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A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients., (© 2024. The Author(s).)

Background: Information about follow-up care in blood cancer survivors is limited. The questionnaire-based "Aftercare in Blood Cancer Survivors" (ABC) study aimed to identify patterns of follow-up care in Germany and compare different types of follow-up institutions., Methods: The study's 18-month prospective part compared the follow-up institutions identified in the preceding retrospective part (academic oncologists, community oncologists, primary care physicians). The questionnaires were completed by the follow-up physicians., Results: Of 1070 physicians named by 1479 blood-cancer survivors, 478 (44.7%) consented to participate. For provision of care, most oncologists relied on published guidelines, while most primary care physicians depended on information from other physicians. Survivors with a history of allogeneic transplantation or indolent lymphoma were mainly seen by academic oncologists, whereas survivors with monoclonal gammopathy, multiple myeloma, or myeloproliferative disorders were often seen by community oncologists, and survivors with a history of aggressive lymphoma or acute leukemia by primary care physicians. Detection of relapse and secondary diseases was consistently viewed as the most important follow-up goal. Follow-up visits were most extensively documented by academic oncologists (574 of 1045 survivors cared for, 54.9%), followed by community oncologists (90/231, 39.0%) and primary care physicians (51/203, 25.1%). Relapse and secondary disease detection rates and the patients' quality of life were similar at the three institutions. Laboratory tests were most often ordered by academic oncologists, and imaging by primary care physicians. Psychosocial issues and preventive care were more often addressed by primary care physicians than by oncologists., Conclusions: Patients at high risk of relapse or late complications were preferentially treated by academic oncologists, while patients in stable condition requiring continuous monitoring were also seen by community oncologists, and patients with curable diseases in long-term remission by primary care physicians. For the latter, transfer of follow-up care from oncologists to well-informed primary care providers appears feasible., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Blood cancer survivors are at increased risk for medical complications., Methods: Our questionnaire-based study involved 1,551 blood cancer survivors with a ≥3-year interval since the last intense treatment. Its goal was to quantify health-related complications during follow-up and assess their impact on the patients' lives., Results: A total of 20.4% of the responding survivors reported a disease relapse, most often in indolent lymphomas. Second primary malignancies occurred in 14.1%, primarily in lymphoma and allogeneic transplantation survivors. The most frequent malignancy was basal cell carcinoma of the skin, but myeloid malignancies, melanoma, bladder, head-and-neck, and thyroid cancer also appeared disproportionately frequent. An increased infection rate was reported by 43.7%, most often after allogeneic transplantation. New cardiovascular diseases were reported by 30.2%, with a high rate of thromboembolic events in multiple myeloma (MM) and myeloproliferative diseases. Polyneuropathies were reported by 39.1%, most often by survivors with a history of MM or aggressive lymphoma. Disease relapse was perceived as the highest burden, followed by second primary malignancy, increased infection frequency, and polyneuropathy. In each area investigated, the range of perceived severities was wide., Conclusions: Health-related complications are frequent during blood cancer follow-up, with significant repercussions on the patients' lives., (© 2024 S. Karger AG, Basel.)

Background: Acute graft-versus-host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification., Methods: In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II-IV aGvHD within 100 days post-HSCT., Results: Using a dynamic longitudinal time-to-event model, we observed a non-monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11 days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II-IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II-IV aGvHD within 100 days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades II-IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios., Conclusion: Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Little is known about changes in the personal living conditions of long-term blood cancer survivors in Germany. To gather information about social relationships, work life, overall well-being, and religion, we performed a questionnaire-based retrospective study on 1551 survivors who had been on follow-up for ≥ 3 years (median, 9 years). Most survivors reported that marital status and relationships with relatives and friends remained constant before and after blood cancer. Vocational activities were temporarily impaired for 47.5%, with a median time of 11 months to return to work. More than a third of the patients (35.6%) discontinued work permanently, with disability and retirement pension rates of 7.9% and 38.1%, respectively, at the time of the survey. Financial problems due to reduced income were reported by 26.2%, in particular after relapse or allogeneic transplantation. Patient reports addressing their quality of life showed large variations. It was best in acute leukemia survivors without a history of allogeneic transplantation and worst in patients with myeloproliferative disorders. Religion tended to become more important after blood cancer. In conclusion, vocational impairment and financial problems are frequent among German blood cancer survivors. Efforts should be made at an early stage to reestablish the patients' ability to work., (© 2023. The Author(s).)

