A Novel Treatment Protocol Successfully Prevented Graft Rejection and Improved Disease-Free Survival in Class 3 Children with Thalassemia

Historically, bone marrow transplantation (BMT) in class 3 thalassemia patients has been associated with a significant risk of graft failure and transplant-related mortality leading to lower disease-free survival. Our initial study showed that class 3 patients treated with a new treatment protocol (Pc 26) had an improved survival and decreased rejection rates compared with previous protocols (Blood 2004;104:1201). An interim analysis of our subsequent experience with BMT in class 3 patients treated with Pc26 showed an increased rejection rate which has prompted us to modify the protocol to overcome this complication. Since February 2007 we have been using the modified Pc26 (Pc26m) in class 3 patients.

Between June 2004 and July 2011 a total of 45 class 3 patients with median age of 10 years (range, 5–16) were treated: 26 patients with original (Pc26) and 19 patients with modified protocol (Pc26m). The two groups were well balanced in respect to baseline demographic and clinical characteristics. Patients had severe iron overload with median serum ferritin and liver iron concentration of 2626 ng/mL (range, 777–10222) and 20,8 mg/g dry weight (range, 5–40.7), respectively. Median liver fibrosis score was 2 (range, 1–5). There were 5 patients with HCV, and 1 with hepatitis B virus (HB Ag-positive) at the time of transplantation. The median number of packed RBC transfusions was 140 units (range, 25–307). The Pc26m consisted of pre-conditioning and conditioning phases. This novel treatment regimen involved an intensified preparation with 3 mg/kg of azathioprine and 30 mg/kg hydroxyurea daily from day -45 from the transplant, fludarabine 30 mg/m2 from day -16 through day -12, followed by the administration of weight based busilvex (since 2006), Thiotepa 10 mg/kg/day and CY 160 mg/kg total dose. GVHD prophylaxis consisted of CSA, low-dose methylprednisolone, and a modified “short course” of methotrexate (MTX).

Four of 26 patients treated with Pc26 and none of 19 patients treated with Pc26m had graft failure. The median time of neutrophil recovery (ANC>500 ×109/L) and platelet recovery (>20 ×109/L) were similar in both group of patients. Transplant outcomes are shown in Table 1.

Overall treatment protocol was well tolerated without any significant toxicity. None of the patients had grade 4 toxicity. Most frequent grade 3 toxicity was AST and ALT elevations. Five patients, 3 treated with Pc26 and 2 with Pc26m had grade 2 hemorrhagic cystitis. One patient in each group had moderate liver VOD resolved with supportive care. Two patients in Pc26 group and one in the Pc26m group had pneumonia. There were 3 patients with bacteremia: 2 in Pc26 and one in Pc26m treated patients. The incidence of CMV reactivation was similar in both group.

This study shows that the modified treatment protocol for class 3 thalassemia patients is highly effective in terms of graft failure leading to a high DFS rate which is comparable to those obtained in class 1 and class 2 patients. It also suggests that this intensified preparative regimen aimed at reducing a large disease burden and increasing immunosuppression over time thus avoiding unacceptable peritransplant drug toxicity is essential for minimizing graft failure in these high-risk patients.

No relevant conflict of interest to declare.

No relevant conflicts of interest to declare.