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Introduction: Chimeric antigen receptor positive T cell (CAR-T cell) treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-Hodgkin's lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in the prevention, diagnosis, and management of short- and long-term complications. Methods: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research, the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. Results: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no – or low quality – clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, IgG substitution, autologous stem cell backups, anti-infective prophylaxis, and vaccinations. Conclusion: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome. [ABSTRACT FROM AUTHOR]

• This article addresses the possible role of allogeneic hematopoietic cell transplantation (allo-HCT) for relapsed and refractory diffuse large B cell lymphoma in the chimeric antigen receptor-engineered T (CART) cell era. • Allo-HCT should be explored for patients failing CART therapy. • Allo-HCT should be considered when CART therapy is not feasible or available. • Allo-HCT and CART outcome data should be collected and analyzed in registries. Chimeric antigen receptor-engineered T (CART) cells are a promising new treatment option for patients with multiply relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL). Because of the favorable outcome data reported for CART cells, uncertainty is emerging if there is still a role for allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of R/R DLBCL. This article provides an overview of available evidence and theoretical considerations to put these 2 types of cellular immunotherapy (CI) into perspective. Altogether, current data suggest that CART cells are preferred now over transplantation as first-choice CI in many clinical situations. However, the majority of patients will fail CART therapy, resulting in an unmet medical need where allo-HCT could be beneficial. In contrast, employing allo-HCT instead of CART cells as first CI should be presently restricted to situations where CART cell therapy is deemed not feasible or useful, such as patients with refractory cytopenia or incipient myelodysplastic syndrome. However, allo-HCT remains a standard treatment option as first CI for patients with chemosensitive R/R DLBCL when CARTs are not available or transplantation is preferred by the patient. Continuous collection and analysis of CI outcome data by professional registries appear to be of key importance for developing rational strategies of CI allocation and sequencing. [ABSTRACT FROM AUTHOR]

High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance (TP53 abnormalities) to treatment with chemoimmunotherapy (CIT).With the availability of pathway inhibitors (PIs), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high-risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI. This category is largely the domain of PI-based therapy, and cellular therapy (ie, allogeneic hematopoietic cell transplantation) remains an option only in selected patients with low individual procedure-related risk. In CLL high-risk-II, CIT- and PI-resistant, characterized by increasing exhaustion of pharmacological treatment possibilities, cellular therapies (including chimeric antigen receptor-engineered T cells) should be considered in patients eligible for these procedures. Moreover, molecular and cellular therapies are not mutually exclusive and could be used synergistically to exploit their full potential. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (HR-CLL; ie, refractory to purine analogs, short response [<24 months] to che-moimmunotherapy, and/or presence of del[17p]/TP53mutations). Currently, treatment algorithms for HR-CLL are being challenged by the introduction of novel classes of drugs. Among them, BCR signal inhibitors (BCRi) and B-cell lymphoma 2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favorable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with HR-CLL about indication for and timing of HSCT. This article provides an overview of currently available evidence and theoretical considerations to guide this difficult decision process. Until the risks and benefits of different treatment strategies are settled, all patients with HR-CLL should be considered for treatment with BCRi/BCL2a. For patients who respond to these agents, there are 2 treatment possibilities: (1) performing an HSCT or (2) continuing treatment with the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when recommending one of these treatments over the other. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the prospective studies on the effect of pretransplant imatinib in patients with blast crisis of chronic myeloid leukemia (BC-CML) after myeloablative allogeneic stem cell transplantation (allo-SCT).

The purpose of this analysis was to provide 6-year follow-up of the CLL3X trial, which studied reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) in patients with poor-risk chronic lymphocytic leukemia (CLL), and to investigate the effect of TP53, SF3B1, and NOTCH1 mutations on HSCT outcome. For 90 allografted patients, 6-year overall survival (OS) was 58% and 6-year event-free survival (EFS) was 38%. TP53, SF3B1, and NOTCH1 mutations were found in 30%, 26%, and 14% of the trial population, respectively. By univariate and multivariate analyses, the mutational status of the TP53, SF3B1, and NOTCH1 genes had no significant effect on OS and EFS. Studies of minimal residual disease confirmed durability of CLL eradication in mutated patients. We conclude that HSCT can provide long-term disease control in patients with poor-risk CLL independent of the presence of TP53, SF3B1, and NOTCH1 mutations. The trial has been registered at the US National Cancer Institute as #EU-20554, NCT00281983. [ABSTRACT FROM AUTHOR]

The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3- 12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 évaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. [ABSTRACT FROM AUTHOR]

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL). In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT) might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies. In addition, autoSCT lacks the potential to overcome the negative impact of biomarkers that confer resistance to chemotherapy or early relapse. The role of autoSCT has also been explored in the context of FCR, and it was demonstrated that its effect is inferior to the currently established optimal treatment regimen. In view of ongoing attempts to improve on FCR, promising clinical activity of new substances even in relapsed/ refractory CLL patients, exciting novel cell therapy approaches and advantages in the understanding of the disease and detection of Minimal Residual Disease (MRD), autoSCT has lost its place as a standard treatment option for CLL. [ABSTRACT FROM AUTHOR]

Despite substantial advancement in the understanding and treatment of chronic lymphocytic leukemia (CLL), a standard curative approach does not exist. The choice of treatment is generally based on the existence of biological and genetic factors associated with the prediction of prognosis, individual response to therapy, and duration of remission. About 20% of patients that require treatment have an aggressive disease course and die within a few years, despite early initiation of intensive therapy (poor-risk CLL). Poor-risk CLL can be predicted by the presence of genomic markers, and the quality and duration of response to purine-analogue-based treatment. Within this patient subgroup alternative treatment approaches such as alemtuzumab or new substances such as flavopiridol or IMiDs® should be considered. To date, the only treatment bearing curative potential is allogeneic stem cell transplantation; in contrast to conventional immunochemotherapy, it can provide long-term disease control, even in patients with del 17p or other unfavorable biological and clinical risk factors. The aim of this review was to outline the current strategies for the diagnosis and management of CLL, with a focus on high-risk CLL. [ABSTRACT FROM AUTHOR]