Despite advances in allogeneic hematopoietic cell transplantation, acute graft-versus-host disease (aGVHD) remains its leading complication, yet with heterogeneous outcomes. Here, we analyzed aGVHD phenotypes and clinical classifications in depth in large, multicenter cohorts involving 3019 patients and addressed prevailing gaps by developing data-driven models. We compared, tested and verified these along with all conventional classifications in independent cohorts and found that data-driven grading outperformed conventional grading in Akaike information criterion and concordance index metrics. Data-driven classifications refined aGVHD assessment with up to 12 severity grades, which were associated with distinct nonrelapse mortality (NRM) and confirmed the key role of intestinal aGVHD. We developed an online calculator for physicians to implement principal component-derived grading (PC1). These results provide substantial insight into the evaluation of aGVHD phenotypes and multiorgan involvement, which relegates the exclusive reporting of overall aGVHD severity grades in transplant registries and clinical trials. Data-driven aGVHD grading provides an expandable platform to refine classification and transplant risk assessment., (© 2023. The Author(s).)

Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update the initial population PK model by inclusion of additional 83 pediatric PK profiles from these 2 trials. The final population PK model was 2-compartmental with dosing in the central compartment, linear elimination, and inter-compartmental clearance. Inter-individual variability was included on clearance (CL), central volume (V1), peripheral volume (V2), and inter-compartmental clearance (Q). The final model described an effect of the body surface area (BSA) on CL, V1, V2, and Q. The final model resulted in a modified dose recommendation for children and advises treosulfan doses of 10 g/m 2 , 12 g/m 2 , and 14 g/m 2 for BSAs of <0.4 m 2 , ≥0.4 to <0.9 m 2 , and ≥0.9 m 2 , respectively. This simplified BSA-dependent dose recommendation was developed for children, ensuring a well comparable treosulfan exposure as a dose of 14 g/m 2 in adults - irrespective of their age and without applying individual therapeutic drug monitoring., Competing Interests: Declaration of competing interest XL, JK, AKM, and JB are employees of medac GmbH. All other authors declare no conflict of interest., (Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: Blood cancer survivors are at increased risk for second primary malignancies, cardiovascular diseases, and infections. Little is known about preventive care in blood cancer survivors., Methods: Our questionnaire-based study included blood cancer patients diagnosed at the University Hospital of Essen before 2010, with a ≥ 3-year interval from the last intense treatment. One section of the retrospective study covered preventive care (cancer screening, cardiovascular screening, vaccination)., Results: Preventive care was delivered by a general practitioner for 1100 of 1504 responding survivors (73.1%), by an oncologist for 125 (8.3%), by a general practitioner together with an oncologist for 156 (10.4%), and by other disciplines for 123 (8.2%). Cancer screening was more consistently performed by general practitioners than by oncologists. The converse was true for vaccination, with particularly high vaccination rates in allogeneic transplant recipients. Cardiovascular screening did not differ between care providers. Cancer and cardiovascular screening rates in survivors eligible for statutory prevention programs were higher than in the general population (skin cancer screening 71.1%; fecal occult blood testing 70.4%; colonoscopy 64.6%; clinical breast examination 92.1%; mammography 86.8%; cervical smear 86.0%; digital rectal examination 61.9%; blood pressure test 69.4%; urine glucose test 54.4%; blood lipid test 76.7%; information about overweight 71.0%). The Streptococcus pneumoniae vaccination rate was higher (37.0%) and the influenza vaccination rate was lower (57.0%) than in the general population., Conclusions: Utilization of preventive care is high among German blood cancer survivors. To ensure widespread delivery and avoid redundancy, communication between oncologists and preventive care providers is essential., (© 2023. The Author(s).)

