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The impact of GVHD and graft-versus-leukemia effect in unrelated cord blood transplantation (UCBT) is controversial. In the Eurocord/ALWP EBMT and JSTCT/JDCHCT collaborative study, we evaluated the impact of GVHD on UCBT outcomes in Japanese and European registries. A total of 3, 690 adult patients with acute leukemia who received their first single UCBT were included. A multivariate analysis of overall survival (OS) revealed a positive impact of grade II acute GVHD compared with grade 0-I GVHD, in the Japanese cohort (hazard ratio (HR), 0.81; P = 0.001), and an adverse impact in the European cohort (HR, 1.37; P = 0.007). A negative impact of grade III-IV acute GVHD on OS was observed regardless of registries. In the analysis of relapse, a positive impact of grade II acutes GVHD compared with grade 0–I GVHD was observed only in the Japanese cohort, regardless of disease risk. The positive impact of limited chronic GVHD on OS was observed only in the Japanese cohort. In conclusion, a positive impact of mild GVHD after a single UCBT was observed only in the Japanese cohort. This could explain the ethnic difference in UCBT outcomes and might contribute to the preference usage of UCBT in Japan., 急性白血病治療における臍帯血移植後の合併症が及ぼす予後への影響 --国際共同研究から明らかになった日欧での違い--. 京都大学プレスリリース. 2021-10-19.

We studied pre-transplant minimal residual disease (MRD) in 224 patients (median age 44 years; range 17-65) with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplant (HSCT) in complete remission. MRD was evaluated on marrow samples using multicolor flow cytometry (MFC) and assessment of WT1 gene expression. Both methods showed a strong prognostic value and their combination allowed the identification of 3 groups of patients with different risk of relapse. In multivariate analysis, combined MRD was the only predictor of cumulative incidence of relapse, regardless of donor type, conditioning regimen, first or second CR at HSCT, HSCT year and ELN risk group. Multivariate regression model showed that only negative combined MRD status (p

Background: Laparoscopic lymph node biopsy through a multi-port access (MPLB) is a well-established technique for intra-abdominal lymphoma diagnosis. The aim of the current study is to assess the f...

Background The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide prophylaxis is gaining traction in patients with acute lymphoblastic leukemia (ALL). Methods The Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation registry was used to evaluate the outcomes of adult patients with ALL who underwent haplo-HCT during 2011 through 2015 and compared them with the outcomes of those who underwent transplantation during 2016 through 2018. Results The analysis consisted of 195 patients, including 79 who underwent transplantation during 2011 through 2015 and 116 who underwent transplantation during 2016 through 2018. Overall, the 2-year leukemia-free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100-day incidence of grade 2 through 4 acute graft-vs-host disease (GVHD) was 34.5%. The rates of nonrelapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia-free survival (64.9% vs 47.3%; P = .019) and OS (75.5% vs 53.5%; P = .006). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%; P = .047). The incidence of relapse, GVHD-free/relapse-free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44; 95% CI, 0.22-0.89; P = .022) and improved OS (hazard ratio, 0.47; 95% CI, 0.26-0.86; P = .014). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes. Conclusions The outcome of adult patients with ALL who receive posttransplant cyclophosphamide has improved over time, with an impressive 2-year OS of 75% and, most recently, an NRM rate of only 17%.

ObjectiveTo determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS.MethodsTo be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required.ResultsTwo hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1–9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening–free survival (95% confidence interval [CI]) was 85.5% (76.9%–94.1%) at 5 years and 71.3% (57.8%–84.8%) at 10 years. In patients with progressive MS, disability worsening–free survival was 71.0% (59.4%–82.6%) and 57.2% (41.8%–72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year −0.09 [95% CI −0.15% to −0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14–0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.ConclusionsaHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.Classification of EvidenceThis study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

We aimed to evaluate the determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) and to describe factors predicting the main post-HCT complications. This retrospective study by the European Society for Blood and Marrow Transplantation included 2916 myelofibrosis patients who underwent first allo-HCT from an HLA-identical sibling or unrelated donor between 2000 and 2016. After a median follow-up of 4.7 years from transplant, projected median survival of the series was 5.3 years. Factors independently associated with increased mortality were age ≥ 60 years and Karnofsky Performance Status

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Chronic hepatitis E virus (HEV) infection in hematopoietic stem cell transplantation (HSCT) recipients is an emerging threat. The aim of this study was to provide data on the HEV burden in an Italian cohort of HSCT recipients and analyze risk factors for HEV seropositivity. This retrospective study reports data from 596 HSCT recipients compiled between 2010 and 2019. It included patients who underwent transplantation between 2010 and 2015 for whom pretransplantation (n = 419) and post-transplantation (n = 161) serum samples were available and tested retrospectively, as well as patients in whom prospective HEV testing was performed during the standard care: pre-HSCT IgG screening in 144, pre-HSCT HEV-RNA screening in addition to IgG screening in 60, and HEV-RNA testing in case of clinical suspicion of HEV infection in 59 (26 of whom were also included in the IgG screening cohorts). The rate of pre-HSCT HEV-IgG positivity was 6.0% (34 of 563). Older age was an independent risk factor for seropositivity (P = .039). None of the 34 HEV-IgG-positive patients had detectable HEV-RNA. One case of transient HEV-RNA positivity pre-HSCT was identified through screening. Two patients were diagnosed with chronic HEV hepatitis, and 1 patient was successfully treated with ribavirin. The burden of HEV infection in HSCT recipients in Italy is limited, and pre-HSCT screening appears to be of no benefit. Timely diagnosis of HEV infection with HEV-RNA is mandatory in cases of clinical suspicion.

BACKGROUND AND PURPOSE The best therapeutic approach for aggressive relapsing-remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing-remitting multiple sclerosis. METHODS The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6-month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24. RESULTS Fifty-seven patients treated with aHSCT (n = 25) or alemtuzumab (n = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.

Graft-versus-host disease (GvHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation includes posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing data in the European Society for Blood and Marrow Transplantation registry, we compared ATG- versus PTCy-based GvHD prophylaxis in 434 adults with acute lymphoblastic leukemia undergoing haploidentical hematopoietic cell transplantation. Of the 434 patients included in this study, ATG was used in 98 and PTCy in 336.. The median follow-up was approximately 2 years. The baseline characteristics of the patients were similar between the groups except that the ATG group was more likely to have had relapsed/refractory acute lymphoblastic leukemia (P=0.008), had conditioning not including total body irradiation (P

This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P.001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.

Background Erythropoiesis‐stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower “standard doses” (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking. Methods A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score‐matched analysis to evaluate hematological improvement‐erythroid (HI‐E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated. Results Overall HI‐E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion‐dependent patients and patients with higher IPSS‐R score obtained a higher HI‐E rate with HD, although without significant impact on overall survival (OS). Achievement of HI‐E resulted in superior OS. At univariate analysis, a higher HI‐E rate was observed in transfusion‐independent patients (P, When compared in a propensity‐score matched analysis, standard doses of rhEPO showed similar effects to those of higher doses in anemic MDS patients. Achievement of favorable response with hematologic improvement in this clinical scenario is possible by reducing drug doses and costs.

Long non-coding RNAs are emerging as essential regulators of gene expression, but their role in normal and neoplastic B cells is still largely uncharacterized. Here, we report on the expression pattern of the LINC00152 in normal B cells and Chronic Lymphocytic Leukemia B cell clones. Higher LINC00152 levels were consistently observed in memory B cell populations when compared to naive B cells in the normal tissues analyzed [peripheral blood (PB), tonsils, and spleen]. In addition, independent stimulation via Immunoglobulins (IG), CD40, or Toll-like Receptor 9 (TLR9) upregulated LINC00152 in PB B cells. The expression of LINC00152 in a cohort of 107 early stage Binet A CLL patients was highly variable and did not correlate with known prognostic markers or clinical evolution. TLR9 stimulation, but not CD40 or IG challenge, was able to upregulate LINC00152 expression in CLL cells. In addition, LINC00152 silencing in CLL cell lines expressing LINC00152 failed to induce significant cell survival or apoptosis changes. These data suggest that, in normal B cells, the expression of LINC00152 is regulated by immunomodulatory signals, which are only partially effective in CLL cells. However, LINC00152 does not appear to contribute to CLL cell expansion and/or survival in a cohort of newly diagnosed CLL patients.

