Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Background Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. Patients and methods This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101). Results In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy. Conclusion We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.

[1]  Sonali M. Smith,et al.  Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation , 2016, British journal of haematology.

[2]  S. Montoto,et al.  Reduced intensity allogeneic stem cell transplantation for follicular lymphoma relapsing after an autologous transplant achieves durable long term disease control. An analysis from the Lymphoma Working Party Of the EBMT. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  David T Yang,et al.  Follicular lymphoma: evolving therapeutic strategies. , 2016, Blood.

[4]  H. Tilly,et al.  Allogeneic stem cell transplantation for patients with mantle cell lymphoma who failed autologous stem cell transplantation: a national survey of the SFGM-TC , 2016, Bone Marrow Transplantation.

[5]  M. Labopin,et al.  Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP–EBMT analysis on patients with AML in remission , 2016, Bone Marrow Transplantation.

[6]  V. Bhatt Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma , 2016, Current Hematologic Malignancy Reports.

[7]  A. Nagler,et al.  Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies , 2015, Bone Marrow Transplantation.

[8]  P. Chiusolo,et al.  Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. , 2015, The Lancet. Oncology.

[9]  M. Labopin,et al.  Higher busulfan dose intensity appears to improve leukemia-free and overall survival in AML allografted in CR2: An analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. , 2015, Leukemia research.

[10]  G. Visani,et al.  Advancement in high dose therapy and autologous stem cell rescue in lymphoma. , 2015, World journal of stem cells.

[11]  Michael L. Wang,et al.  Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. , 2015, Blood.

[12]  S. Solomon,et al.  Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[13]  U. Farooq,et al.  Recent progress: hematopoietic cell transplant for diffuse large B-cell lymphoma , 2015, Leukemia & lymphoma.

[14]  M. Labopin,et al.  Reduced‐toxicity conditioning with fludarabine, once‐daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: Results of a multicenter prospective phase 2 trial , 2015, Cancer.

[15]  P. Chevallier,et al.  Upfront allogeneic stem-cell transplantation for patients with nonlocalized untreated peripheral T-cell lymphoma: an intention-to-treat analysis from a single center. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  R. Bouabdallah,et al.  90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[17]  B. Esterni,et al.  Reduced-toxicity conditioning prior to allogeneic stem cell transplantation improves outcome in patients with myeloid malignancies , 2014, Haematologica.

[18]  M. Labopin,et al.  Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT , 2014, Bone Marrow Transplantation.

[19]  E. Kimby,et al.  The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma , 2014, Leukemia.

[20]  W. Stevens,et al.  Outcome and prognostic factors in patients with mantle-cell lymphoma relapsing after autologous stem-cell transplantation: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT). , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  C. Papadimitriou,et al.  Peripheral T-cell lymphoma: the role of hematopoietic stem cell transplantation. , 2014, Critical reviews in oncology/hematology.

[22]  P. Garagnani,et al.  Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation , 2014, Haematologica.

[23]  G. Marit,et al.  Allogeneic SCT for patients with high-risk peripheral T-cell lymphoma in first response , 2013, Bone Marrow Transplantation.

[24]  E. Kimby,et al.  Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party , 2013, Haematologica.

[25]  P. Armand,et al.  Busulfan dose intensity and outcomes in reduced-intensity allogeneic peripheral blood stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[26]  A. Velardi,et al.  The EBMT activity survey: 1990–2010 , 2012, Bone Marrow Transplantation.

[27]  C. Hofmeister,et al.  Higher busulfan dose intensity does not improve outcomes of patients undergoing allogeneic haematopoietic cell transplantation following fludarabine, busulfan‐based reduced toxicity conditioning , 2011, Hematological oncology.

[28]  P. Thall,et al.  Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[29]  H. Einsele,et al.  Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009 , 2010, Bone Marrow Transplantation.

[30]  B. Sandmaier,et al.  Defining the intensity of conditioning regimens: working definitions. , 2009, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[31]  L. Ramdas,et al.  Altered gene expression in busulfan-resistant human myeloid leukemia. , 2008, Leukemia research.

[32]  A. LaCasce,et al.  Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[33]  J. Rowe,et al.  Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. , 2008, Current drug safety.

[34]  Gary King,et al.  Matching as Nonparametric Preprocessing for Reducing Model Dependence in Parametric Causal Inference , 2007, Political Analysis.

[35]  R. Porcher,et al.  Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). , 2007, Haematologica.

[36]  Sigrid Stroobants,et al.  Revised response criteria for malignant lymphoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  Mark Ende,et al.  Hematopoietic stem-cell transplantation. , 2006, The New England journal of medicine.

[38]  J Murillo,et al.  [B cell lymphoma]. , 2004, Medicina oral : organo oficial de la Sociedad Espanola de Medicina Oral y de la Academia Iberoamericana de Patologia y Medicina Bucal.

[39]  D. Cooper,et al.  Allogeneic peripheral blood stem cell transplantation for high-risk non-Hodgkin's lymphoma , 2003, Bone Marrow Transplantation.

[40]  J Crowley,et al.  Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. , 1999, Statistics in medicine.

[41]  S. Aebi,et al.  The role of DNA mismatch repair in drug resistance. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[42]  L Davies,et al.  Bone marrow transplant. , 1985, Nursing times.

[43]  K. Sullivan,et al.  Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. , 1980, The American journal of medicine.

[44]  P. Neiman,et al.  CLINICAL MANIFESTATIONS OF GRAFT‐VERSUS-HOST DISEASE IN HUMAN RECIPIENTS OF MARROW FROM HL‐A-MATCHED SIBLING DONOR,S , 1974, Transplantation.