26 results on '"van Gelder, Michel"'
Search Results
2. The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL.
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Visentin A, Chatzikonstantinou T, Scarfò L, Kapetanakis A, Demosthenous C, Karakatsoulis G, Minga E, Chamou D, Allsup D, Cabrero AA, Andres M, Antic D, Baile M, Baliakas P, Besikli-Dimou S, Bron D, Chatzileontiadou S, Cordoba R, Correa JG, Cuéllar-García C, De Paoli L, De Paolis MR, Delgado J, Dimou M, Donaldson D, Catherwood M, Doubek M, Efstathopoulou M, Eichhorst B, Elashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Frederiksen H, Fürstenau M, García-Marco JA, García-Serra R, Collado R, Gentile M, Gimeno E, Glenthøj A, da Silva MG, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Innocenti I, Itchaki G, Jaksic O, Janssens A, Kalashnikova ОB, Kalicińska E, Kater AP, Kersting S, Labrador J, Lad D, Laurenti L, Levin MD, Lista E, Lopez-Garcia A, Malerba L, Marasca R, Marchetti M, Marquet J, Mattsson M, Mauro FR, Morawska M, Motta M, Munir T, Murru R, Niemann CU, Rodrigues RN, Olivieri J, Orsucci L, Papaioannou M, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Qvist K, Rigolin GM, Ruchlemer R, Šimkovič M, Špaček M, Sportoletti P, Stanca O, Tadmor T, Capasso A, Del Poeta G, Gutwein O, Karlsson LK, Milosevic I, Mirás F, Reda G, Saghumyan G, Shrestha A, Te Raa D, Tonino SH, Van Der Spek E, van Gelder M, van Kampen R, Wasik-Szczepanek E, Wróbel T, Segundo LYS, Yassin M, Pocali B, Vandenberghe E, Iyengar S, Varettoni M, Vitale C, Coscia M, Rambaldi A, Montserrat E, Cuneo A, Stavroyianni N, Trentin L, Stamatopoulos K, and Ghia P
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- Humans, SARS-CoV-2, Post-Acute COVID-19 Syndrome, Retrospective Studies, COVID-19, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
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In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
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- 2023
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3. Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL.
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van der Straten L, Stege CAM, Kersting S, Nasserinejad K, Dubois J, Dobber JA, Mellink CHM, van der Kevie-Kersemaekers AF, Evers LM, de Boer F, Koene HR, Schreurs J, van der Klift M, Velders GA, van der Spek E, van der Straaten HM, Hoogendoorn M, van Gelder M, Posthuma EFM, Visser HPJ, Houtenbos I, Idink CAM, Issa DE, Dompeling EC, van Zaanen HCT, Veelken JH, Levenga H, Tick LW, Terpstra WE, Tonino SH, Westerweel PE, Langerak AW, Kater AP, and Levin MD
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- Humans, Aged, Quality of Life, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Fatigue chemically induced, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
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Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043., (© 2023 by The American Society of Hematology.)
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- 2023
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4. The European landscape on allogeneic haematopoeietic cell transplantation in Chronic Lymphocytic Leukaemia between 2009 and 2019: a perspective from the Chronic Malignancies Working Party of the EBMT.
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Tournilhac O, van Gelder M, Eikema DJ, Zinger N, Dreger P, Bornhäuser M, Vucinic V, Scheid C, Cornelissen JJ, Schroeder T, Jindra P, Sengeloev H, Nguyen Quoc S, Stelljes M, Blau IW, Mayer J, Paneesha S, Chevallier P, Forcade E, Kröger N, Blaise D, Gribben J, Nielsen B, Johansson JE, Kyriakou C, Beguin Y, Pioltelli P, Sampol A, McLornan DP, Schetelig J, Hayden PJ, and Yakoub-Agha I
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- Humans, Neoplasm Recurrence, Local, Transplantation, Homologous methods, Transplantation Conditioning methods, Retrospective Studies, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Hematopoietic Stem Cell Transplantation methods, COVID-19 etiology
- Abstract
Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009-2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2-3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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5. Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group.
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Raa DGT, van der Straten L, van Gelder M, Kersting S, Levin MD, Mous R, van der Straaten HM, Nijziel MR, van der Spek E, Posthuma EFM, Visser HPJ, van der Klift M, de Heer K, Bellido M, Doorduijn JK, Bruns AHW, Raijmakers RAP, and Kater AP
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- Adult, Humans, Netherlands epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.
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- 2022
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6. Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL.
