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Since 1944, nearly 400 radiologic accidents/incidents have exposed about 3,000 people to substantial doses of ionizing radiation, with more than 125 deaths. Known are the Chernobyl and Fukushima nuclear power facility accidents, but the recent war in Ukraine has refocused attention on this issue. Therapy of acute, high-dose, whole-body exposures to ionizing radiation includes transfusions, antimicrobial drugs, molecularly cloned hematopoietic growth factors, and hematopoietic cell transplants (HCT).We focus on approved therapies including recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim). Animal data indicate sargramostim accelerates marrow recovery and increases survival. In 2018, the United States Food and Drug Administration approved sargramostim for persons acutely exposed to myelosuppressive radiation doses based on two large nonhuman primate studies. In seven radiation accidents since 1986, 28 victims exposed to acute high-dose ionizing radiation received rhu GM-CSF alone or with other hematopoietic growth factors. Therapy appeared effective with few, if any, adverse events; 18 survived.This favorable

The optimal chemotherapy regimen pre-transplantation for adult T-cell acute lymphoblastic leukemia (T-ALL) patients remains unknown. Here, we compared the transplant outcomes in 127 subjects receiving pediatric- (N = 57) or adult-type (N = 70) regimens pre-transplant. The corresponding 3-year cumulative incidences of relapse (CIR) was 7% (95% CI: 3-11%) and 29% (95% CI: 23-35%; P = 0.02), leukemia-free survivals (LFS) was 86% (95% CI: 81-91%) and 57% (95% CI: 51-63%; P = 0.003), overall survivals (OS) was 88% (95% CI: 84-92%) and 58% (95% CI: 52-64%; P = 0.002), the 1-year NRM was 4% (95% CI: 1-7%) and 9% (95% CI: 4-14%; P = 0.40). Multivariate analysis showed that pediatric-type regimen was associated with lower CIR (Hazard Ratio [HR] = 0.31 [95% CI: 0.09-1.00]; P = 0.05), better LFS (HR = 0.34 [95% CI: 0.15-0.78]; P = 0.01) and OS (HR = 0.30 [95% CI: 0.13-0.72]; P = 0.01). Our results suggested that adult T-ALL patients undergoing allo-HSCT might benefit from pediatric-type chemotherapy.

Causes of death in persons with haematological cancers include the index cancer, a new cancer or a seemingly unrelated cause such as cardio-vascular disease. These causes are complex and sometimes confounded. We analyzed trends in cause of death in 683,333 persons with an index haematological cancer diagnosed in 1975–2016 reported in the Surveillance, Epidemiology and End Results dataset. Non-cancer deaths were described using standardized mortality ratios. The index cancer was the predominant cause of death amongst persons with plasma cell myeloma, acute lymphoblastic leukaemia and acute myeloid leukaemia. Non-cancer death was the major cause of death in persons with chronic lymphocytic leukaemia, Hodgkin lymphoma and chronic myeloid leukaemia, mostly from cardio-vascular diseases. The greatest relative decrease in index-cancer deaths was amongst persons with Hodgkin lymphoma, chronic myeloid leukaemia and chronic lymphocytic leukaemia, where the proportion of non-cancer deaths increased substantially. Changing distribution of causes of death across haematological cancers reflects substantial progress in some cancers and suggests strategies to improve the survival of persons with haematological cancers in the future.

CD19-targeted chimeric antigen receptor T (CAR-T) cells using murine single-chain variable fragment (scFv) has shown substantial clinical efficacy in treating relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, potential immunogenicity of the murine scFv domain may limit the persistence of CAR-T cells. In this study, we treated 52 consecutive subjects with R/R ALL with humanized CD19-specific CAR-T cells (hCART19s). Forty-six subjects achieved complete remission (CR) (N = 43) or CR with incomplete count recovery (CRi) (N = 3) within 1 month post infusion. During the follow-up with a median time of 20 months, the 1-year cumulative incidence of relapse was 25% (95% confidence interval [CI] 13-46), and 1-year event-free survival was 45% (95% CI 29-60). To the cutoff date, 20 patients presented CD19

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

This study explored results of therapy of children with acute lymphoblastic leukemia (ALL) in China, recent progress, and challenges. Included are a survey of therapy outcomes of ALL in Chinese children nationwide, comparison of these data with global ALL therapy outcomes, analyses of obstacles to improving outcomes, and suggestions of how progress can be achieved. Therapy outcomes at many Chinese pediatric cancer centers are approaching those of resource-rich countries. However, nationwide outcomes still need improvement. Obstacles include suboptimal clinical trials participation, children without adequate health care funding, human resource shortages, especially physicians expert in pediatric hematology and oncology, and social-economic disparities. We suggest how these obstacles have been and continue to be remedied including expanded access to protocol-based therapy, improved supportive care, health care reforms, recruitment of trained personnel, and international collaborations. China has made substantial progress treating children with ALL. We envision even better outcomes in the near future.

Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In ten accidents since 1996, 30 victims received G-CSF alone or with other growth factors. Twenty-six victims survived. In seven accidents since 1986, 28 victims received GM-CSF alone or with other growth factors; 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorable benefit-to-risk ratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.

Gene fusions have been discussed in the scientific literature since they were first detected in cancer cells in the early 1980s. There is currently no standardized way to denote the genes involved in fusions, but in the majority of publications the gene symbols in question are listed either separated by a hyphen (-) or by a forward slash (/). Both types of designation suffer from important shortcomings. HGNC has worked with the scientific community to determine a new, instantly recognizable and unique separator—a double colon (::)—to be used in the description of fusion genes, and advocates its usage in all databases and articles describing gene fusions.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

Myelodysplastic syndromes (MDS) are a family of myeloid cancers with diverse genotypes and phenotypes characterized by ineffective haematopoiesis and risk of transformation to acute myeloid leukaemia (AML). Some epidemiological data indicate that MDS incidence is increasing in resource-rich regions but this is controversial. Most MDS cases are caused by randomly acquired somatic mutations. In some patients, the phenotype and/or genotype of MDS overlaps with that of bone marrow failure disorders such as aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH) and AML. Prognostic systems, such as the revised International Prognostic Scoring System (IPSS-R), provide reasonably accurate predictions of survival at the population level. Therapeutic goals in individuals with lower-risk MDS include improving quality of life and minimizing erythrocyte and platelet transfusions. Therapeutic goals in people with higher-risk MDS include decreasing the risk of AML transformation and prolonging survival. Haematopoietic cell transplantation (HCT) can cure MDS, yet fewer than 10% of affected individuals receive this treatment. However, how, when and in which patients with HCT for MDS should be performed remains controversial, with some studies suggesting HCT is preferred in some individuals with higher-risk MDS. Advances in the understanding of MDS biology offer the prospect of new therapeutic approaches.

SummaryHematopoietic cell transplants are used to treat some adults with acute lymphoblastic leukemia, especially those with high-risk features, such as those with BCR::ABL1. This strategy may be changing given the safety and efficacy of modern tyrosine kinase inhibitors. Although these transplants are often successful, leukemia relapse remains the dominant cause of transplant failure. There are several approaches to this problem discussed by the authors of a recent article in the journal. The good news is therapy of recurrent leukemia posttransplant seems increasingly successful and for diverse reasons, survival is increasing substantially.See related article by Bazarbachi et al., p. 1004

Data from 1661 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib (n = 1379) or a 2nd-generation tyrosine-kinase inhibitor (2G-TKI; n = 282) were interrogated to determine whether the Sokal or European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS) scores were more accurate responses and outcome predictors. Both scores predicted probabilities of achieving complete cytogenetic response (CCyR), major molecular response (MMR), failure- and progression-free survivals (FFS, PFS), and survival in all subjects and those receiving imatinib therapy. However, the ELTS score was a better predictor of MR4, MR4.5, and CML-related survival than the Sokal score. In subjects receiving 2G-TKI therapy, only the ELTS score accurately predicted probabilities of CCyR, MMR, MR4, FFS, and PFS. In the propensity score matching, subjects classified as intermediate risk by the ELTS score receiving a 2G-TKI had better responses (p p = 0.002), and PFS (p = 0.03) but not survival. Our data suggest better overall prediction accuracy for the ELTS score compared with the Sokal score in CML patients, especially those receiving 2G-TKIs. People identified as intermediate risk by the ELTS score may benefit more from initial 2G-TKI therapy in achieving surrogate endpoints but not survival, especially when a briefer interval to stopping TKI therapy is the therapy objective.

In recent years, genome-based classifications for hematological neoplasms have been proposed successively and proved to be more accurate than histologic classifications. However, some previous studies have reported the racial differences of genetic landscape in persons with hematological neoplasms including myelodysplastic syndromes (MDS), which may cause a genomic classification based on a particular ethnic group does not operate in other races. To determine whether race plays an important role in the genomic-based classification, we validated a newly proposed genomic classification of MDS (J Clin Oncol.2021; JCO2001659), which was based on a large European database, in Chinese patients from our center. Our results showed significant differences between Chinese and European patients including proportion of each group to overall cohort when applying this novel genomic classification. Our data indicate that a genomic classification of hematological neoplasms probably should be revised according to specific genetic features in different races.

Introduction: In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. Methods: This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. Results: Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41–54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. JAK2V617F was present in 10 subjects and CALR mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40–160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5–4.0) and 5.0 events (4.6–5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. Conclusion: Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.

Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein–Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically includingl-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearlybest; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.

My task is to consider whether haematopoietic cell transplants would be considered appropriate today in persons with features like victims of high-dose and dose-rate ionizing radiations after the Chernobyl nuclear power facility accident in 1986 given knowledge and experience gained over the past 35 years. First I consider the conceptual bases for considering an intervention appropriate and then the metric for deciding whether a transplant is appropriate in similar persons. Data needed to support this decision-making process include estimates of dose, dose-rate, dose uniformity, synchronous or metachronous injuries, donor availability and alternative interventions. Many of these co-variates have substantial uncertainties. Fundamental is a consideration of potential benefit-to-risk and risk-to-benefit ratios under conditions of substantial inaccuracy and imprecision. The bottom line is probably fewer transplants would be done and more victims would receive molecularly-cloned haematopoietic growth factors.

Interactions between acute myeloid leukaemia (AML) cells and immune cells are postulated to corelate with outcomes of AML patients. However, data on T-cell function-related signature are not included in current AML survival prognosis models. We examined data of RNA matrices from 1611 persons with AML extracted from public databases arrayed in a training and three validation cohorts. We developed an eight-gene T-cell function-related signature using the random survival forest variable hunting algorithm. Accuracy of gene identification was tested in a real-world cohort by quantifying cognate plasma protein concentrations. The model had robust prognostic accuracy in the training and validation cohorts with five-year areas under receiver-operator characteristic curve (AUROC) of 0.67-0.76. The signature was divided into high- and low-risk scores using an optimum cut-off value. Five-year survival in the high-risk groups was 6%-23% compared with 42%-58% in the low-risk groups in all the cohorts (all p valueslt;0.001). In multivariable analyses, a high-risk score independently predicted briefer survival with hazard ratios of death in the range 1.28-2.59. Gene set enrichment analyses indicated significant enrichment for genes involved in immune suppression pathways in the high-risk groups. Accuracy of the gene signature was validated in a real-world cohort with 88 pretherapy plasma samples. In scRNA-seq analyses most genes in the signature were transcribed in leukaemia cells. Combining the gene expression signature with the 2017 European LeukemiaNet classification significantly increased survival prediction accuracy with a five-year AUROC of 0.82 compared with 0.76 (p lt; 0.001). Our T-cell function-related risk score complements current AML prognosis models.

We used data from 852 consecutive subjects with myelodysplastic neoplasms (MDS) diagnosed according to the 2016 (revised 4th) World Health Organization (WHO) criteria to evaluate the 2022 (5th) edition WHO classification of MDS. 30 subjects previously classified as MDS with an NPM1 mutation were re-classified as acute myeloid leukaemia (AML). 9 subjects previously classified as MDS-U were re-classified to clonal cytopenia of undetermined significance (CCUS). The remaining 813 subjects were diagnosed as: MDS-5q (N = 11 [1%]), MDS-SF3B1 (N = 70 [9%]), MDS-biTP53 (N = 53 [7%]), MDS-LB (N = 293 [36%]), MDS-h (N = 80 [10%]), MDS-IB1 (N = 161 [20%]), MDS-IB2 (N = 103 [13%]) and MDS-f (N = 42 [5%]) and MDS-biTP53 (N = 53 [7%]). 34 of these subjects came from the 53 (64%) MDS-biTP53 previously diagnosed as MDS-EB. Median survival of subjects classified as MDS using the WHO 2022 criteria was 45 months (95% Confidence Interval [CI], 34, 56 months). Subjects re-classified as MDS-biTP53 and MDS-f had significantly briefer median survivals compared with other MDS sub-types (10 months, [8, 12 months] and 15 months [8, 23 months]). In conclusion, our analyses support the refinements made in the WHO 2022 proposal.

Accurate survival prediction of persons with plasma cell myeloma (PCM) is challenging. We interrogated clinical and laboratory co-variates and RNA matrices of 1040 subjects with PCM from public datasets in the Gene Expression Omnibus database in training (N = 1) and validation (N = 2) datasets. Genes regulating plasma cell metabolism correlated with survival were identified and seven used to build a metabolic risk score using Lasso Cox regression analyses. The score had robust predictive performance with 5-year survival area under the curve (AUCs): 0.71 (95% confidence interval, 0.65, 0.76), 0.88 (0.67, 1.00) and 0.64 (0.57, 0.70). Subjects in the high‐risk training cohort (score > median) had worse 5-year survival compared with those in the low‐risk cohort (62% [55, 68%] vs. 85% [80, 90%]; p

Purpose: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. Experimental Design: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. Results: Six flow cytometry–validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. Conclusions: Our immune risk score complements current AML prediction models.

Patients receiving a hematopoietic cell transplant are thought to be at increased risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus infectious disease 2019. Transplant activities at our center continue, and notably, no patient has been infected with SARS-CoV-2. Indeed, social distancing, masking, and education for patients and donors are major pillars of prevention. We recommend potential transplant recipients and donors to be tested for SARS-CoV-2 with qRT-PCR, serum antibody detection, and a lung CT scan pretransplant. If possible, stem cells from HLA-matched unrelated donors by local processing laboratories should be cryopreserved and shipped before initiating pretransplant conditioning. An alternative HLA-haplotype-matched related donor should be identified and evaluated as a backup. The interval immediately after discharge is the time of greatest risk for SARS-CoV-2 infection because of travel and exposure to infected persons. We recommend self-isolation and minimal contact with family members. Nonessential clinic visits should be deferred or substituted with telemedicine consultations if possible. These recommendations are based on our experience at a major transplant center in China. Although some recommendations are evidence based, other recommendations are not and warrant validation in controlled trials.

Ruxolitinib is a safe and effective therapy of myeloproliferative neoplasm-associated (MPN) myelofibrosis. However, often there are dose reductions and/or therapy interruptions because of therapy-related adverse events (AEs), especially anemia and thrombocytopenia. We previously reported combined therapy with prednisone, thalidomide and danazol (PTD) reversed anemia and thrombocytopenia in people with MPN-associated myelofibrosis. We wondered whether adding PTD to ruxolitinib might mitigate the hematologic AEs and thereby avoid the dose reduction of ruxolitinib and improve the efficacy. To test this hypothesis, we conducted a baseline hemoglobin and platelet concentration assignment prospective observational study in 72 patients comparing 3-month dose adjustment and efficacy of ruxolitinib with (N = 53, the study group) or without (N = 19, the control group) PTD. According to the platelet counts, the median daily ruxolitinib doses in the study group increased from 30 to 40 mg by week 12, whereas in the control group it remained at 30 mg (p = 0.019). In the study group 35 patients had a hemoglobin increase ≥10 g/L compared with no patient receiving ruxolitinib only (p 0.001). Platelet increases100 × 10E+9/L were seen in 56.6% and 5.3% of patients in the two groups, respectively (p 0.001). In patients with anemia and thrombocytopenia, 18 patients in the study group had an anemia response at week 12 and 12 had a platelet increase of ≥50 × 10E+9/L. No patient in the control group achieved either response (p 0.001 and p = 0.078). The study group had a more spleen response than the control group (p = 0.046). Peripheral edema and transaminase elevation were the main nonhematologic AEs of PTD. These AEs can be alleviated by adjusting the danazol dose. In conclusion, adding PTD to ruxolitinib improved ruxolitinib-associated anemia and thrombocytopenia, and resulted in a higher ruxolitinib dose.

We interrogated data from 278 consecutive subjects with chronic myeloid leukaemia (CML) presenting in accelerated phase diagnosed by European LeukemiaNet (ELN) criteria receiving initial imatinib (n = 187) or a 2

Importance Matched sibling donors (MSDs) are preferred for allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic syndrome even if they are older. However, whether older MSDs or younger human leukocyte antigen-matched unrelated donors (MUDs) are associated with better outcomes remains unclear. Objective To investigate whether allo-HCT for myelodysplastic syndrome using younger MUDs would be associated with improved disease-free survival and less relapse compared with older MSDs. Design, Setting, and Participants This retrospective cohort study assessed data reported to the Center for International Blood and Marrow Transplant Research database from 1761 adults 50 years or older with myelodysplastic syndrome who underwent allo-HCT using an older MSD or younger MUD between January 1, 2011, and December 31, 2017, with a median follow-up of 48 months. Data analysis was performed from January 8, 2019, to December 30, 2020. Interventions/Exposures Allo-HCT from an older MSD (donor age ���50 years) or a younger MUD (donor age ���35 years). Main Outcomes and Measures The primary outcome was disease-free survival. Secondary outcomes were overall survival, relapse, nonrelapse mortality, acute graft-vs-host disease (GVHD), chronic GVHD, and GVHD-free relapse-free survival. Results Of 1761 patients (1162 [66%] male; median [range] age, 64.9 [50.2-77.6] years in the MSD cohort and 66.5 [50.4-80.9] years in MUD cohort), 646 underwent allo-HCT with an older MSD and 1115 with a younger MUD. In multivariable analysis, the rate of disease-free survival was significantly lower in allo-HCTs with older MSDs compared with younger MUDs (hazard ratio [HR], 1.17; 95% CI, 1.02-1.34; P���=���.02), whereas the difference in overall survival rate of allo-HCT with younger MUDs vs older MSDs was not statistically significant (HR, 1.13; 95% CI, 0.98-1.29; P���=���.07). Allo-HCT with older MSDs was associated with significantly higher relapse (HR, 1.62; 95% CI, 1.32-1.97; P���

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

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

The expression of the CXCR4 chemokine receptor on CD34-positive blood cells is reduced in persons with primary myelofibrosis (PMF). We analyzed the relevance of cytofluorimetric assessment of the percentage of CD34-positive blood cells that had a positive CXCR4 surface expression (CD34/CXCR4-se) in a large cohort of subjects with myeloproliferative neoplasms. Mean CD34/CXCR4-se was lower in subjects with PMF compared with those with essential thrombocythemia (ET) or polycythemia vera (PV). A cutoff value of 39% was associated with a diagnosis of pre-fibrotic PMF vs. ET with a positive predictive value of 97%. In PMF male sex, older age, and MPL mutation were independent correlates of reduced CD34/CXCR4-se and associated with a briefer interval to development of severe anemia, large splenomegaly, thrombocytopenia, leukopenia, elevated CD34-positive blood cells, blast transformation and death. We constructed a prognostic model including age >65 years, hemoglobin 50 × 106/L, and CD34/CXCR4-se

We studied by questionnaire 530 subjects with chronic myeloid leukaemia (CML) in Hubei Province during the recent SARS-CoV-2 epidemic. Five developed confirmed (N = 4) or probable COVID-19 (N = 1). Prevalence of COVID-19 in our subjects, 0.9% (95% Confidence Interval, 0.1, 1.8%) was ninefold higher than 0.1% (0, 0.12%) reported in normals but lower than 10% (6, 17%) reported in hospitalised persons with other haematological cancers or normal health-care providers, 7% (4, 12%). Co-variates associated with an increased risk of developing COVID-19 amongst persons with CML were exposure to someone infected with SARS-CoV-2 (P = 0.037), no complete haematologic response (P = 0.003) and co-morbidity(ies) (P = 0.024). There was also an increased risk of developing COVID-19 in subjects in advanced phase CML (P = 0.004) even when they achieved a complete cytogenetic response or major molecular response at the time of exposure to SARS-CoV-2. 1 of 21 subjects receiving 3rd generation tyrosine kinase-inhibitor (TKI) developed COVID-19 versus 3 of 346 subjects receiving imatinib versus 0 of 162 subjects receiving 2nd generation TKIs (P = 0.096). Other co-variates such as age and TKI-therapy duration were not significantly associated with an increased risk of developing COVID-19. Persons with these risk factors may benefit from increased surveillance of SARS-CoV-2 infection and possible protective isolation.

We performed a meta-analysis to determine safety and efficacy of corticosteroids in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. We searched PubMed, Web of Science, Medline, WanFang Chinese database, and ZhiWang Chinese database using Boolean operators and search terms covering SARS-CoV-2, SARS-CoV, OR MERS-CoV AND corticosteroids to find appropriate studies. Review Manager 5.3 was used to analyze results of meta-analysis. Observational studies were analyzed for quality using the modified Newcastle–Ottawa scale and randomized clinical trials, using the Jadad scale. Subjects were divided into those with severe-only and other (severe and not severe) cohorts based on published criteria. Efficacy endpoints studied included mortality, hospitalization duration, rates of intensive care unit (ICU) admission, use of mechanical ventilation, and a composite endpoint (death, ICU admission, or mechanical ventilation). We included 11 reports including 10 cohort studies and 1 randomized clinical trial involving 5249 subjects (2003–2020). Two discussed the association of corticosteroids and virus clearing and 10 explored how corticosteroids impacted mortality, hospitalization duration, use of mechanical ventilation, and a composite endpoint. Corticosteroid use was associated with delayed virus clearing with a mean difference (MD) = 3.78 days (95% confidence Interval [CI] = 1.16, 6.41 days; I2 = 0%). There was no significant reduction in deaths with relative Risk Ratio (RR) = 1.07 (90% CI = 0.81; 1.42; I2 = 80%). Hospitalization duration was prolonged and use of mechanical ventilation increased. In conclusion, corticosteroid use in subjects with SARS-CoV-2, SARS-CoV, and MERS-CoV infections delayed virus clearing and did not convincingly improve survival, reduce hospitalization duration or ICU admission rate and/or use of mechanical ventilation. There were several adverse effects. Because of a preponderance of observational studies in the dataset and selection and publication biases our conclusions, especially regarding SARS-CoV-2, need confirmation in a randomized clinical trial. In the interim we suggest caution using corticosteroids in persons with COVID-19.

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Dehydropeptidase-1 (DPEP1) is a zinc-dependent metalloproteinase abnormally expressed in many cancers. However, its potential role in adults with B cell acute lymphoblastic leukaemia (ALL) is unknown. We found that in adults with common B cell ALL high DPEP1, transcript levels at diagnosis were independently associated with an increased cumulative incidence of relapse (CIR) and worse relapse-free survival (RFS) compared with subjects with low transcript levels. We show an increased proliferation and prosurvival role of DPEP1 in B cell ALL cells via regulation of phosphCREB and p53, which may be the biological basis of the clinical correlation we report. Our data implicate DPEP1 expression in the biology of common B cell ALL in adults. We report clinical correlates and provide a potential biological basis for these correlations. If confirmed, analysing DPEP1 transcript levels at diagnosis could help predict therapy outcomes. Moreover, regulation of DPEP1 expression could be a therapy target in B cell ALL.

In this provocative commentary, we consider several questions posed by the late chronic myeloid leukaemia (CML) expert Prof. Michele Baccarani, which he challenged us to address after his death. He noted only a small proportion of people with chronic phase CML receiving tyrosine kinase-inhibitor (TKI)-therapy are likely to achieve sustained therapy-free remission (TFR) and even fewer are likely to be cured. Persons most likely to fail TKItherapy can be identified at diagnosis or soon after starting TKI-therapy. These persons are likely to need lifetime TKI-therapy with attendant risks of adverse events, cost and psychological consequences. Allogeneic transplants achieve much higher rates of leukaemia-free survival compared with TKI-therapy but are associated with transplant-related adverse events including an almost 20 percent risk of transplant-related deaths within 1 year post-transplant and a compromised quality-of-life because of complications such as chronic graft-versus-host disease. Subject-, disease- and transplant-related co-variates associated with transplant outcomes are known with reasonable accuracy. Not everyone likely to fail TKI-therapy is a transplant candidate. However, in those who candidates are physicians and patients need to weigh benefits and risks of TKI-therapy versus a transplant. We suggest transplants should be more often considered in the metric when counseling people with chronic phase CML unlikely to achieve TFR with TKI-therapy. We question whether we are discounting a possible important therapy intervention; we think so.

Background : Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Objective : Here, we provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Study Design : We utilized systematic review methodology to summarize incidence, risk factors, screening, prevention and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Results : Most of the evidence regarding male GvHD is still based on limited data, precluding strong therapeutic recommendations. We therefore recommend to systematically screen for male genital GvHD regularly and report it to large registries to allow for a better understanding. Future research should also address treatment since little published evidence is available to date. Male-specific endocrine consequences of HCT include hypogonadism which may also affect bone health. Since the evidence is scarce, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, which warrants offering sperm preservation in all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, hence the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent than in the general population; however, subsequent malignancies in general seem to be more prevalent in males than females, and special attention should be given to skin and oral mucosa. Conclusion : Male-specific late effects, probably more under-reported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplant physicians and specialists from other involved disciplines. Future research should be directed towards better data collection on male-specific late effects and on studies about the interrelationship between these late effects, to allow the development of evidence based effective management practices.

Most national health-care systems approve new drugs based on data of safety and efficacy from large randomized clinical trials (RCTs). Strict selection biases and study-entry criteria of subjects included in RCTs often do not reflect those of the population where a therapy is intended to be used. Compliance to treatment in RCTs also differs considerably from real world settings and the relatively small size of most RCTs make them unlikely to detect rare but important safety signals. These and other considerations may explain the gap between evidence generated in RCTs and translating conclusions to health-care policies in the real world. Real-world evidence (RWE) derived from real-world data (RWD) is receiving increasing attention from scientists, clinicians, and health-care policy decision-makers - especially when it is processed by artificial intelligence (AI). We describe the potential of using RWD and AI in Hematology to support research and health-care decisions.

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradiation (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% Cl, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI,.94 to 1.19; P = .36) for IH and .89 (95% CI,.76 to 1.05; P = .17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.