Background: Follow-up care provides long-term support for cancer survivors. Little is known about follow-up care in hematologic malignancies., Methods: Our questionnaire-based study included blood cancer survivors diagnosed at the University Hospital of Essen before 2010, with a ≥ 3-year interval since the last intense treatment. The primary goal of the retrospective study was the identification and characterization of follow-up institutions., Results: Of 2386 survivors meeting the inclusion criteria, 1551 (65.0%) consented to participate, with a follow-up duration > 10 years in 731. The university hospital provided care for 1045 participants (67.4%), non-university oncologists for 231 (14.9%), and non-oncological internists or general practitioners for 203 (13.1%). Seventy-two participants (4.6%) abstained from follow-up care. The disease spectrum differed among follow-up institutions (p < 0.0001). While allogeneic transplant recipients clustered at the university hospital, survivors with monoclonal gammopathy, multiple myeloma, myeloproliferative disorders, or indolent lymphomas were often seen by non-university oncologists, and survivors with a history of aggressive lymphoma or acute leukemia by non-oncological internists or general practitioners. Follow-up intervals mirrored published recommendations. Follow-up visits were dominated by conversations, physical examination, and blood tests. Imaging was more often performed outside than inside the university hospital. Satisfaction with follow-up care was high, and quality of life was similar in all follow-up institutions. A need for improvement was reported in psychosocial support and information about late effects., Conclusions: The naturally evolved patterns identified in the study resemble published care models: Follow-up clinics for complex needs, specialist-led care for unstable disease states, and general practitioner-led care for stable conditions., (© 2023. The Author(s).)

Introduction: Anti-T-lymphocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy) prevent graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT), yet individual patients benefit differentially., Methods: Given the sparse comparative data on the impact of cellular immune reconstitution in this setting, we studied flow cytometry and clinical outcomes in 339 recipients of 10/10 matched-unrelated donor (MUD) HCT using either ATG (n=304) or PTCy (n=35) for in vivo T cell manipulation along with a haploidentical PTCy control cohort (n=45). Longitudinal cellular immune reconstitution data were analyzed conventionally and with a data science approach using clustering with dynamic time warping to determine the similarity between time-series of T cell subsets., Results: Consistent with published studies, no significant differences in clinical outcomes were observed at the cohort level between MUD-ATG and MUD-PTCy. However, cellular reconstitution revealed preferences for distinct T cell subpopulations associating with GVHD protection in each setting. Starting early after HCT, MUD-PTCy patients had higher regulatory T cell levels after HCT (p <0.0001), while MUD-ATG patients presented with higher levels of γδ T- or NKT cells (both p <0.0001). Time-series clustering further dissected the patient population's heterogeneity revealing distinct immune reconstitution clusters. Importantly, it identified phenotypes that reproducibly associated with impaired clinical outcomes within the same in vivo T cell manipulation platform. Exemplarily, patients with lower activated- and αβ T cell counts had significantly higher NRM (p=0.032) and relapse rates (p =0.01)., Discussion: The improved understanding of the heterogeneity of cellular reconstitution in MUD patients with T cell manipulation both at the cohort and individual level may support clinicians in managing HCT complications., Competing Interests: ATT: Consultancy for CSL Behring and Maat Pharma. DB received travel subsidies from Medac, all outside the submitted work. HCR received consulting and lecture fees from Abbvie, AstraZeneca, Vertex, Novartis, and Merck. HCR received research funding from Gilead Pharmaceuticals and AstraZeneca. HCR is a co-founder and shareholder of CDL Therapeutics GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Leserer, Graf, Franke, Bogdanov, Arrieta-Bolaños, Buttkereit, Leimkühler, Fleischhauer, Reinhardt, Beelen and Turki.)

