Cristiano Gallucci

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.

Thalidomide does not modify the prognosis of plasma cell leukemia patients: Experience of a single center

Plasma cell leukemia (PCL) represents the most advanced stage of multiple myeloma (MM) with the neoplastic cells circulating in the peripheral blood. Its diagnosis requires an absolute peripheral blood plasma cell count of 426 10/l or 420% of the differential white blood cell count [1]. PCL is classified into two clinical types: the primary type occurs in individuals without being preceded by MM, whereas the secondary one is a rare complication of the late-stage MM. Based on observations that in PCL the response to standard therapy is extremely poor and the use of Thalidomide (Thal) in advanced myeloma has resulted in marked responses even in patients with advanced diseases, including those who relapsed after high-dose chemotherapy [2], we decided to use this promising drug also in patients with PCL. According to the schedule reported by Singhal et al. [2], between March 2000 and July 2002, after written informed consent, five PCL (two primary and three secondary) patients were considered eligible for Thal treatment at our Institution. Thal was administered as single agent, according to a compassionate-use protocol. The starting dose of Thal was 100 mg daily for 2 weeks; subsequently, this dosage was increased by 100 mg every other week, to a maximum of 600 mg per day or according to the maximum tolerated dose. According to the International Stage criteria, two patients were in stage III (b2 microglobulin 45.5 mg/dl) and three in stage II (one for a b2 microglobulin of 4.2 mg/dl and two for serum albumin levels of 2.4 and 2.9 g/dl, respectively). No cytogenetics, labeling index or FISH data are available for these patients. Three were males and two females; median age was 68 years (range 51 – 72). Two cases were IgG, 1 IgA and two expressed light chains; one patient had serum creatinine 42 mg/dl. With regard to disease status, three patients (two primary and one secondary PCL) were refractory (defined as progression while on therapy) to prior chemotherapies and two were in relapse. All had been treated with at least two lines of treatment, including high-dose induction therapy for one of them, and were included in this study after 14 months (range 8 – 41) of median follow-up. All patients received Thal for at least 1 month and were, therefore, evaluable for response. No patient responded, although a reduction of circulating PC was observed in two. Survival was very short, all patients died after 40, 45, 60, 75 and 120 days of Thal treatment, respectively. During the same time period we treated with the same protocol 75 MM patients (33 refractory to prior chemotherapies and 42 in relapse). The median age was 63.5 years (range 33 – 84); 47 patients were IgG, 20 IgA and eight had light chain MM. Highdose induction therapy was utilized for 29 of them and the MM patients were included in this study after 36 months of median follow-up from diagnosis. The median daily dose of Thal administered to all patients was 400 mg (range 100 – 600 mg). Among the 75 MM patients, 67 received Thal for at least 1 month and were evaluable for response; the remaining eight patients were not evaluable because four

T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients

The cure for thalassemia involves correcting the genetic defect in a hematopoietic stem cell that results in reduced or absent β-globin synthesis and an excess of α-globin dimers. Intracellular precipitation and accumulation of α- dimers results in ineffective erythropoiesis and hemolytic anemia. Replacing the abnormal thalassemic marrow with allogeneic normal or heterozygous stem cells carrying the functional gene restores appropriate β-globin chain synthesis.

Bone marrow transplantation for thalassemia from alternative related donors: improved outcomes with a new approach

Bone marrow transplantation (BMT) performance can be limited by a lack of ideal donors, and the role of alternative donor hematopoietic cell transplantation in thalassemia is not well established. Here we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients to perform BMT using phenotypically HLA-identical or 1-antigen-mismatched relatives (related donors [RDs]). We compared these results with HLA-matched sibling (matched sibling donors [MSDs]) BMT in 66 patients. The entire RD group and 88% of MSD group had sustained engraftment. Rejection incidence was 0% in the RD and 12% (95% confidence interval [95% CI], 6%-21%) in MSD groups (P = .15), with respective thalassemia-free survival probabilities of 94% (95% CI, 63%-99%) and 82% (95% CI, 70%-89%) (P = .24). Transplant-related mortality was 6% (95% CI, 1%-26%) in the RD group and 8% (95% CI, 3%-16%) in the MSD group (P = .83). The intensified new protocol was not associated with increased nonhematologic toxicity. The present data show that the Pc 26.1 preparative regimen allows thalassemia patients to safely undergo BMT from RDs who are not HLA-matched siblings, with transplant outcomes similar to patients with MSD grafts.

IgM multiple myeloma: report of four cases and review of the literature.

The differential diagnosis between multiple myeloma (MM) and Waldenströms macroglobulinemia (WM) is generally well defined. Consistent with a diagnosis of MM is the presence of a non-IgM monoclonal gammopathy associated to multiple osteolytic lesions and plasma cell infiltration of the bone marrow. Characteristic of WM is the presence of an IgM monoclonal gammopathy associated to lymphoadenopathy, hepatosplenomegaly, anemia and hyperviscosity syndrome in the presence of a monoclonal lymphoplasmacytoid proliferation in the bone marrow. Nonetheless, few cases of IgM myeloma have been reported that display clinico-pathologic features intermediate between MM and WM. Here, this study describes four of 317 (1.2%) patients with an IgM monoclonal gammopathy in whom the morphologic and clinical features were consistent with a diagnosis of IgM myeloma.

Sustained and full fetal hemoglobin production after failure of bone marrow transplant in a patient homozygous for beta 0‐thalassemia: A clinical remission despite genetic disease and transplant rejection

An adult patient affected by β0‐thalassemia major underwent allogeneic bone marrow transplant (BMT) from a matched related donor. Forty days after transplant, allogeneic engraftment failure and autologous β0‐thalassemic bone marrow recovery were documented. Red blood cell transfusions were required until 118 days post‐transplant. Thereafter, the haemoglobin (Hb) levels stabilized over 11.8 gr/dl throughout the ongoing 34‐month follow‐up, abolishing the need for transfusion support. The Hb electrophoresis showed 100% Hb Fetal (HbF). This unexplained case suggests full HbF production may occur in an adult patient with β0‐thalassemia major. Am. J. Hematol. 2009.

Haematopoietic stem cell transplantation in Nigerian sickle cell anaemia children patients

Background: Sickle cell anaemia (SCA) remains associated with high risks of morbidity and early death. Children with SCA are at high risk for ischaemic stroke and transient ischaemic attacks, secondary to intracranial arteriopathy involving carotid and cerebral arteries. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the Black African variant of SCA. Patients and Methods: This study included 31 consecutive SCA patients who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical sibling donors between 2010 and 2014 following a myeloablative-conditioning regimen. Results: The median patient age was 10 years (range 2–17 years). Before transplantation, 14 patients had recurrent, painful, vaso-occlusive crisis; ten patients had recurrent painful crisis in association with acute chest syndrome; three patients experienced ischaemic stroke and recurrent vaso-occlusive crisis; two patients experienced ischaemic stroke; one patient exhibited leukocytosis; and one patient exhibited priapism. Of the 31 patients, 28 survived without sickle cell disease, with Lansky/Karnofsky scores of 100. All surviving patients remained free of any SCA-related events after transplantation. Conclusion: The protocols used for the preparation to the transplant in thalassaemia are very effective also in the other severe haemoglobinopathy as in the sickle cell anaemia with 90% disease free survival. Today, if a SCA patient has a HLA identical family member, the cellular gene therapy through the transplantation of the allogeneic haemopoietic cell should be performed. Tomorrow, hopefully, the autologous genetically corrected stem cell will break down the wall of the immunological incompatibility.