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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.

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) have a poor prognosis. An earlier CIBMTR analysis of allogeneic hematopoietic cell therapy (allo-HCT) (n=868, 1990-2004) showed 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%. Modern supportive care, graft versus host disease (GVHD) prophylaxis and reduced intensity conditioning (RIC) regimens have improved outcomes. Therefore, the Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed 1531 allo-HCT for adults with t-MDS (n = 759) or t-AML (n = 772) performed from 2000 to 2014. Median age was 59 years (18-74) for t-MDS and 52 years (18-77) for t-AML. 24% of patient with t-MDS and 11% of patients with t-AML and had a prior autologous transplant. A myeloablative regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Non-relapse mortality (NRM) at five years was 34% (95% confidence interval (CI) 30-37) and 34% (30-37) for t-MDS and t-AML, respectively. Relapse rates at five years were 46% (43-50) and 43% (40-47), respectively. 5-year OS and DFS was 27% (23-31) and 19% (16-23) for patients with t-MDS and 25% (22-28) and 23% (20-26) for patients with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low risk t-MDS and those receiving MAC HCT during first complete remission (CR1) t-AML, but worse for those with prior autologous HCT, higher risk cytogenetics or IPSS-R score and partially matched unrelated donors (URD). Relapse remains the major cause of treatment failure with little improvement over the past two decades. These data indicate caution in recommending allo-HCT in these conditions and more effective anti-neoplastic approaches before and after allo-HCT. BACKGROUND Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) have a poor prognosis. An earlier CIBMTR analysis of allogeneic hematopoietic cell therapy (allo-HCT) (n=868, 1990-2004) showed 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%. Modern supportive care, graft versus host disease (GVHD) prophylaxis and reduced intensity conditioning (RIC) regimens have improved outcomes. OBJECTIVES The primary objectives are OS and DFS. The secondary objectives are non-relapse mortality (NRM), relapse, GVHD rates and identifying prognostic factors for outcomes after allo-HCT. STUDY DESIGN The Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed 1531 allo-HCT for adults with t-MDS (n = 759) or t-AML (n = 772) performed from 2000 to 2014. Cumulative incidence function was used to estimate relapse, NRM, acute and chronic GVHD. Kaplan-Meier estimate was used to calculate probabilities of OS and DFS. Cox proportional hazards regression model was used to estimate hazard ratio (HR) of patient / disease / transplant related factors for outcomes of interest. RESULTS The median age was 59 years (18-74) for t-MDS and 52 years (18-77) for t-AML. 24% of patient with t-MDS and 11% of patients with t-AML and had a prior autologous transplant. A myeloablative regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Non-relapse mortality (NRM) at five years was 34% (95% confidence interval (CI) 30-37) and 34% (30-37) for t-MDS and t-AML, respectively. Relapse rates at five years were 46% (43-50) and 43% (40-47), respectively. 5-year OS and DFS was 27% (23-31) and 19% (16-23) for patients with t-MDS and 25% (22-28) and 23% (20-26) for patients with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low risk t-MDS and those receiving MAC HCT during first complete remission (CR1) t-AML, but worse for those with prior autologous HCT, higher risk cytogenetics or IPSS-R score and partially matched unrelated donors (URD). CONCLUSIONS Relapse remains the major cause of treatment failure with little improvement over the past two decades. These data indicate caution in recommending allo-HCT in these conditions. Through better patient optimization, more effective conditioning and studies of post-HCT interventions, outcomes for patients with t-MDS and t-AML may improve.

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.

BACKGROUND Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next‐generation hypomethylating agent, could be useful in treating such patients. METHODS In this multicenter, open‐label, phase 2 dose‐expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28‐day cycle (5‐day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10‐day regimen). RESULTS Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2/d, respectively [5‐day regimen] and 53 patients who were assigned to 60 mg/m2/d [10‐day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10‐day regimen versus the 5‐day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10‐day regimen. Early all‐cause mortality was low and similar between regimens. Twenty patients (8 on the 5‐day regimen and 12 on the 10‐day regimen) were bridged to hematopoietic cell transplantation. CONCLUSIONS Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325‐34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Outcomes for patients with relapsed or refractory acute myeloid leukemia are poor. Guadecitabine, a next‐generation hypomethylating agent, has promising clinical activity and an acceptable safety profile and warrants further development in this population. See also pages 242‐4.

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.

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.

To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post-transplantation.

Despite the advent of targeted therapies and novel agents, allogeneic hematopoietic stem cell transplantation remains the only curative modality in the management of hematologic disorders. The necessity to find an HLA-matched related donor is a major obstacle that compromises the widespread application and development of this field. Matched unrelated donors and umbilical cord blood have emerged as alternative sources of donor stem cells; however, the cost of maintaining donor registries and cord blood banks is very high and even impractical in developing countries. Almost every patient has an HLA haploidentical relative in the family, meaning that haploidentical donors are potential sources of stem cells, especially in situations where cord blood or matched unrelated donors are not easily available. Due to the high rates of graft failure and graft-versus-host disease, haploidentical transplant was not considered a feasible option up until the late 20th century, when strategies such as “megadose stem cell infusions” and posttransplantation immunosuppression with cyclophosphamide showed the ability to overcome the HLA disparity barrier and significantly improve the rates of engraftment and reduce the incidence and severity of graft-versus-host disease. Newer technologies of graft manipulation have also yielded the same effects in addition to preserving the antileukemic cells in the donor graft.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.

PTK787/ZK222584 (Vatalanib), an orally active inhibitor of vascular endothelial growth factor receptors (VEGF-Rs), was evaluated in this phase II study of 20 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received once daily PTK787/ZK222584 at a target dose of 1250mg. Eighteen patients were evaluable for response: 1 patient had a complete response (CR), 6 patients had stable disease but subsequently progressed, 10 patients had progressive disease by 3 cycles, and 1 subject withdrew before response evaluation. The patient who attained a CR underwent autologous stem cell transplantation and remains disease free 76 months after study completion. There were no grade 4 toxicities. Grade 3 thrombocytopenia occurred in 20% and grade 3 hypertension occurred in 10%. There were no episodes of grade 3 proteinuria. In conclusion, PTK787/ZK222584 was well tolerated in a heavily pretreated population of DLBCL patients, though its therapeutic potential as a single agent in DLBCL appears limited.

Clinical practice guidelines are developed to improve the quality of care and outcomes for patients. Guidelines facilitate clinical decisions, promote efficient use of health care resources, and provide guidance to practitioners. For chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKIs) have changed the paradigm of therapy by lowering the disease burden and by providing more precise monitoring of response. These advances affect treatment guidelines for CML and inform CML clinical trial protocols.Guidelines developed by the National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) synthesize the best available evidence to support decision-making in the management of CML patients. Both guidelines recognize specific milestones for treatment response. At each time point, the ELN guidelines define overall response benchmarks, and the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) provide an algorithm that specifies the timing for evaluations of cytogenetic and molecular parameters during therapy. The NCCN Guidelines also include strategies for providing supportive care and for managing toxicities. Molecular monitoring now plays a greater role in CML management. Molecular response as a milestone is currently recommended by the ELN but has not yet been adopted by the NCCN. As evidence continues to accumulate, the NCCN and ELN Guidelines are likely to evolve to reflect new data and standards of care.

We report the outcome of early donor lymphocyte infusions (DLIs) after T-cell depleted non-myeloablative transplantation using stem cells from HLA-matched or mismatched donors. Sixty-nine patients with high-risk hematologic malignancies received DLI following fludarabine, CY and alemtuzumab with infusion of stem cells from a matched sibling (52) or partially matched family member donor (17). Patients received the first infusion at a median of 50 days after transplant, and doses ranged from 1 x 10(4) CD3+ cells/kg to 3.27 x 10(8) CD3+ cells/kg, depending on clinical status and the physician's discretion. A median cell dose of 1 x 10(5) CD3+ cells/kg in the mismatched setting and 1 x 10(6) CD3+ cells/kg in the matched sibling setting appears safe with only 1 of 7 (14%) and 4 of 31 patients (13%), respectively, experiencing severe acute GVHD at these doses. Importantly, 38% of patients with persistent disease before DLI attained a remission after infusion. Nine of the 69 patients remain alive and disease-free 32-71 months after the first DLI. In conclusion, low doses of DLI can be safely provided soon after T-cell depleted non-myeloablative therapy and provide a chance of remission. However, long-term survival still remains poor, primarily because of relapse in these patients.

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