In advanced follicular lymphoma (FL), autologous stem cell transplant (ASCT) has been studied extensively in an attempt to prolong remission duration and, possibly, achieve ultimate cure. However, increasing evidence of the benefit of rituximab and various other new drugs has questioned the appropriate place of ASCT in the treatment algorithm of FL in recent years. The purpose of this overview is to propose a definition of the potential role of ASCT in the treatment armamentarium of FL in the light of these new treatment options. Taken together, the absence of an overall survival benefit, the risk of secondary malignancies, and the remarkably good prognosis of patients who receive rituximab and ASCT as salvage therapy in the relapse situation make the use of ASCT as initial therapy difficult to justify. In contrast, evidence is accumulating that, in eligible patients with relapsed FL, rituximab-based chemotherapy followed by ASCT might provide superior disease control in comparison to either modality alone, and has curative potential in a subset of patients. However, these considerations are largely based on retrospective analyses and should be confirmed in prospective randomized trials. [ABSTRACT FROM AUTHOR]

Abstract: Mantle cell lymphoma (MCL) and peripheral T cell lymphoma (PTCL) are distinct lymphoma subtypes that each comprise about ∼10% of the non-Hodgkin lymphomas. Although both subtypes are characterized by high remission rates to frontline chemotherapy, the prognosis is generally poor because of inevitable relapse within 1-2 years or less, depending on the specific histology. Patients with MCL who achieve a complete remission with upfront conventional chemotherapy currently have several options for consolidative therapy including maintenance therapy with rituximab, autologous hematopoietic cell transplantation (HCT), and more recently, allogeneic HCT utilizing a reduced intensity conditioning (RIC) regimen. In the autologous HCT setting, the added efficacy of rituximab is under active investigation as a method of in vivo purging during hematopoietic cell mobilization, as part of the conditioning regimen and as post-HCT maintenance therapy. For patients with PTCL, autologous HCT is commonly offered at relapse but there are a few prospective series utilizing autologous HCT as consolidation of CR1 with encouraging results. There is no conclusive evidence regarding the efficacy of allogeneic HCT, but outcomes with RIC regimens appear promising. This review summarizes the current role of HCT for patients with MCL in first remission and for patients with PTCL as consolidation and for relapsed/refractory disease. [Copyright &y& Elsevier]

Purpose: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia.A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality.ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1–26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively.Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome.Methods: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia.A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality.ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1–26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively.Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome.Results: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia.A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality.ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1–26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively.Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome.Conclusions: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia.A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality.ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1–26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively.Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome. [ABSTRACT FROM AUTHOR]

Waldenström's macroglobulinaemia (WM) is an incurable lymphoproliferative disorder. The purpose of this study was to investigate the role of autologous peripheral blood stem cell transplantation (ASCT) for the treatment of WM. Seven patients (untreated or after first-line therapy) with symptomatic WM underwent two or three cycles of Dexa-BEAM chemotherapy + G-CSF with stem cell harvesting and proceeded to total body irradiation and high-dose cyclophosphamide followed by reinfusion of ex-vivo B-cell-depleted stem cells. Engraftment was prompt, and procedure-related deaths did not occur. A strong reduction or normalization of BM infiltration and serum IgM levels occurred in all evaluable patients, but immunofixation electrophoresis revealed persistent paraproteinaemia in five of them. With 3–30 months of follow-up, all patients are alive without clinical or serological signs of disease progression. This pilot trial shows for the first time that high-dose radiochemotherapy with purged stem cells is effective and may improve the course of patients with WM. In the majority of cases, however, complete eradication of the disease does not appear to be possible with ASCT alone. [ABSTRACT FROM AUTHOR]

Introduction: This study explored qualitatively, in a sample of German hematologists working in clinical allogeneic hematopoietic stem cell transplantation (alloHSCT), perceptions of barriers and facilitators to participate in continuous medical education (CME), to provide detailed information on how to improve participation in CME activities related to alloHSCT, which may also be applicable to other areas of medicine. Methods: Based on a recruitment campaign of the German Association for Hematopoietic Stem Cell Transplantation (DAG-HSZT), 21 semi-structured telephone interviews were conducted, transcribed, and analyzed using framework analysis. Results: Three clusters of barriers were identified that explain why alloHSCT physicians may or may not participate in CME: individual constraints (e.g., better networking, young physicians being overwhelmed by the complexity of alloHSCT), structural constraints (e.g., time and financial issues, tailoring CME courses according to the targeted audience), and content-related constraints (e.g., requirement of CME sessions, provision of an overview of CME courses, more flexible offers). We discuss the ten most frequently raised issues, including the use of incentives and the need for support at the start of residency, staff shortages, and requirements for learning sessions. Conclusion: There is a need for a paradigm shift in CME related to alloHSCT toward a more individualized and needs-based approach. Close monitoring of residents' needs and learning progress, as well as feedback systems, could help identify appropriate CME courses that should be integrated into a tiered learning system. CME should be more targeted to specific audiences (i.e., residents, fellows, and attendees) to provide training that is tailored to individual CME needs. On-demand courses can help balance work and family obligations. Finally, peer-reviewed, up-to-date information platforms should be expanded. [ABSTRACT FROM AUTHOR]

Physical capacity prior allogeneic stem cell transplantation (allo-HCT) has been shown as a relevant prognostic factor for survival after transplant. Therefore, we evaluated feasibility and preliminary efficacy of a high-intensity interval training (HIIT) and moderate to high-intensity resistance exercise (RE) to increase physical capacity in patient's prior allo-HCT. In this multicentre single arm pilot study, a supervised exercise program was performed twice weekly for 4–12 weeks prior allo-HCT, depending on the individual time remaining. Outcomes were feasibility (recruitment, adherence, safety), physical capacity (cardiorespiratory fitness [VO2peak], muscle strength) and patient reported outcomes (physical functioning, fatigue). Thirty patients were intended, 16 could be included, and 14 completed post intervention assessment (75% male, 55 ± 11 years). The study was stopped early due to a low recruitment rate. Nine patients (64%) reached the initial minimum planned number of eight exercise sessions. Individual adherence was high with 92% for HIIT and 85% for RE. 87% of all performed exercise sessions were completed without complaints and VO2peak increased significantly from 20.4 to 23.4 ml/kg/min. The low recruitment rate suggests that initiation of the intervention concept immediately before allo-HCT is feasible only in a small number of patients. In particular, the timeframe directly prior allo-HCT seems too short for exercise interventions, although the exercise program was designed to improve outcomes in a very short time frame. HIIT and RE were feasible, effective and well accepted by the included patients. [ABSTRACT FROM AUTHOR]

Physical capacity prior allogeneic stem cell transplantation (allo-HCT) has been shown as a relevant prognostic factor for survival after transplant. Therefore, we evaluated feasibility and preliminary efficacy of a high-intensity interval training (HIIT) and moderate to high-intensity resistance exercise (RE) to increase physical capacity in patient's prior allo-HCT. In this multicentre single arm pilot study, a supervised exercise program was performed twice weekly for 4–12 weeks prior allo-HCT, depending on the individual time remaining. Outcomes were feasibility (recruitment, adherence, safety), physical capacity (cardiorespiratory fitness [VO2peak], muscle strength) and patient reported outcomes (physical functioning, fatigue). Thirty patients were intended, 16 could be included, and 14 completed post intervention assessment (75% male, 55 ± 11 years). The study was stopped early due to a low recruitment rate. Nine patients (64%) reached the initial minimum planned number of eight exercise sessions. Individual adherence was high with 92% for HIIT and 85% for RE. 87% of all performed exercise sessions were completed without complaints and VO2peak increased significantly from 20.4 to 23.4 ml/kg/min. The low recruitment rate suggests that initiation of the intervention concept immediately before allo-HCT is feasible only in a small number of patients. In particular, the timeframe directly prior allo-HCT seems too short for exercise interventions, although the exercise program was designed to improve outcomes in a very short time frame. HIIT and RE were feasible, effective and well accepted by the included patients. [ABSTRACT FROM AUTHOR]

Purpose: Cardiorespiratory fitness (CRF) seems to be prognostic prior to allogeneic stem cell transplantation (allo-HSCT). Influencing factors of CRF in allo-HSCT candidates have not been studied so far. Aim was to identify potentially influencing factors on CRF. Methods: To assess CRF, a maximal cardiopulmonary exercise test (CPET) was performed on average 2.6 ± 7.2 days prior to admission. A regression analysis was conducted, with the following predictors: gender, age, body mass index (BMI), time between last therapy and allo-HSCT (t_Therapies), number of cardiotoxic therapies (n_Cardiotox), number of transplantations (n_Transplantations), comorbidity index (HCT-CI), hemoglobin level of the last 3 months (area under the curve), and physical activity. Results: A total of 194 patients performed a CPET. VO2peak was significantly reduced compared with reference data. In total, VO2peak was 21.4 ml/min/kg (− 27.5%, p < 0.05). Men showed a significant larger percentage difference from reference value (− 29.1%, p < 0.05) than women (− 24.4%). VO2peak was significantly (p < 0.05) influenced by age (β = − 0.11), female gender (β = − 3.01), BMI (β = − 0.44), n_Cardiotox (β = − 0.73), hemoglobin level (β = 0.56), and physical activity prior to diagnosis (β = 0.10). Conclusions: Our study demonstrates a decreased CRF indicating the potential need of prehabilitative exercise. We revealed some influencing factors on CRF. Those patients could benefit the most from exercise. [ABSTRACT FROM AUTHOR]

Patient numbers for EASIX calculation are listed in following order (no neutropenic fever or sepsis / neutropenic fever without sepsis/neutropenic fever with sepsis) for the different timepoints: prior conditioning n = 125/200/27, day-3 n = 85/159/23, day 0 n = 84/159/23, day 3 n = 86/157/23, day 5 n = 87/153/22, day 7 n = 89/157/22, day 14 n = 108/161/20, day 21 n = 119/185/21, day 28 n = 120/194/17. As numbers of patients with sepsis were still small, these results warrant confirmation in larger multicenter trials with more sepsis patients. Sepsis patients were subgrouped by no neutropenic fever or sepsis, and neutropenic fever without and with sepsis. [Extracted from the article]

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative treatment option for relapsed follicular lymphoma (FL), yet questions remain about the optimal timing. This study analyzed long-term outcomes and associated factors among recipients of allo-HCT with FL.Methods: Patients with relapsed FL who underwent allo-HCT from 2001 to 2011 with a human leukocyte antigen (HLA)-matched donor were included. Outcome analyses for overall survival (OS), progression-free survival (PFS), transplant-related mortality (TRM), and disease relapse/progression were calculated. A multivariate analysis was performed to determine factors associated with outcomes, and a prognostic score for treatment failure was developed in a subset analysis of patients.Results: In all, 1567 patients with relapsed FL were included; the median follow-up was 55 months. The 5-year probabilities of OS and PFS were 61% and 52%, respectively. The 5-year cumulative incidences of disease progression/relapse and TRM were 29% and 19%, respectively. Chemoresistant disease, older age, heavy pretreatment, poor performance status (PS), and myeloablative protocols were predictors for worse survival. The prognostic score, using age, lines of prior therapy, disease status, and PS, stratified patients into 3 groups-low, intermediate, and high risk-with 5-year PFS rates of 68%, 53%, and 46%, respectively, and 5-year OS rates of 80%, 62%, and 50%, respectively.Conclusions: Allo-HCT should be considered for patients with relapsed FL and available HLA-matched donors. Outcomes are better in earlier phases of the disease, and reduced-intensity conditioning should be preferred. The prognostic score presented here can assist in counseling patients and determining the time to proceed to transplantation. Cancer 2018;124:1733-42. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Summary: Young adults (YA) represent a minority among recipients of allogeneic haematopoietic stem cell transplantation (HSCT). In order to describe the outcome of YA following HSCT in Germany, 9299 patients who were registered with the German Registry for Stem Cell Transplantation were included in this retrospective analysis of the years 1998–2019. The impact of the variables, such as patient age and sex, sex differences, stem cell source, donor type, conditioning, year of HSCT, the diagnosis, and the achieved remission status were tested in univariable and multivariable analysis for overall, event‐free and relapse‐free survival as well as for the cumulative incidences of non‐relapse and therapy‐related mortality. Altogether, the outcome of YA after HSCT improved over time and was determined by the underlying disease, the age at disease onset, stem cell source, and donor type. Patients were most likely to die from relapse, and survival of HSCT recipients after 10 years was reduced by more than half in comparison to the general population of YA. Deeper understanding of modifiable risk factors may be gained by studies comparing the outcome of YA post‐HSCT with that of children, adolescents and elderly patients. A deliberate and strong patient selection may further improve mortality rates. [ABSTRACT FROM AUTHOR]

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA. [ABSTRACT FROM AUTHOR]

Background: Allogeneic haematopoietic stem cell transplantation (alloSCT) often remains the only curative therapy for hematologic malignancies. Although the management of transplant‐associated adverse events considerably improved over the last decades, nonrelapse mortality (NRM) remains a challenge, and endothelial dysfunction was identified as a major contributor to NRM. Methods: Statin‐based endothelial prophylaxis (SEP) has been implemented in the standard of care in our transplant centre to reduce NRM caused by endothelial injury. Here, we retrospectively analysed the impact of SEP on clinical outcome in a cohort of 347 alloSCT patients. Results: SEP (n = 209) was associated with significantly reduced NRM (hazard ratio 0.61, 95% CI 0.38–0.96) and better overall survival (OS) after acute graft‐versus‐host disease (HR 0.59, 95% CI 0.37–0.93). Subgroup analyses showed that the NRM benefit was mainly found in patients with an intermediate endothelial activation and stress index (EASIX), while relapse risk was not affected. On day 100 post‐alloSCT, patients receiving SEP had significantly higher levels of the rate‐limiting enzyme of tryptophan metabolism, indoleamine 2,3‐dioxygenase (IDO), higher kynurenine to tryptophan ratios as a proxy of IDO activity and tended to have lower levels of the endothelial injury marker ST2 (p =.055). No significant differences in interferon‐gamma or IL18 levels were observed. These biomarker signatures suggest that the beneficial effects of SEP might be mediated by both endothelial protection and immunomodulation. Conclusions: Together, these data suggest that SEP improves NRM and OS post‐alloSCT in particular in patients with intermediate endothelial risk and provide first mechanistic clues about its potential mode of action. [ABSTRACT FROM AUTHOR]

Background: Evidence from randomized controlled trials is growing that exercise interventions are beneficial in cancer patients receiving allogeneic stem cell transplantation (allo-HCT). However, information about adherence to exercise interventions and exercise contamination in control groups is lacking. This information is crucial for the interpretation of study results. We therefore examined the determinants of exercise adherence and contamination in different treatment periods during (inpatient) and after (outpatient) allo-HCT.Methods: One hundred fifty-three patients scheduled for allo-HCT were randomized to a 1-year partly supervised exercise intervention (endurance and resistance exercise) or to a control group. Adherence was assessed via exercise logs and contamination via questionnaires.Results: Adherence varied between 66 % (inpatient) and 78 % (outpatient) in different treatment periods. During (inpatient) transplantation period, higher adherence was significantly associated with lower fatigue (P = 0.004) and with having children at home (P = 0.049). Adherence after discharge was positively associated with endurance performance (P = 0.003); higher adherence after day 100 was associated with exercise activity prior allo-HCT (P = 0.010) and higher adherence after discharge (P = 0.001). Contamination among controls was high with 54 % and significantly associated with muscle strength (P = 0.025) and fatigue (P = 0.050).Conclusion: Exercise adherence in different treatment periods was determined by different variables, and contamination among controls was evident. These findings may have important implications for correct interpretation of randomized exercise intervention trials. [ABSTRACT FROM AUTHOR]

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression. Synopsis: Combined perturbation by microenvironmental stimuli and drugs of chronic lymphocytic leukaemia cells annotated for genetic alterations reveals distinct response patterns and molecular modulators. CLL samples fall into four subgroups with distinct progression dynamics based on their microenvironmental response.Trisomy 12 enhances the response to microenvironmental stimulation and has a distinct transcription factor activity profile which is inhibited by IBET‐762 treatment.Linear modelling reveals different types of drug ‐ stimuli interactions, the most common being drug resistance induced by microenvironmental stimulation.IL4 and TLR signalling is more active in CLL infiltrated lymph nodes, and higher IL4 signalling activity correlates with faster disease progression. [ABSTRACT FROM AUTHOR]

Background: Allogeneic stem cell transplantation (allo-HCT) is associated with high treatment-related mortality and innumerable physical and psychosocial complications and side-effects, such as high fatigue levels, loss of physical performance, infections, graft-versus-host disease (GvHD) and distress. This leads to a reduced quality of life, not only during and after transplantation, but also in the long term. Exercise interventions have been shown to be beneficial in allo-HCT patients. However, to date, no study has focused on long-term effects and survival. Previous exercise studies used 'usual care' control groups, leaving it unclear to what extent the observed effects are based on the physical effects of exercise itself, or rather on psychosocial factors such as personal attention. Furthermore, effects of exercise on and severity of GvHD have not been examined so far. We therefore aim to investigate the effects and biological mechanisms of exercise on side-effects, complications and survival in allo-HCT patients during and after transplantation. Methods/design: The PETRA study is a randomized, controlled intervention trial investigating the effects of a yearlong partly supervised mixed exercise intervention (endurance and resistance exercises, 3-5 times per week) in 256 patients during and after allogeneic stem cell transplantation. Patients in the control group perform progressive muscle relaxation training (Jacobsen method) with the same frequency. Main inclusion criterion is planned allo-HCT. Main exclusion criteria are increased fracture risk, no walking capability or severe cardiorespiratory problems. Primary endpoint is overall survival after two years; secondary endpoints are non-relapse mortality, median survival, patient reported outcomes including cancer related fatigue and quality of life, physical performance, body composition, haematological/immunological reconstitution, inflammatory parameters, severity of complications and side-effects (e.g. GvHD and infections), and cognitive capacity. Discussion: The PETRA study will contribute to a better understanding of the physiological and psychological effects of exercise training and their biological mechanisms in cancer patients after allo-HCT. The ultimate goal is the implementation of optimized intervention programs to reduce side-effects and improve quality of life and potentially prognosis after allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Allogeneic stem cell transplantation (allo-HCT) is associated with high treatment-related mortality and innumerable physical and psychosocial complications and side-effects, such as high fatigue levels, loss of physical performance, infections, graft-versus-host disease (GvHD) and distress. This leads to a reduced quality of life, not only during and after transplantation, but also in the long term. Exercise interventions have been shown to be beneficial in allo-HCT patients. However, to date, no study has focused on long-term effects and survival. Previous exercise studies used ‘usual care’ control groups, leaving it unclear to what extent the observed effects are based on the physical effects of exercise itself, or rather on psychosocial factors such as personal attention. Furthermore, effects of exercise on and severity of GvHD have not been examined so far. We therefore aim to investigate the effects and biological mechanisms of exercise on side-effects, complications and survival in allo-HCT patients during and after transplantation. Methods/design: The PETRA study is a randomized, controlled intervention trial investigating the effects of a yearlong partly supervised mixed exercise intervention (endurance and resistance exercises, 3–5 times per week) in 256 patients during and after allogeneic stem cell transplantation. Patients in the control group perform progressive muscle relaxation training (Jacobsen method) with the same frequency. Main inclusion criterion is planned allo-HCT. Main exclusion criteria are increased fracture risk, no walking capability or severe cardiorespiratory problems. Primary endpoint is overall survival after two years; secondary endpoints are non-relapse mortality, median survival, patient reported outcomes including cancer related fatigue and quality of life, physical performance, body composition, haematological/immunological reconstitution, inflammatory parameters, severity of complications and side-effects (e.g. GvHD and infections), and cognitive capacity. Discussion: The PETRA study will contribute to a better understanding of the physiological and psychological effects of exercise training and their biological mechanisms in cancer patients after allo-HCT. The ultimate goal is the implementation of optimized intervention programs to reduce side-effects and improve quality of life and potentially prognosis after allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Purpose: The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan. Methods: Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation. Results: Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels. Conclusions: Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML. [ABSTRACT FROM AUTHOR]

Background: Graft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present "Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD" - Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients.Methods: IRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion.Discussion: To our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment.Trial Registration: ClinicalTrials.gov : NCT05111834 . Registered 8 November 2021 - Retrospectively registered. [ABSTRACT FROM AUTHOR]

• ECP was able to increase Tfh cells to ameliorate GvHD. • Upregulation of Th22 cells was observed in aGvHD patients with CR. • Tim-3 expression was downregulated on effector T cells by ECP. • ECP shows immunomodulatory effects in GvHD setting. Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4+CD8+ T cells. Additionally, Tim-3–expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD. [ABSTRACT FROM AUTHOR]

Finally, other potential treatment options to reduce relapse/progression post alloSCT include post-transplantation cyclophosphamide (ptCy). Keywords: myeloma therapy; stem cell transplantation; cytogenetics EN myeloma therapy stem cell transplantation cytogenetics 244 248 5 12/27/21 20220101 NES 220101 Treatment of patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (autoSCT) remains challenging. Consequently, a future goal in MM therapy is to combine modern treatment concepts and alloSCT in suitable patients to reduce disease burden and enhance disease control in patients with relapsed high-risk MM. Details on re-induction treatment and response rates prior to alloSCT, engraftment and post alloSCT response rates, maintenance therapy, donor lymphocyte infusions (DLI) and relapse therapies are shown in Table I. The median age at alloSCT was 50 (range 34-64) years. [Extracted from the article]

Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29; p < 0.001). Whereas therapy with foscarnet could be completely avoided in the LET group, 7 out of 80 patients in the control cohort received foscarnet, resulting in 151 extra in-patient days for foscarnet administration (p = 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 [95%CI 0.43–1.30]; p < 0.306). This study confirms efficacy and safety of LET for prophylaxis of CS-CMVi after alloHCT in a real-world setting, resulting in a significant patient benefit by reducing hospitalization needs and exposure to potentially toxic antiviral drugs for treatment of CMV reactivation. [ABSTRACT FROM AUTHOR]

Patients who developed sepsis had higher median EASIX values before conditioning (EASIX-pre) and at any later time point until day+28 irrespective of pathogen detection (Fig. Using this cut-off for multivariable Cox regression analysis in the validation cohort, we observed a cause-specific HR of 16.1 (7.0-36.9) for EASIX > 2.32 with respect to time to sepsis, corresponding to 7/462 sepsis events (1.5%) in the low-risk group vs 40/172 (23%) in the high-risk group (Suppl. 1 A Box plot comparison of EASIX before and after alloSCT in patients who did or did not develop sepsis within 50 days after transplantation (full cohort). [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Evidence on volume outcome associations for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is limited. We investigated ASCT utilization patterns and volume outcome associations in the German National Registry for Stem Cell Transplants (DRST). MM patients with an upfront ASCT between 1998 and 2014 registered in the DRST were included. ASCT utilization increased strongly from 6% to 17% between 1999 and 2013 with the largest increase for patients aged 60–64 years (8–34%). The mean number of ASCTs conducted in the hospitals per year varied (quintiles, Q1:0.0–8.2 to Q5:31.0–102.7). Center volume was not associated with survival after upfront ASCT (lowest vs. highest center volume, hazard ratios and 95% confidence intervals: 0.95 (0.76–1.18), p = 0.92). Our findings may reflect a high standard of care and degree of specialization of centers performing ASCT for MM in Germany. [ABSTRACT FROM AUTHOR]

• CAR T cells might be a salvage option for lymphoma relapse after alloHCT. • Information on CAR T cells in B cell lymphoma after a prior alloHCT is limited. • After prior alloHCT, CD19 CAR T cell treatment in lymphoma is feasible and effective. • CAR T cells did not induce or exacerbate the risk of acute or chronic GVHD. • Protracted cytopenia after CAR T cell treatment is a matter of concern. Although CD19-directed chimeric antigen receptor (CAR) T cells have been successfully used after a preceding allogeneic stem cell transplant (alloHCT) in patients with acute lymphoblastic leukemia, little is known about the feasibility and outcome of CAR T cell treatment in patients who have been previously allotransplanted for lymphoma. In a single-center retrospective analysis, course and outcome of all allografted patients treated with CD19 CAR constructs for B cell lymphoma between October 2018 and November 2019 were studied. CAR therapy consisted either of a third-generation CAR (HD-CAR-1) or of commercially manufactured axicabtagene ciloleucel (axi-cel; Gilead, Santa Monica, U.S.). Altogether, 10 CAR T cell dosings using recipient leukapheresis products were performed in 8 patients: 4 patients (2 mantle cell lymphoma, 2 chronic lymphocytic leukemia) received 6 dosings with HD-CAR-1 and 4 patients (all with diffuse large B cell lymphoma) received 4 dosings with axi-cel. Overall, 6 of 8 patients (75%) responded. CAR treatment was well tolerated with grade ≥ 3 cytokine release syndrome and neurotoxicity each being observed after 1 of 10 dosings. A single patient had moderate chronic graft-versus-host disease. Of note, 3 of 4 patients who received axi-cel had ongoing grade ≥ 3 cytopenia 3 months postdosing, whereas prolonged cytopenia was not observed in 9 alloHCT-naive patients who received axi-cel during the same time period. In conclusion, CAR T cell treatment from recipient-derived leukapheresis products after a prior alloHCT appears to be feasible, effective, and safe in patients with B cell lymphoma. Protracted cytopenia after axi-cel treatment is a matter of concern and requires further exploration. [ABSTRACT FROM AUTHOR]

This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Summary: Haploidentical stem cell transplantation (haploSCT) is becoming a major transplant modality for lymphoma. To assess the effects of donor characteristics, stem cell source and conditioning on outcomes, we identified 474 adults with Hodgkin (HL; 240), peripheral T‐cell (PTCL; 88), diffuse large B‐cell (77), mantle cell (40) or follicular lymphoma (FL; 29), who received haploSCT with post‐transplant cyclophosphamide. Median follow‐up of alive patients was 32 months. On multivariate analysis, acute graft‐versus‐host disease (GVHD) grade 2–4 was lower with offspring donors or bone marrow cells, whereas extensive chronic GVHD was higher in partial response at haploSCT or when using sisters, haploidentical donors beyond first degree, or female donors in male patients. Progression‐free survival (PFS) was better for FL, HL and PTCL, whereas overall survival (OS) was better for HL and PTCL. Complete remission at haploSCT improved PFS and OS whereas these were negatively affected by cytomegalovirus donor positive/recipient positive status. No other donor characteristics (age, gender, human leucocyte antigen mismatch, ABO incompatibility) affected PFS or OS except use of haploidentical donors beyond first degree, which negatively affected OS. PFS and OS are mostly influenced by disease status and lymphoma subtype, supporting the use of any first degree haploidentical family member as a donor. [ABSTRACT FROM AUTHOR]

Purpose: The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. Methods: We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. Results: The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. Conclusion: Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) induces B-cell proliferation with high efficiency through expression of latent proteins and microRNAs. This process takes place in vivo soon after infection, presumably to expand the virus reservoir, but can also induce pathologies, e.g. an infectious mononucleosis (IM) syndrome after primary infection or a B-cell lymphoproliferation in immunosuppressed individuals. In this paper, we investigated the growth characteristics of EBV-infected B-cells isolated from transplant recipients or patients with IM. We found that these cells grew and withstood apoptosis at highly variable rates, suggesting that the expansion rate of the infected B-cells widely varies between individuals, thereby influencing the size of the B-cell reservoir and the ability to form tumors in infected individuals. All viruses investigated were type 1 and genetically close to western strains. EBV-infected B-cells expressed the transforming EBV latent genes and microRNAs (miRNAs) at variable levels. We found that the B-cell growth rates positively correlated with the BHRF1 miRNA levels. Comparative studies showed that infected B-cells derived from transplant recipients with iEBVL on average expressed higher levels of EBV miR-BHRF1 miRNAs and grew more rapidly than B-cells from IM patients, suggesting infection by more transforming viruses. Altogether, these findings suggest that EBV infection has a highly variable impact on the B-cell compartment that probably reflects the genetic diversity of both the virus and the host. It also demonstrates the unexpected finding that B-cells from different individuals can grow at different speed under the influence of the same virus infection. [ABSTRACT FROM AUTHOR]

