436 results on '"Cornelissen, Jan"'
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2. Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: a study of the ALWP of the EBMT
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Mohty, Razan, Bazarbachi, Abdul Hamid, Labopin, Myriam, Esteve, Jordi, Kröger, Nicolaus, Cornelissen, Jan J., Blaise, Didier, Socié, Gerard, Maury, Sébastien, Ganser, Arnold, Gedde-Dahl, Tobias, von dem Borne, Peter, Bourhis, Jean Henri, Bulabois, Claude Eric, Yakoub-Agha, Ibrahim, Pabst, Caroline, Nguyen, Stéphanie, Chevallier, Patrice, Huynh, Anne, Bazarbachi, Ali, Nagler, Arnon, Ciceri, Fabio, and Mohty, Mohamad
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Isocitrate dehydrogenase 1 and 2 (IDH1and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1and IDH2mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n= 241) carried IDH1mutation (mIDH1), and 26.27% (n= 398) IDH2mutation (mIDH2) and 57.82% (n= 876) had no-IDH mutation. NPM1was frequently encountered with IDH1mutation (no-IDH group, n= 217, 24.8%, mIDH1, n= 103, 42.7%, mIDH2, n= 111, 27.9%, p< 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1and mIDH2compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% CI 0.47–0.91), p= 0.011; HR = 0.73 (95% CI 0.56–0.96), p= 0.025, respectively). In the mIDH1group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48–0.94), p= 0.021), whereas mIDH2was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34–0.7), p< 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95% CI 0.55–0.9), p= 0.004) and OS (HR = 0.74 (95% CI 0.56–0.97), p= 0.027). In the subgroup of NPM1wild type, only IDH2was associated with improved outcomes. In conclusion, our data suggest that IDH1and IDH2mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1.
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- 2024
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3. Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning
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Sijs-Szabo, Aniko, Dinmohamed, Avinash G., Versluis, Jurjen, van der Holt, Bronno, Bellido, Mar, Hazenberg, Mette D., van Gelder, Michel, Schaap, Nicolaas P.M., Meijer, Ellen, van der Wagen, Lotte E, Halkes, Constantijn J.M., Rijneveld, Anita W., and Cornelissen, Jan J.
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- 2023
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4. Allogeneic hematopoietic cell transplantation for patients with AML aged 70 years or older in first remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
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Maffini, Enrico, Ngoya, Maud, Galimard, Jacques-Emmanuel, Harbi, Samia, Kröger, Nicolaus, Platzbecker, Uwe, Sengeloev, Henrik, Craddock, Charles, Potter, Victoria, Choi, Goda, Chevallier, Patrice, Stölzel, Friedrich, Tholouli, Eleni, Maertens, Johan, Ciceri, Fabio, Cornelissen, Jan, Sanz, Jaime, Spyridonidis, Alexandros, Lanza, Francesco, Nagler, Arnon, and Mohty, Mohamad
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Accessibility to allogeneic hematopoietic cell transplantation (HCT) programs for older patients is growing constantly. We report on the clinical outcomes of a group of 701 adults aged ≥70 years, with acute myeloid leukemia (AML) in first complete remission (CR1), who received a first HCT, from HLA-matched sibling donors (MSD), 10/10 HLA-matched unrelated donors (UD), 9/10 HLA-mismatched unrelated donors (mUD) or haploidentical (Haplo) donors. The 2-year overall survival (OS) was 48.1%, leukemia-free survival (LFS) 45.3%, relapse incidence (RI) 25.2%, non-relapse mortality (NRM) 29.5% and GVHD-free, relapse-free survival (GRFS), 33.4%. Compared to MSD, patients transplanted from Haplo and UD presented lower RI (HR 0.46, 95% CI 0.25–0.8, p= 0.02 and HR 0.44, 95% CI: 0.28–0.69, p= 0.001, respectively); this translated into prolonged LFS for Haplo (HR 0.62, 95% CI: 0.39–0.99, p= 0.04). Patients transplanted from mUD exhibited the highest NRM incidence (HR 2.33, 95% CI: 1.26–4.31, p= 0.007). HCT in selected adult CR1 AML patients >70 years is feasible and could be associated with good clinical outcomes. Prospective clinical trials are warranted.
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- 2023
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5. An early post-transplant relapse prediction score in multiple myeloma: a large cohort study from the chronic malignancies working party of EBMT
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Beksac, Meral, Iacobelli, Simona, Koster, Linda, Cornelissen, Jan, Griskevicius, Laimonas, Rabin, Neil K., Stoppa, Anne Marie, Meijer, Ellen, Mear, Jean-Baptiste, Zeerleder, Sacha, Mayer, Jiri, Fenk, Roland, Fegueux, Nathalie, Chevallier, Patrice, Konirova, Eva, Snowden, John A., Engelhardt, Monika, Orchard, Kim, Hulin, Cyrille, Schaap, Nicolaas, Sossa, Claudia, Elmaagacli, Ahmet, McLornan, Donal P., Hayden, Patrick J., Schönland, Stefan, and Yakoub-Agha, Ibrahim
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Early relapse (ER) following Autologous Hematopoietic Cell Transplantation (AHCT) confers a poor prognosis. We therefore developed a novel scoring system to predict ER. A total of 14,367 AHCT-1 patients were transplanted between 2014 and 2019, and were conditioned with Melphalan 200 mg/m2(Mel200) (n= 7228; 2014–2017) (training cohort); Mel200 (n= 5616; 2018–2019) or Mel140 (n= 1523; 2018–2019) (validation cohorts). PFS-12 and the Cumulative Incidence of Relapse at 12 months were 84.1% and 14.7% (training Mel200), 87.2% and 11.6% (validation Mel200), and 80.3% and 16.9% (validation Mel140), respectively. The points in the risk score were: 0, 1,2 for ISS stages I, II, and III; Disease status: 0 (CR/VGPR); 1 (PR); 2 (SD/MR); 4 (Relapse/Progression); and 1 for Karnofsky ≤ 70. The distribution of scores: 0 (24%), 1 (33.9%), 2 (29.6 %), 3 (9.5%), and ≥4 (2.7%). The score separated PFS-12, with the lowest risk group (n= 1752) having a PFS-12 of 91.7% and the highest risk group (n= 195) 57.1%. This also applied in cytogenetically high-risk patients. If the pre-score baseline risks are 15% (standard risk) and 25% (high-risk), a score of ≥4 confers calculated risks of 38% and 54%, respectively. This novel EBMT ER score, therefore, allows for the identification of five discrete prognostic groups.
