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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.

Relapsed acute myeloid leukemia (AML) after an allogeneic hematopoietic cell transplant (allo-HCT) entails a poor prognosis. Treating these cases is challenging due to lack of effective therapies and, in some cases, poor performance status and/or presence of graft-versus-host disease (GVHD), among others. No randomized controlled trial (RCT) has ever been conducted comparing a second allo-HCT against other treatments. Existing data are mainly from observational studies or registries. Success of a second allo-HCT is dependent on appropriately selecting patients who might achieve best outcomes with reasonable non-relapse mortality (NRM) risk. Several factors are associated with worse outcomes, namely a shorter time from first allo-HCT to relapse or to the second allo-HCT, and AML not being in complete hematologic remission (CR). Patients relapsing earlier than 6 months or having active/persistent disease should be enrolled in clinical trials. Limitations of the published literature include retrospective small size studies, a heterogeneous population, and absence of information on somatic mutations, among others. Future studies assessing the role of a second allo-HCT should evaluate the impact of IDH1, IDH2, or others on outcomes; and the feasibility and efficacy of targeted therapies in the pre-, peri-, or post-second allo-HCT setting.

Hematopoietic cell transplantation (HCT) activity is increasing at an unprecedented pace with > 50,000 allogeneic transplants occurring annually worldwide. Establishing a functional HCT donor registry can be very challenging with respect to ethnicities, financial, technical, and geopolitical issues. Extensive planning steps are essential to overcome the expected challenges while establishing the registry, and to maintain its functionality. A few strategies can help move past those challenges and push the development of such registries forward. Authorities involved in HCT donor registry establishment will have to balance the advantages and costs of such a project and accommodate the emerging alternatives such as cord blood or related haploidentical transplants. Miscalculations and incomplete understanding of the various aspects of the process can have tremendous impact on the optimization of a HCT donor registry especially in developing countries. Herein we present some challenges in establishing such a registry and present potential solutions.

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cell has changed the treatment landscape of B-cell non-Hodgkin’s lymphoma (NHL), especially for aggressive B-cell lymphomas. Single-center and multicenter clinical trials with anti-CD19 CAR T-cell therapy have shown great activity and long-term remissions in poor-risk diffuse large B-cell lymphoma (DLBCL) when no other effective treatment options are available. Two CAR T-cell products [axicabtagene ciloleucel (axi-cel) and tisagenlecleucel] have obtained US Food and Drug Administration approval for the treatment of refractory DLBCL after two lines of therapy. A third product, liso-cel, is currently being evaluated in clinical trials and preliminary results appear very promising. CAR T-cell-related toxicity with cytokine-release syndrome and neurotoxicity remain important potential complications of this therapy. Here, we review the s biology, structure, clinical trial results and toxicity of two commercially approved CAR T-cell products and others currently being studied in multicenter clinical trials in B-cell NHLs.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for patients with malignant and benign hematologic conditions. Graft-versus-host disease (GVHD) is a known complication of allo-HCT that results in significant morbidity and mortality. A common GVHD prophylaxis strategy combines a calcineurin inhibitor with methotrexate. When mucositis and organ toxicity develop, the day +11 dose is frequently omitted to limit further organ damage. The potential impact of this practice on allo-HCT outcomes is unclear as published data show conflicting results. Thus, we performed a systematic review/meta-analysis of the available literature to assess the impact of omitting day +11 methotrexate on allo-HCT recipients. Data were extracted in relation to benefits (overall survival [OS], progression-free survival [PFS]) and harms (acute and chronic GVHD, non-relapse mortality [NRM], and relapse). Pooled OS rate favored those who received day +11 methotrexate vs. those who did not (HR = 1.21; 95% CI = 1.02–1.43; p = 0.03). There was no significant difference in pooled rates of PFS (HR = 0.96; 95% CI = 0.60–1.52; p = 0.85), acute GVHD (HR = 1.03; 95% CI = 0.35–2.98; p = 0.96), chronic GVHD (HR = 0.83; 95% CI = 0.44–1.57; p = 0.57), NRM (HR = 0.86; 95% CI = 0.67–1.11; p = 0.25), and relapse (HR = 0.97; 95% CI = 0.75–1.26; p = 0.83) between the two groups. Large prospective multicenter studies are needed to better define the significance of day +11 methotrexate omission.