Allogeneic hematopoietic stem cell transplantation (HCT) is standard treatment for adult high-risk (HR) acute lymphoblastic leukemia (ALL) and contributed to the overall improved outcome. We report a consecutive cohort of prospectively defined HR patients treated on German Multicenter Acute Lymphoblastic Leukemia trials 06/99-07/03 with similar induction/consolidation therapy and HCT in first remission. A total of 542 patients (15-55 years) with BCR-ABL-negative ALL were analyzed. Sixty-seven percent received HCT from matched unrelated donors (MUD) and 32% from matched sibling donors (MSD). The incidence of non-relapse mortality (NRM) was 20% at 5 years. NRM occurred after median 6.6 months; the leading cause (46%) was infection. NRM after MUD decreased from 39% in trial 06/99 to 16% in trial 07/03 (P < .00001). Patient age was the strongest predictor of NRM. The 5-year relapse incidence was 23% using MSD and 25% using MUD. Minimal residual disease (MRD) was the strongest predictor of relapse (45% for molecular failure versus 6% for molecular CR; P < .0001). The median follow-up was 67 months, and the 5-year survival rate was 58%. Age, subtype/high risk feature, MRD status, trial and acute GvHD were significant prognostic factors. We provide a large reference analysis with long follow-up confirming a similar outcome of MSD and MUD HCT and improved NRM for MUD HCT over years. MRD has a strong impact on relapse risk, whereas age was the strongest predictor of NRM. New adapted conditioning strategies should be considered for older patients combined with the goal to reduce the MRD level before stem cell transplantation., Competing Interests: Declaration of Competing Interest M.B. received personal fees from Incyte (advisory board) and Roche Pharma AG, financial support for reference diagnostics from Affimed and Regeneron, grants and personal fees from Amgen (advisory board, speakers bureau, travel support), and personal fees from Janssen (speakers bureau). G.K. received research funding from Celgene and Amgen, Lecture fees, advisory board fees and travel support from Celgene, Amgen, Pfizer, Jazz, Neovii, Takeda, Medac, Biotest, Eurocept, MSD, Roche, Iqone, Novartis, Gilead and Abbvie N.A received honoraria for lectures from Amgen; honoraria for advisory board from Gilead, MSD Sharp & Dohme GmbH, Pfizer, Amgen, Travel grant from Gilead, MSD Sharp & Dohme GmbH, Pfizer and Amgen. N.G. received speaker honoraria, travel support or advisory board fees from Amgen, Celgene, Gilead, Novartis, Pfizer, Jazz Pharmaceuticals, Incyte, Cellestia, Erytech and Morphosys and research support (institution) from Amgen, Pfizer, Novartis, Shire/Servier, Jazz Pharmaceuticals and Incyte., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (HCT) effectively treats high-risk hematologic diseases but can entail HCT-specific complications, which may be minimized by appropriate patient management, supported by accurate, individual risk estimation. However, almost all HCT risk scores are limited to a single risk assessment before HCT without incorporation of additional data. We developed machine learning models that integrate both baseline patient data and time-dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These gradient boosting machine models provide well-calibrated, time-dependent risk predictions and achieved areas under the receiver-operating characteristic of 0.92 and 0.83 and areas under the precision-recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21-day time window. Both models were successfully validated in a prospective, non-interventional study and performed on par with expert hematologists in a pilot comparison., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Measurable residual disease (MRD) assessment before allogeneic hematopoietic cell transplantation (HCT) may help physicians to identify a subgroup of patients at high risk of relapse for de novo acute myeloid leukemia (AML) but its relevance among patients affected by secondary AML (sAML) is still unknown. We assessed the impact of MRD among 318 adult patients with sAML who received an allogeneic HCT in first complete remission. At the time of HCT, a total of 208 (65%) patients achieved MRD negativity, while 110 (35%) had positive MRD. 2-year overall survival (OS) was 58.8 % (95% CI 52.2-64.9) with leukemia-free survival (LFS) of 50.0 % (95% CI 43.7-56.1), relapse incidence of 34.2% (95% CI 28.4-40.1) and non-relapse mortality (NRM) of 23.3 % (95% CI 19-27.7) for the entire cohort. In multivariate analysis, HCT recipients with KPS ≥ 90 experienced less disease recurrence (HR 0.61, 95% CI 0.4-0.94) with better LFS (HR 0.63, 95% CI 0.44-0.89) and OS (HR 0.58, 95% CI 0.39-0.86). There were no differences in major clinical endpoints between patients with MRD-positive and MRD-negative status at the time of HCT. Pre-transplantation assessment of MRD was not informative on post-HCT outcomes in this retrospective registry-based analysis among patients affected by sAML., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients., (© 2022 by The American Society of Hematology.)

