National Cancer Institute’s First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Summary and Recommendations from the Organizing Committee

The National Cancer Institute’s First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Each of the Workshop’s 6 Working Committees has published individual reports of ongoing basic, translational, and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention, and treatment. This document summarizes each committee’s recommendations and suggests 3 major initiatives for a coordinated research effort to address the problem of relapse after allo-HSCT: (1) to establish multicenter correlative and clinical trial networks for basic/translational, epidemiologic, and clinical research; (2) to establish a network of biorepositories for the collection of samples before and after allo-HSCT to aid in laboratory and clinical studies; and (3) to further refine, implement, and study the Workshop-proposed definitions for disease-specific response and relapse and recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplantation organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse after allo-HSCT

A Systematic Review of Studies That Aim to Determine Which Outcomes to Measure in Clinical Trials in Children

Ian Sinha and colleagues show, in a systematic review of published studies, that there are very few studies that address the appropriate choice of outcomes for clinical research with children

Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS)

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia years "?>and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P =.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P <.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P =.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P =.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival

MAGIC observations provide compelling evidence of hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7

Context. Certain types of supernova remnants (SNRs) in our Galaxy are assumed to be PeVatrons, capable of accelerating cosmic rays (CRs) to ∼ PeV energies. However, conclusive observational evidence for this has not yet been found. The SNR G106.3+2.7, detected at 1- 100 TeV energies by different γ-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape, which can be divided into a head and a tail region with different physical conditions. However, in which region the 100 TeV emission is produced has not yet been identified because of the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear as to whether the origin of the γ-ray emission is leptonic or hadronic. Aims. With the better angular resolution provided by new MAGIC data compared to earlier γ-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1 resolution at TeV energies. Methods. We observed the SNR G106.3+2.7 using the MAGIC telescopes for 121.7 h in total - after quality cuts - between May 2017 and August 2019. The analysis energy threshold is ∼0.2 TeV, and the angular resolution is 0.07-0.1. We examined the γ-ray spectra of different parts of the emission, whilst benefitting from the unprecedented statistics and angular resolution at these energies provided by our new data. We also used measurements at other wavelengths such as radio, X-rays, GeV γ-rays, and 10 TeV γ-rays to model the emission mechanism precisely. Results. We detect extended γ-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detect a significant γ-ray emission with energies above 6.0 TeV from only the tail region suggests that the emissions above 10 TeV detected with air shower experiments (Milagro, HAWC, Tibet ASγ and LHAASO) are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of ∼1 PeV for that region. Such high-energy emission in this middle-aged SNR (4-10 kyr) can be explained by considering a scenario where protons escaping from the SNR in the past interact with surrounding dense gases at present. Conclusions. The γ-ray emission region detected with the MAGIC telescopes in the SNR G106.3+2.7 is extended and spatially coincident with the radio continuum morphology. The multi-wavelength spectrum of the emission from the tail region suggests proton acceleration up to ∼PeV, while the emission mechanism of the head region could either be hadronic or leptonic