Multiple myeloma is a plasma cell dyscrasia characterized by focal and non-focal bone lesions. Radiomic techniques extract morphological information from computerized tomography images and exploit them for stratification and risk prediction purposes. However, few papers so far have applied radiomics to multiple myeloma. A retrospective study approved by the institutional review board: n = 51 transplanted patients and n = 33 (64%) with focal lesion analyzed via an open-source toolbox that extracted 109 radiomics features. We also applied a dedicated tool for computing 24 features describing the whole skeleton asset. The redundancy reduction was realized via correlation and principal component analysis. Fuzzy clustering (FC) and Hough transform filtering (HTF) allowed for patient stratification, with effectiveness assessed by four skill scores. The highest sensitivity and critical success index (CSI) were obtained representing each patient, with 17 focal features selected via correlation with the 24 features describing the overall skeletal asset. These scores were higher than the ones associated with a standard cytogenetic classification. The Mann–Whitney U-test showed that three among the 17 imaging descriptors passed the null hypothesis. This AI-based interpretation of radiomics features stratified relapsed and non-relapsed MM patients, showing some potentiality for the determination of the prognostic image-based biomarkers in disease follow-up.

To ensure that observed differences in the scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) reflect actual differences in health-related quality of life (HRQoL) rather than measurement bias, measurement invariance needs to be established. We investigated the assumption of measurement invariance of the EORTC QLQ-C30 in patients with hematological malignancies across age, sex, comorbidity, disease type, and time. We used a large database of patients with hematological malignancies, which included HRQoL data collected with the EORTC QLQ-C30. We used the structural equation modeling approach to test for measurement (metric and scalar) invariance across groups (age, sex, comorbidity, disease) and time (baseline, 1 month and 2 month follow-up). Longitudinal invariance was examined in a subgroup of patients diagnosed with myelodysplastic syndromes. Confirmatory factor analyses demonstrated full measurement invariance for age and comorbidity and over time, while support for partial scalar invariance was obtained for sex and disease. Violations of invariance for sex were observed for items of the physical functioning scale and the emotional functioning scale, while for disease type, violations of invariance were observed for items of the physical functioning scale, emotional functioning scale, and the cognitive functioning scale. Our findings support measurement invariance of the EORTC QLQ-C30 in a large sample of patients with hematological malignancies. The results showed that the number of non-invariant items was negligible, suggesting that this questionnaire is a valid and robust measurement tool in patients with hematological malignancies, also for comparisons across groups and time.

This is an update on acute and chronic graft-versus-host disease (GvHD) in 425 patients with hematologic malignancies, undergoing an unmanipulated haploidentical (HAPLO) graft from related donors, with a modified post-transplant cyclophosphamide (PT-CY) regimen. All patients received a myeloablative conditioning regimen, either based on thiotepa busulfan fludarabine (TBF), or on full-dose total body irradiation (TBI). The cumulative incidence of acute GvHD-grade II-IV was 29%, and the CI of GvHD-grade III-IV was 4%. We found older donors and older patients to have higher rates of grade II-IV acute GvHD; female donors, diagnosis, disease phase, year of transplant, and the conditioning regimen had no predictive effect on acute GvHD. There was no impact of grade II GvHD, but a significant impact of grade III-IV acute GvHD, on overall survival. The CI of moderate-severe chronic GvHD was 18%: the major predictor was a previous acute GvHD, followed by combined donor and recipients age. In conclusion, PT-CY given on days+3 + 5 results in a relatively low, but not insignificant risk of acute and chronic GvHD, in patients grafted from the related HAPLO donors. The use of young donors appears to reduce this risk.

Background Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients. Objectives To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity. Methods From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity. Results A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64–8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023–0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P Conclusions Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Diagnosis of invasive aspergillosis (IA) is challenging, particularly in high-risk patients with lung lesions other than typical according to 2008-EORTC/MSG criteria. Even if microbiology is positive, they still remain unclassified according to 2008-EORTC/MSG. Quantitative polymerase chain reaction (qPCR) provides new mycological documentation of IA. This retrospective study assessed Aspergillus fumigatus real time qPCR (MycoGENIE®) in BAL to diagnose IA and identify azole-resistant strains. Clinical, radiological, and microbiological data from 114 hematology patients (69% HSCT recipients; 29% on mould active agents) from years 2012-2017 were collected; and 123 BAL samples were tested with qPCR (cutoff: Ct < 40) and galactomannan (GM, Platelia®, cutoff: 0.5 ODI). Patients were classified as proven/probable, possible, and no-IA. "Atypical-IA" referred to patients with lesions other than typical according to 2008-EORTC/MSG and positive mycology. Proven IA was diagnosed in two cases (1.6%), probable in 28 (22.8%), possible in 27 (22%), atypical in 14 (11.4%). qPCR was positive in 39 samples (31.7%). Sensitivity and specificity of qPCR for proven/probable IA (vs no-IA; atypical-IA excluded) were 40% (95% confidence interval [CI]: 23–59) and 69% (95%CI: 55–81), respectively. Sensitivity of qPCR was higher when combined with GM (83%, 95%CI: 65–94) and in those receiving mould-active agents at BAL (61%, 95%CI: 32–86). One sample had TR34/L98H mutation. In conclusion, in high-risk hematology patients with various lung lesions, A. fumigatus qPCR in BAL contributes to diagnosing IA, particularly if combined with GM and in patients receiving mould-active agents might allow detecting azole-resistant mutations in culture negative samples.

International audience; Therapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains heterogeneous. We retrospectively analyzed 216 patients undergoing a second allo-HCT for either relapse (56%) or graft failure (31%) between 2010 and 2017. Median age was 57.3 years (range 51–63). The same donor as for the first allo-HCT was chosen in 66 patients (31%) of whom 19 received an HLA-identical sibling donor, whereas a different donor was chosen for 116 patients (54%). Median follow-up was 40 months. Three-year overall survival (OS) and relapse-free survival (RFS) were 42% and 39%, respectively. Three-year non-relapse mortality (NRM) and relapse rates were 36% and 25%, respectively. Grade II-IV and III-IV acute GVHD occurred in 25% and 11% of patients, respectively, and the 3-year incidence of chronic GVHD was 33% including 14% for extensive grade. Graft-failure incidence at 1 year was 14%. In conclusion, our data suggest that a second allo-HCT is a potential option for patients failing first allo-HCT for MF albeit careful patient assessment is fundamental to identify individual patients who could benefit from this approach.

We compared transplant outcomes of 708 acute myeloid leukemia (AML) patients receiving haploidentical allogeneic hematopoietic-cell transplantation using thiotepa/busulfan/fludarabine (TBF) conditioning with posttransplant cyclophosphamide (ptCy), to 2083 patients receiving matched unrelated donor (MUD) transplantation using fludarabine/busulfan (FB) conditioning and in vivo T-cell depletion. For intermediate cytogenetic risk AML transplanted in first complete remission (CR1), multivariate analysis revealed that haplo-TBF significantly increased nonrelapse mortality (NRM) (HR 2.1; p = 0.0006) but did not affect relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), or graft-versus-host disease-free, relapse-free survival (GRFS). For high cytogenetic risk AML transplanted in CR1, haplo-TBF significantly increased NRM (HR = 2.7; p = 0.02), decreased RI (HR = 0.45; p = 0.03) but had no influence on LFS, OS, or GRFS. For AML transplanted in CR2, haplo-TBF significantly increased NRM (HR = 2.36; p = 0.008), decreased RI (HR = 0.38; p = 0.005), but had no influence on LFS, OS, or GRFS. Finally, for AML patients transplanted with active disease, haplo-TBF had no influence on transplant outcomes. In conclusion, compared to MUD-FB, haplo-TBF increased NRM, reduced RI in high-risk AML in CR, resulting in similar LFS, OS, and GRFS. These results comparing two different approaches support the use of a haploidentical family donor for high-risk AML patients lacking a matched sibling donor.

We performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis between 1995 and 2018 across 278 centres. Activity increased steadily across the four analysed eras (

PURPOSE Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations ( SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia–like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.

Purpose: Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor. Experimental Design: We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy. Results: The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2–4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival. Conclusions: The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.

Objectives: Limited data is available on HCV directly acting agents (DAAs) in haematopoietic stem cell transplant (HSCT) recipients. This study aimed at reporting the characteristics, treatment practices and treatment efficacy in HSCT recipients with chronic HCV. Methods: Prospective observational study from EBMT Infectious Diseases Working Party (IDWP). Patients with chronic HCV infection were included. Results: Between 12/2015 and 07/2018, 45 patients were included: male in 53%; median age 49 years (range, 8-75); acute leukaemia in 48.9%, lymphoma in 17.7%, non-malignant disorders in 22.3%; allogeneic HSCT in 84%; 77.8% no immunosuppressive treatment. Genotypes 1, 2, 3 and 4 were detected in 54.5%, 20.5%, 13.6% and 11.4%, respectively; advanced fibrosis in 40%, including cirrhosis in 11.4%. Overall, 37 (82.2%) patients received DAAs, at a median of 8.4 years after HSCT (16.2% within 6 months from HSCT). Sofosbuvir-based treatment was given to 62.2%. Thirty-five patients completed planned treatment course, with sustained virological response (SVR) of 89.1%, and 94.3% (33/35) in those who completed the treatment. Side effects possibly related to DAAs were reported in 5 (14%) and did not require treatment discontinuation. Conclusions: DAAs treatment was effective, saf e and feasible in this cohort of mainly allogeneic HSCT recipients with mild/moderate liver damage. (c) 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

We report the outcome of 19 patients who experienced primary graft failure (PrGF) after a haploidentical (HAPLO), unmanipulated bone marrow transplant. The median age of patients was 52 years; the conditioning regimen of the first HAPLO transplant was either full dose total body irradiation (TBI) or fludarabine, busulfan, and thiotepa (TBF); PTCY was given to all patients together with cyclosporine and mycophenolate. All 19 patients with PrGF received a second HAPLO graft, at a median interval of 42 days (34–82) after HSCT, using the Baltimore protocol and G-CSF mobilized PB from the same (n = 13) or another HAPLO family donor (n = 6). GvHD prophylaxis was again PTCY-based; 14/19 patients had trilineage recovery (74%) and 1-year survival was 66%. Engraftment at second HAPLO was seen in 7/8 patient with, and in 5/7 patients without donor-specific antibodies (DSA). In a multivariate logistic regression analysis on the original group of 503 patients, there was a trend for a reduced dose of busulfan, to increase the risk of PrGF (p = 0.1). In conclusion, patients with PrGF following a HAPLO transplant, can be rescued with a second early HAPLO transplant, using the same or a different donor.

The use of haplo-HCT with posttransplant cyclophosphamide (PT-Cy) is a new standard in the treatment of hematological diseases. A paucity of data exists on risk factors for engraftment failure in haplo-HCT with PT-Cy. We analyzed 1939 adults with acute myeloid leukemia (AML) who received a first haplo-HCT from 2010 to 2019. Status at haplo-HCT was first complete remission (CR1) in 72.5% of patients, secondary AML was reported in 9.9%. Median follow-up was 24.4 months and median age at haplo-HCT was 51 years. Stem cell source was bone marrow (BM) in 42% and peripheral blood stem cell (PBSC) in 58%, and 64% of patients received a myeloablative conditioning (MAC) regimen. Cumulative incidence of primary graft failure (GF) was 6%; GF was reported in 110 patients and 54 died before day +30 with no sign of cell recovery. Overall, 33 patients underwent a second HCT in a median time of 45 days and 13 were alive at last follow-up, the 2-year overall survival (OS) after second HCT being 32.4%. In multivariate analysis, factors independently associated with the risk of nonengraftment were: secondary AML (HR 1.30, p = 0.003), use of RIC (HR 1.22, p

The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01- 2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14- 0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P < .001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P < .001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P = .004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival.

