Allogeneic Stem Cell Transplantation From Matched Related Donor in Patients Over the Age of 55 Years: A Prospective Multicenter Phase II Study of a Reduced Intensity Conditioning Associating Fludarabin-IV Busulfan and Thymoglobulin
Authors: Blaise Didier , Mohty Mohamad , Milpied Noel , Lecorroller Anne Gaelle , Fegueux Nathalie , Furst Sabine , Chevallier Patrice , Tabrizi Reza , Michallet Mauricette , Cahn Jean Yves , Sirvent Anne , Bay Jacques-Olivier , Cheikh Jean El , Faucher Catherine , Crocchiolo Roberto , Boyer-Chamard Agnes , Castagna Luca , Boher Jean Marie 
Published: October 2019

Abstract
Abstract 1952
Reduced intensity conditioning (RIC) regimens has been developed with the aim to perform safer allogeneic (Allo) stem cell transplantation (SCT) in population previously discarded because of higher SCT-related mortality. In this regard, the age of 55 years has been a long-lasting threshold above which standard Allo-SCT prepared with myeloablative conditioning (MAC) has been of limited use. Since a decade we now know that RIC can be safely used in this population. The RIC intensity remains however an issue: the more intensive, the more toxic but the less intensive, the less effective.
In this study we prospectively assess, in patients (pts) over 55 years, eligible for an matched sibling Allo-SCT, the impact of a RIC with Fludarabin (30 mg/m2/day (D-5 to D-1)), IV Busulfan (0.8 mg/kg × 4/day (D-4 to D-3)) and rabbit anti-Thymocyte globulin (ATG) (2.5 mg/kg/day (D-2 to D-1). This phase II study followed a one-step Fleming procedure aiming to detect a decrease in non-relapse mortality (NRM) of 20% (α=0.01; β=0.10) as compared to literature data using standard MAC. To achieve this goal, a minimum of 74 analyzable pts were necessary and the inclusion of 82 pts were scheduled to anticipate drop-off after inclusion.
Eventually, from 03/07 to 06/10, 82 pts have been included in 9 centers, of which 79 have been transplanted. Median follow-up is 24 months (10–50). All grafts were PBSC from a HLA identical sibling. CSA (2 mg/kg) was started on day −2. Median age is 60 (55–70) and male/female ratio 47/32. Karnofsky score was 90 (60–90). Diagnoses: AML=32; MDS=13; ALL=6; NHL=10; MM=13; CLL=4; Waldenström=1); 54 pts were in CR (CR1=31; CR2=15; CR>2=8), 22 in PR or SD and 3 in PD after a median of 2 (1–7) lines of chemotherapy. All pts engrafted and 46 presented with aGVHD (Grade: 1 n=32; Grade 2: n=7; grade 3–4: n=6) for a 17% (10–23) cumulative incidence of G≥ 2 aGVHD. A total of 47 pts experienced cGVHD (Limited: N=28; extensive: N=19) at a median of 4.5 months (3–21) after transplant for a one year overall and extensive cumulative incidence of 57% (46–68) and 34% (25–45) respectively. 12 patients died from NRM. The 6 month and overall cumulative incidences of NRM were 5% (0–10) and 16% (9–23) respectively. Karnofsky score was not predictive of NRM. 25 patients relapsed at a median of 4.2 months (0.8–12) for a cumulative incidence of 32% (23–42). Relapse incidence differed according to disease pre-transplant status (9 of 46 CR1/CR2 vs. 16 of 33 beyond CR2 pts; p=0.008). Three year overall and disease-free survival probabilities were 59% (45–71) and 79% (67–87) respectively. Considering the CR1 AML population (N=21), median age was 61 years (56–70) and probabilities of NRM, relapse, OS and LFS were 14% (IC95=0–27), 14% (IC95=2-26XX), 72% (IC95=47–86) and 67%(IC95=43-83) respectively.
Economical data covering transplant and first 18 month post-transplant periods have been prospectively collected and are under analysis. HRQL (Health Related Quality of Life) was assessed over a 1-year period with the EORTC QLQ-C30 questionnaire (Days −7, +80,+180,+360). The lowest functioning scores and highest symptom scores were experienced 80 days after transplantation. Thereafter the level of functioning and level of symptoms returned to baseline levels, which is reassuring in this population.
This study presents prospective data in pts of 55 years and older and treated in a multicenter trial with RIC but not non-myeloablative CDT. Taking account patient characteristics, they first confirm that Allo-SCT is a valid option in this population. Second they prospectively put in light that in elderly people the use of RIC is associated with similar NRM than after non-myeloablative conditioning regimen. The use of two days of rabbit ATG is associated with a low GVHD-induced NRM without a high relapse risk. This is likely due to the good efficacy/toxicity balance achieved by combining IV Busulfan and ATG. Further refining of this association, by cautious tuning of the IV Busulfan dose, is under process in our program. Comprehensive phase II studies of this type, including economical and QOL data, have become a prerequisite prior to further more ambitious trials of novel modalities and strategies.

Disclosures:
Blaise: Laboratoire Pierre Fabre: Research Funding; Celgene: Research Funding.