Patients with relapsed and/or refractory (R/R) follicular lymphoma (FL) and mantle cell lymphoma (MCL) have a poor prognosis with anticipated short progression-free and overall survivals. Two CD19-directed chimeric antigen receptor T-cell (CAR T) therapies are approved in the United States for R/R FL, namely, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel. The results of ZUMA-5 and ELARA studies led to the approval of axi-cel and tisagenlecleucel, respectively, after demonstrating high overall (ORR) and complete response (CR) rates in this high-risk population of FL patients who had received a median of 3 (range = 2–4) and 4 (range = 2–13) prior lines of therapies, respectively. For instance, the ORR for ZUMA-5 was 94% (CR = 79%), and for ELARA, it was 86% (CR = 69.1%). Pertaining to MCL, brexucabtagene autoleucel is approved for R/R MCL based on results of the ZUMA-2 study. In the latter study, despite the fact that all R/R MCL patients had been exposed to prior Bruton’s tyrosine kinase inhibitors, the reported ORR was 91%, with 68% achieving a CR. These results undoubtedly demonstrate a strong efficacy of CAR T therapy in both R/R FL and MCL; yet, one must acknowledge the relatively short follow-up time of all aforementioned studies. Thus, longer follow-up showing durability of responses and long-term safety is definitely needed.

The challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T‐cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T‐cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B‐cell activating factor receptor (BAFF‐R) as a promising target for CAR design against CLL. BAFF‐R is essential for B‐cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF‐R CAR T‐cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19‐knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF‐R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient‐derived CAR T cells against autologous tumor cells. Given these promising results, BAFF‐R CAR T‐cell therapy has the potential to meet the long‐standing need for an effective treatment on CLL patients. BAFF‐R CAR T cells were created (A) using a lentiviral system and tested against various malignant B‐cell lines, including CLL cells. CLL patient‐derived BAFF‐R CAR T cells were also generated to test their cytotoxicity on autologous primary malignant B cells (B). The cytotoxicity of CAR T cells was measured using degranulation, interferon‐γ release, and green fluorescent protein‐labeled killing assays (C).

Graft-versus-host disease (GVHD) remains a limiting factor for successful allogeneic hematopoietic cell transplantation (allo-HCT). Conflicting data exist on the benefit of ATG on post-transplant survival. We performed a systematic review of randomized controlled trials (RCTs) to assess benefits and harms of thymoglobulin and Fresenius (re-branded as Grafalon) ATG formulations in patients undergoing allo-HCT for a variety of hematologic malignancies and bone marrow failure syndromes. A comprehensive search of MEDLINE, EMBASE, and Cochrane Library was performed. Data on methodological quality, benefits, and harms were extracted for each trial and pooled under a random-effects model. Eight RCTs (1134 patients) met the inclusion criteria. Methodological quality ranged from moderate to very low. Pooled results showed no difference in overall survival (OS) with the use of ATG (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.74–1.28; P = 0.83). ATG reduced grade II/III acute GVHD (risk ratio (RR) = 0.61; 95% CI = 0.48–0.77; P < 0.0001), grade III/IV acute GVHD (RR = 0.52; 95% CI = 0.34–0.81; P = 0.004), and chronic GVHD (RR = 0.52; 95% CI = 0.40–0.69; P < 0.00001) without an increase in non-relapse mortality (NRM) (RR = 0.91; 95% CI = 0.74–1.13; P = 0.40). Future studies with better methodological quality are needed to provide conclusive answers related to optimal dosing and timing of ATG for prevention of GVHD.