Background There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). Methods We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. Results Median age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. Conclusions Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

BACKGROUND Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.

Optimal donor choice for a second allogeneic hematopoietic cell transplant (allo-HCT) in relapsed acute lymphoblastic leukemia (ALL) remains undefined. We compared outcomes using HLA-matched unrelated donors (MUD) versus haploidentical donors in this population. Primary endpoint was overall survival (OS). The MUD allo-HCT group comprised 104 patients (male = 56, 54%), median age 36 years, mostly (76%) with B-cell phenotype in complete remission (CR) (CR2/CR3 + = 76, 73%). The 61 patients (male = 38, 62%) in the haploidentical group were younger, median age 30 years (p = 0.002), had mostly (79%) a B-cell phenotype and the majority were also in CR at time of the second allo-HCT (CR2/CR3 + = 40, 66%). Peripheral blood stem cells was the most common cell source in both, but a significantly higher number in the haploidentical group received bone marrow cells (26% vs. 4%, p < 0.0001). A haploidentical donor second allo-HCT had a 1.5-fold higher 2-year OS (49% vs. 31%), albeit not statistically significant (p = 0.13). A longer time from first allo-HCT to relapse was associated with improved OS, leukemia-free survival, graft-versus-host disease-free-relapse-free survival, and lower cumulative incidences of relapse and non-relapse mortality. Results suggest no major OS difference when choosing either a MUD or haploidentical donor for ALL patients needing a second allo-HCT.

Introduction Acute and chronic graft vs. host disease (a/cGVHD) are major causes of treatment failure and non-relapse mortality (NRM) in multiple myeloma (MM) patients (pts) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Use of post-transplant cyclophosphamide (PTCy) is now an established method for GVHD prophylaxis after HLA haplo-identical (haplo)-HCT. We previously reported data in MM pts undergoing haplo-HCT (EBMT/CIBMTR) and showed that PTCy was associated with promising overall survival (OS) (Sahebi et al., BBMT 2019). However, data using PTCy for GVHD prophylaxis in other donor types are very limited in MM. Methods We evaluated PTCy as GVHD prophylaxis in MM pts who underwent a first allo-HCT using matched related (MRD), matched unrelated (MUD), mismatched related or unrelated (MMRD/MMUD, one antigen), and haplo donors within EBMT centers. OS and progression free survival (PFS) were determined by means of the Kaplan-Meier estimator. Neutrophil and platelet engraftment, relapse and NRM, and a/cGVHD were analyzed individually in a competing risks framework with relapse and death as competing events. Cox proportional hazards regression was used in the multivariable analyses. All estimates include 95% confidence intervals. All included covariates are listed in the Table. Patient Characteristics Between 2012-2018, a total of 295 MM pts received PTCy as GVHD prophylaxis. Median age at transplant was 55 yrs. Allo-HCT was given at a median interval of 34.9 mo from MM diagnosis. The conditioning regimen included reduced intensity (RIC, 193, 65.4%) and myeloablative (MAC, 102, 34.6%). All pts except 10 (3.4%) had prior autologous HCT; all of these 10 pts received a haplo-HCT. GVHD prophylaxis included PTCy + cyclosporine A or tacrolimus +/- mycophenolate mofetil in the majority of patients (239, 81%), and this combination was used in nearly every patient with haplo-HCT. Overall, peripheral blood was used as the stem cell source in about 80% of pts, but bone marrow was used in nearly 40% of haplo-HCTs. Results (Median and 95% confidence interval are provided)1) Median time to neutrophil engraftment was 19 d (18-19 d) with no apparent difference among donor types.2) Median time to platelet engraftment was 23 d (21-26 d), whereas haplo-HCT engraftments were longer (27 d (25-33 d)).3) NRM at 1 yr was 18% (12-22%) and at 2 yrs was 19% (14-24%), with no significant difference among different donor types. Age < 50 yrs significantly decreased NRM to 9% (2-16%, p=0.027) at 2 yrs.4) Cumulative incidence of grade II-IV aGVHD at +100 d was 30% (25-36%), and 1 yr cGVHD was 27% (21-32%), with no apparent difference among donor types.5) OS was 63% (57-69%) at 1 yr and 51% (45-58%) at 2 yrs for the whole group, with no statistical difference among different donor types after a median follow-up of 26.1 mo. Disease status at transplant < PR significantly decreased OS to 35% (22-47%, p=0.005) at 2 yrs.6) PFS was 42% (36-49%) at 1 yr and 26% (20-32%) at 2 yrs for the whole group without apparent significant difference among donor types. Disease status at transplant < PR significantly decreased PFS to 16% (6-26%, p=0.028) at 2 yrs.7) However, in multivariable analyses, donor type using haplo, HR 1.65 (0.56-1.67, p=0.03), was associated with increased mortality in addition to disease status at allo-HCT < PR, HR 1.93 (1.25-2.97, p=0.003). Finally, MUD was associated with an improved PFS, HR=0.63 (0.4-0.99, p=0.04). Disease status < PR, HR=1.85 (1.24-2.74, p=0.002) was again associated with inferior PFS. Summary PTCy in MM patients undergoing allo-HCT throughout donor types resulted in a low incidence of aGVHD grade II-IV of 30% and cGVHD of 27%, with OS of 51% and PFS of 26% at 2 yr. Our first donor comparison using PTCy revealed improved survival in matched (MRD and MUD) versus haplo allo-HCT after adjusting for other risk factors. Disclosures Blaise: Jazz Pharmaceuticals: Honoraria. Tarella:TG-therapeutics: Research Funding; ImmunoGen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Milpied:Roche: Honoraria, Other: Travel support; Astellas: Honoraria; Gilead Sciences: Other: consultancy or advisory role; Celgene: Other: Travel support; Sandoz: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Schonland:Janssen: Honoraria, Other: travel support to meetings, Research Funding; Prothena: Honoraria, Other: travel support to meetings, Research Funding; Takeda: Honoraria, Other: travel support to meetings, Research Funding.

