Search

When prepared for transplantation with busulfan (BU) 14 mg/kg and cyclophosphamide (CY) 120 to 160 mg/kg, patients with thalassemia in risk class 3, aged younger than 17 years, who receive transplants from HLA-identical donors, had a 30% incidence of transplant rejection with recurrence of thalassemia. This, relatively poor, outcome was ascribed to insufficient immune suppression or to inadequate eradication of the thalassemic marrow, or both. In an attempt to enhance both immune suppression and eradication of the thalassemic clones, hydroxyurea, azathioprine, and fludarabine were added to the BU and CY. This regimen, called protocol 26, was applied to 33 consecutive patients with class 3 thalassemia aged younger than 17 years and was well tolerated with 93% survival. The incidence of recurrent thalassemia after the transplantation decreased from 30% to 8%.

Acute myeloid leukemia (AML) patients with core binding factor abnormalities [inv(16) or t(8;21)] have a relatively good prognosis, especially patients with inv(16) when treated with high-dose cytosine arabinoside (AraC) containing regimens, whereas in the case of t(8;21) evidences in favor of such regimen are contrasting. We previously demonstrated that blast cells from inv(16)-positive AML patients are characterized by an increased sensitivity to AraC with higher incorporation of 3H AraC into DNA and the increase of induced apoptosis in vitro. In the present study we tested the sensitivity of leukemic cells from 15 t(8;21)-positive AML patients to AraC and compared it with the results obtained from cells of 74 patients with inv(16), "intermediate" or "unfavourable" karyotype at diagnosis (for a total of 89 patients). The incorporation of 3H AraC into DNA in cells with t(8;21) was significantly lower than in cells with inv(16) (P = 0.02) or normal karyotype (P = 0.04). Interestingly, the incorporation of the drug into DNA in t(8;21) cells was similar to those with "unfavourable" karyotype. Furthermore, AraC induced apoptosis in t(8;21)-positive AML cells was not increased. These data suggest that the mechanism of response to chemotherapy for t(8;21)-positive cells is probably different then in AML cells with inv(16), underlining the possible importance for patients carrying the t(8;21) of repeated high-dose regimens and not necessarily of high-dose AraC based ones.

Chronic graft-versus-host disease (cGvHD) continues to be the major problem in long-term survivors of allogeneic haematopoietic stem cell transplants and is the principal cause of morbidity and non-relapse mortality. Over the past twenty years, diagnosis, prophylaxis and treatment of cGvHD have slowly evolved. An effective therapy for cGvHD is designed to prevent complications through targeting the disease mechanisms. None of the present therapies for cGvHD are successful in the majority of patients. Conventional drugs in different combinations can control the disease in approximately 50% of patients. Attempts to improve survival have led to evaluation of several alternative approaches in the treatment of refractory cGvHD with varying degrees of success. Clinical trials are needed to establish the role of these new approaches in the treatment of cGvHD as first line or salvage therapy without causing significant side effects. This review summarises the currently available knowledge on conventional and new treatment approaches for cGvHD.

Early trials of allogenic bone marrow transplantation (BMT) for homozygous beta 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 14 mg/kg, cyclophosphamide 200 mg/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.

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) micrograms/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."

No experience has been reported to date in treating chronic hepatitis C virus (HCV) infection with interferon (IFN) therapy after BMT, mainly due to concerns related to the impact of an immunomodulatory drug in patients who are immunologic and haematologic chimeras. However, chronic inflammatory activity related to HCV infection results in a chronic fibrogenous mechanism potentially leading to liver cirrhosis and hepatocellular carcinoma. Moreover, patients transplanted for beta-thalassemia could be at greater risk because of concomitant iron overload and pre-existing fibrous liver damage. Eleven patients with serological, biochemical, histological and molecular biological evidence of HCV infection were included in the study and treated for 6-12 months with recombinant IFN 24-65 months following BMT. The serum alanine aminotransferase (ALT) was persistently elevated (range 85-1242 U/l; mean 416) for at least 1 year prior to IFN treatment. Ten patients completed the protocol; five were considered as responders to treatment. In these five patients the liver histology showed an overall reduction of inflammation and necrosis: histological inflammatory activity improved from chronic active hepatitis (CAH) to chronic persistent hepatitis (three patients) or minimal residual inflammatory activity (two patients). The Knodell total activity score varied from 5.4 (range 3-9) to 1.4 (range 1-2; P = 0.05). All responding patients revealed negativization of serum HCV-RNA, that has been persistent in four (follow-up 1-3 years). ALT level fell to 15-80 U/l (mean 52; P = 0.0027). No major complications occurred during the therapy and no influence on marrow engraftment parameters were noted. We conclude that IFN therapy does not adversely interfere with engraftment and that it is a feasible therapy for treatment of chronic hepatitis C virus after BMT.

