266 results on '"Finke, Jürgen"'
Search Results
2. Does IPSS-R downstaging before transplantation improve the prognosis of patients with myelodysplastic neoplasms?
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Scheid C, Eikema DJ, van Gelder M, Salmenniemi U, Maertens J, Passweg J, Blaise D, Byrne JL, Kröger N, Sockel K, Chevallier P, Bourhis JH, Cornelissen JJ, Sengeloev H, Finke J, Snowden JA, Gedde-Dahl T, Cornillon J, Schanz U, Patel A, Koster L, de Wreede LC, Hayden P, Raj K, Drozd-Sokolowska J, Gurnari C, Onida F, McLornan DP, Robin M, and Yakoub-Agha I
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- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Prognosis, Adult, Neoplasm Staging, Treatment Outcome, Young Adult, Myelodysplastic Syndromes therapy, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Hematopoietic Stem Cell Transplantation methods
- Abstract
Abstract: In patients with myelodysplastic syndrome (MDS), higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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3. Hope for Motherhood: Pregnancy After Allogeneic Hematopoietic Cell Transplantation - a National Multicenter Study.
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Sockel K, Neu A, Goeckenjan M, Ditschkowski M, Hilgendorf I, Kroeger N, Ayuk FA, Stölzel F, Middeke JM, Eder M, Bethge WA, Finke J, Bertz H, Kobbe G, Kaufmann M, Platzbecker U, Beverungen D, Schmid C, von Bonin M, Egger-Heidrich K, Heberling L, Trautmann-Grill K, Teipel R, Bug G, Tischer J, Fraccaroli A, Fante MA, Wolff D, Luft T, Winkler J, Schäfer-Eckart K, Scheid C, Holtick U, Klein S, Blau I, Burchert A, Wulf GG, Hasenkamp J, Schwerdtfeger R, Kaun S, Junghanss C, Wortmann F Dr. med, Winter S, Neidlinger H, Theuser C, Beyersmann J, Bornhäuser M, Schmeller S, and Schetelig J
- Abstract
Improved long-term survival rates after allogeneic hematopoietic cell transplantation (alloHCT) make family planning for young adult cancer survivors an important topic. However, treatment-related infertility risk poses challenges. To assess pregnancy and birth rates in a contemporary cohort, we conducted a national multicenter study using data from the German Transplant Registry, focusing on adult women aged 18-40 who underwent alloHCT between 2003 and 2018. Out of 2,654 transplanted women, 50 women experienced 74 pregnancies, occurring at a median of 4.7 years post-transplant. Fifty-seven of these resulted in live births (77%). The annual first birth rate among HCT recipients was 0.45% (95%CI: 0.31 - 0.59%), which is more than six times lower than in the general population. The probability of a live birth 10 years after HCT was 3.4 % (95%CI: 2.3- 4.5%). Factors associated with an increased likelihood of pregnancy were younger age at alloHCT, non-malignant transplant indications, no total-body-irradiation (TBI) or a cumulative dose of <8 Gray, and non-myeloablative/reduced-intensity conditioning. 72% of pregnancies occurred spontaneously, with assisted reproductive technologies (ART) used in the remaining cases. Preterm delivery and low birth weight were more common than in the general population. This study represents the largest dataset reporting pregnancies in a cohort of adult female alloHCT recipients. Our findings underscore a meaningful chance of pregnancy in alloHCT recipients. ART techniques are important and funding should be made available. However, the potential for spontaneous pregnancies should not be underestimated, and patients should be informed of the possibility of unexpected pregnancy despite reduced fertility. Further research is warranted to understand the impact of conditioning decisions on fertility preservation., (Copyright © 2024 American Society of Hematology.)
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- 2024
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4. Allogeneic hematopoietic cell transplantation for older patients with AML with active disease. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
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Maffini E, Labopin M, Kröger N, Finke J, Stelljes M, Schroeder T, Einsele H, Tischer J, Bornhäuser M, Bethge W, Brecht A, Rösler W, Dreger P, Schäfer-Eckart K, Passweg J, Blau IW, Nagler A, Ciceri F, and Mohty M
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- Humans, Aged, Male, Female, Retrospective Studies, Transplantation, Homologous methods, Europe, Unrelated Donors, Survival Rate, Disease-Free Survival, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute mortality
- Abstract
Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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5. Incidence and outcome of central nervous system relapse after hematopoietic stem cell transplantation in patients suffering from acute myeloid leukemia and acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
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Blum S, Chalandon Y, Labopin M, Finke J, Gedde-Dahl T, Othman TB, Cornelissen JJ, Jindra P, Labussière-Wallet H, Collin M, Lenhoff S, Kobbe G, Gutiérrez NC, Nagler A, and Mohty M
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- Humans, Incidence, Male, Adult, Female, Middle Aged, Adolescent, Europe epidemiology, Recurrence, Young Adult, Treatment Outcome, Aged, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Central Nervous System Neoplasms therapy
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- 2024
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6. Allogeneic hematopoietic stem-cell transplantation for patients with Richter transformation: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.
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Guièze R, Eikema DJ, Koster L, Schetelig J, Sengeloev H, Passweg J, Finke J, Arat M, Broers AEC, Stölzel F, Byrne J, Castilla-Llorente C, Dreger P, Eder M, Gedde-Dahl T, Kröger N, Ribera Santasusana JM, Richardson D, Rambaldi A, Yañez L, Van Gelder M, Drozd-Sokolowska J, Raj K, Yakoub-Agha I, Tournilhac O, and McLornan DP
- Subjects
- Humans, Middle Aged, Retrospective Studies, Male, Female, Transplantation, Homologous methods, Transplantation Conditioning methods, Graft vs Host Disease mortality, Adult, Allografts, Hematopoietic Stem Cell Transplantation methods
- Abstract
Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3-63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9-11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54-77) and 39% (27-51) and 53% (41-65) and 29% (18-40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs. 21%, p = 0.032). Cumulative incidences of grade II-IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29-53) and chronic GVHD at 3 years was 53% (95% CI 41-65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26-50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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7. Long term results of a prospective multicenter observational study on the use of anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation (ATOS study).
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Finke J, Schmoor C, Ayuk F, Hasenkamp J, Verbeek M, Wagner EM, Biersack H, Schäfer-Eckart K, Wolf D, Stuhler G, Reibke R, Schmid C, Kaufmann M, Eder M, Bertz H, and Grishina O
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- Humans, Middle Aged, Adult, Male, Prospective Studies, Female, Aged, Adolescent, Graft vs Host Disease prevention & control, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation methods, Young Adult, Hematologic Neoplasms therapy, Hematologic Neoplasms mortality, Disease-Free Survival, Follow-Up Studies, T-Lymphocytes immunology, Unrelated Donors
- Abstract
ATOS is a prospective observational study evaluating the outcome of patients receiving anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation. Primary endpoint was severe GvHD and relapse-free survival (SGRFS). GvHD prophylaxis consisted of ATLG and CSA/ MTX or MMF. Outcome was compared to the ATLG arm of our prospective randomized phase III multicenter trial trial (RCT) [1, 2]. 165 patients, median age 54 (18; 77) years, with haematological malignancies with early (45.5%), intermediate (17.6%), and advanced (37.0%) disease were included. ATLG dose differed between centers according to local practise (median total ATLG dose of 46 (IQR 32-60, range 15-91) mg/kg). Median follow-up was 70 months. Estimated probabilities at 5 years follow up were for SGRFS 0.27, OS 0.52, DFS 0.43, NRM 0.23, relapse 0.34, acute GvhD °III/IV 0.13, severe chronic GvHD 0.27. OS rates differed dependent on disease status. An effect of the given ATLG dose could not be separated from potential center effects. Despite higher age and more advanced disease in ATOS, outcome was similar to the ATLG arm of our RCT. This long-term, multicenter, experience in routine clinical practice confirms the GvHD-protective effect of ATLG without compromising relapse and non-relapse mortality rates.Clinical Trial Registry: German clinical trials register DRKS00004581., (© 2024. The Author(s).)
