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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]

Background: Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia.Methods and Findings: We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures-including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue-the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case.Conclusions: allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs. [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]

T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL. The use of nelarabine for relapsed and refractory T-ALL results in responses in a substantial minority of patients. Allogeneic hematopoietic cell transplantation (HCT) still plays a key role in patients with high-risk or relapsed/ refractory disease. y-Secretase inhibitors hold promise for the treatment of patients with NOTCH1 mutations, and the results of clinical trials with these agents are eagerly awaited. It is recommended that younger patients receive a pediatricintensive regimen. Older and unfit patients can receive suitable multiagent chemotherapy and be allocated to HCT based on their response, risk factors, and comorbidities. Although advances in the treatment of T-ALL have lagged behind those of B-cell ALL, it is hoped that the molecular revolution will enhance our understanding of the pathogenesis and treatment of this aggressive lymphoid malignancy. [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]

Describes the emergence of quinolone-resistant viridans group (VG) streptococci in connection with the use of levofloxacin prophylaxis during autologous peripheral blood stem cell transplantation (APBSCT)-associated neutropenia. Definition of neutropenia; Determination of antimicrobial susceptibility; Characteristics of patients with levofloxacin-nonsusceptible VG streptococcal bacteremia during the neutropic period following APBSCT and of isolates recovered from the patients.

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]

Many tumors are believed to be maintained by a small number of cancer stem-like cells, where cure is thought to require eradication of this cell population. In this study, we investigated the dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease initiation, progression, and therapeutic response. This investigation used a mathematical model of hematopoiesis and a dataset derived from the North American Intergroup Study INT0129. The known phenotypic constraints of APL could be explained by a combination of differentiation blockade of PML-RARα-positive cells and suppression of normal hematopoiesis. All-trans retinoic acid (ATRA) neutralizes the differentiation block and decreases the proliferation rate of leukemic stem cells in vivo. Prolonged ATRA treatment after chemotherapy can cure patients with APL by eliminating the stem-like cell population over the course of approximately one year. To our knowledge, this study offers the first estimate of the average duration of therapy that is required to eliminate stem-like cancer cells from a human tumor, with the potential for the refinement of treatment strategies to better manage human malignancy. [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]

Abstract: Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international Internet-based survey of 458 patients with MF we created a 20-item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials. [Copyright &y& Elsevier]