Donor selection contributes to improve clinical outcomes of T-cell–replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.

Recently, after years of research often characterized by disappointments and frustrations, finally a new drug impacting on pathological human erythropoiesis has been developed and approved. This drug, luspatercept-aamt (Reblozyl), proved to be effective in both malignant and nonmalignant disease characterized by ineffective erythropoiesis with consequent life-threatening severe anemia. Moreover, for the first time, a medication demonstrated efficacy and effectiveness in β-thalassemia where no other drug, including recombinant human erythropoietin, showed effectiveness in improving anemia. Despite recent impressive advances in understanding human normal and abnormal erythropoiesis, there are few new drugs and limited pharma research focusing on ineffective erythropoiesis. This review will discuss recent advances in understanding normal and pathological erythropoiesis that represent the background to discuss pharmacology, toxicology, efficacy, safety and effectiveness of this new drug for the treatment of human β-thalassemia.

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We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

Background Optimal myeloablative conditioning (MAC) in the setting of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is unknown. We studied the outcomes of total body irradiation (TBI) vs. chemotherapy (CT) based MAC regimens in acute myelogenous leukemia (AML) pts undergoing haplo-HCT and reported to EBMT. Methods The study included 1008 AML pts who underwent haplo-HCT during 2010-2018, following TBI (n=89, 9%) or CT (n=919, 91%) based MAC. Regimen intensity was defined by EBMT criteria and the cases with busulfan dose Results In univariate analysis, day 100 incidence of acute GVHD (aGVHD) II-IV and III-VI was 22% vs. 27% (p-0.44) and 12% vs. 12% (p-0.92) in TBI and CT cohorts, respectively. Two-yr total and severe chronic GVHD (cGVHD) incidence were 42% vs. 27% (p In a subgroup analysis of pts Conclusions In this large relatively homogenous cohort of AML patients who received haplo-HCT with PTCy, TBI based MAC was associated with higher incidence of overall cGVHD without impacting other transplant outcomes compared to CT based MAC. A prospective study is needed to validate these findings.

We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.

Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity.We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib.During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death.First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.