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Summary: Venetoclax (VEN) is an FDA‐approved selective inhibitor of B‐cell leukaemia/lymphoma‐2 (BCL‐2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high‐risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41‐mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach. [ABSTRACT FROM AUTHOR]

Trabectedin is an FDA-approved DNA minor groove binder that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia-free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. [ABSTRACT FROM AUTHOR]

The optimal antithrombin(AT) activity parameters for replacement as thromboprophylaxis following asparaginase remains unclear. This single-center, retrospective study evaluated two sets of AT replacement thresholds and targets in adults receiving asparaginase-containing chemotherapy. AT supplementation adhered to institutional standards, which lowered the AT activity target from 100% to 80% in 6/2014. Ninety-two patients were evaluated. Cumulative thrombosis incidence was 16% at 6 months (95%CI:6.8–24.0, maximum follow-up 315 days) with similar incidence between the 80% and 100% target groups, 14% (2 of the 14) and 13% (10 of the 78), respectively, with a small non-Line-Related DVT incidence (3%). Most thrombotic events occurred during induction chemotherapy and demonstrated no associations with replacement target, cumulative days or cumulative area under AT activity target, number of asparaginase doses, or cumulative asparaginase dose. Median estimated AT replacement expenditure was $34,963USD (IQR $16,260USD to $79,319USD) per patient. Cost-effectiveness and optimization of AT replacement for thromboprophylaxis following asparaginase requires prospective evaluation. [ABSTRACT FROM AUTHOR]

MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasm) overlap syndromes are myeloid malignancies for which allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative. We describe transplant outcomes of 43 patients – 35 with chronic myelomonocytic leukemia, CMML (of which 17 had blast transformation, BT) and eight with MDS/MPN-unclassifiable (MDS/MPN,U). At median follow-up of 21 months, overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 55%, 29%, and 25% respectively in CMML without BT and 47%, 40%, and 34% respectively in CMML with BT. Higher HSCT-comorbidity index (HSCT-CI >3 versus ≤3;p = 0.015) and splenomegaly (p = 0.006) predicted worse OS in CMML without BT. In CMML with BT, engraftment failure (p = 0.006) and higher HSCT-CI (p = 0.03) were associated with inferior OS, while HSCT within 1-year of diagnosis was associated with improved OS (p = 0.045). In MDS/MPN,U, at median follow-up of 15 months, OS, CIR, and NRM were 62%, 30%, and 14%, respectively. [ABSTRACT FROM AUTHOR]

Momelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in myelofibrosis ( MF). Momelotinib treatment-emergent peripheral neuropathy ( TE- PN) was documented in 44 (44%) of 100 MF patients treated at our institution; median time of TE- PN onset was 32 weeks and duration 11 months. Improvement after drug dose reduction or discontinuation was documented in only two patients. TE- PN was significantly associated with treatment response ( P = 0·02) and longer survival ( P = 0·048) but significance was lost during multivariate analysis that included treatment duration. TE- PN did not correlate with initial or maximum momelotinib dose or previous treatment with JAK inhibitor or thalidomide. [ABSTRACT FROM AUTHOR]

We conducted a phase I/II trial to assess the efficacy of cladribine, thiotepa and antithymocyte globulin as a reduced-intensity conditioning regimen for refractory or high-risk hematologic malignancy. The preparative regimen consisted of cladribine 5 mg/m2/day for 5 days, thiotepa 200 mg/m2/day for 3 days and ATG 3 mg/kg/day (day − 5) followed by allogeneic peripheral blood stem cell transplant. Twelve patients were transplanted from a human leukocyte antigen (HLA) matched family member. Two patients were treated at dose level I but both experienced grade IV dose limiting toxicities, and therefore the thiotepa dose was reduced to 133 mg/m2/day (dose level II). Only two of the next six patients experienced dose limiting toxicities. Median age was 46 years. At dose level II, the median time to neutrophil and platelet engraftment was 17 and 20 days, respectively. The incidence of acute and chronic graft-versus-host disease (GVHD) was 40% and 30%, respectively. Day + 100 non-relapse mortality was 0% and at 1 year was 20%. Median overall survival (OS) was 42 months and 2-year OS was 70%. Median progression-free survival (PFS) was 11 months and 2-year PFS was 40%. We conclude that the reduced-intensity conditioning regimen of cladribine, thiotepa and ATG achieved excellent donor chimerism with acceptable toxicity. [ABSTRACT FROM AUTHOR]

Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney—an organ ordinarily not involved in graft-versus-host reactions—can be targeted by sensitized donor lymphocytes. [Copyright &y& Elsevier]

The author comments on research appearing within this issue of the journal concerning allogeneic hematopoietic stem cell transplantion (AHCT) for the treatment of chronic lymphocytic leukemia (CLL) and small lympocytic lymphoma. Particular attention is paid to the study "Long-term toxicity of allogeneic stem cell transplantation in fludarabine-refractory chronic lymphocytic leukemia." The author argues that AHCT may not be suitable for the majority of patients with CLL.

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV 1 ). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases and included studies that compared azithromycin with placebo or no intervention in the treatment of OB or bronchiolitis obliterans syndrome (BOS) in patients who had undergone allogeneic HSCT. Ninety-one unique publications were identified, and 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV 1 were measured between 12 and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV 1 of 30 mL (95% confidence interval, −260 to +330 mL; P  = .82) after initiation of azithromycin. One patient death was reported but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS after HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting. [ABSTRACT FROM AUTHOR]

Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively ( P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively ( P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB ( P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients. [Copyright &y& Elsevier]