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- 2024
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8. Continuously improving outcome over time after second allogeneic stem cell transplantation in relapsed acute myeloid leukemia: an EBMT registry analysis of 1540 patients.
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Schmälter AK, Ngoya M, Galimard JE, Bazarbachi A, Finke J, Kröger N, Bornhäuser M, Stelljes M, Stölzel F, Tischer J, Schroeder T, Dreger P, Blau IW, Savani B, Giebel S, Esteve J, Nagler A, Schmid C, Ciceri F, and Mohty M
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- Humans, Middle Aged, Male, Female, Adult, Aged, Young Adult, Adolescent, Transplantation, Homologous, Recurrence, Transplantation Conditioning methods, Treatment Outcome, Graft vs Host Disease etiology, Graft vs Host Disease epidemiology, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute mortality, Registries, Hematopoietic Stem Cell Transplantation methods
- Abstract
Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000-2004) and last (2015-2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5-35%, LFS: 14.5-24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2., (© 2024. The Author(s).)
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- 2024
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9. Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT.
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Polverelli N, Bonneville EF, de Wreede LC, Koster L, Kröger NM, Schroeder T, Peffault de Latour R, Passweg J, Sockel K, Broers AEC, Clark A, Dreger P, Blaise D, Yakoub-Agha I, Petersen SL, Finke J, Chevallier P, Helbig G, Rabitsch W, Sammassimo S, Arcaini L, Russo D, Drozd-Sokolowska J, Raj K, Robin M, Battipaglia G, Czerw T, Hernández-Boluda JC, and McLornan DP
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- Humans, Body Mass Index, Retrospective Studies, Transplantation Conditioning, Primary Myelofibrosis therapy, Neoplasms, Hematopoietic Stem Cell Transplantation
- Abstract
Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT., (© 2024 Wiley Periodicals LLC.)
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- 2024
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10. Improvements in Posttransplant Outcomes Over Two Decades in Older Patients with Acute Myeloid Leukemia in the EBMT ALWP Study.
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Bazarbachi A, Labopin M, Moukalled N, Kröger N, Rautenberg C, Schetelig J, Finke J, Blau IW, Blaise D, Stelljes M, Eder M, Platzbecker U, Dreger P, Bethge W, Tischer J, Burns D, Sengeloev H, Brissot E, Giebel S, Nagler A, Ciceri F, and Mohty M
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- Humans, Aged, Female, Male, Aged, 80 and over, Treatment Outcome, Transplantation, Homologous, Follow-Up Studies, Graft vs Host Disease etiology, Graft vs Host Disease epidemiology, Transplantation Conditioning methods, Remission Induction, Retrospective Studies, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute mortality, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Purpose: Acute myeloid leukemia (AML) is a disease of older patients. Progress in allogeneic hematopoietic cell transplantation (allo-HCT) allowed the delivery of allo-HCT to older patients. We assessed changes over time in transplant characteristics and outcomes in patients with AML ages 65 years and above., Patients and Methods: We identified 7,215 patients with AML (median age 68 years, range 65-80) allografted between 2000 and 2021 in first complete remission (CR1; 64%), second or subsequent remission (CR2+; 14%), or active disease (22%)., Results: Median follow-up was 40 months. The 3-year cumulative relapse incidence (RI) gradually and significantly decreased from 37% to 31%, then to 30% (P = 0.001) over the three time periods (2000-2009; 2010-2014; 2015-2021), whereas nonrelapse mortality (NRM) decreased from 31% and 31% to 27% (P = 0.003). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved from 32% to 38%, and then to 44% (P = 0.001) and from 37% to 42%, and then to 49% (P = 0.001), respectively. In multivariate analysis, significant improvement in the RI, LFS, and OS were noted after 2015, whereas NRM was not significantly affected. This improvement was observed regardless of disease status at transplant., Conclusions: In older patients with AML, we observed an impressive improvement over time in posttransplant outcomes, mostly attributed to decreased RI rather than decreased NRM, and regardless of disease status at transplant. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option., (©2024 American Association for Cancer Research.)
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- 2024
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11. Impact of post-transplant cyclophosphamide (PTCy)-based prophylaxis in matched sibling donor allogeneic haematopoietic cell transplantation for patients with myelodysplastic syndrome: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.
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Salas MQ, Eikema DJ, Koster L, Maertens J, Passweg J, Finke J, Broers AEC, Koc Y, Kröger N, Ozkurt ZN, Pascual-Cascon MJ, Platzbecker U, Van Gorkom G, Schroeder T, López-Lorenzo JL, Martino M, Chiusolo P, Kaufmann M, Onida F, Gurnari C, Scheid C, Drozd-Sokolowska J, Raj K, Robin M, and McLornan DP
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- Humans, Retrospective Studies, Siblings, Cyclophosphamide therapeutic use, Cyclophosphamide pharmacology, Unrelated Donors, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Myelodysplastic Syndromes complications, Neoplasms complications
- Abstract
We retrospectively compared outcomes of 404 MDS patients undergoing 1st matched sibling donor allo-HCT receiving either PTCy-based (n = 66) or other "conventional prophylaxis" (n = 338; mostly calcineurin inhibitor + methotrexate or MMF). Baseline characteristics were balanced, except for higher use of myeloablative regimens in the PTCy group (52.3% vs. 38.2%, p = 0.047). Incidences of neutrophil (Day +28: 89% vs. 97%, p = 0.011) and platelet (Day +100: 89% vs. 97%, p < 0.001) engraftment were lower for PTCy-based. Day +100 cumulative incidences of grade II-IV and III-IV aGVHD, and 5-year CI of extensive cGVHD were 32%, 18% and 18% for PTCy-based and 25% (p = 0.3), 13% (p = 0.4) and 31% (p = 0.09) for the conventional cohort. Five-year OS (51% vs. 52%, p = 0.6) and GRFS (33% vs. 25%, p = 0.6) were similar between groups. Patients receiving PTCy had a trend to a lower cumulative incidence of relapse (20% vs. 33%, p = 0.06), not confirmed on multivariable analysis (p = 0.3). Although higher NRM rates were observed in patients receiving PTCy (32% vs. 21%, p = 0.02) on univariate analysis, this was not confirmed on multivariate analysis (HR 1.46, p = 0.18), and there was no resultant effect on OS (HR 1.20, p = 0.5). Based on these data, PTCy prophylaxis appears to be an attractive option for patients with MDS undergoing MSD allo-HCT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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12. In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT.
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Beksac M, Eikema DJ, Koster L, Hulin C, Poiré X, Hamladji RM, Gromek T, Bazarbachi A, Ozkurt ZN, Pabst T, Ben Othman T, Finke J, Pirogova O, Wu D, Hayat A, Hilgendorf I, Tholouli E, de Wreede LC, Schönland S, Garderet L, Drozd-Sokolowska J, Raj K, Hayden PJ, Yakoub-Agha I, and McLornan DP
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- Humans, Bortezomib pharmacology, Bortezomib therapeutic use, Melphalan pharmacology, Melphalan therapeutic use, Prospective Studies, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols, Multiple Myeloma drug therapy, Multiple Myeloma diagnosis, Hematopoietic Stem Cell Transplantation
- Abstract
Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27-2.25, p < 0.001) and OS (HR:1.46 (1.14-1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33-1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18-1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25-1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study., (© 2024. The Author(s).)
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- 2024
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13. Identification of clinical factors impacting outcome in patients undergoing autologous hematopoietic cell transplantation after BEAM and TEAM conditioning.
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Gherman RF, Ewald S, Ihorst G, Strüßmann T, Zeiser R, Wäsch R, Bertz H, Stolz D, Duyster J, Finke J, Marks R, Engelhardt M, and Duque-Afonso J
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- Humans, Thiotepa, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols adverse effects, Transplantation, Autologous, Cytarabine adverse effects, Etoposide therapeutic use, Transplantation Conditioning adverse effects, Transplantation Conditioning methods, Melphalan adverse effects, Carmustine adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods
- Abstract
Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto-HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety-six patients undergoing auto-HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto-HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT-CI score ≥ 4, and cardiac disease before auto-HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto-HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non-relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto-HSCT., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2024
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14. Allogeneic haematopoietic cell transplantation for therapy-related myeloid neoplasms arising following treatment for lymphoma: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.
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Nabergoj M, Eikema DJ, Koster L, Platzbecker U, Sockel K, Finke J, Kröger N, Forcade E, Nagler A, Eder M, Tischer J, Broers AEC, Kuball J, Wilson KMO, Hunault-Berger M, Collin M, Russo D, Corral LL, Helbig G, Mussetti A, Scheid C, Gurnari C, Raj K, Drozd-Sokolowska J, Yakoub-Agha I, Robin M, and McLornan DP
- Subjects
- Humans, Middle Aged, Retrospective Studies, Recurrence, Transplantation Conditioning, Leukemia, Myeloid, Acute therapy, Lymphoma etiology, Lymphoma therapy, Neoplasms, Second Primary etiology, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease etiology
- Abstract
Therapy-related myeloid neoplasms (t-MN), either myelodysplastic neoplasms (t-MDS) or acute myeloid leukemias (t-AML), have a poor prognosis and allogeneic haematopoietic cell transplantation (allo-HCT) represents the only curative option. In this multicenter, registry-based study, we analyzed outcomes of 378 patients undergoing first allo-HCT between 2006-2017 for t-MN arising secondary to lymphoma treatment. Median age was 58 years at allo-HCT; 222 (59%) had a diagnosis of t-MDS and 156 (41%) of t-AML, respectively. At the time of allo-HCT, 46% of t-MN cases were reported as in complete remission (CR) and 15% of lymphomas were recorded as not in remission. A reduced intensity conditioning regimen was used in 70% of cases. For the entire cohort, 5-year OS, and t-MN PFS, relapse incidence and NRM were 32%, 28%, 35% and 37%, respectively. In multivariable analysis, undergoing allo-HCT with t-MN not in CR and older age were associated with significantly worse OS, PFS and NRM. At 5 years post allo-HCT, the relapse incidence of lymphoma was low at 3%, while the rate of secondary malignancies was 8%. This analysis shows the curative potential of allo-HCT for patients with t-MN arising secondary to lymphoma treatment in approximately a third of patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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15. Improved early outcome prediction by MRI-based 3D tumor volume assessment in patients with CNS lymphomas.
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Lauer EM, Riegler E, Mutter JA, Alig SK, Bleul S, Kuehn J, Ranganathan L, Klingler C, Demerath T, Würtemberger U, Rau A, Weiß J, Eisenblaetter M, Bamberg F, Prinz M, Finke J, Duyster J, Illerhaus G, Diehn M, Alizadeh AA, Schorb E, Reinacher PC, and Scherer F
- Subjects
- Humans, Tumor Burden, Prognosis, Magnetic Resonance Imaging, Lymphoma, Non-Hodgkin, Lymphoma diagnostic imaging, Central Nervous System Neoplasms diagnostic imaging
- Abstract
Background: Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment., Methods: We explored various MRI features including semi-automated 3D tumor volume measurements at different disease milestones and their association with survival in 93 CNSL patients undergoing curative-intent treatment., Results: At diagnosis, patients with more than 3 lymphoma lesions, periventricular involvement, and high 3D tumor volumes showed significantly unfavorable PFS and OS. At first interim MRI during treatment, the IPCG criteria failed to discriminate outcomes in responding patients. Therefore, we randomized these patients into training and validation cohorts to investigate whether 3D tumor volumetry could improve outcome prediction. We identified a 3D tumor volume reduction of ≥97% as the optimal threshold for risk stratification (=3D early response, 3D_ER). Applied to the validation cohort, patients achieving 3D_ER had significantly superior outcomes. In multivariate analyses, 3D_ER was independently prognostic of PFS and OS. Finally, we leveraged prognostic information from 3D MRI features and circulating biomarkers to build a composite metric that further improved outcome prediction in CNSL., Conclusions: We developed semi-automated 3D tumor volume measurements as strong and independent early predictors of clinical outcomes in CNSL patients. These radiologic features could help improve risk stratification and help guide future treatment approaches., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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16. The impact of pre-transplantation diabetes and obesity on acute graft-versus-host disease, relapse and death after allogeneic hematopoietic cell transplantation: a study from the EBMT Transplant Complications Working Party.
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Gjærde LK, Ruutu T, Peczynski C, Boreland W, Kröger N, Blaise D, Schroeder T, Peffault de Latour R, Gedde-Dahl T, Kulagin A, Sengeløv H, Yakoub-Agha I, Finke J, Eder M, Basak G, Moiseev I, Schoemans H, Koenecke C, Penack O, and Perić Z
- Subjects
- Adult, Humans, Chronic Disease, Neoplasm Recurrence, Local, Obesity, Retrospective Studies, Transplantation, Homologous adverse effects, Diabetes Mellitus epidemiology, Graft vs Host Disease pathology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Obesity and diabetes can modulate immune responses, which may impact allogeneic HCT outcomes and GvHD. From the EBMT registry, we included 36,539 adult patients who underwent allogeneic HCT for a hematological malignancy between 2016 and 2020. Of these, 5228 (14%) had obesity (BMI ≥ 30 kg/m
2 ), 1415 (4%) had diabetes (requiring treatment with insulin or oral hypoglycemics), and 688 (2%) had obesity + diabetes pre-transplantation. Compared with patients without diabetes or obesity, the hazard ratio (HR) of grade II-IV acute GvHD was 1.00 (95% confidence interval [CI] 0.94-1.06, p = 0.89) for patients with obesity, 0.95 (CI 0.85-1.07, p = 0.43) for patients with diabetes, and 0.96 (CI 0.82-1.13, p = 0.63) for patients with obesity + diabetes. Non-relapse mortality was higher in patients with obesity (HR 1.08, CI 1.00-1.17, p = 0.047), diabetes (HR 1.40, CI 1.24-1.57, p < 0.001), and obesity + diabetes (HR 1.38, CI 1.16-1.64, p < 0.001). Overall survival after grade II-IV acute GvHD was lower in patients with diabetes (HR 1.46, CI 1.25-1.70, p < 0.001). Pre-transplantation diabetes and obesity did not influence the risk of developing acute GvHD, but pre-transplantation diabetes was associated with poorer survival after acute GvHD., (© 2023. The Author(s).)- Published
- 2024
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17. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype.
