Buket Erer

Bone Marrow Transplantation in Thalassemia: The Experience of Pesaro

Abstract: Early trials of allogenic bone marrow transplantation (BMT) for homozygous β thalassemia and the analyses of results of transplantation in patients under 17 years of age have allowed us to identify 3 classes of risk using the criteria of degree of hepatomegaly, the degree of portal fibrosis, and the quality of the chelation treatment given before the transplant. Patients for whom all 3 criteria were adverse constituted Class 3, patients with none of the adverse criteria constituted Class 1, and patients with 1 or various associations of 2 of the adverse criteria formed Class 2. Most patients older than 16 years have disease characteristics that place them in Class 3, with very few in Class 2. For all the patients with an HLA identical donor we are actually using 2 protocols to which the patient is assigned on the basis of the Class he belongs to at the time of BMT and independently from the age of the patient. For 104 patients in Class 1 and for 262 patients in Class 2 prepared for the transplant with busulfan 14mg/kg, cyclophosphamide 200mg/kg and cyclosporine alone, the probabilities of survival and of event‐free survival are 95% and 90% for Class 1 and 87% and 84% for Class 2. For 33 Class 3 patients prepared for the transplant with busulfan 14 mg/kg, cyclophosphamide reduced to 160 mg/kg, cyclosporine, and “short” methotrexate, the probabilities of survival and event‐free survival are 89% and 64%. For 57 adult patients (17 to 35 years), who underwent the transplant after preparation with the same protocol used for Class 3, the probabilities of survival and of event‐free survival are 70% and 68%, respectively. BMT remains the only form of radical treatment for thalassemia in those patients with an HLA‐identical donor.

Purified T-depleted, CD34+ peripheral blood and bone marrow cell transplantation from haploidentical mother to child with thalassemia.

Fetomaternal microchimerism suggests immunological tolerance between mother and fetus. Thus, we performed primary hematopoietic stem cell transplantation from a mismatched mother to thalassemic patient without an human leukocyte antigen-identical donor. Twenty-two patients with thalassemia major were conditioned with 60 mg/kg hydroxyurea and 3 mg/kg azathioprine from day -59 to -11; 30 mg/m(2) fludarabine from day -17 to -11; 14 mg/kg busulfan starting on day -10; and 200 mg/kg cyclophosphamide, 10 mg/kg thiotepa, and 12.5 mg/kg antithymocyte globulin daily from day -5 to -2. Fourteen patients received CD34(+)-mobilized peripheral blood and bone marrow progenitor cells; 8 patients received marrow graft-selected peripheral blood stem cells CD34(+) and bone marrow CD3/CD19-depleted cells. T-cell dose was adjusted to 2 x 10(5)/kg by fresh marrow cell addback at the time of transplantation. Both groups received cyclosporine for graft-versus-host disease prophylaxis for 2 months after transplantation. Two patients died (cerebral Epstein-Barr virus lymphoma or cytomegalovirus pneumonia), 6 patients reject their grafts, and 14 showed full chimerism with functioning grafts at a median follow-up of 40 months. None of the 14 patients who showed full chimerism developed acute or chronic graft-versus-host disease. These results suggest that maternal haploidentical hematopoietic stem cell transplantation is feasible in patients with thalassemia who lack a matched related donor.

Graft-versus-host disease after bone marrow transplantation for thalassemia: an analysis of incidence and risk factors.

We analyzed risk factors in 724 patients evaluable for acute graft-versus-host disease (GVHD) and in 614 patients evaluable for chronic GVHD who had received bone marrow transplantation (BMT) from HLA-identical siblings and/or parents for thalassemia and/or microdrepanocytosis, in a single institution. The overall incidence of grade II-IV and III-IV acute GVHD (aGVHD) was 26.9% and 13.5%, respectively. The cumulative incidence of grade II-IV aGVHD in patients treated with cyclosporine (CsA)/methylprednisolone (MP) or CsA/methotrexate (MTX)/MP was 32% and 17%, respectively (P=0.001). In logistic regression analysis, the risk factors associated with the onset of grade II-IV aGVHD in the entire group of patients were: patient age < or = 4 years (P=0.009), male patient sex (P=0.023), GVHD prophylaxis with CsA/MP or MTX/MP (P=0.000), more than twofold elevated alanine aminotransferase (P=0.001), and patient seropositivity for two to three herpes viruses (P=0.007). In patients treated with CsA/MP, splenomegaly > 2 cm (P=0.042) and donor age > or = 17 years (P=0.034) predicted aGVHD. Risk factors for grade III-IV aGVHD were similar to the risk factors identified for grade II-IV aGVHD. Moreover, moderate and severe liver fibrosis or cirrhosis predicted grade III-IV aGVHD (P=0.018). The incidence of chronic GVHD (cGVHD) was 27.3%. The probability of cGVHD at 2 years after BMT in patients with grade 0, I, II, and III-IV aGVHD was 15%, 32%, 53%, and 54%, respectively. Among patients with absent or grade I-IV aGVHD, prior aGVHD (P=0.000), female donor sex (P=0.000), use of alloimmune female donors for male patients (0.009), and GVHD prophylaxis with CsA/MP or MTX/MP (P=0.003) predicted cGVHD. This data should be considered in clinical management and in future investigations for improvement of immunosuppressive prophylaxis in BMT patients with thalassemia.

Treatment of Iron Overload in the “Ex-Thalassemic”: Report from the Phlebotomy Programa

Abstract: After successful marrow transplantation (BMT) iron overload remains an important cause of morbidity in Thalassemia. After BMT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy so that this procedure can be contemplated as a method of mobilizing iron from overloaded tissues. Forty‐one patients (mean age 16±2.9 years) with prolonged follow‐up (range 2‐7 years) after BMT were submitted to a moderate intensity phlebotomy program (6 ml/kg blood withdrawal at 14‐day intervals) to reduce iron overload. Values are expressed as mean ± SD or as median with a range (25th‐75th percentile). Serum ferritin decreased from 2,587 (2,129‐4,817) to 280 (132‐920) μg/l (p < 0.0001), total transferrin increased from 2.34±0.37 to 2.9±0.66 g/l (p= 0.0001), transferrin saturation decreased from 90%±14% to 39%±34% (p < 0.0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5‐28.1) to 3 (0.9‐14.6) mg/g dry weight (p < 0.0001). Alanine amino‐transaminase from 5.2±3.4 to 1.6±1.2 (p < 0.0001) times the upper level of normality. The histological grading for chronic hepatitis (Histology Activity Index) decreased from 4.2±2.4 to 2.3±1.8 (p < 0.0001). Phlebotomy is a safe, efficient, and widely applicable method to decrease iron overload in “ex‐thalassemic.”