A phase I clinical trial of lenalidomide combined with bortezomib for acute myeloid leukemia or myelodysplastic syndrome relapsing after allogeneic stem cell transplantation.

Background: Allogeneic hematopoietic cell transplantation (HCT) may improve long-term survival in patients with MDS or AML but disease relapse following HCT is common, with limited subsequent treatment options and extremely poor post-relapse outcomes. Lenalidomide and bortezomib are therapies which, in this setting, may exert antiproliferative effects, enhance graft-vs-leukemia immune responses, and potentiate chemotherapeutic drugs.

Objectives: We sought to evaluate the safety and preliminary efficacy of bortezomib in combination with high dose lenalidomide in patients with AML or MDS relapsing after HCT.

Parkinsonism reversed from treatment of pineal non-germinomatous germ cell tumor.

Background: Parkinsonism is a rare complication of non-germinomatous germ cell tumors (NGGCTs) arising from the pineal region.

Case Description: We describe a 23-year-old man who presented with Parinaud syndrome, fatigue, and hypersomnia that were caused by a pineal region NGGCT with yolk sac component and an initial α-fetoprotein (AFP) of 1011.0 ng/ml.

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days.

Casting a wider protective net: Anti-infective vaccine strategies for patients with hematologic malignancy and blood and marrow transplantation.

Patients who have hematologic malignancies are at high risk for infections but vaccinations may be effective prophylaxis. The increased infection risk derives from immune defects secondary to malignancy, the classic example being CLL, and chemotherapies and immunotherapy used to treat the malignancies. Therapy of hematologic malignancies is being revolutionized by introduction of novel targeted agents and immunomodulatory medications, improving the survival of patients.

The prevention and management of asparaginase-related venous thromboembolism in adults: Guidance from the SSC on Hemostasis and Malignancy of the ISTH.

Venous thromboembolism is a common complication of asparaginase-based chemotherapy regimens for the treatment of acute lymphoblastic leukemia. Thrombosis associated with asparaginase administration poses a number of specific and often clinically challenging management decisions. This review provides guidance on the prevention and treatment of thrombosis associated with asparaginase in adults including discussions on antithrombin repletion, pharmacologic thromboprophylaxis, cerebral venous thrombosis, and therapeutic anticoagulation.

Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.

Background: Increased aurora A kinase (AAK) expression occurs in acute myeloid leukaemia; AAK inhibition is a promising therapeutic target in this disease. We therefore aimed to assess the activity of alisertib combined with 7 + 3 induction chemotherapy in previously untreated patients with high-risk acute myeloid leukaemia.

Methods: We did a single-arm, phase 2 trial of patients recruited from the Dana-Farber/Harvard Cancer Center in the USA.

Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine.

Acute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell-mediated killing.

Possible reactivation of chromosomally integrated human herpesvirus 6 after treatment with histone deacetylase inhibitor.

HDAC inhibitors might induce ciHHV-6 reactivation. In ciHHV-6 HSCT recipients posttransplant viral load can estimate persistent host chimerism when the donor is ciHHV-6 negative.

Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase 1 clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T-cell activation via costimulatory blockade, in the treatment of SR-cGVHD.

Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results.

Aprior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after human leukocyte antigen (HLA)-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft--host disease incidence, with promising overall and progression-free survival. We performed an open-label three-arm 1:1:1 phase II randomized controlled trial comparing grade II-IV acute graft--host disease between conventional tacrolimus/methotrexate (A) bortezomib/tacrolimus/methotrexate (B), and bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors. The primary endpoint was grade II-IV acute graft--host disease incidence rate by day +180.

A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia.

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML.

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation.

Background: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways.

Methods: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy.

A multicenter, retrospective, case-cohort study of the epidemiology and risk factors for Clostridium difficile infection among cord blood transplant recipients.

Background: Clostridium difficile infection (CDI) is the leading cause of health-care associated infectious diarrhea. The aim of this study was to evaluate the epidemiology and risk factors for CDI in the 100 days following umbilical cord blood transplantation (UCBT) at three Boston hospitals.

Methods: We performed a multicenter, retrospective, case-cohort study of 226 UCBT recipients at Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and Dana Farber/Brigham and Women's Cancer Center from 2003 to 2012.

MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia.

Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls.

Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions.

We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells.