Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France

Abstract

Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-versus-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.

Figure 1.

Matched-sibling donor hematopoietic stem cell transplantation (MSD-SCT) performed in France (1988-2012) after myeloablative conditioning regimen (n=234). Only 2% of patients were not prepared with anti-thymocyte globulin (ATG) in the second cohort versus 20.5% in the first cohort. The transplantation procedure and prophylaxis for graft-versus-host disease (GvHD) were as previously reported, except that busulfan has been administered intravenously since year 2001 (Busilvex® Pierre Fabre Médicaments, Boulogne-Billancourt, France) from day –10 to day –7 at the total dose of 12.8 mg/kg for patients weighing >34 kg, 15.2 mg/kg for patients weighing 23-34 kg, 17.6 mg/kg for patients weighing 16-23 kg, or 19.2 mg/kg for patients weighing 9-16 kg. Busulfan pharmacokinetics were not performed for the majority of patients (n=202). In addition, cyclosporine was replaced by mycophenolate mofetil after 2002 in case of GvHD requiring steroid therapy. (A) Proportion of patients younger or older than 15 years. (B) ATG doses. NP: not precise; these patients received ATG, but the exact dose was not recorded.

Figure 2.

Rejection probability and event-free-survival (EFS) in sickle cell anemia (SCA) patients transplanted with matched-sibling donor (MSD) after myeloablative conditioning regimen. (A) Probability of rejection according to the anti-thymocyte globulin (ATG) dose. Overall cumulative incidence of rejection at five years was 20.0% (95%CI: 3.0-37.0%) in patients prepared without ATG and only 1.4% (95%CI: 0.0-3.0%) (P<0.001) in those prepared with ATG. However, the risk of rejection was not associated with the ATG dose (5-15 mg/kg vs. 20 mg/kg). (B) EFS according to the ATG dose. EFS was similar after bone marrow transplantation (BMT) and cord blood transplantation (CBT), and in patients prepared with 5-15 mg/kg ATG than in those prepared with 20 mg/kg. (C) EFS in 234 patients depending on the period of transplant. EFS improved strongly as it was only 73.3% (95%CI: 58.7-87.9%) among the 38 patients transplanted before year 2000 and 97.4% (95%CI: 95.0 -99.8%) in the 196 patients transplanted after year 2000. (D) EFS according to age over or under 15 years. EFS was similar in patients younger or older than 15 at transplant.

Figure 3.

Relationship of graft-versus-host disease (GvHD) and donor/recipient (D/R) cytomegalovirus (CMV) status, anti-thymocyte globulin (ATG) dose and recipient age. (A) Acute GvHD according to the D/R CMV status. Cumulative incidence of acute-GvHD at day 100 according to the D/R CMV status. (B) Chronic GvHD according to the ATG dose. Cumulative incidence of chronic GvHD at five years was significantly lower in the patients having received the high dose of ATG (20 mg/kg) (5.4%, 95%CI: 1.8-9.0%) versus those not prepared with ATG (25%, 95%CI: 5.6-44.4%) and those having received lower doses (5-15 mg/kg): 27.0%, 95%CI: 12.4-41.6%) (Log Rank P<0.001). (C) Chronic graft-versus-host disease (GvHD) according to recipient age at transplant. Cumulative incidence of chronic GvHD in children under 15 years of age was 7.6% (95%CI: 3.8-11.4%) versus 29.7% (95%CI: 13.1-46.3%) in those older than 15.

Figure 4.

Relationship between % donor cells and hemoglobin S percentage (HbS%), hemoglobin (Hb) level, and reticulocyte count. All biological data (HbS%, Hb and reticulocytes) recorded at the same time as the chimerism during the overall follow up were used for these box-plots. (A) Box-plot of HbS% according to the donor cell% category. This graph shows that HbS% is similar to that of the donor (AA or AS) as long as donor cell% is higher than 50%. (B) Box plot of Hb level according to donor cell% category. Hb level remains higher than 100g/L as long as donor cell% is higher than 50%. (C) Box plot of reticulocyte count according to % donor cells. Reticulocyte count remains lower than 100x10⁹/L as long as % donor cells is higher than 50%.