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Poiré X, Labopin M, Polge E, Ganser A, Socié G, Gedde-Dahl T, Forcade E, Finke J, Chalandon Y, Bulabois CE, Yakoub-Agha I, Aljurf M, Kröger N, Blau IW, Nagler A, Esteve J, and Mohty M
- Subjects
- Humans, Karyotype, Prognosis, Recurrence, Transplantation Conditioning, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute complications
- Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p = 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p = 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p = 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p = 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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18. Allogeneic hematopoietic stem cell transplantation in patients aged 60-79 years in Germany (1998-2018): a registry study.
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Weller JF, Lengerke C, Finke J, Schetelig J, Platzbecker U, Einsele H, Schroeder T, Faul C, Stelljes M, Dreger P, Blau IW, Wulf G, Tischer J, Scheid C, Elmaagacli A, Neidlinger H, Flossdorf S, Bornhäuser M, Bethge W, Fleischhauer K, Kröger N, De Wreede LC, and Christopeit M
- Subjects
- Humans, Transplantation, Homologous adverse effects, Germany epidemiology, Chronic Disease, Transplantation Conditioning adverse effects, Recurrence, Retrospective Studies, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology
- Abstract
Incidences of diseases treated with transplantation frequently peak at higher age. The contribution of age to total risk of transplantation has not been estimated amidst an aging society. We compare outcomes of 1,547 patients aged 70-79 years and 9,422 patients aged 60-69 years transplanted 1998-2018 for myeloid, lymphoid and further neoplasia in Germany. To quantify the contribution of population mortality to survival, we derive excess mortality based on a sex-, year- and agematched German population in a multistate model that incorporates relapse and graft-versus-host-disease (GvHD). Overall survival, relapse-free survival (RFS) and GvHD-free-relapse-free survival (GRFS) is inferior in patients aged 70-79 years, compared to patients aged 60-69 years, with 36% (95% Confidence Interval [CI]: 34-39%) versus 43% (41-44%), 32% (30- 35%) versus 36% (35-37%) and 23% (21-26%) versus 27% (26-28%) three years post-transplant (P<0.001). Cumulative incidences of relapse at three years are 27% (25-30%) for patients aged 70-79 versus 29% (29-30%) (60-69 years) (P=0.71), yet the difference in non-relapse mortality (NRM) (40% [38-43%] vs. 35% [34-36%] in patients aged 70-79 vs. 60-69 years) (P<0.001) translates into survival differences. Median OS of patients surviving >1 year relapse-free is 6.7 (median, 95% CI: 4.5-9.4, 70-79 years) versus 9 (8.4-10.1, 60-69 years) years since landmark. Three years after RFS of one year, excess NRM is 14% (95% CI: 12-18%) in patients aged 70-79 versus 12% [11-13%] in patients aged 60-69, while population NRM is 7% (6-7%) versus 3% (3-3%). Mortality for reasons other than relapse, GvHD, or age is as high as 27% (24-29%) and 22% (22-23%) four years after transplantation. In conclusion, survival amongst older patients is adequate after allogeneic stem cell transplantation.
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- 2024
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19. Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.
- Author
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Duque-Afonso J, Finke J, Ngoya M, Galimard JE, Craddock C, Raj K, Bloor A, Nicholson E, Eder M, Kim O, Valerius T, Snowden JA, Tholouli E, Crawley C, Collin M, Wilson KMO, Gadisseur A, Protheroe R, Wagner-Drouet EM, Savani BN, Spyridonidis A, Ciceri F, Nagler A, and Mohty M
- Subjects
- Humans, Adult, Melphalan pharmacology, Melphalan therapeutic use, Carmustine, Thiotepa pharmacology, Thiotepa therapeutic use, Busulfan, Antineoplastic Combined Chemotherapy Protocols adverse effects, Transplantation Conditioning methods, Transplantation, Homologous adverse effects, Recurrence, Pathologic Complete Response, Alkylating Agents, Retrospective Studies, Leukemia, Myeloid, Acute, Hematopoietic Stem Cell Transplantation methods, Graft vs Host Disease etiology, Vidarabine analogs & derivatives
- Abstract
Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m
2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2 . We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT., (© 2023. The Author(s).)- Published
- 2024
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20. Upper and/or Lower Respiratory Tract Infection Caused by Human Metapneumovirus After Allogeneic Hematopoietic Stem Cell Transplantation.
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Piñana JL, Tridello G, Xhaard A, Wendel L, Montoro J, Vazquez L, Heras I, Ljungman P, Mikulska M, Salmenniemi U, Perez A, Kröger N, Cornelissen J, Sala E, Martino R, Geurten C, Byrne J, Maertens J, Kerre T, Martin M, Pascual MJ, Yeshurun M, Finke J, Groll AH, Shaw PJ, Blijlevens N, Arcese W, Ganser A, Suarez-Lledo M, Alzahrani M, Choi G, Forcade E, Paviglianiti A, Solano C, Wachowiak J, Zuckerman T, Bader P, Clausen J, Mayer J, Schroyens W, Metafuni E, Knelange N, Averbuch D, and de la Camara R
- Subjects
- Adult, Humans, Cohort Studies, Retrospective Studies, Adrenal Cortex Hormones therapeutic use, Metapneumovirus, Respiratory Tract Infections epidemiology, Respiratory Tract Infections etiology, Respiratory Tract Infections drug therapy, Paramyxoviridae Infections epidemiology, Hematopoietic Stem Cell Transplantation adverse effects, Lymphopenia
- Abstract
Background: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area., Methods: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT., Results: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases., Conclusions: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases., Competing Interests: Potential conflicts of interest. P. B. declares research grants from Neovii, Riemser, and Medac (to institution); advisory board membership for Novartis, Cellgene, Amgen, Medac, and Servier (personal and to institution); speakers bureau for Miltenyi, Jazz, Riemser, Novartis, and Amgen (to institution); and patent und royalties from Medac. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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21. Long-term follow-up of patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation after primary induction failure.
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Mozaffari Jovein M, Ihorst G, Duque-Afonso J, Wäsch R, Bertz H, Wehr C, Duyster J, Zeiser R, Finke J, and Scherer F
- Subjects
- Humans, Remission Induction, Follow-Up Studies, Retrospective Studies, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute therapy
- Abstract
Primary induction failure (PIF) in acute myeloid leukemia (AML) patients is associated with poor outcome, with allogeneic hematopoietic stem cell transplantation (HCT) being the sole curative therapeutic option. Here, we retrospectively evaluated long-term outcomes of 220 AML patients undergoing allogeneic HCT after PIF who never achieved remission, and identified clinical and molecular risk factors associated with treatment response and ultimate prognosis. In this high-risk population, disease-free survival was 25.2% after 5 years and 18.7% after 10 years, while overall survival rates were 29.8% and 21.6% after 5 and 10 years of HCT, respectively. 10-year non-relapse mortality was 32.5%, and 48.8% of patients showed disease relapse within 10 years after allogeneic HCT. Adverse molecular risk features determined at initial diagnosis, poor performance status at the time of allogeneic HCT, and long diagnosis-to-HCT intervals were associated with unfavorable prognosis. Collectively, our data suggests that immediate allogeneic HCT after PIF offers long-term survival and cure in a substantial subset of cases and that high-risk AML patients who never achieved complete response during induction might benefit from early donor search., (© 2023. The Author(s).)