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m 2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies., (© 2022 by The American Society of Hematology.)

Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies ( n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59-0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT.

Aims: The aim of this work is the development of a mechanistic physiologically-based pharmacokinetic (PBPK) model using in vitro to in vivo extrapolation to conduct a drug-drug interaction (DDI) assessment of treosulfan against two cytochrome p450 (CYP) isoenzymes and P-glycoprotein (P-gp) substrates., Methods: A PBPK model for treosulfan was developed de novo based on literature and unpublished clinical data. The PBPK DDI analysis was conducted using the U.S. Food and Drug Administration (FDA) DDI index drugs (probe substrates) midazolam, omeprazole and digoxin for CYP3A4, CYP2C19 and P-gp, respectively. Qualified and documented PBPK models of the probe substrates have been adopted from an open-source online model database., Results: The PBPK model for treosulfan, based on both in vitro and in vivo data, was able to predict the plasma concentration-time profiles and exposure levels of treosulfan applied for a standard conditioning treatment. Medium and low potentials for DDI on CYP3A4 (maximum area under the concentration-time curve ratio (AUCR max  = 2.23) and CYP2C19 (AUCR max  = 1.6) were predicted, respectively, using probe substrates midazolam and omeprazole. Treosulfan was not predicted to cause a DDI on P-gp., Conclusion: Medicinal products with a narrow therapeutic index (eg, digoxin) that are substrates for CYP3A4, CYP2C19 or P-gp should not be given during treatment with treosulfan. However, considering the comprehensive treosulfan-based conditioning treatment schedule and the respective pharmacokinetic properties of the concomitantly used drugs (eg, half-life), the potential for interaction on all evaluated mechanisms would be low (AUCR < 1.25), if concomitantly administered drugs are dosed either 2 hours before or 8 hours after the 2-hour intravenous infusion of treosulfan., (© 2021 medac GmbH. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse, is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in vivo T cell depletion with antithymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (P = .0002) than for patients in first complete remission (CR1, P = .0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (P = .796), while it inverted its effect into increased relapse for CR1 patients (P = .0428). CMV reactivation was associated with significantly increased nonrelapse mortality in CR1 patients without ATG (P = .0187) but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared with patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between antivirus and antitumor immunity., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4 + helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4 + reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4 + subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38-73.8, p = 0.023), while patients from the R-/very high CD4 + subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12-81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4 + T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.

Programmed cell death protein-1 (PD-1) is an inhibitory co-receptor required for regulating immune responsiveness and maintaining immune homeostasis. As PD-1 can be released as bioactive soluble molecule, we investigated the clinical significance of soluble PD-1 (sPD-1) after allogeneic hematopoietic stem cell transplantation (HSCT) regarding graft-versus-host disease (GvHD), relapse, and overall survival (OS) in a mono-centric cohort of 82 patients. Compared to pre-HSCT and to healthy controls, post-HSCT sPD-1 plasma levels were significantly increased during an observation time of three months. Univariate analysis revealed that low sPD-1 plasma levels at month one, two or three post HSCT were associated with acute GvHD grade III-IV, the onset of moderate/severe chronic GvHD (cGvHD) and inferior OS, DFS, and TRM, respectively. No relationship was detected to relapse rates. sPD-1 plasma levels were significantly increased in ATG-treated patients compared to ATG-untreated patients. Multivariate analysis revealed that a low sPD-1 plasma levels status at one or two month(s) after HSCT is an independent indicator for inferior OS, DFS, or TRM. A low sPD-1 plasma levels status at month three post HSCT is predictive for the onset of moderate/severe cGvHD. Thus, our study pinpoints the soluble inhibitory co-receptor PD-1 as a promising candidate molecule for the prediction of clinical HSCT outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kordelas, Buttkereit, Heinemann, Horn, Giebel, Beelen, Reinhardt and Rebmann.)

