Phase 2 Study of Allogeneic Stem Cell Transplantation (ASCT) From Matched Related Donor (MRD) In Patients Older Than 55 Years After Reduced Intensity Conditioning (RIC) Associating Fludarabine, Intravenous Busulfan and Rabbit Thymoglobulin

Abstract 1320

ASCT is a powerful treatment for many hematological malignancies but the frequency of these diseases increases with age notably after 55 years. Indeed, this age cut-off has been a long time edge for performing ASBMT because of the increased non relapse mortality (NRM) probability making this therapy not available for this population. RIC development has recently modified this border. However because of the population characteristics non myeloablative regimen are more often considered than RIC because of the anticipated NRM with higher myeloablation. This might be questionable if we consider the antitumoral activity of conditioning.

We designed a phase 2 study (ITAC protocol: EudraCT NB: 2005–005051-17) aiming to assess in patients older than 55 years the one year NRM after ASCT prepared with a RIC delivering intermediate myeloablation by associating: Fludarabine (Fludara®)(30mg/m²/d from D–5 to D-1), IV Busulfan (Busilvex®) (0.8 mg/kg × 4/d on D-4 and D-3) and rabbit anti-T cell globulins (Thymoglobuline®) (2.5 mg/kg/D on day –2 and -1) (F5BX2A2 regimen). Patients older than 55 years with poor prognosis hematologic malignancies were eligible for this program if they have a matched related donor. All grafts were peripheral blood stem cell (PBSC) mobilized with Neupogen®. IV cyclosporine A (CSA) (2 mg/kg/d) was started on day -2. It was calculated that 82 patients were looked-for to identify a one year NRM under 25% with adequate power (P<= .01; β=.9). Eight centers actively participated including these 82 patients between March 2007 and May 2010. Median age was 60 (55-70); Diagnoses: Acute leukemia (45%), myelodysplasic syndrome (19%); multiple myeloma (15%), diverse lymphoid malignancies (19%) and others (2%). Disease status: Complete remission (66%); Partial remission (26%); Progression or Stable disease (8%).

Median follow-up of alive patients is 400 days (141-1086) and 63 (77%) patients have a minimal follow-up of one year. All patients engrafted. The cumulative incidence of grade 2–4 AGVHD, limited and extensive CGVHD were respectively of 17% (7-27), 35% (23-47) and 17% (7-27). Median time for grade 2–4 AGVHD and CGVHD were 40 (34-91) and 146 (90-316) days respectively. A single patient died prior day 100 on day 60 from sepsis. The cumulative incidence of NRM at 1 year was 18% (8-28). The cumulative incidences of relapse at 1 year and overall were respectively of 27 % (16-38) and 32% (20-44) with a median of 171 (22-775) days for relapse (patients in CR vs. more advanced at transplant: 28% vs. 42%; p=.26). The probabilities of overall survival at one and two years were 75% and 61% (45-75) respectively. The probabilities of disease free survival at one and two year 53% and 42% respectively.

In conclusion these results are quite promising for older patients with hematological malignancies. This study prospectively shows that F5BX2A2 RIC is well adapted to a population older than 55 years inducing a limited NRM. This is in line with the low AGVHD probability, probably related to the use of ATG. Disease control is probably preserved by the use of 2 days of IV BU and the existence of a high rate of CGVHD (52%). However, it looks like that the use of 2 days of ATG allows limited CGVHD while limiting the rate of extensive GVHD, stem of mortality and poor quality of life (QOL). On the grounds of the limited NRM, we are presently studying various tuning of this RIC to improve disease control. Prospectively assessed details including economic and QOL evaluations, quite important for this population, will be presented.