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- 2023
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22. Allogeneic hematopoietic cell transplantation in patients with CALR-mutated myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT.
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Hernández-Boluda JC, Eikema DJ, Koster L, Kröger N, Robin M, de Witte M, Finke J, Finazzi MC, Broers A, Raida L, Schaap N, Chiusolo P, Verbeek M, Hazenberg CLE, Halaburda K, Kulagin A, Labussière-Wallet H, Gedde-Dahl T, Rabitsch W, Raj K, Drozd-Sokolowska J, Battipaglia G, Polverelli N, Czerw T, Yakoub-Agha I, and McLornan DP
- Subjects
- Humans, Transplantation, Homologous adverse effects, Retrospective Studies, Chronic Disease, Recurrence, Transplantation Conditioning adverse effects, Primary Myelofibrosis genetics, Primary Myelofibrosis therapy, Primary Myelofibrosis complications, Hematopoietic Stem Cell Transplantation adverse effects, Neoplasms complications, Graft vs Host Disease etiology
- Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for myelofibrosis (MF) but assessing risk-benefit in individual patients is challenging. This complexity is amplified in CALR-mutated MF patients, as they live longer with conventional treatments compared to other molecular subtypes. We analyzed outcomes of 346 CALR-mutated MF patients who underwent allo-HCT in 123 EBMT centers between 2005 and 2019. After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR- and JAK2-mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versus-host disease-free and relapse-free survival (GRFS) in CALR-mutated patients. These findings confirm the improved prognosis associated with CALR mutation in allo-HCT and support molecular profiling in prognostic scoring systems to predict OS after transplantation in MF., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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23. Impact of pre-transplantation depression and anxiety on the outcome of allogeneic hematopoietic stem cell transplantation: a study from the Transplant Complications Working Party of the EBMT.
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Gjærde LK, Peczynski C, Polge E, Kröger N, de Latour RP, Finke J, Holler E, Blaise D, Helbig G, Salmenniemi U, Potter V, Bunjes D, Erzsebet L, Penack O, Schoemans H, Koenecke C, Basak GW, and Perić Z
- Subjects
- Humans, Transplantation, Homologous, Anxiety etiology, Retrospective Studies, Transplantation Conditioning, Depression, Hematopoietic Stem Cell Transplantation
- Published
- 2023
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24. Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP).
- Author
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Gavriilaki E, Sakellari I, Labopin M, Bornhäuser M, Hamladji RM, Casper J, Edinger M, Zák P, Yakoub-Agha I, Ciceri F, Schroeder T, Zuckerman T, Kobbe G, Yeshurun M, Narni F, Finke J, Diez-Martin JL, Berceanu A, Hilgendorf I, Verbeek M, Olivieri A, Savani B, Spyridonidis A, Nagler A, and Mohty M
- Abstract
We compared FT14 (fludarabine 150-160 mg/m
2 , treosulfan 42 g/m2 ) versus FB4 (fludarabine 150-160 mg/m2 , busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4. We studied 346 patients, 113 transplanted with FT14, and 233 with FΒ4. FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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25. Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients - the randomized phase III PRIMA-CNS trial.
- Author
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Isbell LK, Uibeleisen R, Friedl A, Burger E, Dopatka T, Scherer F, Orban A, Lauer E, Malenica N, Semenova I, Vreden A, Valk E, Wendler J, Neumaier S, Fricker H, El Rabih AAH, Gloggengießer C, Hilbig D, Bleul S, Weis J, Gmehlin D, Backenstrass M, Wirtz S, Ihorst G, Finke J, Illerhaus G, and Schorb E
- Subjects
- Aged, Humans, Quality of Life, Procarbazine, Rituximab, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Lymphoma drug therapy
- Abstract
Background: Older primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed., Methods: This open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT., Discussion: The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach., Trial Registration: German clinical trials registry DRKS00024085 registered March 29, 2023., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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26. Are syngeneic donors a viable donor option in allogeneic haematopoietic cell transplantation for MDS? A brief report on behalf of the Chronic Malignancies Working Party of the EBMT and review of current literature.
- Author
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Robin M, Gras L, Koster L, Saccardi R, Finke J, Forcade E, Rovira M, Kobbe G, Reményi P, Apperley J, Smaranda A, Bay JO, Casper J, de Wreede LC, Giebel S, Grillo G, Heras I, Potter V, Tischer J, Trociukas I, Nachbaur D, Drozd-Sokolowska J, Raj K, Gurnari C, Yakoub-Agha I, Onida F, Scheid C, and McLornan D
- Subjects
- Humans, Tissue Donors, Retrospective Studies, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation, Neoplasms, Graft vs Host Disease
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- 2023
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27. Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial.
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Schubert ML, Schmitt A, Hückelhoven-Krauss A, Neuber B, Kunz A, Waldhoff P, Vonficht D, Yousefian S, Jopp-Saile L, Wang L, Korell F, Keib A, Michels B, Haas D, Sauer T, Derigs P, Kulozik A, Kunz J, Pavel P, Laier S, Wuchter P, Schmier J, Bug G, Lang F, Gökbuget N, Casper J, Görner M, Finke J, Neubauer A, Ringhoffer M, Wolleschak D, Brüggemann M, Haas S, Ho AD, Müller-Tidow C, Dreger P, and Schmitt M
- Subjects
- Humans, Adult, Leukapheresis, Adaptor Proteins, Signal Transducing, Antigens, CD19 therapeutic use, Neurotoxicity Syndromes
- Abstract
Background: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL)., Methods: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10
6 and 50 × 106 CARTs/m2 . Leukapheresis, manufacturing and administration of CARTs were performed in-house., Results: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response., Conclusion: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www., Clinicaltrials: gov as NCT03676504., (© 2023. The Author(s).)- Published
- 2023
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28. Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
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Abou Dalle I, Labopin M, Kröger N, Schroeder T, Finke J, Stelljes M, Neubauer A, Blaise D, Yakoub-Agha I, Salmenniemi U, Forcade E, Itäla-Remes M, Dreger P, Bug G, Passweg J, Heuser M, Choi G, Brissot E, Giebel S, Nagler A, Ciceri F, Bazarbachi A, and Mohty M
- Subjects
- Adult, Humans, Bone Marrow, Transplantation, Homologous, Recurrence, Neoplasm, Residual, Cost of Illness, Retrospective Studies, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute
- Abstract
Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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29. Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study.
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Fein JA, Shouval R, Galimard JE, Labopin M, Socié G, Finke J, Cornelissen JJ, Malladi R, Itälä-Remes M, Chevallier P, Orchard KH, Bunjes D, Aljurf M, Rubio MT, Versluis J, Mohty M, and Nagler A
- Subjects
- Adult, Humans, Middle Aged, Retrospective Studies, Transplant Recipients, Comorbidity, Transplantation Conditioning adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease etiology, Leukemia, Myeloid, Acute etiology
- Abstract
Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95% CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches., (© 2023 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.)
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- 2023
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30. Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
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Giebel S, Labopin M, Houhou M, Caillot D, Finke J, Blaise D, Fegueux N, Ethell M, Cornelissen JJ, Forcade E, Yakoub-Agha I, Lussana F, Maertens J, Bourhis JH, Jindra P, Gorin NC, Nagler A, and Mohty M
- Subjects
- Aged, Humans, Retrospective Studies, Bone Marrow, Prospective Studies, Transplantation, Homologous methods, Acute Disease, Recurrence, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Graft vs Host Disease etiology
- Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n = 209) or matched unrelated donor (MUD, n = 209) with autologous (auto, n = 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p = 0.11) while overall survival (OS) rates were 42% versus 45% (p = 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p = 0.22) and 25% versus 10% (p = 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p = 0.02) and MUD-HCT (HR = 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p = 0.01) and OS (HR = 1.62, p = 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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31. Outcomes after allogeneic hematopoietic cell transplant in patients diagnosed with blast phase of myeloproliferative neoplasms: A retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.
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Ortí G, Gras L, Zinger N, Finazzi MC, Sockel K, Robin M, Forcade E, Avenoso D, Kröger N, Finke J, Radujkovic A, Hunault-Berger M, Schroyens W, Zuckerman T, Bourhis JH, Chalandon Y, Bloor A, Schots R, de Wreede LC, Drozd-Sokolowska J, Raj K, Polverelli N, Czerw T, Hernández-Boluda JC, McLornan D, and Yakoub-Agha I
- Subjects
- Humans, Retrospective Studies, Transplantation, Homologous adverse effects, Blast Crisis therapy, Bone Marrow, Neoplasm Recurrence, Local etiology, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation adverse effects, Myeloproliferative Disorders therapy, Myeloproliferative Disorders etiology
- Abstract
Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) <90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active disease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS ≥90 and in CR at transplant had a better prognosis., (© 2023 Wiley Periodicals LLC.)
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- 2023
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32. Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas.
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Mutter JA, Alig SK, Esfahani MS, Lauer EM, Mitschke J, Kurtz DM, Kühn J, Bleul S, Olsen M, Liu CL, Jin MC, Macaulay CW, Neidert N, Volk T, Eisenblaetter M, Rauer S, Heiland DH, Finke J, Duyster J, Wehrle J, Prinz M, Illerhaus G, Reinacher PC, Schorb E, Diehn M, Alizadeh AA, and Scherer F
- Subjects
- Humans, Prognosis, Risk Assessment, Brain, Biomarkers, Tumor genetics, Mutation, Circulating Tumor DNA genetics, Lymphoma, Non-Hodgkin, Supratentorial Neoplasms
- Abstract
Purpose: Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL., Patients and Methods: We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL., Results: Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value., Conclusion: We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL., [Media: see text].
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- 2023
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33. Primary Cancer Matters in Therapy-related Myeloid Neoplasm Patients Receiving Allogeneic Hematopoietic Cell Transplantation: A Study From the Chronic Malignancies Working Party of the EBMT.
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Robin M, de Wreede LC, Schroeder T, Stölzel F, Kröger N, Koster L, Platzbecker U, Finke J, Ganser A, Blaise D, Ciceri F, Maertens J, Labussière Wallet H, Wang J, Chevallier P, Passweg J, Cornelissen JJ, Nguyen S, Forcade E, Charbonnier A, Bonifazi F, Hayden P, McLornan DP, and Yakoub-Agha I
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- 2023
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34. Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters.
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Bruch PM, Dietrich S, Finel H, Boumendil A, Greinix H, Heinicke T, Bethge W, Beelen D, Schmid C, Martin H, Castagna L, Scheid C, Schäfer-Eckart K, Bittenbring J, Finke J, Sengeloev H, Heiblig M, Cornelissen J, Chevallier P, Mohty M, Robinson S, Montoto S, and Dreger P
- Subjects
- Adult, Aged, Humans, Middle Aged, Young Adult, Acute Disease, Dendritic Cells pathology, Neoplasm Recurrence, Local pathology, Retrospective Studies, Transplantation Conditioning, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Myeloproliferative Disorders pathology, Skin Neoplasms pathology
- Abstract
Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20-73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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35. Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma.
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Keppler-Hafkemeyer A, Greil C, Wratil PR, Shoumariyeh K, Stern M, Hafkemeyer A, Ashok D, Hollaus A, Lupoli G, Priller A, Bischof ML, Ihorst G, Engelhardt M, Marks R, Finke J, Bertrand H, Dächert C, Muenchhoff M, Badell I, Emmerich F, Halder H, Spaeth PM, Knolle PA, Protzer U, von Bergwelt-Baildon M, Duyster J, Hartmann TN, Moosmann A, and Keppler OT
- Subjects
- Humans, COVID-19 Vaccines, BNT162 Vaccine, SARS-CoV-2, T-Lymphocytes, Antibodies, Neutralizing, Vaccination, Multiple Myeloma, COVID-19 prevention & control, Hematologic Neoplasms, Lymphoma, B-Cell
- Abstract
Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies., (© 2022. The Author(s).)
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- 2023
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36. Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy.
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Dertschnig S, Gergely P, Finke J, Schanz U, Holler E, Holtick U, Socié G, Medinger M, Passweg J, Teshima T, Stylianou C, Oehen S, Heim D, and Bucher C
- Subjects
- Humans, Graft vs Host Disease prevention & control, Leukemia, Myeloid, Acute drug therapy, Methotrexate therapeutic use, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Immunosuppressive Agents adverse effects, Sphingosine-1-Phosphate Receptors antagonists & inhibitors
- Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the sole curative option for patients with acute myelogenous leukemia. Outcomes are limited by leukemia relapse, graft-versus-host disease (GVHD), and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GVL) activity while reducing GVHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GVHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing a sufficient GVL effect in the lymphoid, where malignant cells usually reside. The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimod-phosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single- and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials.gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplantation outcomes. Our results indicate that mocravimod is safe and support a larger study to investigate its efficacy in a homogeneous acute myelogenous leukemia patient population undergoing allo-HSCT., Competing Interests: Declaration of Competing Interest S.D. is an employee of Priothera SAS. P.G. is an employee of Novartis. S.O. was an employee of Novartis and is currently an employee of Priothera SAS., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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37. Long-term complete remission of refractory severe idiopathic immune thrombocytopenia (ITP) treated with daratumumab.
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Strüßmann T, Jung J, Heinz J, Duque Afonso J, Wäsch R, Engelhardt M, Duyster J, Finke J, and Marks R
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- Humans, Platelet Count, Antibodies, Monoclonal therapeutic use, Remission Induction, Purpura, Thrombocytopenic, Idiopathic therapy
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- 2023
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38. Correction to: Impact of conditioning regimen intensity on outcomes of second allogeneic hematopoietic cell transplantation for secondary acute myelogenous leukemia.
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Nagler A, Peczynski C, Dholaria B, Labopin M, Valerius T, Dreger P, Kröger N, Reinhardt HC, Finke J, Franke GN, Ciceri F, Verbeek M, Blau IW, Bornhäuser M, Spyridonidis A, Bug G, Bazarbachi A, Schmid C, Yakoub-Agha I, Savani BN, and Mohty M
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- 2022
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39. Long-Term Results of Allogeneic Stem Cell Transplantation in Adult Ph- Negative High-Risk Acute Lymphoblastic Leukemia.
