The Association of Fludarabin, Oral Busulfan and Thymoglobulin Prior to Matched-Related Allo-SCT Allows for High Long Term Outcome for Both Patients with Myeloid or Lymphoid Malignancies and Reveals the Impact of CD34+ Graft Cell Dose On Cgvhd and Outcome: Long Term Analysis of a Homogenous Cohort of 100 Consecutive Patients.
Authors: Blaise Didier , Farnaut Laure , Esterni Benjamin , Faucher Catherine , Furst Sabine , El Cheikh Jean , Ladaique Patrick , Vey Norbert , Bouabdallah Reda , Stoppa Anne Marie , Lemarie Claude , Calmels Boris , Castagna Luca , Mohty Mohamad , Chabannon Christian 
Published: October 2019

Abstract
Abstract 3374
Poster Board III-262
Long term follow-up of RIC-based allogeneic stem cell transplants are still scarce. While RIC are presently commonly used, most reports analyzed together patients (pts) with different intensities of conditioning, donor types and graft sources. In addition, most published reports are associated with short-term follow-up. As a consequence, results are unlikely to be helpful in assessing the real impact of RIC allograft in given pts population.
In this perspective, we analysed a single-centre cohort of 100 consecutive pts treated between 2000 and 2006 with a minimal and median follow-up of respectively 28 and 56 months. All pts presented a haematological malignancy; all pts were treated with PBSC allo-SCT from a matched-related sibling donor. All pts were to receive the same RIC without TBI: oral busulfan (8mg/m2), thymoglobuline (2.5mg/kg) and fludarabine (150mg/m2 over 5 days) and the same CSA-based post graft immunosuppression. Median age was 50 (18-64). Diagnoses included acute leukemia (AL) (39%), myeloid malignancies (HMY) (16%) (Studied together: AL+HMY=55%) and lymphoid malignancies (HLY) (45%). Respectively 53, 14 and 33 pts were in CR, progression or stable disease (AL+HMY: 85%, 13%, 2%; HLY: 13%, 16%, 71%, p<.0001). EBMT disease stage evaluation was early (0-1), intermediate (2-3), and high stage (4-6) for respectively 5, 52, 41 pts (AL+HMY: 7%, 73%, 20%; HLY: 2%, 27%, 71%, p<.0001). Hematopoietic cell transplantation comorbidity index (HCT-CI) was 0, 1-2 and >2 in 31, 39 and 23 of the 92 assessable pts (AL+HMY: 36%, 35%, 29%; HLY: 25%, 56%, 19%, p=NS). Grafts were monitored for CD34, CD3, CD4, CD8, CD19, CD56 and CFU-GM cells (notably CD34: 5.6 (1.5-22.2) x10e6/kg, CD3: 316 (112-887) x 10e6/kg). All but one engrafted. Median time to neutrophil and platelet recovery was 18 (8-27) and 9 (50-99) days. aGVHD and cGVHD cumulative incidences (CI) were 43% (33-54) and 81% (73-89) respectively. cGVHD was associated with low CD34 dose (.0001) and previous Grade ≥ 2 aGVHD (.036). DLI was administered in 16 pts for purpose of mixed chimerism or disease progression in respectively 3 and 13 cases. TRM CI at 12 months and 5 years were 15% (8-22) and 25% (16-34) respectively. TRM was strongly associated with aGVHD (p=.00004) but not with EBMT score nor HCT-CI index. Overall, on the 56 assessable pts with measurable disease at transplantation, 36 (64%) achieved objective response (no difference between 2 groups). Relapse or progression occurred at a median of 11 months (1-52) in respectively 21 pts for a CI of 22.4% (11-33.7) and 22.5% (8.7-36.2) respectively in AL+HMY and HLY groups. In a landmark analysis, disease progression was associated with the absence of grade ≥2 aGVHD (p=.0045) and the absence of cGVHD (p=.0035). Five years OS and PFS probability estimate was 63% (51-78) and 61% (49-75) for HMY+LA group and 55%(42-72) and 45%(31-64) for HLY group. In multivariate analysis, improved PFS was related to CR at transplantation (p=.009) and low CD34 dose (under median) (p=.028). To conclude: results suggested a high efficiency of a RIC combining Fludarabin and limited myeloablation (busulfan) and limited thymoglobuline dose in a wide population in term of age, HSCT-CI, EBMT disease stage evaluation for both lymphoid and not lymphoid malignancies. An interest of the analysis of such an homogeneous cohort of patient is to re-evaluate the impact of scores developed in more heterogeneous populations (HSCT-CI, EBMT score) and to study the impact of other parameters generally concealed by population disparity. In this perspective, lower stem cell dose (but not other graft cells) was associated with more cGVHD and improved PFS. This observation deserves further investigation, notably inviting to revisit the impact of GCSF mobilization in RIC context.

Disclosures:
Bouabdallah: Roche: Research Funding.