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On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m(2) per d days 1-10, consisting of grade 3-4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m(2) per d days 1-10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m(2) per d decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL.

Historically, treatment of chronic lymphocytic leukemia (CLL) essentially had been palliative. During the past two decades, effective new therapies for the treatment of CLL have emerged. The advent of fludarabine, a purine analog with activity against chlorambucil-resistant CLL, showed promising results with high response rates in previously untreated patients. These improvements in response and delays in disease progression have not translated into a survival benefit, indicating that chlorambucil may be the preferred first-line therapy when treatment is indicated. Allogeneic hematopoietic stem cell transplantation, by combining the cytoreductive effects of conditioning with a potent graft-versus-tumor effect, is the only treatment modality with the prospect of cure for patients with CLL. However, conventional hematopoietic stem cell transplantation can be offered only to select patients with CLL because of older age and comorbid conditions. Novel methods of transplantation exploiting the graft-versus-leukemia effect while reducing the toxicity of the pretransplant conditioning are promising approaches that may enable more patients to benefit from this therapy. Monoclonal antibodies such as rituximab or alemtuzumab (Campath-1H; llex Pharmaceuticals, San Antonio, TX) are agents with activity in untreated and resistant CLL. Efforts are being focused on combining these monoclonal antibodies with chemotherapy and the development of rationally designed drugs.