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Beelen DW, Arnold R, Stelljes M, Alakel N, Brecht A, Bug G, Bunjes D, Faul C, Finke J, Franke GN, Holler E, Kobbe G, Kröger N, Rösler W, Scheid C, Schönland S, Stadler M, Tischer J, Wagner-Drouet E, Wendelin K, Brüggemann M, Reiser L, Hoelzer D, and Gökbuget N
- Subjects
- Adult, Humans, Siblings, Neoplasm, Residual etiology, Recurrence, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease epidemiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
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.)
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40. Thiotepa-fludarabine-treosulfan conditioning for 2nd allogeneic HCT from an alternative unrelated donor for patients with AML: a prospective multicenter phase II trial.
- Author
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Finke J, Schmoor C, Stelljes M, Burchert A, Dreger P, Hegenbart U, Wagner-Drouet EM, Bornhäuser M, Sohlbach K, Schub N, Reicherts C, Kobbe G, Glass B, Bertz H, and Grishina O
- Subjects
- Humans, Middle Aged, Thiotepa therapeutic use, Transplantation Conditioning, Unrelated Donors, Retrospective Studies, Prospective Studies, Neoplasm Recurrence, Local drug therapy, Vidarabine therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute
- Abstract
Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to a 2nd allogeneic HCT. Available data are based on retrospective single center or registry studies. The aim of this multicenter trial was to investigate prospectively intensive conditioning with Thiotepa, Fludarabine and Treosulfan (TFT) for 2nd allogeneic HCT from an alternative unrelated donor in patients with AML relapse > 6 months after a 1st allogeneic HCT. Primary endpoint was disease-free survival (DFS) at one year after 2nd HCT. 50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32-0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13-0.36); 0.36 (0.25-0.52); 0.40 (0.29-0.57); and 0.24 (0.13-0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT. Still, relapse rates and NRM after 2nd allogeneic HCT remain a challenge. The trial is registered in the German Clinical Trials Registry (number DRKS00005126)., (© 2022. The Author(s).)
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- 2022
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41. Cellular and Humoral SARS-CoV-2 Vaccination Responses in 192 Adult Recipients of Allogeneic Hematopoietic Cell Transplantation.
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Meyer T, Ihorst G, Bartsch I, Zeiser R, Wäsch R, Bertz H, Finke J, Huzly D, and Wehr C
- Abstract
To determine factors influencing the vaccination response against SARS-CoV-2 is of importance in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) as they display an increased mortality after SARS-CoV-2 infection, an increased risk of extended viral persistence and reduced vaccination response. Real-life data on anti-SARS-CoV-2-S1-IgG titers ( n = 192) and IFN-γ release ( n = 110) of allo-HCT recipients were obtained using commercially available, validated assays after vaccination with either mRNA (Comirnaty™, Pfizer-BioNTech™, NY, US and Mainz, Germany or Spikevax™, Moderna™, Cambridge, Massachusetts, US) or vector-based vaccines (Vaxzevria™,AstraZeneca™, Cambridge, UK or Janssen COVID-19 vaccine™Johnson/Johnson, New Brunswick, New Jersey, US), or after a heterologous protocol (vector/mRNA). Humoral response (78% response rate) was influenced by age, time after transplantation, the usage of antithymocyte globulin (ATG) and ongoing immunosuppression, specifically corticosteroids. High counts of B cells during the vaccination period correlated with a humoral response. Only half (55%) of participants showed a cellular vaccination response. It depended on age, time after transplantation, ongoing immunosuppression with ciclosporin A, chronic graft-versus-host disease (cGvHD) and vaccination type, with vector-based protocols favoring a response. Cellular response failure correlated with a higher CD8+ count and activated/HLA-DR+ T cells one year after transplantation. Our data provide the basis to assess both humoral and cellular responses after SARS-CoV2 vaccination in daily practice, thereby opening up the possibility to identify patients at risk.
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- 2022
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42. Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis.
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Nagler A, Ngoya M, Galimard JE, Labopin M, Bornhäuser M, Stelljes M, Finke J, Ganser A, Einsele H, Kröger N, Brecht A, Bethge W, Edinger M, Kulagin A, Passweg J, Blau IW, Elmaagacli A, Schäfer-Eckart K, Platzbecker U, Schroeder T, Bunjes D, Tischer J, Martin S, Spyridonidis A, Giebel S, Savani B, and Mohty M
- Subjects
- Humans, Middle Aged, Recurrence, Retrospective Studies, Stem Cell Transplantation, Transplantation Conditioning, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute complications
- Abstract
Purpose: We evaluated outcomes of unrelated transplantation for primary refractory/relapsed (ref/rel) acute myeloid leukemia (AML), comparing two cohorts according to the year of transplant, 2000-2009 and 2010-2019., Patients and Methods: Multivariable analyses were performed using the Cox proportional-hazards regression model., Results: 3,430 patients were included; 876 underwent a transplant between 2000-2009 and 2554 in 2010-2019. Median follow-up was 8.7 (95% CI, 7.8-9.4) and 3.4 (95% CI, 3.1-3.6) years (P < 0.001). Median age was 52 (18-77) and 56 (18-79) years (P > 0.0001); 45.5% and 55.5% had refractory AML while 54.5% and 44.5% had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery and day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GvHD) were similar between the two periods. Two-year relapse incidence was higher for patients undergoing transplant in the 2000-2009 period versus those undergoing transplant in 2010-2019: 50.2% versus 45.1% (HR, 0.85; 95% CI, 0.74-0.97; P = 0. 002). Leukemia-free survival; overall survival; and GvHD-free, relapse-free survival were lower for the 2000-2009 period: 26% versus 32.1% (HR, 0.87; 95% CI, 0.78-0.97; P = 0.01), 32.1% versus 38.1% (HR, 0.86; 95% CI, 0.77-0.96; P = 0.01), and 21.5% versus 25.3% (HR, 0.89; 95% CI, 0.81-0.99; P = 0.03), respectively. Two-year nonrelapse mortality was not significantly different (23.8% vs. 23.7%; HR, 0.91; 95% CI, 0.76-1.11; P = 0.34)., Conclusions: Outcome of unrelated transplantation for patients with ref/rel AML has improved in the last two decades, rescuing about one third of the patients. See related commentary by Adrianzen-Herrera and Shastri, p. 4167., (©2022 American Association for Cancer Research.)
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- 2022
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43. Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract.
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Biavasco F, Ihorst G, Wäsch R, Wehr C, Bertz H, Finke J, and Zeiser R
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- Glucocorticoids pharmacology, Glucocorticoids therapeutic use, Humans, Nitriles, Pyrazoles therapeutic use, Pyrimidines, Retrospective Studies, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Acute graft-versus-host disease (aGVHD) is a major life-threatening complication of allogeneic hematopoietic cell transplantation. While most studies report therapy-response of aGVHD including a cumulative grade of skin, liver and intestinal tract manifestations, there is a lack of information specifically on lower gastrointestinal tract aGVHD (GI-GVHD) therapy-response, which is highly relevant in light of novel therapies that target intestinal regeneration such as IL-22, R-spondin or GLP-2. Here we retrospectively analyzed patients who developed GI-GVHD over a 6-year period. A total of 144 patients developed GI-GVHD and 82 (57%) were resistant to glucocorticoid-therapy (SR). The most commonly used second-line therapy was ruxolitinib (74%). Overall and complete response (CR) to ruxolitinib on day 28 were 44.5% and 13%, respectively. SR-GVHD patients experienced a lower 5-year overall survival (OS) (34.8 vs 53.3%, p = 0.0014) and higher incidence of 12-months non-relapse-mortality (39.2 vs 14.3%, p = 0.016) compared to glucocorticoid-sensitive patients. SR-GI-GVHD patients, that achieved a CR on day 28 after ruxolitinib start, experienced a higher OS compared to non-CR patients (p = 0.04). These findings indicate that therapy response of SR-GI-GVHD to different immunosuppressive approaches is still low, and that novel therapies specifically aiming at enhanced intestinal regeneration should be tested in clinical trials., (© 2022. The Author(s).)
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- 2022
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44. Prognostic value of CPSS cytogenetic risk classification in patients with CMML after allogeneic hematopoietic cell transplantation: a retrospective multicenter study of the Chronic Malignancies Working Party of the EBMT.
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Koenecke C, Eikema DJ, Hazelaar S, Schroeder T, Potter V, Kröger N, Bornhäuser M, Finke J, Platzbecker U, Radujkovic A, Ganser A, Salmenniem U, Blaise D, Kobbe G, Meijer E, Friis L, Maertens J, Caballero D, Cornelissen JJ, Olivieri A, Gulsum O, Hayden PJ, Onida F, Robin M, and Yakoub-Agha I
- Subjects
- Cytogenetic Analysis, Humans, Prognosis, Retrospective Studies, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Neoplasms etiology
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- 2022
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45. Role of allogeneic transplantation in chronic myelomonocytic leukemia: an international collaborative analysis.
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Robin M, de Wreede LC, Padron E, Bakunina K, Fenaux P, Koster L, Nazha A, Beelen DW, Rampal RK, Sockel K, Komrokji RS, Gagelmann N, Eikema DJ, Radujkovic A, Finke J, Potter V, Killick SB, Legrand F, Solary E, Broom A, Garcia-Manero G, Rizzoli V, Hayden P, Patnaik MM, Onida F, Yakoub-Agha I, and Itzykson R
- Subjects
- Adolescent, Adult, Aged, Humans, Male, Middle Aged, Retrospective Studies, Transplantation, Homologous, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic therapy, Leukemia, Myelomonocytic, Juvenile
- Abstract
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.)
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- 2022
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46. Favourable outcomes of double-hit/double-expressor lymphoma and high-grade B-cell lymphoma, not otherwise specified after early dose-intensive treatment and up-front autologous stem cell transplantation: a single-centre retrospective experience.
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Strüßmann T, Glatzki F, Engelhardt M, Mertelsmann R, Duyster J, Finke J, and Marks R
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Proto-Oncogene Proteins c-myc, Retrospective Studies, Stem Cell Transplantation, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse therapy
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- 2022
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47. Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.
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Duque-Afonso J, Finke J, Labopin M, Craddock C, Protheroe R, Kottaridis P, Tholouli E, Byrne JL, Orchard K, Salmenniemi U, Hilgendorf I, Hunter H, Nicholson E, Bloor A, Snowden JA, Verbeek M, Clark A, Savani BN, Spyridonidis A, Nagler A, and Mohty M
- Subjects
- Acute Disease, Adult, Bone Marrow Transplantation adverse effects, Busulfan analogs & derivatives, Busulfan therapeutic use, Humans, Melphalan, Middle Aged, Registries, Retrospective Studies, Transplantation Conditioning methods, Vidarabine analogs & derivatives, Vidarabine pharmacology, Vidarabine therapeutic use, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute
- Abstract
In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m
2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT., (© 2022. The Author(s).)- Published
- 2022
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48. Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial.
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Beelen DW, Stelljes M, Reményi P, Wagner-Drouet EM, Dreger P, Bethge W, Ciceri F, Stölzel F, Junghanß C, Labussiere-Wallet H, Schaefer-Eckart K, Grigoleit GU, Scheid C, Patriarca F, Rambaldi A, Niederwieser D, Hilgendorf I, Russo D, Socié G, Holler E, Glass B, Casper J, Wulf G, Basara N, Bieniaszewska M, Stuhler G, Verbeek M, La Rocca U, Finke J, Benedetti F, Pichlmeier U, Klein A, Baumgart J, and Markiewicz M
- Subjects
- Aged, Busulfan analogs & derivatives, Busulfan therapeutic use, Humans, Middle Aged, Prospective Studies, Transplantation Conditioning methods, Vidarabine therapeutic use, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
- Abstract
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.)- Published
- 2022
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49. Monitoring of Measurable Residual Disease Using Circulating DNA after Allogeneic Hematopoietic Cell Transplantation.
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Waterhouse M, Pennisi S, Pfeifer D, Scherer F, Zeiser R, Duyster J, Bertz H, Finke J, and Duque-Afonso J
- Abstract
Relapse of the underlying disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we describe the clinical utility of measurable residual disease (MRD) and mixed chimerism (MC) assessment in circulating cell-free DNA (cfDNA) analysis to detect earlier relapse in patients with hematological malignancies after allo-HSCT. A total of 326 plasma and peripheral blood mononuclear cell (PBMCs) samples obtained from 62 patients with myeloid malignancies were analyzed by droplet-digital PCR (median follow-up: 827 days). Comparison of MC in patients at relapse and in complete remission identified an optimal discriminating threshold of 18% of recipient-derived cfDNA. After performing a targeted next-generation sequencing (NGS) panel, 136 mutations in 58 patients were detected. In a total of 119 paired samples, the putative mutations were detected in both cfDNA and PBMCs in 73 samples (61.3%). In 45 samples (37.8%) they were detected only in cfDNA, and in only one patient (0.9%) were they detected solely in DNA from PBMCs. Hence, in 6 out of 23 patients (26%) with relapse after allo-HSCT, MRD positivity was detected earlier in cfDNA (mean 397 days) than in DNA derived from PBMCs (mean 451 days). In summary, monitoring of MRD and MC in cfDNA might be useful for earlier relapse detection in patients with myeloid malignancies after allo-HSCT.
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- 2022
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50. Impact of conditioning regimen intensity on outcomes of second allogeneic hematopoietic cell transplantation for secondary acute myelogenous leukemia.
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Nagler A, Peczynski C, Dholaria B, Labopin M, Valerius T, Dreger P, Kröger N, Reinhardt HC, Finke J, Franke GN, Ciceri F, Verbeek M, Blau IW, Bornhäuser M, Spyridonidis A, Bug G, Bazarbachi A, Schmid C, Yakoub-Agha I, Savani BN, and Mohty M
- Subjects
- Humans, Recurrence, Retrospective Studies, Transplantation Conditioning methods, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute, Neoplasms, Second Primary
- Abstract
Limited data is available on factors impacting the outcomes of second hematopoietic cell transplantation (HCT2) in patients with secondary acute myeloid leukemia (sAML). This study aimed to assess HCT2 outcome for sAML comparing reduced-intensity (RIC) to myeloablative (MAC) conditioning. Two hundred and fifteen patients were included: RIC (n = 134), MAC (n = 81). The median follow-up was 41.1 (95% CI: 26.7-69.3) and 28.5 (95% CI: 23.9-75.4) months, respectively. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. MVA showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8, p = 0.006)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98, p = 0.042)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5, p = 0.74)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17, p = 0.18)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36, p = 0.6)]. In conclusion, MAC was associated with a lower RI and superior LFS. These results support the use of MAC for eligible patients with sAML who are being considered for HCT2., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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