Highlights • Haploidentical allogeneic hematopoietic cell transplantation is feasible as salvage therapy in myeloma. • Two-year progression-free survival was 17%, and overall survival (OS) was 48%. • At 2 years, the cumulative risk of relapse/progression was 56%, and 1-year nonrelapse mortality was 21%. • The use of post-transplantation cyclophosphamide and bone marrow as the stem cell source were associated with improved OS at 2 years. Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression-free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% CI, 13% to 29%). The incidences of acute graft-versus-host-disease (GVHD) grades II-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P =.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P =.001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM. [ABSTRACT FROM AUTHOR]

Despite the arrival of novel therapies, multiple myeloma (MM) remains incurable and new treatment options are needed. Chimeric antigen receptor (CAR) T cells are genetically modified T cells that express a CAR directed against specific tumour antigens. CAR T cells are able to kill target tumour cells and may result in long-lasting immune responses in vivo. The rapid development of CAR technologies has led to clinical trials in haematological cancers including MM, and CAR T cells might evolve into a standard treatment in the next few years. Only small patient cohorts with relapsed or refractory disease have so far been investigated, but promising preliminary results with high response rates have been  obtained in phase I clinical trials with B cell maturation antigen (BCMA), CD19, CD38 and κ-light-chain CAR T cells. Additional preclinical studies on CD38 and SLAMF7-CAR T cells in MM treatment yielded preclinical results that merit further investigation. Beyond the T cell approach, recent studies have focussed on CAR natural killer (NK) cells in order to increase the reactivity of these effector cells. Finally, to investigate the targeting of intracellular antigens, cellular therapies based on engineered T cell receptors (TCRs) are in development. In this review, we discuss results from preclinical and early-phase clinical trials testing the feasibility and safety of CAR T cell administration in MM, as well as early studies into approaches that utilise CAR NK cell and genetically modified TCRs. [ABSTRACT FROM AUTHOR]

Abstract More than 60% of patients with non-Hodgkin lymphoma (NHL) are age >60 years at presentation. The purpose of this study was to compare the potential risks and benefits of allogeneic hematopoietic cell transplantation (alloHCT) in elderly patients with NHL with younger patients in a large sample, also taking into account comorbidity information. All patients age ≥18 years who had undergone alloHCT from a matched sibling or unrelated donor for NHL between 2003 and 2013 and were registered with the European Society for Blood and Marrow Transplantation were eligible for the study. The primary study endpoint was 1-year nonrelapse mortality (NRM). A total of 3919 patients were eligible and were categorized by age: young (Y), 18 to 50 y (n = 1772); middle age (MA), 51 to 65 y (n = 1967); or old (O), 66 to 77 y (n = 180). Follicular lymphoma was present in 37% of the patients; diffuse large B cell lymphoma, in 30%; mantle cell lymphoma, in 21%, and peripheral T cell lymphoma, in 11%. At the time of alloHCT, 85% of the patients were chemosensitive and 15% were chemorefractory. With a median follow-up of 4.5 years in survivors, NRM at 1 year was 13% for the Y group. 20% for the MA group, and 33% for the O group (P <.001), whereas relapse incidence and overall survival (OS) at 3 years in the 3 groups were 30%, 31%, and 28% (P =.355) and 60%, 54%, and 38% (P <.001), respectively. Multivariable adjustment for confounders, including sex, NHL subset, time from diagnosis, chemosensitivity, donor, and conditioning, confirmed older age as a significant predictor for NRM and OS, but not for relapse risk. Although comorbidity was a significant predictor of NRM in a subset analysis restricted to the 979 patients with comorbidity information available, age retained its significant impact on NRM. In conclusion, our data show that alloHCT in patients age >65 y provides similar NHL control as seen in younger patients but is associated with a higher NRM that is not fully explained by comorbidity. Thus, although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group. [ABSTRACT FROM AUTHOR]

Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production. Peripheral blood mononuclear cells of healthy donors and untreated chronic lymphocytic leukemia (CLL) patients without or with positive selection for CD3+ T cells were transduced with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Activation of peripheral blood mononuclear cells was performed by CD3/CD28, CD3/CD28/retronectin, or CD3/retronectin. Interleukin-7 and -15 were supplemented to all cultures. Retronectin was used in all three activation protocols for retroviral transduction. Expansion was assessed by trypan blue staining. Viability, transduction efficiency, immune phenotype, and cytokine production were longitudinally analyzed by flow cytometry. Cytotoxic capacity of generated CART cells was evaluated using a classical chromium-51 release assay. Retronectin-mediated activation resulted in an enrichment of CD8+ cytotoxic CART cells and less-differentiated naïve-like T cells (CD45RA+CCR7+). Retronectin-activated CART cells showed increased cytotoxic activity. However, activation with retronectin decreased viability, expansion, transduction efficiency, and cytokine production, particularly of CLL patient-derived CART cells. Both retronectin-mediated activation protocols promoted a less-differentiated CART cell phenotype without comprising cytotoxic properties of healthy donor–derived CART cells. However, up-front retronectin resulted in reduced viability and expansion in CLL patients. This effect is probably attributed to the retronectin-mediated activation of B cells with prolonged CLL persistence. Consequently, CART cell expansion and generation failed. In summary, activation with retronectin should be performed with caution and may be limited to patients without a higher percentage of tumor cells in the peripheral blood. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To improve monitoring of myeloid neoplasms by flow cytometry‐based minimal residual disease (MRD) analysis, we analyzed the significance of leukemia‐associated immunophenotype (LAIP) markers in 44 patients. Methods: In a pilot study cohort, peripheral blood or bone marrow samples from 13 patients with myeloid neoplasms and one case of B lymphoblastic leukemia in complete hematologic remission after allogeneic bone marrow or stem cell transplantation were subjected to selection for leukemia‐specific phenotypes by fluorescence‐activated cell sorting using individual marker combinations, followed by PCR‐based chimerism analysis. Results: The feasibility of this method could be demonstrated, with selection being successful in 12 cases, including two cases where mixed chimerism was found exclusively in sorted cells. Interestingly, four specimens displayed full donor chimerism in cells expressing the presumably aberrant combination CD34+/CD7+. Further analyses, including assessment of an independent cohort of 25 patients not affected by neoplastic bone marrow infiltration, revealed that normal myeloid precursors usually include a population coexpressing CD34, CD13, CD33, and CD7. Conclusion: We conclude that the combination CD34+/CD7+ might not be suitable as an LAIP for MRD diagnostics and that a subset of normal myeloid precursors in the bone marrow expresses CD7. [ABSTRACT FROM AUTHOR]

The role of autologous stem cell transplantation (autoSCT) as consolidating treatment for peripheral T-cell lymphoma (PTCL) is unsettled. The aim of this analysis was to investigate the impact of autoSCT in the upfront setting by intent-to-treat and to study salvage strategies after relapse. Retrospective follow-up of all patients aged 18-70 years and treated at our institution for ALK-PTCL diagnosed between 2001 and 2014. Of 117 eligible patients, diagnosis was PTCL-NOS in 34, ALCL ALK- in 31, AITL in 28, and other PTCL in 24 patients. Disregarding 20 patients who received first-line treatment externally, upfront autoSCT was not intended in 34 due to comorbidity, higher age, low IPI, physician's decision or unknown reasons (nITT), while intent-to-transplant (ITT) was documented in 63 patients. ITT was not associated with significant benefits for 5-year progression-free survival (PFS) and overall survival (OS) with 46 and 23% in the ITT group vs. 42 and 25% in the nITT group, even after multivariate adjustment for confounders. Altogether, 91 of all 117 patients relapsed or progressed. Thirty-one patients managed to proceed to salvage allografting and achieved a 5-year OS of 52%. In contrast, all 7 patients receiving salvage autoSCT relapsed and died, and only 3 of the 51 patients not eligible for SCT salvage survived. In this study, a significant benefit of intending first-line autoSCT over non-transplant induction in patients with ALK-PTCL did not emerge. Most patients fail first-line treatment and have a poor outlook if salvage alloSCT cannot be performed. [ABSTRACT FROM AUTHOR]

Telomere length in chronic lymphocytic leukemia (CLL) is described as an independent prognostic factor based largely on previously untreated patients from chemotherapy based trials. Here, we studied telomere length associations in high-risk, relapsed/refractory CLL treated with alemtuzumab in the CLL2O study (n = 110) of German and French CLL study groups. Telomere length (median 3.28 kb, range 2.52-7.24 kb) was relatively short, since 84.4% of patients had 17p- which is generally associated with short telomeres. Median telomere length was used for dichotomization into short and long telomere subgroups. Telomere length was associated with s-TK (p = .025) and TP53 mutations (p = .050) in untreated patients, while no association with clinical/biological characteristics was observed in relapsed/refractory CLL. Short telomeres had significant association with shorter PFS (p = .018) only in refractory CLL. Presence of short telomeres, loss of genes maintaining genomic integrity (SMC5) and increased incidence of chromothripsis, indicated the prevalence of genomic instability in this high-risk cohort (clinicaltrials.gov: NCT01392079). [ABSTRACT FROM AUTHOR]

Secondary acute myeloid leukemia (sAML) has been associated with inferior outcomes compared with de novo AML. Little is known about patient risk factors and outcomes in sAML after allogeneic hematopoietic stem cell transplantation (HCT); thus, this large systemic analysis of the European Society for Blood and Bone Marrow Transplantation registry was performed. This study included 4997 patients with sAML who received HCT from 2000 to 2016. In univariate analysis the 2-year cumulative incidence of chronic graft-versus-host disease (GVHD), relapse, and nonrelapse mortality (NRM) were 33.5% (95% confidence interval [CI], 32% to 34.9%), 33.7% (95% CI, 32.3% to 35.1%), and 27.5% (95% CI, 26.1% to 28.7%), respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) at 2 years were 44.5% (95% CI, 43% to 46%), 38.8% (95% CI, 37.4% to 40.3%), and 27.2% (95% CI, 25.9% to 28.6%), respectively. In multivariate analysis, patients receiving myeloablative regimens had decreased relapse (hazard ratio, .859; 95% CI, .761 to .97; P  = .01), higher NRM (hazard ratio, 1.175; 95% CI, 1.03 to 1.341; P  = .02), and no differences in OS, LFS, and GRFS compared with patients receiving reduced-intensity conditioning regimens. Active disease, adverse cytogenetics, older age, Karnofsky performance status (≤80%), ex vivo T cell depletion, other malignant hematologic diseases, and patient cytomegalovirus seropositivity were associated with inferior OS and LFS. These variables should be considered in patients with sAML in need of HCT, and further study regarding the impact of conditioning regimens on relapse is needed. [ABSTRACT FROM AUTHOR]

Purpose: In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL.Methods: The database of the German Registry for Stem Cell Transplantation (DRST) was screened for patients who underwent allo-HCT for tFL 1998-2008. Confirmation of tFL-diagnosis by local and/or pathologists of the National NHL Board was mandatory for enrolment. Gaps in reported EBMT Minimum Essential Data datasets (MED-A) were filled by local DRST data managers. Relevant HCT outcome variables were evaluated by uni- and multivariate statistical analysis.Results: Median age of enrolled 33 patients was 51 years with a post allo-HCT median follow-up of 7.1 years of surviving patients. At time of HCT 24/33 patients had chemosensitive disease. In 24/33 patients reduced intensity conditioning (RIC) was used. Estimated 1, 2, 5-year overall survival (OS) and event-free survival rates were 49/39/33, and 33/30/24%. Cumulative 100 days non-relapse mortality was 25%. Chemosensitive disease, RIC, and limited chronic GvHD were identified as independent prognostic factors for OS.Conclusions: Allo-HCT offers the chance of cure for tFL. [ABSTRACT FROM AUTHOR]