Bone Marrow Transplantation For Thalassemia Using Related Other Than HLA- Identical Siblings: Improved Transplant Outcomes With a Novel Approach

Although in some areas of the world a chance of finding a related HLA- matched non sibling donor could be as high as 13% to 18%, and approximately 13% of patients could have a one-antigen mismatched related donor, the role of such alternative donor HSCT in thalassemia is not well established. Our previous study (BMT 2000,25:815) examining alternative related BMT for thalassemia was not successful due to a high graft failure, GVHD, and low disease-free survival rates. In 2005 we adopted a new transplant approach for alternative related donor transplantation in thalassemia and here we report transplant outcomes.

Here we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients (median age 9.6 years; range 1.4-24 years) to perform BMT using phenotypically HLA-identical or one-antigen mismatched related donors (related donors-RDs). We compared these results with HLA matched sibling donor (matched sibling donors-MSDs) BMT in 66 patients (median age 10 years; range, 1.8-27 years). The two groups were similar in terms of disease and demographic characteristics. Patients in the RD group received pre transplant cytoreduction/immunosuppression with hydroxyurea, azathioprine from day -45 pretransplant, and fludarabine from day -16 through day -12. Their conditioning regimen consisted of weight based targeted i.v. Busulfan (Bu), thiotepa (TT) (10 mg/kg), Cyclophosphamide (CY) (200 mg/kg), and Thymoglobulin 10 mg/kg. The conditioning regimen in the MSD group consisted of BuCY200 ±TT10 for class 2 patients and BuCY90-160 preceded by preconditioning cytoreduction/immunosuppression for class 3 patients. All patients received cyclosporine, methylprednisolone, and methotrexate as GVHD prophylaxis. Most patients in both groups were heavily transfused before transplantation and had moderately severe iron overload and liver fibrosis. In the RD group 11 of 16 donors were HLA-phenotypically identical (parents eight, cousin two, and uncle one), and 5 were one-antigen mismatched (siblings three, mother or aunt one).

In total, 16 patients in the RD and 58 (88%) in the MSD group had sustained engraftment. The median times to an ANC>0.5 x 10⁹/L or to a platelet count >20 x 10⁹/L were similar in both groups. Graft rejection occurred in 8 MSD group patients but in none of the RD group patients. The cumulative incidence of rejection was 12% (95% CI, 6–21%) in the MSD group and 0% in the RD group, which was not statistically significant (P = 0.15). The cumulative incidence of acute GVHD (grades 2–4) in the RD group (19%; 95% CI, 4–41%) was less than that in the MSD group (36%; 95% CI, 24–48%), but the difference was not statistically significant (P = 0.21). Two patients in the RD group and six in the MSD group had chronic extensive GVHD. At present, all patients are off immunosuppressive medication. The cumulative incidence of transplant-related mortality (TRM) at 100 days and 1 year was 0% and 6% (95%CI 1-26%) in the RD and 8% and 8% (95% CI, 3–16%) in the MSD group, respectively (P = 0.77). At the time of survival analysis, 15 patients (94%) in the RD group and 61 patients in the MSD group (92%) were alive, with median follow-up durations of 72 months (range, 17–93 months) and 80 months (range, 25–107 months), respectively. The probabilities of overall survival were 94% (95% CI, 63–99%) for the RD group and 92% (95% CI, 83–97%) for the MSD group (P = 0.83). The respective probabilities of thalassemia-free survival were 94% (95% CI, 63–99%) and 82% (95% CI, 70–89%), with no statistically significant difference (P = 0.24). Despite the preexisting disease and treatment-related organ damage this intensified preparative regimen was well tolerated as no significant toxicity was observed. The treatment-related toxicities were similar for the two group of patients, and none of the patients experienced grade 4 toxicity.

The novel treatment protocol Pc 26.1 effectively and safely prevented graft rejection and ensured a high thalassemia-free survival rate in patients who received BMT from related donors who were not HLA-matched siblings. Our data show that thalassemia patients treated with Pc26.1 and receiving RD transplant have similar outcomes (rates of OS, TFS, GVHD, and TRM) to recipients of MSD transplantation. These findings are significant because they expand the availability of the treatment to more patients.

No relevant conflicts of interest to declare.