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Antic D, Milic N, Chatzikonstantinou T, Scarfò L, Otasevic V, Rajovic N, Allsup D, Alonso Cabrero A, Andres M, Baile Gonzales M, Capasso A, Collado R, Cordoba R, Cuéllar-García C, Correa JG, De Paoli L, De Paolis MR, Del Poeta G, Dimou M, Doubek M, Efstathopoulou M, El-Ashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Lopez-Garcia A, García-Marco JA, García-Serra R, Gentile M, Gimeno E, da Silva MG, Gutwein O, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Itchaki G, Jaksic O, Janssens A, Kalashnikova OB, Kalicińska E, Kater AP, Kersting S, Koren-Michowitz M, Labrador J, Lad D, Laurenti L, Fresa A, Levin MD, Mayor Bastida C, Malerba L, Marasca R, Marchetti M, Marquet J, Mihaljevic B, Milosevic I, Mirás F, Morawska M, Motta M, Munir T, Murru R, Nunes R, Olivieri J, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Reda G, Rigolin GM, Shrestha A, Šimkovič M, Smirnova S, Špaček M, Sportoletti P, Stanca O, Stavroyianni N, Te Raa D, Tomic K, Tonino S, Trentin L, Van Der Spek E, van Gelder M, Varettoni M, Visentin A, Vitale C, Vukovic V, Wasik-Szczepanek E, Wróbel T, Segundo LYS, Yassin M, Coscia M, Rambaldi A, Montserrat E, Foà R, Cuneo A, Carrier M, Ghia P, and Stamatopoulos K
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- Aged, Anticoagulants, COVID-19 Testing, Hemorrhage, Heparin, Low-Molecular-Weight, Humans, SARS-CoV-2, Leukemia, Lymphocytic, Chronic, B-Cell, Thrombosis, Venous Thromboembolism, COVID-19 Drug Treatment
- Abstract
Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19., Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting., Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively)., Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration., (© 2022. The Author(s).)
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- 2022
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7. Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial.
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Kersting S, Dubois J, Nasserinejad K, Dobber JA, Mellink C, van der Kevie-Kersemaekers AF, Evers LM, de Boer F, Koene HR, Schreurs J, van der Klift M, Velders GA, van der Spek E, van der Straaten HM, Hoogendoorn M, van Gelder M, Posthuma EFM, Visser HPJ, Houtenbos I, Idink CAM, Issa DE, Dompeling EC, van Zaanen HCT, Veelken H, Levenga H, Tick LW, Terpstra WE, Tonino SH, Boyer M, Mobasher M, Levin MD, and Kater AP
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- Adolescent, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Female, Humans, Male, Sulfonamides, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Background: Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status., Methods: We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27)., Findings: Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths., Interpretation: Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests APK reports personal fees from AbbVie, LAVA, Genmab, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb; and research funding from AbbVie, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb. EvdS reports honoraria from Janssen and Amgen; and support for attending meetings from Janssen. JD reports research funding from Roche/Genentech. SK reports personal fees from Janssen, AbbVie, Novartis, Gilead, and Celgene; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. M-DL reports personal fees from AbbVie, Janssen, and Roche; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. SHT reports personal fees from Roche, Takeda, Incyte, Kite/Gilead, and Celgene. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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8. COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study.
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Chatzikonstantinou T, Kapetanakis A, Scarfò L, Karakatsoulis G, Allsup D, Cabrero AA, Andres M, Antic D, Baile M, Baliakas P, Bron D, Capasso A, Chatzileontiadou S, Cordoba R, Correa JG, Cuéllar-García C, De Paoli L, De Paolis MR, Del Poeta G, Demosthenous C, Dimou M, Donaldson D, Doubek M, Efstathopoulou M, Eichhorst B, El-Ashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Frederiksen H, Fürstenau M, García-Marco JA, García-Serra R, Gentile M, Gimeno E, Glenthøj A, Gomes da Silva M, Gutwein O, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Innocenti I, Itchaki G, Jaksic O, Janssens A, Kalashnikova ОB, Kalicińska E, Karlsson LK, Kater AP, Kersting S, Labrador J, Lad D, Laurenti L, Levin MD, Lista E, Lopez-Garcia A, Malerba L, Marasca R, Marchetti M, Marquet J, Mattsson M, Mauro FR, Milosevic I, Mirás F, Morawska M, Motta M, Munir T, Murru R, Niemann CU, Rodrigues RN, Olivieri J, Orsucci L, Papaioannou M, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Qvist K, Reda G, Rigolin GM, Ruchlemer R, Saghumyan G, Shrestha A, Šimkovič M, Špaček M, Sportoletti P, Stanca O, Stavroyianni N, Tadmor T, Te Raa D, Tonino SH, Trentin L, Van Der Spek E, van Gelder M, van Kampen R, Varettoni M, Visentin A, Vitale C, Wasik-Szczepanek E, Wróbel T, San Segundo LY, Yassin M, Coscia M, Rambaldi A, Montserrat E, Foà R, Cuneo A, Stamatopoulos K, and Ghia P
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- COVID-19 diagnosis, COVID-19 virology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Leukemia, Lymphocytic, Chronic, B-Cell virology, Mortality, Prognosis, Risk Factors, SARS-CoV-2, Severity of Illness Index, Survival Analysis, COVID-19 complications, COVID-19 mortality, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell mortality
- Abstract
Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41-0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02-1.04; HR = 1.79, 95% CI:1.04-3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated., (© 2021. The Author(s).)
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- 2021
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9. Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia: Results of a prospective observational study.
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Schetelig J, Hoek J, Stilgenbauer S, Middeke JM, Andersen NS, Fox CP, Lenhoff S, Volin L, Shimoni A, Schroyens W, van Gelder M, Bunjes D, van Biezen A, Baldauf H, de Wreede LC, Tournilhac O, Kröger N, Yakoub-Agha I, and Dreger P
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- Humans, Prospective Studies, Transplantation, Homologous, Tumor Suppressor Protein p53 genetics, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy
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- 2021
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10. Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party.