Even in the era of PCR-based monitoring, prophylaxis, and preemptive therapy, Cytomegalovirus (CMV) viremia remains a relevant cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, studies using binary analysis (presence/absence of CMV) reported contradicting data for NRM, overall survival and leukemia relapse. Here, we analyzed CMV replication kinetics in 11 508 whole blood PCR samples of 705 patients with HCT between 2012 and 2017. Using two independent models based on CMV peak titers and on the time point of first CMV reactivation, we stratified patients into risk cohorts. Each cohort had distinct cellular immune reconstitution profiles and differentiated for relevant clinical outcomes. Patients with high CMV peak titers had significantly reduced overall survival (HR 2.13, 95% CI 1.53-2.96; p < .0001), due to high NRM. Early impaired T cell reconstitution was a risk factor for high CMV peak titers, however relevant CMV viremia also related to boosted T cell reconstitution. Importantly, intermediate CMV peak titers associated with a significantly reduced relapse probability (HR 0.53, 95% CI 0.31-0.91; p = .022). In short, CMV kinetics models distinguished relevant clinical outcome cohorts beyond the R+ serostatus with distinct immune reconstitution patterns and resolve in part contradicting results of previous studies exclusively focused on the presence or absence of CMV., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The inclusion of mutation status improved risk stratification for newly diagnosed patients with chronic myelomonocytic leukemia (CMML). Stem cell transplantation is a potentially curative treatment option, and patient selection is critical because of relevant transplant-related morbidity and mortality. We aimed to evaluate the impact of mutation status together with clinical presentations on posttransplant outcome. Our study included 240 patients with a median follow-up of 5.5 years. A significant association with worse survival was identified for the presence of mutations in ASXL1 and/or NRAS. In multivariable analysis, ASXL1- and/or NRAS-mutated genotype (hazard ratio [HR], 1.63), marrow blasts >2% (HR, 1.70), and increasing comorbidity index (continuous HR, 1.16) were independently associated with worse survival. A prognostic score (CMML transplant score) was developed, and the following points were assigned: 4 points for an ASXL1- and/or NRAS-mutated genotype or blasts >2% and 1 point each for an increase of 1 in the comorbidity index. The CMML transplant score (range, 0-20) was predictive of survival and nonrelapse mortality (P < .001 for both). Up to 5 risk groups were identified, showing 5-year survival of 81% for a score of 0 to 1, 49% for a score of 2 to 4, 43% for a score of 5 to 7, 31% for a score of 8 to 10, and 19% for a score >10. The score retained performance after validation (concordance index, 0.68) and good accuracy after calibration. Predictions were superior compared with existing scores designed for the nontransplant setting, which resulted in significant risk reclassification. This CMML transplant score, which incorporated mutation and clinical information, was prognostic in patients specifically undergoing transplantation and may facilitate personalized counseling., (© 2021 by The American Society of Hematology.)

In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors are associated with improved outcomes compared with nonpermissive mismatches, but the underlying mechanism is incompletely understood. Here, we used mass spectrometry, T-cell receptor-β (TCRβ) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T-cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared with their nonpermissive counterparts, resulting in lower frequency and diversity of alloreactive TCRβ clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM or the presence of its antagonist, HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT and show that permissiveness is dependent on HLA-DM-mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia., (© 2021 by The American Society of Hematology.)

The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two "reduced-toxicity" regimens: intravenous busulfan at a total dose of 9.6 mg/kg (3 days) + fludarabine (Bu3/Flu) and total body irradiation at a dose of 8 Gy + fludarabine (TBI8Gy/Flu). In the entire study cohort (n = 518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p = 0.051), 59.5% vs. 65% (p = 0.15), 30% vs. 20% (p = 0.01), and 10% vs. 14% (p = 0.18), respectively. In multivariate model for patients <50 years old, TBI8Gy/Flu was associated with improved LFS (hazard ratio (HR) = 0.5, p = 0.04), OS (HR = 0.31, p = 0.004), and survival free from both graft-versus-host disease and relapse (HR = 0.55, p = 0.03), as well as tendency to reduced risk of relapse (HR = 0.53, p = 0.08). Among patients aged 50 years or older the use of TBI8Gy/Flu was associated with increased incidence of NRM (HR = 3.9, p = 0.0009), with no significant impact on other outcome measures. We conclude that the use of TBI8Gy/Flu as "reduced-toxicity" regimen may be advised in younger patients with AML referred for allo-HCT.

The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability.