortality due to MM was 69% (n = 101) in the auto/allo group and 83% (n = 229) deaths in auto/auto group. In multivariate analysis, both cohorts had a similar risk of death in the first year after relapse (hazard ratio [HR], .72; P = .12); however, for time points beyond 12 months after relapse, overall survival was superior in the auto/allo cohort (HR for death in auto/auto =1.55; P = .005). Other factors associated with superior survival were enrollment in a clinical trial for HCT, male sex, and use of novel agents at induction before HCT. Our findings shown superior survival afterrelapse in auto/allo HCT recipients compared with auto/auto HCT recipients. This likely reflects a better response to salvage therapy, such as immunomodulatory drugs, potentiated by a donor-derived immunologic milieu. Further augmentation of the post-allo-HCT immune system with new immunotherapies, such as monoclonal antibodies, checkpoint inhibitors, and others, merit investigation.

Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor-recipient histoincompatibility can augment the graft-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA matching. Here, we used our recently refined HLA-matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new matching criteria identifies substantially more frequent mismatching than older, less precise "6 of 6 antigen-matched" URD-HCT. Under the new criteria, only 37% of those previously deemed "HLA- matched" were HLA well matched, and 44% were partially matched. Using our refined matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD-recipient pairs compared with either sibling or well-matched URD-recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-matching scheme in analyzing retrospective data sets when fully informative, allele-level typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD, but does not improve protection against relapse; thus the best donor remains the most closely matched donor.

To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS).