Reduced-Intensity (FB2) Vs Reduced-Toxicity Myeloablative (FB3/FB4) Fludarabine/Busulfan Based Conditioning Regimens for Non-Hodgkin Lymphoma (NHL) Allografted Adult Patients: A Retrospective Study on Behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
Authors: Le Bourgeois Amandine , Labopin Myriam , Blaise Didier , Ceballos Patrice , Vigouroux Stéphane , Peffault De Latour Regis , Suarez Felipe , Deconick Eric , Chantepie Sylvain , Bay Jacques-Olivier , Bulabois Claude-Eric , Daguindau Etienne , Contentin Nathalie , Yakoub-Agha Ibrahim , Cornillon Jerome , Francois Sylvie , Turlure Pascal , Charbonnier Amandine , Rohrlich Pierre-Simon , Nguyen Stephanie , Maillard Natacha , Marchand Tony , Mohty Mohamad , Chevallier Patrice 
Published: October 2019

Abstract
Introduction: Allogeneic stem cell transplantation is a potentially curative treatment for patients with high-risk non-Hodgkin lymphoma (NHL). Fludarabine/busulfan based conditioning regimens are widely used in Europe for this purpose. Busulfan dose intensity discriminates between reduced intensity (FB2, 2 days of busulfan at 4 mg/Kg/d per os or 3.2 mg/kg/d iv) and reduced-toxicity myeloablative (FB3/FB4, 3 or 4 days of busulfan at 4 mg/Kg/d per os or 3.2 mg/kg/d iv) conditioning regimens (Bacigalupo, 2009). While some data have been recently published showing some advantages of higher busulfan dose intensity for myeloid malignancies, there is no such data available in the lymphoid setting.
Methods: This was a large retrospective study conducted on behalf of the SFGM-TC including all adults allografted in France between January 2004 and December 2014 for NHL (n=378). Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. We aim to compare various outcomes (overall (OS) and lymphoma free (LFS) survivals, relapse incidence (RI), non-relapse mortality (NRM), acute and chronic GVHD) between those who received FB2 (n=277) or FB3/FB4 (n=101) as conditioning regimens. GVHD free relapse free survival (GRFS) was also studied (defined as alive with no previous grade III-IV aGvHD, no moderate or severe chronic GvHD (cGvHD) and no relapse).
Results: Both groups were comparable for the following variables: median follow-up (FB2: 24.9 vs FB3/4: 23 months), gender (male 61% vs 53%), disease type (low-grade lymphoma 25% vs 21%, mantle-cell lymphoma 17% vs 13%, high-grade lymphoma 25% vs 21%, T cell lymphoma 32% vs 45%), disease status at transplant (complete remission/very good partial response 64% vs 62%, partial response 28% vs 31%, active disease 8% vs 7%), donor type (sibling 43% vs 49.5%, matched unrelated 56% vs 47), median number of previous courses of treatment (2 vs 2, p=0.44), stem cell source (peripheral blood 96% vs 95%). FB2 patients were significantly older (median 57.3 vs 53.1 years, p=0.07), have been transplanted more recently (median year of transplant: 2011 vs 2010, p=0.001) and have been more previously autografted (69% vs 50.5%, p=0.001). FB3/4 patients have been allotransplanted earlier during the evolution of their disease (median time between diagnosis and allograft 18.2 vs 33.8 months, p<0.0001). The majority of patients (n=353, 98.4%) received ATG as GVHD prophylaxis.
Engraftment was observed in 97.8% of FB2 patients vs 100% of FB3/4 cases (p=0.13). In univariate analysis, 2-years OS (FB2 66.5% vs 60.3%, p=0.33), LFS (FB2 57.9% vs 49.8%, p=0.26), RI (FB2 23% vs 29.1%, p=0.32) and NRM (FB2 19% vs 21.1%, p=0.91) were similar between both groups. Cumulative incidence of grade 3-4 acute (FB2 11.2% vs 18%, p=0.08) and extensive chronic (FB2: 17.3% vs 10.7%, p=0.18) GVHD were also comparable as well as 2-year GRFS (FB2: 44.4% vs 42.8%, p=0.38). When considering patients allografted before or after the median time between diagnosis and the time of allograft for the whole cohort (< or >=30 months), there were also no significant differences between both groups in terms of OS, LFS, RI or NRM. In multivariate analysis there was a trend for worse outcome using FB3/FB4 regimens (OS: HR 1.46, 95%CI: 0.96-2.23, p=0.07; LFS: HR: 1.43, 95%CI: 0.99-2.06, p=0.05; RI: HR 1.54; 95%CI: 0.95-2.48, p=0.07). These results were also confirmed using a propensity score-matching strategy including 184 FB2 and 98 FB3/4 patients.
Conclusion: This large retrospective study showed that reduced toxicity myeloablative fludarabine/busulfan regimens did not improve outcomes of adults allografted for NHL. FB2 conditioning regimen still should be considered as the standard of care conditioning regimen in this setting. To validate these results, prospective studies are needed, like the French prospective trial currently ongoing for myeloid diseases (NCT01985061). Also, new conditioning regimens and post-allograft strategies should be tested to improve outcomes of patients.

Disclosures
Peffault De Latour: NOVARTIS: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding.