Pre-Conditioning Steroids and Hydroxyurea Followed By Reduced Toxicity Conditioning (RTC) with ATG-Bu-FLU Is Safe and Effective in Allo-Sib-HSCT in Adolescents and Adults with Sickle Cell Anemia (SCA)

AIM OF THE STUDY:  to assess safety and efficacy of pre-conditioning use of prednisone and Hydroxyurea and   Fludarabine, iv-Busulfan and low dose ATG in young adults with SCA.

PATIENTS AND METHODS

Nine consecutive SCA patients, median age 18 y (14 -30y) transplanted between 23/1/11 and 1/7/ 14 from identical siblings (7 BM, 1 PB and 1 BM+PB) ,  median CD34+ cell dose 5.8 x10_6/kg (2.7-8.2).Indications of HSCT were recurrent severe VOC (n:9; 100%) , Acute chest syndrome (n: 3; 33% ), stroke (2; 22% ), AVN (n; 2; 22%.  HLA-matching was 10/10 in all pairs (100%); 3 donors (33%) had sickle cell trait. One patient (11.1) rejected a previous allosib-HSCT after Campath-based NMA conditioning.

Preconditioning Phase: a) Cytoreduction with hydroxyurea plus prednisone 0.5 mg/kg every other day  for >3 weeks.

CONDITIONING: FLU: 40mg/m2/d (d-9 to d-6), iv Busulfan: 0.8mg/kg q6h x14 doses (d-7 to d-4) (total 11.2mg/kg) and ATG(Thymoglobulin; Genzyme): 1.5mg/kg/d (d-4 to d-2) (total 4.5mg/kg); 2 patients received 5.5 mg/kg.

GVHD PROPHYLAXIS: Cyclosporine (CSA) (d-1 to d+ 9 months) and Methotrexate (15mg/m2 d+1, 10mg/m2 d+3 and d+6). Supportive care was as per institutional protocol.

RESULTS: Median F/U was 22 mo (3.5 -45 mo). All patients tolerated prednisone-hydroxyurea; only one episode of short (3days) neurtopenic fever occured before protocol evolution; no case of VOC or ACS or stroke or worsening of AVN (cumulative 109 weeks-patients).

There was no (0%) transplant related mortality (TRM) and all are alive (OS 100%) and free of VOC and transfusion (TFS 100%). Engraftment: ANC recovery occurred in all (100%) at a median of 19 days (range 0-26 d), Platelet recovery to 20,000/ul  in 100% at a median of 16d (10-36) and to 50,000 in 100% at a median of 16d ( 11- 50 d); 8 patients (89%) reached 50,000 in 21d . Hb electrophoresis changed to donor type. Chimerism: all patient (100%) had full (100%) myeloid chimerism. Lymphoid chimerism was high (>50% donor) in 6 (67%), intermediate in 1 (11%) and fluctuated between 15-31% in 2 (22%).

GVHD: one (11.1%) patient  developed grade II a-GVHD , responded to steroids and only one (12.5%) of the 8 evaluable patients  developed cGVHD that responded to steroids. Peri-transplant morbidities:  Mucositis occurred in 4 (44%; grade I in 22%, grade II in 11% and Grade III in 11%);  one (11%) patient bled due to gastritis,  delayed serum sickness  in 1 (11%).  4 (44%) had culture-neg neutropenic fever without sepsis and 1 (11.1%) developed line related infection. No reported invasive fungal disease or hemorrhagic cystitis.

CONCLUSIONS: Conditioning for allo-sib- HSCT for adults with SCA could safely and effectively be divided into : 1) Pre-conditioning phase with steroids and Hydroxyurea to help reduce the chronic inflammatory status and 2) Reduced Toxicity Conditioning with ATG-Bu-FLU which allowed engraftment of all patients with no peri-transplant mortality and low rate of acute and chronic GVHD.