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- 2023
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6. Matched related versus unrelated versus haploidentical donors for allogeneic transplantation in AML patients achieving first complete remission after two induction courses: a study from the ALWP/EBMT
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Nagler, Arnon, Labopin, Myriam, Mielke, Stephan, Passweg, Jakob, Blaise, Didier, Gedde-Dahl, Tobias, Cornelissen, Jan J., Salmenniemi, Urpu, Yakoub-Agha, Ibrahim, Reményi, Péter, Socié, Gerard, van Gorkom, Gwendolyn, Labussière-Wallet, Hélène, Huang, Xiao-Jun, Rubio, Marie Thérèse, Byrne, Jenny, Craddock, Charles, Griškevičius, Laimonas, Ciceri, Fabio, and Mohty, Mohamad
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We compared transplants (HSCT) from matched related siblings (MSD) with those from matched 10/10 and mismatched 9/10 unrelated (UD) and T-replete haploidentical (Haplo) donors in acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions, a known poor prognostic factor. One thousand two hundred and ninety-five patients were included: MSD (n= 428), UD 10/10 (n= 554), UD 9/10 (n= 135), and Haplo (n= 178). Acute GVHD II–IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55–4.11, p= 0.0002) and UD 10/10 (HR = 1.48; 95% CI 1.03–2.13, p= 0.036) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26–2.49, p= 0.0009). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20–2.03, p= 0.0009) but not in those from UD 10/10 (HR = 1.13, p= 0.22) and Haplo donors (HR = 1.12, p= 0.43) compared to MSD. In conclusion, in AML patients undergoing HSCT in CR1 achieved after two induction courses 10/10 UD and Haplo but not 9/10 UD donors are comparable alternatives to MSD.
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- 2023
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7. Outcomes of subsequent neoplasms after umbilical cord blood transplantation in Europe
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Rafii, Hanadi, Ruggeri, Annalisa, Kenzey, Chantal, Sanz, Jaime, Peffault De La Tour, Régis, Esquirol, Albert, Michel, Gérard, Chevallier, Patrice, Rubio, Marie-Thérèse, Cornelissen, Jan J., Michallet, Mauricette, Volt, Fernanda, Rivera-Franco, Monica M., Scigliuolo, Graziana Maria, Cappelli, Barbara, Rocha, Vanderson, and Gluckman, Eliane
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•Subsequent neoplasms observed in recipients of umbilical cord blood transplantation are rare, although associated with poor survival.•Determining risk factors and lifelong screening for early detection of subsequent neoplasms are mandatory to improve survival.
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- 2023
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8. Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study
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Fein, Joshua A., Shouval, Roni, Galimard, Jacques-Emmanuel, Labopin, Myriam, Socié, Gérard, Finke, Jürgen, Cornelissen, Jan J., Malladi, Ram, Itälä-Remes, Maija, Chevallier, Patrice, Orchard, Kim H., Bunjes, Donald, Aljurf, Mahmoud, Rubio, Marie Thérèse, Versluis, Jurjen, Mohty, Mohamad, and Nagler, Arnon
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•Comorbidities used to evaluate allogeneic transplantation candidates have differential impact on NRM in low-intensity conditioning settings.•Among prevalent comorbidities, cardiac disease (including arrhythmia and valvular disease) may confer significant additional NRM risk.
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- 2023
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9. 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, Sebastian, Labopin, Myriam, Houhou, Mohamed, Caillot, Denis, Finke, Jürgen, Blaise, Didier, Fegueux, Nathalie, Ethell, Mark, Cornelissen, Jan J., Forcade, Edouard, Yakoub-Agha, Ibrahim, Lussana, Federico, Maertens, Johan, Bourhis, Jean Henri, Jindra, Pavel, Gorin, Norbert Claude, Nagler, Arnon, and Mohty, Mohamad
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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.
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- 2023
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10. HLA-E–restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD
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Vietzen, Hannes, Furlano, Philippe L., Cornelissen, Jan J., Böhmig, Georg A., Jaksch, Peter, and Puchhammer-Stöckl, Elisabeth
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Primary Epstein-Barr virus (EBV) infections may cause infectious mononucleosis (IM), whereas EBV reactivations in solid organ and hematopoietic stem cell transplant recipients are associated with posttransplantation lymphoproliferative disorders (PTLDs). It is still unclear why only a minority of primary EBV-infected individuals develop IM, and why only some patients progress to EBV+PTLD after transplantation. We now investigated whether nonclassic human leukocyte antigen E (HLA-E)–restricted immune responses have a significant impact on the development of EBV diseases in the individual host. On the basis of a large study cohort of 1404 patients and controls as well as on functional natural killer (NK) and CD8+ T-cell analyses, we could demonstrate that the highly expressed HLA-E∗0103/0103 genotype is protective against IM, due to the induction of potent EBV BZLF1-specific HLA-E–restricted CD8+ T-cell responses, which efficiently prevent the in vitro viral dissemination. Furthermore, we provide evidence that the risk of symptomatic EBV reactivations in immunocompetent individuals as well as in immunocompromised transplant recipients depends on variations in the inhibitory NKG2A/LMP-1/HLA-E axis. We show that EBV strains encoding for the specific LMP-1 peptide variants GGDPHLPTL or GGDPPLPTL, presented by HLA-E, elicit strong inhibitory NKG2A+ NK and CD8+ T-cell responses. The presence of EBV strains encoding for both peptides was highly associated with symptomatic EBV reactivations. The further progression to EBV+PTLD was highly associated with the presence of both peptide-encoding EBV strains and the expression of HLA-E∗0103/0103 in the host. Thus, HLA-E–restricted immune responses and the NKG2A/LMP-1/HLA-E axis are novel predictive markers for EBV+PTLD in transplant recipients and should be considered for future EBV vaccine design.
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- 2023
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11. HLA-E–restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD
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Vietzen, Hannes, Furlano, Philippe L., Cornelissen, Jan J., Böhmig, Georg A., Jaksch, Peter, and Puchhammer-Stöckl, Elisabeth
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•The development of EBV-associated infectious mononucleosis depends on the host HLA-Eallele and HLA-E–restricted CD8+T-cell responses.•The risk for EBV+PTLD is highly associated with the HLA-E/LMP-1/NKG2A axis and depends on specific EBV and host variations in this pathway.
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- 2023
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12. Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters
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Bruch, Peter-Martin, Dietrich, Sascha, Finel, Herve, Boumendil, Ariane, Greinix, Hildegard, Heinicke, Thomas, Bethge, Wolfgang, Beelen, Dietrich, Schmid, Christoph, Martin, Hans, Castagna, Luca, Scheid, Christof, Schäfer-Eckart, Kerstin, Bittenbring, Jörg, Finke, Jürgen, Sengeloev, Henrik, Heiblig, Mael, Cornelissen, Jan, Chevallier, Patrice, Mohty, Mohamad, Robinson, Stephen, Montoto, Silvia, and Dreger, Peter
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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.
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- 2023
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13. 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, Olivier, van Gelder, Michel, Eikema, Dirk-Jan, Zinger, Nienke, Dreger, Peter, Bornhäuser, Martin, Vucinic, Vladan, Scheid, Christof, Cornelissen, Jan J., Schroeder, Thomas, Jindra, Pavel, Sengeloev, Henrik, Nguyen Quoc, Stephanie, Stelljes, Matthias, Blau, Igor Wolfgang, Mayer, Jiri, Paneesha, Shankara, Chevallier, Patrice, Forcade, Edouard, Kröger, Nicolaus, Blaise, Didier, Gribben, John, Nielsen, Bendt, Johansson, Jan-Erik, Kyriakou, Charalampia, Beguin, Yves, Pioltelli, Pietro, Sampol, Antònia, McLornan, Donal P., Schetelig, Johannes, Hayden, Patrick J., and Yakoub-Agha, Ibrahim
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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.
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- 2023
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14. Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT
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Chen, Jia, Labopin, Myriam, Pabst, Thomas, Zhang, Xi, Jiang, Erlie, Tucci, Alessandra, Cornelissen, Jan, Meijer, Ellen, Khevelidze, Irma, Polge, Emmanuelle, Wu, Depei, Mohty, Mohamad, and Gorin, Norbert-Claude
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In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p< 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p< 0.001), similar LFS (65.9% vs 63.8%; p= 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p= 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p= 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p= 0.007) and similar OS (73.5% vs 61.9%; p= 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.
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- 2023
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15. Increased LFS Following Hematopoietic Cell Transplantation As Compared to Conventional Consolidation Therapy in Patients >60 Years with AML in First Complete Remission and a Matched Donor: Results of a Randomized Phase III Study
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Niederwieser, Dietger, Hasenclever, Dirk, Berdel, Wolfgang E., Biemond, Bart J., Al-Ali, Haifa Kathrin, Chalandon, Yves, Van Gelder, Michel, Junghanss, Christian, Gahrton, Goesta, Haenel, Mathias, Hehlmann, Rüdiger, Heinicke, Thomas, Hochhaus, Andreas, Iacobelli, Simona, Kooy, Rien van Marwijk, Kröger, Nicolaus, Janssen, Jeroen J.W.M., Jentzsch, Madlen, Breywisch, Frank, Mohty, Mohamad, Masouridi-Levrat, Stavroula, Ossenkoppele, Gert, Passweg, Jakob, Pönisch, Wolfram, Schetelig, Johannes, Schliemann, Christoph, Schwind, Sebastian, Stelljes, Matthias, Valk, Peter JM, Lowenberg, Bob, and Cornelissen, Jan J.
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- 2022
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16. Increased LFS Following Hematopoietic Cell Transplantation As Compared to Conventional Consolidation Therapy in Patients >60 Years with AML in First Complete Remission and a Matched Donor: Results of a Randomized Phase III Study
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Niederwieser, Dietger, Hasenclever, Dirk, Berdel, Wolfgang E., Biemond, Bart J., Al-Ali, Haifa Kathrin, Chalandon, Yves, Van Gelder, Michel, Junghanss, Christian, Gahrton, Goesta, Haenel, Mathias, Hehlmann, Rüdiger, Heinicke, Thomas, Hochhaus, Andreas, Iacobelli, Simona, Kooy, Rien van Marwijk, Kröger, Nicolaus, Janssen, Jeroen J.W.M., Jentzsch, Madlen, Breywisch, Frank, Mohty, Mohamad, Masouridi-Levrat, Stavroula, Ossenkoppele, Gert, Passweg, Jakob, Pönisch, Wolfram, Schetelig, Johannes, Schliemann, Christoph, Schwind, Sebastian, Stelljes, Matthias, Valk, Peter JM, Lowenberg, Bob, and Cornelissen, Jan J.
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- 2022
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17. Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versustwo induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
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Nagler, Arnon, Labopin, Myriam, Cornelissen, Jan J., Forcade, Edouard, Chevallier, Patrice, Fegueux, Nathalie, Sierra, Jorge, Desmier, Deborah, Labussière-Wallet, Hélène, Byrne, Jenny L., Loschi, Michael, Blaise, Didier, Baron, Frederic, Ruggeri, Annalisa, and Mohty, Mohamad
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We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p= 0.02). Incidence of acute GVHD was similar, 38% and 36% (p= 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p= 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p= 0.87), 25% vs. 30% (p= 0.4), 52% vs. 46% (p= 0.3), 59% vs. 50% (p= 0.2), and 44% vs. 41% (p= 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6–1.8, p= 0.7), RI (HR = 1.4; 95% CI, 0.9–2.3, p= 0.1), LFS (HR = 1.3; 95% CI, 0.9–1.8, p= 0.2), OS (HR = 1.3; 95% CI, 0.9–1.9, p= 0.1), and GRFS (HR = 1.1; 95% CI, 0.8–1.5, p= 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar.
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- 2022
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18. Comparison of Outcomes after Unrelated Double-Unit Cord Blood and Haploidentical Peripheral Blood Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia: A Study on Behalf of Eurocord and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
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Ruggeri, Annalisa, Galimard, Jacques-Emmanuel, Labopin, Myriam, Rafii, Hanadi, Blaise, Didier, Ciceri, Fabio, Diez-Martin, Jose-Luiz, Cornelissen, Jan, Chevallier, Patrice, Sanchez-Guijo, Fermin, Nicholson, Emma, Castagna, Luca, Forcade, Edouard, Kuball, Jürgen, Rovira, Montserrat, Koc, Yener, Pavlu, Jiri, Gulbas, Zafar, Vydra, Jan, Baron, Frederic, Sanz, Jaime, Spyridonidis, Alexandros, Savani, Bipin, Gluckman, Eliane, Nagler, Arnon, and Mohty, Mohamad
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•Double umbilical cord blood transplantation and haploidentical post-transplantation cyclophosphamide with peripheral blood stem cell transplantation are useful strategies for treating adults with acute myelogenous leukemia in complete remission.•The conditioning regimen and graft-versus-host disease prophylaxis should be tailored to provide an antileukemia effect and prevent disease recurrence.
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- 2022
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19. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial
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Broers, Annoek E. C., de Jong, Cornelis N., Bakunina, Katerina, Hazenberg, Mette D., van Marwijk Kooy, Marinus, de Groot, Marco R., van Gelder, Michel, Kuball, Jürgen, van der Holt, Bronno, Meijer, Ellen, and Cornelissen, Jan J.
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Graft-versus-host disease (GVHD) is the most important complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). We performed a prospective randomized, multicenter, phase 3 trial to study whether posttransplant cyclophosphamide (PT-Cy) combined with a short course of cyclosporine A (CsA) would result in a reduction of severe GVHD and improvement of GVHD-free, relapse-free survival (GRFS) as compared with the combination of CsA and mycophenolic acid (MPA) after nonmyeloablative (NMA) matched related and unrelated peripheral blood alloHSCT. Between October 2013 and June 2018, 160 patients diagnosed with a high-risk hematological malignancy and having a matched related or at least 8 out of 8 HLA-matched unrelated donor were randomized and allocated in a 1:2 ratio to CsA/MPA or PT-Cy/CsA; a total of 151 patients were transplanted (52 vs 99 patients, respectively). The cumulative incidence of grade 2 to 4 acute GVHD at 6 months was 48% in recipients of CsA/MPA vs 30% following PT-Cy/CsA (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.82; P = .007). The 2-year cumulative incidence of extensive chronic GVHD was 48% vs 16% (HR, 0.36; 95% CI, 0.21-0.64; P < .001). The 1-year estimate of GRFS was 21% (11% to 32%) vs 45% (35% to 55%), P < .001. With a median follow-up of 56.4 months, relapse incidence, progression-free survival, and overall survival were not significantly different between the 2 treatment arms. PT-Cy combined with a short course of CsA after NMA matched alloHSCT significantly improves GRFS due to a significant reduction in severe acute and chronic GVHD.
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- 2022
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20. Prognostic value of a new clinically-based classification system in patients with CMML undergoing allogeneic HCT: a retrospective analysis of the EBMT-CMWP
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Onida, Francesco, Sbianchi, Giulia, Radujkovic, Aleksandar, Sockel, Katja, Kröger, Nicolaus, Sierra, Jorge, Socié, Gerard, Cornelissen, Jan, Poiré, Xavier, Raida, Luděk, Bourhis, Jean Henri, Finke, Jürgen, Passweg, Jakob, Salmenniemi, Urpu, Schouten, Harry C., Beguin, Yves, Martin, Sonja, Deconinck, Eric, Ganser, Arnold, Zver, Samo, Lioure, Bruno, Rohini, Radia, Koster, Linda, Hayden, Patrick, Iacobelli, Simona, Robin, Marie, and Yakoub-Agha, Ibrahim
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Recently a new three-group clinical classification was reported by an International Consortium to stratify CMML patients with regard to prognosis. The groups were defined as follows: (1) Myelodysplastic (MD)-CMML: WBC ≤ 10 × 109/l, circulating immature myeloid cells (IMC) = 0, no splenomegaly; (2) MD/MP (overlap)–CMML: WBC 10–20 × 109/l or WBC ≤ 10 × 109/l but IMC > 0 and/or splenomegaly; (3) Myeloproliferative (MP)-CMML: WBC > 20 × 109/l. By analysing EBMT Registry patients who underwent allo-HCT for CMML between 1997 and 2016, we aimed to determine the impact of this classification on transplantation outcome and to make a comparison with the conventional WHO classification (CMML-0/CMML-1/CMML-2). Patient grouping was based on the data registered at time of transplantation, with IMC replaced by peripheral blasts. Among 151 patients included in the analysis, 38% were classified as MD-CMML, 42% as MD/MP-CMML and 20% as MP-CMML. With a median survival of 17 months in the whole series, MD-CMML patients were distinguished as a low-risk group with higher CR rate at transplant and a longer post-transplant 2-year progression-free survival in comparison to others (44.5% vs 33.5%, respectively), whereas the WHO classification was superior in identifying high-risk patients (CMML-2) with inferior survival outcomes.
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- 2022
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21. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome
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Grob, Tim, Al Hinai, Adil S. A., Sanders, Mathijs A., Kavelaars, François G., Rijken, Melissa, Gradowska, Patrycja L., Biemond, Bart J., Breems, Dimitri A., Maertens, Johan, van Marwijk Kooy, Marinus, Pabst, Thomas, de Weerdt, Okke, Ossenkoppele, Gert J., van de Loosdrecht, Arjan A., Huls, Gerwin A., Cornelissen, Jan J., Beverloo, H. Berna, Löwenberg, Bob, Jongen-Lavrencic, Mojca, and Valk, Peter J. M.
- Abstract
Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.
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- 2022
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22. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial
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Rijneveld, Anita W., van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjen A., van der Wagen, Lotte E., Bellido, Mar, van Gelder, Michel, van der Velden, Walter J. F. M., Selleslag, Dominik, van Lammeren-Venema, Daniëlle, Halkes, Constantijn J. M., Fijnheer, Rob, Havelange, Violaine, van Sluis, Geerte L., Legdeur, Marie-Cecile, Deeren, Dries, Gadisseur, Alain, Sinnige, Harm A. M., Breems, Dimitri A., Jaspers, Aurélie, Legrand, Ollivier, Terpstra, Wim E., Boersma, Rinske S., Mazure, Dominiek, Triffet, Agnes, Tick, Lidwine W., Beel, Karolien, Maertens, Johan A., Beverloo, H. Berna, Bakkus, Marleen, Homburg, Christa H. E., de Haas, Valerie, van der Velden, Vincent H. J., and Cornelissen, Jan J.
- Abstract
Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD− after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004.
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- 2022
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23. HEV infection in stem cell transplant recipients—retrospective study of EBMT Infectious Diseases Working Party
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Mikulska, Malgorzata, Penack, Olaf, Wendel, Lotus, Knelange, Nina, Cornelissen, Jan J., Blijlevens, Nicole, Passweg, Jakob, Kroger, Nicolaus, Bruns, Anke, Koenecke, Christian, Bierings, Marc, Piñana, José Luis, Labussiere-Wallet, Helene, Ghesquieres, Herve, Diaz, Miguel Angel, Sampol, Antonia, Averbuch, Diana, de la Camara, Rafael, and Styczynski, Jan
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HEV infection is an emerging cause of acute and chronic hepatitis in stem cell transplant (SCT) recipients. We performed a retrospective observational study among EBMT centers with the aim of describing characteristics, management and outcome of HEV after SCT. There were 34 cases of HEV infection from 12 centers in 6 countries, diagnosed in median 4.5 months after SCT; 20 of acute and 14 of chronic infection. Non-hepatic findings possibly associated with HEV infection were present in 9 (26%). Patients with chronic infection had more characteristics associated with severely immunocompromised status. Ribavirin was provided to 16 patients (47%; 40% with acute and 57% with chronic infection), in median for 75 days. Three (19%) patients discontinued it due to side effects. HEV-RNA clearance occurred in 29 patients (85%; 85% in acute and 86% in chronic infection). HEV was considered a cause of death in 3 (9%), with 2 cases with late diagnosis. Reduction of immunosuppression in those receiving it, and ribavirin treatment in those with chronic infection were associated with shorter time to HEV-RNA clearance. Policy on HEV testing varied between the centers. In conclusion, acute and chronic HEV hepatitis should be promptly diagnosed and managed in SCT recipients.
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- 2022
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24. Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT
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Spyridonidis, Alexandros, Labopin, Myriam, Brissot, Eolia, Moiseev, Ivan, Cornelissen, Jan, Choi, Goda, Ciceri, Fabio, Vydra, Jan, Reményi, Péter, Rovira, Montserrat, Meijer, Ellen, Labussière-Wallet, Hélène, Blaise, Didier, van Gorkom, Gwendolyn, Kröger, Nicolaus, Koc, Yener, Giebel, Sebastian, Bazarbachi, Ali, Savani, Bipin, Nagler, Arnon, and Mohty, Mohamad
- Abstract
In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p< 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p= 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.
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- 2022
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25. Allogeneic hematopoietic cell transplantation in patients with therapy-related myeloid neoplasm after breast cancer: a study of the Chronic Malignancies Working Party of the EBMT
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Nabergoj, Mitja, Mauff, Katya, Beelen, Dietrich, Ganser, Arnold, Kröger, Nicolaus, Stölzel, Friedrich, Finke, Jürgen, Passweg, Jakob, Cornelissen, Jan, Schub, Natalie, Veelken, Joan Hendrik, Beguin, Yves, Wilson, Keith, Zuckerman, Tsila, Hunault-Berger, Mathilde, Lioure, Bruno, Porras, Rocio Parody, Turlure, Pascal, Kerre, Tessa, Koster, Linda, Hayden, Patrick J., Onida, Francesco, Scheid, Christof, Chalandon, Yves, Robin, Marie, and Yakoub-Agha, Ibrahim
- Abstract
We performed a registry study on therapy-related myeloid neoplasm (t-MN), both therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for breast cancer who underwent a first allogeneic hematopoietic cell transplant (allo-HCT). Of 252 identified female patients (median age 57 years), 77% were transplanted for t-AML and 23% for t-MDS, with a median time from breast cancer diagnosis to the diagnosis of tMN and subsequent allo-HCT of 3.7 and 4.6 years, respectively. At transplant, 191 patients were in remission for breast cancer, while 4 were not (57 missing). T-MN was in a complete remission at the time of transplant in 67% of patients. 2-year overall survival, relapse free-survival, relapse incidence and non-relapse mortality were 50%, 45%, 33%, and 22%, respectively. Multivariable analysis revealed that if the t-MN was not in CR pre-transplant, this was associated with lower OS, RFS, and a higher relapse incidence. Seventeen cases of breast cancer recurrence were recorded after a median of 2.4 years post-transplant, and relapse of primary breast cancer accounted for 7% of deaths. This study indicates that allo-HCT for t-MN following treatment for breast cancer shows encouraging transplant outcomes. The incidence of breast cancer relapse post-transplant remains a cause for concern.
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- 2022
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26. 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, Christian, Eikema, Dirk-Jan, Hazelaar, Sheree, Schroeder, Thomas, Potter, Victoria, Kröger, Nicolaus, Bornhäuser, Martin, Finke, Jürgen, Platzbecker, Uwe, Radujkovic, Aleksandar, Ganser, Arnold, Salmenniem, Urpu, Blaise, Didier, Kobbe, Guido, Meijer, Ellen, Friis, Lone, Maertens, Johan, Caballero, Dolores, Cornelissen, Jan J., Olivieri, Attilio, Gulsum, Ozet, Hayden, Patrick J., Onida, Francesco, Robin, Marie, and Yakoub-Agha, Ibrahim
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- 2022
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27. The HOVON 100 Study in Adult Acute Lymphoblastic Leukemia Re-Analysed By Multi-State Modeling: Benefits and Risks of Clofarabine
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Hermans, Sjoerd J.F., Norden, Yvette, Versluis, Jurjen, Rijneveld, Anita W., De Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjan A., Van der Wagen, Lotte E., Bellido, Mar, Van Gelder, Michel, Van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren, Danielle, van der Velden, Vincent H.J., de Wreede, Liesbeth C., Postmus, Douwe, Pignatti, Francesco, and Cornelissen, Jan J.
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- 2022
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28. Bayesian Inference for Optimization of Interim Analysis in Clinical Trials By Incorporation of Historical Data: Reanalysis of the HOVON AML 132 Clinical Trial
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Van Der Maas, Niek, Nasserinejad, Kazem, Pabst, Thomas, Maertens, Johan A., Breems, Dimitri A., Manz, Markus G, Cloos, Jacqueline, Ossenkoppele, Gert J., Floisand, Yngvar, Gradowska, Patrycja, Lowenberg, Bob, Huls, Gerwin A., Postmus, Douwe, Pignatti, Francesco, Cornelissen, Jan J., and Versluis, Jurjen
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- 2022
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29. The HOVON 100 Study in Adult Acute Lymphoblastic Leukemia Re-Analysed By Multi-State Modeling: Benefits and Risks of Clofarabine
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Hermans, Sjoerd J.F., Norden, Yvette, Versluis, Jurjen, Rijneveld, Anita W., De Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjan A., Van der Wagen, Lotte E., Bellido, Mar, Van Gelder, Michel, Van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren, Danielle, van der Velden, Vincent H.J., de Wreede, Liesbeth C., Postmus, Douwe, Pignatti, Francesco, and Cornelissen, Jan J.
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- 2022
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30. Bayesian Inference for Optimization of Interim Analysis in Clinical Trials By Incorporation of Historical Data: Reanalysis of the HOVON AML 132 Clinical Trial
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Van Der Maas, Niek, Nasserinejad, Kazem, Pabst, Thomas, Maertens, Johan A., Breems, Dimitri A., Manz, Markus G, Cloos, Jacqueline, Ossenkoppele, Gert J., Floisand, Yngvar, Gradowska, Patrycja, Lowenberg, Bob, Huls, Gerwin A., Postmus, Douwe, Pignatti, Francesco, Cornelissen, Jan J., and Versluis, Jurjen
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- 2022
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31. Optimizing Donor Choice and GVHD Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.
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Holtan, Shernan G, Versluis, Jurjen, Weisdorf, Daniel J, and Cornelissen, Jan J
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- 2021
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32. Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT
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Esteve, Jordi, Giebel, Sebastian, Labopin, Myriam, Czerw, Tomasz, Wu, Depei, Volin, Liisa, Socié, Gerard, Yakoub-Agha, Ibrahim, Maertens, Johan, Cornelissen, Jan J., Pigneux, Arnaud, Shimoni, Avichai, Schwerdtfeger, Rainer, Labussière-Wallet, Hélène, Russell, Nigel, Schattenberg, Anton, Chevallier, Patrice, Koza, Vladimir, Foà, Robin, Schmid, Christoph, Peric, Zinaida, Mohty, Mohamad, and Nagler, Arnon
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Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n= 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p< 0.001), OS (HR = 0.14, p< 0.001), RI (HR = 0.23, p= 0.001), and NRM (HR = 0.16, p= 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p= 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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- 2021
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33. Second- and third-generation tyrosine kinase inhibitors for Philadelphia-positive adult acute lymphoblastic leukemia relapsing post allogeneic stem cell transplantation—a registry study on behalf of the EBMT Acute Leukemia Working Party
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Hirschbühl, Klaus, Labopin, Myriam, Houhou, Mohamed, Gabellier, Ludovic, Labussière-Wallet, Hélène, Lioure, Bruno, Beelen, Dietrich, Cornelissen, Jan, Wulf, Gerald, Jindra, Pavel, Tilly, Hervé, Passweg, Jakob, Niittyvuopio, Riita, Bug, Gesine, Schmid, Christoph, Nagler, Arnon, Giebel, Sebastian, and Mohty, Mohamad
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Second- and third-generation tyrosine kinase inhibitors (TKI) play an important role in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, data on feasibility and efficacy of using these drugs for persisting or relapsed Ph + ALL after allogeneic stem cell transplantation (alloSCT) are scarce. Based on the EBMT Acute Leukemia Working Party registry, we evaluated the use of second-/third-generation TKI in 140 patients with Ph + ALL, suffering from measurable residual disease (MRD, n= 6), molecular relapse (MRel, n= 23), or hematological relapse (HRel, n= 111) following alloSCT. Treatment included dasatinib in 104, nilotinib in 18, or ponatinib in 18 patients. Forty-nine patients received TKI monotherapy, while 91 received additional treatment. Toxicity of second-/third-generation TKI post alloSCT was comparable to pretransplant use and could be managed with dose reduction or temporary discontinuation. Response rates were 71% (overall) and 61% (following TKI monotherapy). For the entire cohort, 2- and 5-year overall survival (OS) was 49% and 33%, respectively. OS was comparable among patients treated for persisting MRD/MRel and HRel. Among patients treated with TKI monotherapy, 2- and 5-year OS was 38% and 33%, respectively. The data underscore that second-/third-generation TKI are important compounds for the management of active Ph + ALL post alloSCT.
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- 2021
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34. Impact of the Type of Tyrosine Kinase Inhibitor (imatinib or dasatinib) Used Before allo-HCT on Outcome of Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia. A Study on Behalf of the Acute Leukemia Working Party of the EBMT
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Giebel, Sebastian, Labopin, Myriam, Peric, Zinaida, Passweg, Jakob, Blaise, Didier, Salmenniemi, Urpu, Beauvais, David, Reményi, Péter, Chevallier, Patrice, Mielke, Stephan, Gedde-Dahl, Tobias, Cornelissen, Jan J., Balsat, Marie, Bug, Gesine, Bazarbachi, Ali, Brissot, Eolia, Nagler, Arnon, Ciceri, Fabio, and Mohty, Mohamad
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•The choice of TKI (imatinib or dasatnib) has no impact on survival after allo-HCT in Ph+ ALL.•Pre-transplant dasatinib may result in increased risk of severe acute GVHD.•Results of allo-HCT for Ph+ ALL are improving over time.
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- 2024
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35. Does IPSS-R downstaging before transplantation improve the prognosis of patients with myelodysplastic neoplasms?
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Scheid, Christof, Eikema, Diderik-Jan, van Gelder, Michel, Salmenniemi, Urpu, Maertens, Johan, Passweg, Jakob, Blaise, Didier, Byrne, Jenny L., Kröger, Nicolaus, Sockel, Katja, Chevallier, Patrice, Bourhis, Jean Henri, Cornelissen, Jan J., Sengeloev, Henrik, Finke, Jürgen, Snowden, John A., Gedde-Dahl, Tobias, Cornillon, Jerome, Schanz, Urs, Patel, Amit, Koster, Linda, de Wreede, Liesbeth C., Hayden, Patrick, Raj, Kavita, Drozd-Sokolowska, Joanna, Gurnari, Carmelo, Onida, Francesco, McLornan, Donal P., Robin, Marie, and Yakoub-Agha, Ibrahim
- Abstract
•Changes in IPSS-R score between diagnosis and transplantation did not affect transplant outcome when no prior therapy was applied.•Downstaging IPSS-R scores by chemotherapy improved transplant outcome, however stable or worse IPSS-R scores after therapy correlated with worst outcome.
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- 2024
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36. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial
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Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J., Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W., Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J.F.M., Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W.J., Bargetzi, Mario, Klein, Saskia K., Gadisseur, Alain, Westerweel, Peter E., Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A., Hoogendoorn, Mels, Legdeur, Marie-Cecile J.C., Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T., Janssen, Jeroen J.W.M., Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J.M., van Elssen, Catharina H.M.J., Manz, Markus G., Floisand, Yngvar, and Ossenkoppele, Gert J.
- Abstract
Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)–adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.
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- 2021
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37. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial
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Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J., Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W., Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J. F. M., Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W. J., Bargetzi, Mario, Klein, Saskia K., Gadisseur, Alain, Westerweel, Peter E., Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A., Hoogendoorn, Mels, Legdeur, Marie-Cecile J. C., Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T., Janssen, Jeroen J. W. M., Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J. M., van Elssen, Catharina H. M. J., Manz, Markus G., Floisand, Yngvar, and Ossenkoppele, Gert J.
- Abstract
Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)–adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.
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- 2021
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38. Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia
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Lorentino, Francesca, Labopin, Myriam, Ciceri, Fabio, Vago, Luca, Fleischhauer, Katharina, Afanasyev, Boris, Kröger, Nicolaus, Cornelissen, Jan J., Lovira, Montserrat, Meijer, Ellen, Vitek, Antonin, Elmaagacli, Ahmet, Blaise, Didier, Ruggeri, Annalisa, Chabannon, Christian, Nagler, Arnon, and Mohty, Mohamad
- Abstract
HLA-matching largely contributes to unrelated donor hematopoietic cell transplantation (UD-HCT) success but, due to the selective deletion of alloreactive T-cells, post-transplantation cyclophosphamide (PTCy) could modulate its negative impact on outcomes. We retrospectively compared acute leukemia patients receiving 10/10 or 9/10 HLA allele-matched UD-HCT with PTCy-GvHD prophylaxis between 2010 and 2017, reported to EBMT registry. The 100-day incidence of grade =2 and grade =3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28%, p?=?0.8 and 10% versus 8%, p?=?0.5, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, p?=?0.2 and 21% versus 20%, p?=?0.6, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT (p?=?0.1). Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT (p?=?0.4). Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, p?=?0.6, respectively), with comparable overall survival (62 and 59%, p?=?0.9, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival. PTCy could alleviate the detrimental effect of HLA-allele mismatching in UD-HCT, potentially expanding the donor pool for acute leukemia patients.
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- 2021
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39. Allogeneic stem cell transplantation for AML patients with RUNX1 mutation in first complete remission: a study on behalf of the acute leukemia working party of the EBMT
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Waidhauser, Johanna, Labopin, Myriam, Esteve, Jordi, Kröger, Nicolaus, Cornelissen, Jan, Gedde-Dahl, Tobias, Van Gorkom, Gwendolyn, Finke, Jürgen, Rovira, Montserrat, Schaap, Nicolaas, Petersen, Eefke, Beelen, Dietrich, Bunjes, Donald, Savani, Bipin, Schmid, Christoph, Nagler, Arnon, and Mohty, Mohamad
- Abstract
Acute myeloid leukemia with runt-related transcription factor 1 gene mutation (RUNX1+ AML) is associated with inferior response rates and outcome after conventional chemotherapy. We performed a retrospective, registry-based analysis to elucidate the prognostic value of RUNX1mutation after allogeneic stem cell transplantation (alloSCT). All consecutive adults undergoing alloSCT for AML in first complete remission (CR1) between 2013 and 2019 with complete information on conventional cytogenetics and RUNX1mutational status were included. Endpoints of interest were cumulative relapse incidence, non-relapse mortality, overall and leukemia-free survival (OS/LFS), and GvHD-free/relapse-free survival. A total of 674 patients (183 RUNX1+, 491 RUNX1−) were identified, with >85% presenting as de novoAML. Median follow-up was 16.4 (RUNX1+) and 21.9 (RUNX1−) months. Survival rates showed no difference between RUNX1+ and RUNX1− patients either in univariate or multivariate analysis (2-year OS: 67.7 vs. 66.1%, p= 0.7; 2-year LFS: 61.1 vs. 60.8%, p= 0.62). Multivariate analysis identified age, donor type and poor cytogenetics as risk factors for inferior outcome. Among patients with RUNX+AML, older age, reduced intensity conditioning and minimal residual disease at alloSCT predicted inferior outcome. Our data provide evidence that the negative influence of RUNX1mutations in patients with AML can be overcome by transplantation in CR1.
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- 2021
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40. Determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation
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Hernández-Boluda, Juan Carlos, Pereira, Arturo, Kröger, Nicolaus, Beelen, Dietrich, Robin, Marie, Bornhäuser, Martin, Angelucci, Emanuele, Vitek, Antonin, Blau, Igor Wolfgang, Niittyvuopio, Riitta, Finke, Jürgen, Cornelissen, Jan J., Passweg, Jakob, Dreger, Peter, Petersen, Eefke, Kanz, Lothar, Sanz, Jaime, Zuckerman, Tsila, Zinger, Nienke, Iacobelli, Simona, Hayden, Patrick, Czerw, Tomasz, McLornan, Donal, and Yakoub-Agha, Ibrahim
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We aimed to evaluate the determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) and to describe factors predicting the main post-HCT complications. This retrospective study by the European Society for Blood and Marrow Transplantation included 2916 myelofibrosis patients who underwent first allo-HCT from an HLA-identical sibling or unrelated donor between 2000 and 2016. After a median follow-up of 4.7 years from transplant, projected median survival of the series was 5.3 years. Factors independently associated with increased mortality were age?=?60 years and Karnofsky Performance Status <90% at transplant, and occurrence of graft failure, grades III–IV acute graft-vs.-host disease (aGVHD), and disease progression/relapse during follow-up. The opposing effects of chronic graft-vs.-host disease (GVHD) on non-relapse mortality and relapse incidence resulted in a neutral influence on survival. Graft failure increased in unrelated donor recipients and decreased with myeloablative conditioning (MAC) and negative donor/recipient cytomegalovirus serostatus. Risk of grades III–IV aGVHD was higher with unrelated donors and decreased with MAC. Relapse incidence tended to be higher in patients with intermediate-2/high-risk DIPSS categories and to decrease in CALR-mutated patients. Acute and chronic GVHD reduced the subsequent risk of relapse. This information has potential implications for patient counseling and clinical decision-making.
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- 2021
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41. Impact of early candidemia on the long-term outcome of allogeneic hematopoietic stem cell transplant in non-leukemic patients: an outcome analysis on behalf of IDWP–EBMT
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Cesaro, Simone, Tridello, Gloria, Knelange, Nina Simone, Blijlevens, Nicole, Martin, Murray, Snowden, John A., Malladi, Ram, Ljungman, Per, Deconinck, Eric, Gedde-Dahl, Tobias, Byrne, Jennifer, Xhaard, Alienor, Chevallier, Patrice, Maertens, Johan, Zuckerman, Tsila, Lioure, Bruno, Petersen, Eefke, Cornelissen, Jan J., Arcese, William, Blaise, Didier, Milpied, Noel, Cahn, Jean Yves, Aljurf, Mahmoud, de Wreede, Liesbeth, Mauro, Margherita, de la Camara, Rafael, Averbuch, Diana, Mikulska, Malgorzata, and Styczynski, Jan
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We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0–100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p< 0.0001), and 100-day OS was lower (HR 3.22, p< 0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p< 0.0001, 28.2% vs.18.8%, p< 0.0001, and 25.3% vs. 27.2%, p= 0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.
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- 2021
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42. Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT
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Baron, Frédéric, Ngoya, Maud, Labopin, Myriam, Cornelissen, Jan J., Ganser, Arnold, Forcade, Edouard, Sengeloev, Henrik, Socié, Gérard, Blaise, Didier, Bornhäuser, Martin, Valerius, Thomas, Reinhardt, Hans Christian, Kröger, Nicolaus, Ruggeri, Annalisa, Nagler, Arnon, and Mohty, Mohamad
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Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P= 0.36) and 84% in UD 9/10 patients (P= 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P< 0.001), male gender (P< 0.001), second complete remission (CR2) versus CR1 (P= 0.05), secondary AML (P= 0.01), antecedent of chronic GVHD (P< 0.001) and poor-risk cytogenetics (P= 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.
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- 2021
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43. Panobinostat and decitabine prior to donor lymphocyte infusion in allogeneic stem cell transplantation
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Kalin, Burak, van Norden, Yvette, van Gelder, Michel, Breems, Dimitri, Maertens, Johan, Jongen-Lavrencic, Mojca, Broers, Annoek E. C., Braakman, Eric, Grob, Tim, Zeijlemaker, Wendelien, Ossenkoppele, Gert J., Meijer, Ellen, and Cornelissen, Jan J.
- Abstract
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post–allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.
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- 2020
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44. Panobinostat and decitabine prior to donor lymphocyte infusion in allogeneic stem cell transplantation
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Kalin, Burak, van Norden, Yvette, van Gelder, Michel, Breems, Dimitri, Maertens, Johan, Jongen-Lavrencic, Mojca, Broers, Annoek E.C., Braakman, Eric, Grob, Tim, Zeijlemaker, Wendelien, Ossenkoppele, Gert J., Meijer, Ellen, and Cornelissen, Jan J.
- Abstract
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2(PNB/DAC20 group) or decitabine 10 mg/m2(PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post–allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.
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- 2020
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45. Comparison of reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia >45 years undergoing allogeneic stem cell transplantation—a retrospective study by the Acute Leukemia Working Party of EBMT
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Peric, Zinaida, Labopin, Myriam, Peczynski, Christophe, Polge, Emmanuelle, Cornelissen, Jan, Carpenter, Ben, Potter, Mike, Malladi, Ram, Byrne, Jenny, Schouten, Harry, Fegueux, Nathalie, Socié, Gerard, Rovira, Montserrat, Kuball, Jurgen, Gilleece, Maria, Giebel, Sebastian, Nagler, Arnon, and Mohty, Mohamad
- Abstract
The optimal reduced-intensity conditioning (RIC) for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 417 patients?>?45 years with ALL in first complete remission who underwent a matched sibling or unrelated allo-HSCT and compared outcomes between fludarabine/busulfan (FLUBU, n?=?127), fludarabine/melphalan (FLUMEL, n?=?190), and fludarabine-TBI (FLUTBI, n?=?100) conditioning. At 2 years, there were no differences between the groups in terms of cumulative incidence (CI) of relapse (40% for FLUBU vs 36% for FLUMEL vs 41% for FLUTBI, p?=?0.21); transplant-related mortality (TRM) (18% for FLUBU, 22% for FLUMEL, 14% for FLUTBI, p?=?0.09); overall survival (55% for FLUBU, 50% for FLUMEL, 60% for FLUTBI, p?=?0.62) or leukemia-free survival (43% for FLUBU, 42% for FLUMEL, 45% for FLUTBI, p?=?0.99), but GVHD-relapse-free survival was significantly lower in the FLUTBI group than FLUBU and FLUMEL group (18% vs 35% vs 28%, p?=?0.02). However, this difference was lost in the multivariate analysis when adjusted for the in vivo T-cell depletion. Finally, the FLUMEL regimen was shown to be an independent risk factor for a higher TRM (HR 1.97, 95% CI 1.05–3.72, p?=?0.04). We conclude that the three most popular RIC regimens yield similar transplant outcomes.
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- 2020
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46. Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status
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Carapito, Raphael, Aouadi, Ismail, Pichot, Angélique, Spinnhirny, Perrine, Morlon, Aurore, Kotova, Irina, Macquin, Cécile, Rolli, Véronique, Cesbron, Anne, Gagne, Katia, Oudshoorn, Machteld, van der Holt, Bronno, Labalette, Myriam, Spierings, Eric, Picard, Christophe, Loiseau, Pascale, Tamouza, Ryad, Toubert, Antoine, Parissiadis, Anne, Dubois, Valérie, Paillard, Catherine, Maumy-Bertrand, Myriam, Bertrand, Frédéric, von dem Borne, Peter A., Kuball, Jürgen H. E., Michallet, Mauricette, Lioure, Bruno, Peffault de Latour, Régis, Blaise, Didier, Cornelissen, Jan J., Yakoub-Agha, Ibrahim, Claas, Frans, Moreau, Philippe, Charron, Dominique, Mohty, Mohamad, Morishima, Yasuo, Socié, Gérard, and Bahram, Seiamak
- Abstract
Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1and MICAloci. HLA-DPtyping was further available. MICB98mismatches were significantly associated with an increased incidence of acute (grade II–IV: HR, 1.20; 95% CI, 1.15 to 1.24; P< 0.001; grade III–IV: HR, 2.28; 95% CI, 1.56 to 3.34; P< 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P< 0.001). MICB98matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P< 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
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- 2020
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47. Prognostic impact of Epstein-Barr virus serostatus in patients with nonmalignant hematological disorders undergoing allogeneic hematopoietic cell transplantation: the study of Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation
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Styczynski, Jan, Tridello, Gloria, Gil, Lidia, Ljungman, Per, Mikulska, Malgorzata, van der Werf, Steffie, Knelange, Nina Simone, Averbuch, Diana, Socié, Gerard, Veelken, Hendrik, Dalle, Jean-Hugues, Aljurf, Mahmoud, Kupesiz, Alphan, Bertrand, Yves, Tbakhi, Abdelghani, Afanasyev, Boris, Lioure, Bruno, Labussière-Wallet, Hélène, Poiré, Xavier, Maertens, Johan, Petersen, Eefke, Chevallier, Patrice, Milpied, Noel, Snowden, John A., Yakoub-Agha, Ibrahim, Cornelissen, Jan, Schaap, Nicolaas, Dufour, Carlo, de Latour, Regis Peffault, Lankester, Arjan, and Cesaro, Simone
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- 2020
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48. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients
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Spyridonidis, Alexandros, Labopin, Myriam, Savani, Bipin N., Niittyvuopio, Riitta, Blaise, Didier, Craddock, Charles, Socié, Gerard, Platzbecker, Uwe, Beelen, Dietrich, Milpied, Noel, Cornelissen, Jan J., Ganser, Arnold, Huynh, Anne, Griskevicius, Laimonas, Giebel, Sebastian, Aljurf, Mahmoud, Brissot, Eolia, Malard, Florent, Esteve, Jordi, Peric, Zinaida, Baron, Frédéric, Ruggeri, Annalisa, Schmid, Christoph, Gilleece, Maria, Gorin, Norbert-Claude, Lanza, Francesco, Shouval, Roni, Versluis, Jurjen, Bug, Gesine, Fløisand, Yngvar, Ciceri, Fabio, Sanz, Jamie, Bazarbachi, Ali, Nagler, Arnon, and Mohty, Mohamad
- Abstract
To address limitations of the currently used reduced-intensity/myeloablative conditioning (RIC/MAC) classification scheme we aimed to develop a tool that can capture more standardized the conditioning intensity of allogeneic hematopoietic cell transplantation (HCT). We assigned intensity weight scores for frequently used conditioning regimen components and used their sum to generate the transplant conditioning intensity (TCI) score. We retrospectively tested the impact of TCI on 8255 adult (45–65 years) acute myeloid leukemia patients who underwent HCT in first complete remission. A Cox model for early nonrelapse mortality (NRM) yielded a 3-group TCI risk scheme (low, intermediate, high) with respective TCI scores of [1–2], [2.5–3.5] and [4–6]. On multivariate modeling, TCI grouping was highly and better predictive for early (day 100 and 180) NRM, 2-year NRM and relapse (REL) as compared with the RIC/MAC classification. Validation was done on 200 bootstrap samples. Moreover, TCI scoring enabled the identification of a distinct subgroup of RIC and MAC conditioning regimens with an intermediate TCI [2.5–3.5] score that had identical outcomes and which are frequently referred as “reduced toxicity conditioning”. TCI scheme provides an improvement of the RIC/MAC classification. We propose TCI as a new tool to define and measure the conditioning regimen intensity.
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- 2020
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49. Ibrutinib as a salvage therapy after allogeneic HCT for chronic lymphocytic leukemia
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Michallet, Mauricette, Dreger, Peter, Sobh, Mohamad, Koster, Linda, Hoek, Jennifer, Boumendil, Ariane, Scheid, Christof, Fox, Christopher P., Wulf, Gerald, Krüger, William, van Gelder, Michel, Corradini, Paolo, Russo, Domenico, Passweg, Jakob, Schoemans, Hélène, Bethge, Wolfgang, Schaap, Nicolaas, Cornelissen, Jan, Browne, Paul, Durakovic, Nadira, Muller, Lutz, Montoto, Silvia, Kroger, Nicolaus, and Schetelig, Johannes
- 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.
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- 2020
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50. Fludarabine/busulfan versus fludarabine/total-body-irradiation (2 Gy) as conditioning prior to allogeneic stem cell transplantation in patients (≥60 years) with acute myelogenous leukemia: a study of the acute leukemia working party of the EBMT
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Heinicke, Thomas, Labopin, Myriam, Polge, Emmanuelle, Niederwieser, Dietger, Platzbecker, Uwe, Sengelov, Henrik, Choi, Goda, Cornelissen, Jan, Blaise, Didier, Kuball, Jürgen, van Gorkom, Gwendolyn, Schaap, Nicolaas, Potter, Victoria, Paul, Franciane, Savani, Bipin N., Nagler, Arnon, and Mohty, Mohamad
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Nonmyeloablative (NMA) conditioning regimens facilitate allogeneic stem cell transplantation (alloSCT) in elderly patients and/or in those with comorbidities. The acute leukemia working party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) compared the outcomes of patients ≥60 years with AML in first complete remission (CR1), that had received an alloSCT following NMA conditioning, i.e. either fludarabine/busulfan (FB2) or fludarabine/total-body-irradiation-2Gy (FluTBI2Gy). A total of 1088 patients were included (median age 65 years). Donors were matched siblings (MSD) and matched unrelated donors (MUD) in 47% and 53%, respectively. In vivo T-cell depletion (TCD) was applied to 79% and none (0%) of patients in the FB2 and FluTBI2Gy groups, respectively. In the MSD group we found a trend for less extensive cGVHD in patients receiving FB2 with in vivo TCD, HR: 0.49, p= 0.08, and in those without worse NRM, HR: 2.14, p= 0.04, and a trend for more total cGVHD, HR: 1.61, p= 0.09. Patients transplanted from MUDs had a significantly higher incidence of total cGVHD, extensive cGVHD and a worse GRFS with FluTBI2Gy in comparison to FB2, HR: 2.44; p< 0.0001; HR 4.59; p< 0.00001 and HR: 1.35; p= 0.03, respectively. No differences were observed with respect to LFS, OS, RI, NRM, and aGVHD.
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- 2020
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