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Schetelig J, Chevallier P, van Gelder M, Hoek J, Hermine O, Chakraverty R, Browne P, Milpied N, Malagola M, Socié G, Delgado J, Deconinck E, Damaj G, Maury S, Beelen D, Quoc SN, Shankara P, Brecht A, Mayer J, Hunault-Berger M, Bittenbring J, Thieblemont C, Lepretre S, Baldauf H, de Wreede LC, Tournilhac O, Yakoub-Agha I, Kröger N, and Dreger P
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- Humans, Middle Aged, Purines, Quinazolinones, Retrospective Studies, Transplantation Conditioning, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53
mut/del CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.- Published
- 2021
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11. Proteomic markers with prognostic impact on outcome of chronic lymphocytic leukemia patients under chemo-immunotherapy: results from the HOVON 109 study.
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Saberi Hosnijeh F, van der Straten L, Kater AP, van Oers MHJ, Posthuma WFM, Chamuleau MED, Bellido M, Doorduijn JK, van Gelder M, Hoogendoorn M, de Boer F, Te Raa GD, Kerst JM, Marijt EWA, Raymakers RAP, Koene HR, Schaafsma MR, Dobber JA, Tonino SH, Kersting SS, Langerak AW, and Levin MD
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- Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Biomarkers, Tumor blood, Chlorambucil, Disease-Free Survival, Female, Gene Expression, Humans, Immunoglobulin Heavy Chains blood, Immunoglobulin Heavy Chains genetics, Immunotherapy methods, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Mutation, Prognosis, Proteinase Inhibitory Proteins, Secretory blood, Proteomics methods, Receptors, IgE blood, Rituximab, Signaling Lymphocytic Activation Molecule Family blood, Treatment Outcome, Tumor Necrosis Factor Receptor Superfamily, Member 7 blood, Tumor Necrosis Factor Receptor Superfamily, Member 7 genetics, Biomarkers, Tumor genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Proteinase Inhibitory Proteins, Secretory genetics, Receptors, IgE genetics, Signaling Lymphocytic Activation Molecule Family genetics
- Abstract
Despite recent identification of several prognostic markers, there is still a need for new prognostic parameters able to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients. Here, we aimed to validate the prognostic ability of known (proteomic) markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL. To this end, baseline serum samples of 51 CLL patients treated with chemo-immunotherapy were analyzed for 360 proteomic markers, using Olink technology. Median event-free survival (EFS) was 23 months (range: 1.25-60.9). Patients with high levels of sCD23 (>11.27, p = 0.026), sCD27 (>11.03, p = 0.04), SPINT1 (>1.6, p = 0.001), and LY9 (>8.22, p = 0.0003) had a shorter EFS than those with marker levels below the median. The effect of sCD23 on EFS differed between immunoglobulin heavy chain variable gene-mutated and unmutated patients, with the shortest EFS for unmutated CLL patients with sCD23 levels above the median. Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients., Competing Interests: Conflict of interest disclosure None of the authors declared a conflict of interest., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
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- 2020
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12. Ibrutinib as a salvage therapy after allogeneic HCT for chronic lymphocytic leukemia.
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Michallet M, Dreger P, Sobh M, Koster L, Hoek J, Boumendil A, Scheid C, Fox CP, Wulf G, Krüger W, van Gelder M, Corradini P, Russo D, Passweg J, Schoemans H, Bethge W, Schaap N, Cornelissen J, Browne P, Durakovic N, Muller L, Montoto S, Kroger N, and Schetelig J
- Subjects
- Adenine analogs & derivatives, Humans, Male, Piperidines, Retrospective Studies, Salvage Therapy, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
The purpose of our study is to provide information on safety and efficacy of ibrutinib as salvage treatment after allo-HSCT for CLL. A total of 56 patients were included, 36 (64%) males; median age at transplantation was 48 years (range: 35-64) and the median number of treatment lines prior to transplantation was 3 (1-10). The median time between allo-HSCT and Ibrutinib was 30 months (range: 1-140). Overall, 40 (71%) patients responded to Ibrutinib; 23 (41%) PR, and 17 (30%) CR. At time of ibrutinib initiation, ten patients had active chronic GVHD that resolved under Ibrutinib, whilst a single patient developed limited de novo chronic GVHD on Ibrutinib. Fourteen patients discontinued ibrutinib, four because of toxicity and ten because of disease progression. Overall, 14 patients progressed (median PFS = 24 months) among them 10 died. Two-year OS and PFS probabilities were 72% (95% CI: 52-84) and 50% (95% CI: 32-66), respectively. Patients with late relapse after allo-HSCT (≥24 months) had a better PFS after ibrutinib. Our study shows that ibrutinib can be safely administered for CLL relapse after allo-HSCT, with comparable efficacy to non-transplanted patients with high-risk disease.
- Published
- 2020
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13. Reduced intensity conditioning regimens including alkylating chemotherapy do not alter survival outcomes after allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia compared to low-intensity non-myeloablative conditioning.
- Author
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Andersen NS, Bornhäuser M, Gramatzki M, Dreger P, Vitek A, Karas M, Michallet M, Moreno C, van Gelder M, Henseler A, de Wreede LC, Schönland S, Kröger N, and Schetelig J
- Subjects
- Adult, Aged, Busulfan administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Female, Follow-Up Studies, Graft vs Host Disease epidemiology, Humans, Incidence, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Melphalan administration & dosage, Middle Aged, Prognosis, Remission Induction, Retrospective Studies, Survival Rate, Transplantation, Homologous, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Transplantation Conditioning mortality
- Abstract
Purpose: The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown., Methods: We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC., Results: The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS., Conclusion: Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.
- Published
- 2019
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14. Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia.
- Author
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Kater AP, van Oers MHJ, van Norden Y, van der Straten L, Driessen J, Posthuma WFM, Schipperus M, Chamuleau MED, Nijland M, Doorduijn JK, Van Gelder M, Hoogendoorn M, De Croon F, Wittebol S, Kerst JM, Marijt EWA, Raymakers RAP, Schaafsma MR, Dobber JA, Kersting S, and Levin MD
- Subjects
- Adolescent, Adult, Chlorambucil administration & dosage, Disease-Free Survival, Feasibility Studies, Female, Humans, Lenalidomide administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Rituximab administration & dosage, Survival Rate, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality
- Abstract
Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m
2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34 ., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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15. Ibrutinib for bridging to allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia or mantle cell lymphoma: a study by the EBMT Chronic Malignancies and Lymphoma Working Parties.
- Author
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Dreger P, Michallet M, Bosman P, Dietrich S, Sobh M, Boumendil A, Nagler A, Scheid C, Cornelissen J, Niederwieser D, Müller L, Vandenberghe E, Scortechini I, Schoemans H, Andersen NS, Finke J, Russo D, Ljungman P, Passweg J, van Gelder M, Durakovic N, Labussiere-Wallet H, Berg T, Wulf G, Bethge W, Bunjes D, Stilgenbauer S, Canepari ME, Schaap M, Fox CP, Kröger N, Montoto S, and Schetelig J
- Subjects
- Adenine analogs & derivatives, Adult, Aged, Allografts, Disease-Free Survival, Female, Humans, Male, Middle Aged, Piperidines, Survival Rate, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Lymphoma, Mantle-Cell mortality, Lymphoma, Mantle-Cell therapy, Pyrazoles administration & dosage, Pyrimidines administration & dosage
- Abstract
The aim of this retrospective study was to investigate the safety and efficacy of allogeneic hematopoietic cell transplantation (alloHCT) in patients pre-treated with ibrutinib. Eligible were patients aged >18 years allotransplanted for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) after prior exposure to ibrutinib who were registered with the EBMT registry. Seventy patients (CLL 48, MCL 22) were included. At the time of alloHCT, 73% of the patients were ibrutinib responsive. All patients except one engrafted, and acute GVHD grade 2-4 (3-4) was observed in 49% (12%) of 68 evaluable patients. The cumulative incidence of chronic GVHD was 54% 1 year after transplant. In the CLL group, 12-month non-relapse mortality, relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) were 10, 30, 60, and 72%, respectively, and in the MCL group 5, 19, 76, and 86%, respectively. Pre-transplant ibrutinib failure and poor performance status predicted inferior RI, PFS and OS in the CLL group. In conclusion, ibrutinib does not affect the safety of a subsequent alloHCT. While the relatively high post-transplant relapse risk in ibrutinib-exposed patients with CLL deserves further study, in patients with MCL consolidating disease responses to ibrutinib with alloHCT seems to be a promising option.
- Published
- 2019
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16. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies.
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Dreger P, Ghia P, Schetelig J, van Gelder M, Kimby E, Michallet M, Moreno C, Robak T, Stilgenbauer S, and Montserrat E
- Subjects
- Allografts, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Adoptive Transfer, Drug Resistance, Neoplasm genetics, Drug Resistance, Neoplasm immunology, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance ( TP53 abnormalities) to treatment with chemoimmunotherapy (CIT). With the availability of pathway inhibitors (PIs), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high-risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI. This category is largely the domain of PI-based therapy, and cellular therapy (ie, allogeneic hematopoietic cell transplantation) remains an option only in selected patients with low individual procedure-related risk. In CLL high-risk-II, CIT- and PI-resistant, characterized by increasing exhaustion of pharmacological treatment possibilities, cellular therapies (including chimeric antigen receptor-engineered T cells) should be considered in patients eligible for these procedures. Moreover, molecular and cellular therapies are not mutually exclusive and could be used synergistically to exploit their full potential., (© 2018 by The American Society of Hematology.)
- Published
- 2018
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17. Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT.
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van Gorkom G, van Gelder M, Eikema DJ, Blok HJ, van Lint MT, Koc Y, Ciceri F, Beelen D, Chevallier P, Selleslag D, Blaise D, Foá R, Corradini P, Castagna L, Moreno C, Solano C, Müller LP, Tischer J, Hilgendorf I, Hallek M, Bittenbring J, Theobald M, Schetelig J, and Kröger N
- Subjects
- Adult, Aged, Cyclophosphamide therapeutic use, Female, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation mortality, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Retrospective Studies, Survival Analysis, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Transplantation, Haploidentical mortality
- Abstract
Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT.
- Published
- 2018
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18. Clinical Practice Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) in The Netherlands.
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Kersting S, Neppelenbroek SIM, Visser HPJ, van Gelder M, Levin MD, Mous R, Posthuma W, van der Straaten HM, and Kater AP
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- Guidelines as Topic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Netherlands, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Introduction: In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations., Materials and Methods: The working party discussed a set of questions regarding diagnostic tests and treatment and wrote the draft guideline. This was evidence-based whenever possible, but in cases of low evidence, an expert-based recommendation was formulated with input of the entire working party. The draft guideline was sent to all hematologists in the Netherlands for comment and was subsequently approved., Results: Recommendations were formulated on diagnostic tests and work-up before treatment. Also, recommendations were made for treatment with fludarabine-cyclophosphamide-rituximab, bendamustine-rituximab, chlorambucil with anti-CD20 antibody, ibrutinib, idelalisib-rituximab, venetoclax, and allogeneic stem cell transplantation., Conclusion: In the revised Dutch CLL guidelines, chemo-immunotherapy is still the cornerstone of CLL treatment with novel targeted drugs for specific risk groups., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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19. Baseline Characteristics Predicting Very Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Patients With High Cytogenetic Risk Chronic Lymphocytic Leukemia - A Retrospective Analysis From the Chronic Malignancies Working Party of the EBMT.
- Author
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van Gelder M, Ziagkos D, de Wreede L, van Biezen A, Dreger P, Gramatzki M, Stelljes M, Andersen NS, Schaap N, Vitek A, Beelen D, Lindström V, Finke J, Passweg J, Eder M, Machaczka M, Delgado J, Krüger W, Raida L, Socié G, Jindra P, Afanasyev B, Wagner E, Chalandon Y, Henseler A, Schoenland S, Kröger N, and Schetelig J
- Subjects
- Adult, Aged, Female, HLA Antigens, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Tissue Donors, Transplantation Conditioning adverse effects, Transplantation Conditioning methods, Transplantation, Homologous, Treatment Outcome, Chromosome Aberrations, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Background: Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population., Patients and Methods: Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90.4 months) by Cox regression modeling, and predicted probabilities of NRM and PFS of 2 reference patients with favorable or unfavorable characteristics were plotted., Results: Predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.1-2.5) and partially human leukocyte antigen (HLA)-mismatched unrelated donor (HR, 2.8; 95% CI, 1.5-5.2). The latter variable also predicted a higher risk of 2-year NRM (HR, 4.0; 95% CI, 1.4-11.6) compared with HLA-matched sibling donors. Predicted 2-year NRM and 8-year PFS of a high cytogenetic risk (del(17p) and/or del(11q)) patient in remission with a matched related donor were 12% (95% CI, 3%-22%) and 54% (95% CI, 38%-69%), and for an unresponsive patient with a female partially HLA-matched unrelated donor 37% (95% CI, 12%-62%) and 38% (95% CI, 13%-63%)., Conclusion: Low predicted NRM and high 8-year PFS in favorable transplant high cytogenetic risk patients compares favorably with outcomes with KI or BCL2i. Taking into account the amount of uncertainty for predicting survival after alloHCT and after sequential administration of KI and BCL2i, alloHCT remains a valid option for younger patients with high cytogenetic risk chronic lymphocytic leukemia with a well-HLA-matched donor., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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20. Centre characteristics and procedure-related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT).
- Author
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Schetelig J, de Wreede LC, Andersen NS, Moreno C, van Gelder M, Vitek A, Karas M, Michallet M, Machaczka M, Gramatzki M, Beelen D, Finke J, Delgado J, Volin L, Passweg J, Dreger P, Schaap N, Wagner E, Henseler A, van Biezen A, Bornhäuser M, Iacobelli S, Putter H, Schönland SO, and Kröger N
- Subjects
- Adult, Aged, Delivery of Health Care statistics & numerical data, Europe epidemiology, Female, Humans, Kaplan-Meier Estimate, Karnofsky Performance Status, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Recurrence, Registries, Retrospective Studies, Risk Factors, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation methods, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Professional Practice statistics & numerical data
- Abstract
The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [CI], 34-42%). Larger numbers of CLL alloHCTs (hazard ratio [HR] 0·96, P = 0·002), certification of quality management (HR 0·7, P = 0·045) and a higher gross national income per capita (HR 0·4, P = 0·04) improved EFS. In vivo T-cell depletion (TCD) with alemtuzumab compared to no TCD (HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient (HR 1·4, P = 0·02) had a negative impact on EFS, but not non-myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2017
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21. Outcomes of Cord Blood Transplantation Using Reduced-Intensity Conditioning for Chronic Lymphocytic Leukemia: A Study on Behalf of Eurocord and Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation, and the Societé Française de Greffe de Moelle et Therapie Cellulaire.
- Author
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Xavier E, Cornillon J, Ruggeri A, Chevallier P, Cornelissen JJ, Andersen NS, Maillard N, Nguyen S, Blaise D, Deconinck E, Veelken H, Milpied N, Van Gelder M, Peffault de Latour R, Gluckman E, Kröger N, Schetelig J, and Rocha V
- Subjects
- Adult, Aged, Disease-Free Survival, Europe, Female, Humans, Male, Middle Aged, Retrospective Studies, Risk Factors, Treatment Outcome, Cord Blood Stem Cell Transplantation adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Transplantation Conditioning adverse effects
- Abstract
Outcomes after umbilical cord blood transplantation (UCBT) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are unknown. We analyzed outcomes of 68 patients with poor-risk CLL/SLL who underwent reduced-intensity (RIC) UCBT from 2004 to 2012. The median age was 57 years and median follow-up 36 months; 17 patients had del 17p/p53mutation, 19 patients had fludarabine-refractory disease, 11 relapsed after autologous stem cell transplantation, 8 had diagnosis of prolymphocytic leukemia, 4 had Richter syndrome, and 8 underwent transplantation with progressive or refractory disease. The most common RIC used was cyclophosphamide, fludarabine, and total body irradiation (TBI) in 82%; 15 patients received antithymocyte globulin. Most of the cord blood grafts were HLA mismatched and 76% received a double UCBT. Median total nucleated cells collected was 4.7 × 10(7)/kg. The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 72% at 60 and 180 days respectively; day 100 graft-versus-host disease (GVHD) (grade II to IV) was 43% and 3-year chronic GVHD was 32%. The CI of relapse, nonrelapse mortality, overall survival, and progression-free survival (PFS) at 3 years were 16%, 39%, 54%, and 45%, respectively. Fludarabine-sensitive disease at transplantation and use of low-dose TBI regimens were associated with acceptable PFS. In conclusion, use of RIC-UCBT seems to be feasible in patients with poor-risk CLL/SLL and improved outcomes were observed in patients with fludarabine-sensitive disease who received low-dose TBI regimens., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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22. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents?
- Author
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Dreger P, Schetelig J, Andersen N, Corradini P, van Gelder M, Gribben J, Kimby E, Michallet M, Moreno C, Stilgenbauer S, and Montserrat E
- Subjects
- Algorithms, Cell Transformation, Neoplastic, Clinical Trials as Topic, Decision Making, Drug Therapy methods, Genes, p53, Graft vs Leukemia Effect, Hematopoietic Stem Cell Transplantation, Humans, Immunotherapy methods, Prognosis, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcr antagonists & inhibitors, Quality of Life, Recurrence, Remission Induction, Risk Factors, Treatment Outcome, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Stem Cell Transplantation
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (HR-CLL; ie, refractory to purine analogs, short response [<24 months] to chemoimmunotherapy, and/or presence of del[17p]/TP53 mutations). Currently, treatment algorithms for HR-CLL are being challenged by the introduction of novel classes of drugs. Among them, BCR signal inhibitors (BCRi) and B-cell lymphoma 2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favorable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with HR-CLL about indication for and timing of HSCT. This article provides an overview of currently available evidence and theoretical considerations to guide this difficult decision process. Until the risks and benefits of different treatment strategies are settled, all patients with HR-CLL should be considered for treatment with BCRi/BCL2a. For patients who respond to these agents, there are 2 treatment possibilities: (1) performing an HSCT or (2) continuing treatment with the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when recommending one of these treatments over the other., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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23. Improved relapse-free survival after autologous stem cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study.
- Author
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de Wreede LC, Watson M, van Os M, Milligan D, van Gelder M, Michallet M, Dreger P, Dearden CE, Homewood J, Dupuis J, Leporrier M, Karas M, Corront B, Baerlocher GM, Herr W, Choquet S, Niederwieser DW, Sutton L, Kröger N, de Witte TM, and Schetelig On Behalf Of The Chronic Malignancies Working Party Of The Ebmt And The Uk Medical Research Council J
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Recurrence, Surveys and Questionnaires, Transplantation Conditioning, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell psychology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Quality of Life
- Abstract
In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2014
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24. Centre characteristics and procedure-related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT)
- Author
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Schetelig, Johannes, de Wreede, Liesbeth C., Andersen, Niels S., Moreno, Carol, van Gelder, Michel, Vitek, Antonin, Karas, Michal, Michallet, Mauricette, Machaczka, Maciej, Gramatzki, Martin, Beelen, Dietrich, Finke, Jürgen, Delgado, Julio, Volin, Liisa, Passweg, Jakob, Dreger, Peter, Schaap, Nicolaas, Wagner, Eva, Henseler, Anja, van Biezen, Anja, Bornhäuser, Martin, Iacobelli, Simona, Putter, Hein, Schönland, Stefan O., Kröger, Nicolaus, Esteve, Jordi, Ljungman, Per, de Witte, Theo, Stelljes, Matthias, Sierra, Jorge, Socié, Gerard, Ganser, Arnold, Wulf, Gerhard G., Deconinck, Eric, Faber, Edgar, Feguex, Nathalie, Gedde-Dahl, Tobias, Kolbe, Karin, Chalandon, Yves, Krüger, William, Huynh, Anne, Bourhis, Jean Henri, Schouten, Harry, Ribera Santasusana, Josep M., Interne Geneeskunde, MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Chalandon, Yves
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Oncology ,Male ,Transplantation Conditioning ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Chronic lymphocytic leukemia ,Medizin ,QUALITY MANAGEMENT-SYSTEM ,Kaplan-Meier Estimate ,risk factor analysis ,GUIDELINES ,Biochemistry ,allogeneic stem cell transplantation ,centre effects ,chronic lymphocytic leukaemia ,frailties ,Transplantation Conditioning / methods ,0302 clinical medicine ,Recurrence ,Risk Factors ,Leukemia, Lymphocytic, Chronic, B-Cell / mortality ,Registries ,Delivery of Health Care / statistics & numerical data ,IBRUTINIB ,ddc:616 ,0303 health sciences ,ALEMTUZUMAB ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Professional Practice ,Hematology ,Middle Aged ,3. Good health ,Europe ,030220 oncology & carcinogenesis ,ABT-199 ,Cohort ,SURVIVAL ,Alemtuzumab ,Female ,Europe / epidemiology ,medicine.drug ,Adult ,medicine.medical_specialty ,Allogeneic transplantation ,Immunology ,Lower risk ,DIAGNOSIS ,Settore MED/01 - Statistica Medica ,03 medical and health sciences ,Leukemia, Lymphocytic, Chronic, B-Cell / therapy ,Hematopoietic Stem Cell Transplantation / methods ,Internal medicine ,medicine ,Humans ,Karnofsky Performance Status ,030304 developmental biology ,Aged ,Retrospective Studies ,business.industry ,Proportional hazards model ,CHRONIC LYMPHOCYTIC-LEUKEMIA ,Retrospective cohort study ,STEM-CELL TRANSPLANTATION ,Cell Biology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Confidence interval ,Surgery ,Professional Practice / statistics & numerical data ,Transplantation ,business ,Delivery of Health Care ,030215 immunology ,RESPONSES - Abstract
Introduction:Even in the era of novel targeted therapies for the treatment of Chronic Lymphocytic Leukemia (CLL) patients, such as BTK, PI3K and BCL2 inhibitors, allogeneic hematopoietic stem cell transplantations (alloHCT) will remain an important treatment option for a subset of patients with very high risk CLL. The current study focused on the impact of center and procedure-related factors on outcomes after alloHCT, taking into account the impact of patient- and disease-related risk factors. Patients and Methods:Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analyzed. Their data were collected as part of the EBMT CLL Data Quality Initiative. Outcomes of interest were Event-Free Survival (EFS) up to 5 years after transplantation and mortality in the first 100 days after alloHCT. Outcomes were analyzed by means of the Kaplan-Meier method and Cox proportional hazards models with a frailty (random effects) component to take into account unexplained center heterogeneity. The following factors describing center characteristics or the transplant procedure were analyzed: experience in alloHCT in general and, for CLL specifically, accreditation by the Joint Accreditation Committee-ISCT & EBMT (JACIE), Gross National Income (GNI)/capita based on purchasing power parity (PPP) (GNI/cap), donor type, donor-patient sex-match, type of conditioning, stem cell source and T-cell depletion (TCD). Results:Five-year EFS of the whole cohort was 37% (95% Confidence Interval, 33%-42%), Day-100 survival was 90% (88%-92%). Experience of the transplant center was measured by the number of all alloHCTs, and alloHCTs for patients with CLL respectively. The median total number of alloHCTs per center per year was 45 (range 0-169) and the median number of CLL alloHCTs was only 2 per center per year (range 0-19). Greater experience with transplantation of patients with CLL (Hazard Ratio (HR) 0.96 per additional transplant, p=0.002), JACIE accreditation (HR 0.7, p=0.045) and a higher GNI/cap (HR 0.4, 95% CI 0.2-0.96, p=0.04) showed a protective impact on 5-year EFS in the Cox model. In vivo TCD with alemtuzumab (HR 1.5 compared to no TCD, p=0.03) and a female donor for a male patient (HR 1.4 compared to a male donor for a male patient, p=0.02) were the only procedure-related factors significantly associated with EFS. Event-Free Survival after in vivo TCD with Anti-Thymocyte-Globulin or after ex vivo TCD was comparable to EFS without TCD (HR 0.9, 0.7-1.3, p=0.6; HR 0.9, 0.5-1.6, p=0.8). Non-myeloablative conditioning did not have a negative impact on 5-year EFS, and exposed patients to a lower risk of non-relapse mortality. Measured and unmeasured center characteristics did not have a significant impact on 100-day mortality. Even when correcting for patient-, procedure- and center-related characteristics, there was still significant variation in center outcome, expressed by center-specific HRs derived from the frailty models, ranging from 0.6 to 1.2. Their impact is illustrated in a model-based plot for EFS (see Figure) which shows outcomes for three reference patients with the same characteristics who would be transplanted in three centers with the same measured characteristics but with the highest, average and lowest HRs in the dataset. These unexplained center effects likely represent a mixture of differences which could apply to the location of the transplant center, unmeasured characteristics of the patient population transplanted at this center, selection criteria which were not reported and factors determining the success of the transplant procedure which might differ between centers. Conclusion: We have confirmed that both center- and procedure-related factors have a significant impact on the EFS of patients with CLL undergoing alloHCT. Our results may help to interpret outcomes of single or multicenter studies better. Since non-myeloablative conditioning did not have a negative impact on EFS and exposed patients to a lower risk of non-relapse mortality, this approach should be favored for future alloHCT for CLL. Probability of Event-Free Survival up to Five Years Post-HCT for three Reference Patients Contribution: J.S. designed the research and wrote the paper. L.C.d.W conducted the statistical analysis and produced the figure. Figure Figure. Disclosures Schetelig: Sanofi: Honoraria. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Dreger:Gilead: Consultancy; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy.
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- 2017
25. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors
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Emili Montserrat, Stephan Stilgenbauer, Peter Dreger, Paolo Ghia, Johannes Schetelig, Tadeusz Robak, Mauricette Michallet, Michel van Gelder, Eva Kimby, Carol Moreno, Dreger, Peter, Ghia, Paolo, Schetelig, Johanne, Van Gelder, Michel, Kimby, Eva, Michallet, Mauricette, Moreno, Carol, Robak, Tadeusz, Stilgenbauer, Stephan, Montserrat, Emili, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, and MUMC+: MA Hematologie (9)
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Adoptive cell transfer ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Hematopoietic stem cell transplantation ,Somatic evolution in cancer ,Biochemistry ,Cell therapy ,MARROW TRANSPLANTATION ,03 medical and health sciences ,RETROSPECTIVE ANALYSIS ,0302 clinical medicine ,GCLLSG CLL3X TRIAL ,Chemoimmunotherapy ,VERSUS-HOST-DISEASE ,medicine ,Humans ,ALLOGENEIC TRANSPLANTATION ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Cell Biology ,RICHTER TRANSFORMATION ,Allografts ,medicine.disease ,OPEN-LABEL ,Adoptive Transfer ,Leukemia, Lymphocytic, Chronic, B-Cell ,CLONAL EVOLUTION ,EUROPEAN-SOCIETY ,Transplantation ,Leukemia ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,business ,FOLLOW-UP ,030215 immunology - Abstract
High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance (TP53 abnormalities) to treatment with chemoimmunotherapy (CIT). With the availability of pathway inhibitors (PIs), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high-risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI. This category is largely the domain of PI-based therapy, and cellular therapy (ie, allogeneic hematopoietic cell transplantation) remains an option only in selected patients with low individual procedure-related risk. In CLL high-risk-II, CIT- and PI-resistant, characterized by increasing exhaustion of pharmacological treatment possibilities, cellular therapies (including chimeric antigen receptor-engineered T cells) should be considered in patients eligible for these procedures. Moreover, molecular and cellular therapies are not mutually exclusive and could be used synergistically to exploit their full potential.
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- 2018
26. Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT
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Gwendolyn Van Gorkom, Patrice Chevallier, Nicolaus Kröger, Fabio Ciceri, Carol Moreno, Johannes Schetelig, Henric-Jan Blok, Paolo Corradini, Roberto Foa, Yener Koc, M. T. Van Lint, Dietrich W. Beelen, Didier Blaise, Johanna Tischer, Dominik Selleslag, Lutz P. Müller, Inken Hilgendorf, Joerg Thomas Bittenbring, Matthias Theobald, Dirk-Jan Eikema, Michel van Gelder, Michael Hallek, Carlos Solano, Luca Castagna, van Gorkom, Gwendolyn, van Gelder, Michel, Eikema, Dirk-Jan, Blok, Henric-Jan, van Lint, M. T., Koc, Yener, Ciceri, Fabio, Beelen, Dietrich, Chevallier, Patrice, Selleslag, Dominik, Blaise, Didier, Foá, Roberto, Corradini, Paolo, Castagna, Luca, Moreno, Carol, Solano, Carlo, Müller, Lutz Peter, Tischer, Johanna, Hilgendorf, Inken, Hallek, Michael, Bittenbring, Jörg, Theobald, Matthia, Schetelig, Johanne, Kröger, Nicolaus, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Interne Geneeskunde, and MUMC+: MA Hematologie (9)
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Oncology ,Male ,BLOOD ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Medizin ,MULTICENTER ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Medicine ,POSTTRANSPLANTATION CYCLOPHOSPHAMIDE ,Cumulative incidence ,ALLOGENEIC TRANSPLANTATION ,DONOR TRANSPLANTATION ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,EUROPEAN-SOCIETY ,surgical procedures, operative ,Treatment Outcome ,Transplantation ,030220 oncology & carcinogenesis ,SURVIVAL ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Allogeneic transplantation ,Cyclophosphamide ,MINIMAL RESIDUAL DISEASE ,03 medical and health sciences ,Internal medicine ,Humans ,Aged ,Retrospective Studies ,business.industry ,Retrospective cohort study ,medicine.disease ,Minimal residual disease ,BONE-MARROW-TRANSPLANTATION ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,Transplantation, Haploidentical ,business ,CLL ,030215 immunology - Abstract
Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT.
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- 2017
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