In thalassemia after successful bone marrow transplantation (BMT), iron overload remains an important cause of morbidity. 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. A phlebotomy program (6 mL/kg blood withdrawal at 14-day intervals) was proposed to 48 patients with prolonged follow-up (range, 2 to 7 years) after BMT. Seven patients were not submitted to the program (five because of refusal and two because of reversible side effects). The remaining 41 patients (mean age, 16 +/- 2.9 years) were treated for a mean period of 35 +/- 18 months. All were evaluated before and after 3 +/- 0.6 years of follow-up. Values are expressed as mean +/- standard deviation (SD) or as median with a range (25 to 75 percentile). Serum ferritin decreased from 2,587 (2,129 to 4,817) to 417 (210 to 982) microg/L (P < .0001), total transferrin increased from 2.34 +/- 0.37 to 2.7 +/- 0.58 g/L (P = .0001), transferrin saturation decreased from 90% +/- 14% to 50% +/- 29% (P < .0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5 to 28.1) to 4.2 (1.6 to 14.6) mg/g dry weight (P < .0001). Aspartate transaminase decreased from 2.7 +/- 2 to 1.1 +/- 0.6 (P < .0001) and alanine transaminase from 5.2 +/- 3.4 to 1.7 +/- 1.2 (P < .0001) times the upper level of normality. The Knodell score for liver histological activity decreased from 6.9 +/- 3 to 4.9 +/- 2.8 (P < .0001). These data indicate that phlebotomy is safe, efficient, and widely applicable to ex-thalassemics after BMT.

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.

Cyclosporin A (CsA) has been shown to be useful in the prophylaxis of acute graft-versus-host-disease (GVHD). However, this immunosuppressive agent produces multiple side-effects including nephrotoxicity, hypertension, hypertricosis, gum hyperplasia, infections, and neurotoxicity. We report a retrospective analysis of neurotoxicity in 625 recipients transplanted for thalassemia and given CsA as part of GVHD prophylaxis. Neurotoxicity consisted in mental status changes, tremor, headache (grade 1), visual disturbance and cortical blindness (grade 2) and seizures and coma (grade 3). The overall toxicity was 28.8% and the incidence of convulsions was 10.1%. Neurological findings were reversible after temporary reduction or discontinuation of CsA. Class 3 patients, when prepared with protocol 6 (Bu 14 + Cy 200 and CsA for GVHD) or when they developed acute GVHD, had the highest risk of convulsions. Age, sex, different conditioning regimens, different anticonvulsive prophylaxis, liver damage due to iron-overload and/or to chronic inflammation did not influence the occurrence of CsA-related CNS toxicity. The occurrence of acute GVHD with concomitant use of high-dose corticosteroids is the single significant predisposing factor in the occurrence of convulsions. Grades 1 and 2 of neurotoxicity occurred earlier and were not influenced even by acute GVHD.

We report four cases of mucormycosis that occurred among 711 patients who underwent BMT for thalassemia, and review 18 additional cases among BMT recipients that were reported in the English-language literature. All these patients were polytransfused and were in advanced phase of disease with severe acquired hemochromatosis. The sites of infection were sinonasal, rhinocerebral-pulmonary, pulmonary and pulmonary-central nervous system. Mucormycosis was the primary cause of death in three of four patients. Two infections were detected within the first 100 days after BMT. Only one of the four patients had partial resolution of sinonasal mucormycosis following aggressive antifungal therapy combined with hyperbaric oxygen treatment.

Background: Thalassemia patients with heavy iron overload risk further increase of body iron stores after bone marrow transplantation (BMT) due to intensive red-cell transfusions in the post BMT course and to massive mobilization of iron deposits from marrow cells following the conditioning regimen. Nevertheless, iron chelation has not yet been used during the transplant period, mainly for concerns related to the toxicity and antiproliferative properties of the drug., Methods: Fifteen thalassemic patients received desferrioxamine (DFO) before and during BMT according to two different schedules (first: from day -9 to day +60, and second: from day -9 to day -2, then from day +28 to day +60) at a dose of 40 mg/kg/day as a 24-hour intravenous infusion., Results: The median time to neutrophil, platelet and erythrocyte recovery showed no difference between DFO-treated patients and the control group (18 days vs. 15, 16 vs. 18 and 22 vs. 23, respectively; p: N.S.). The incidence of acute GVHD was 23% in the DFO group and 13% in controls (p: N.S.). The median serum ferritin (SF) at 6 months after BMT was significantly lower in the DFO-treated patients (2081 versus 4187; p: 0.007) than in the control group. This difference continued to be evident, though not statistically significant, during longer follow-up., Conclusions: Intravenous DFO therapy during BMT does not seem to have affected the engraftment parameters or the incidence of infections or GVHD. No adverse effects were observed during the therapy. Therefore thalassemic patients with heavy iron overload can be candidates for a course of i.v. chelation during the transplant period. This therapy could also be followed by post-BMT iron removal (i.e. phlebotomies or desferrioxamine) to accelerate the clearance of body iron deposits.

Thirty-four patients with chronic myelogenous leukemia in chronic phase were treated with busulfan 16 mg/kg and cyclophosphamide 120 or 200 mg/kg before allogeneic bone marrow transplantation from an HLA-identical sibling. Cyclosporine, methotrexate and prednisone were used for graft-versus-host disease (GVHD) prophylaxis. The actuarial probabilities of survival and relapse-free survival at 82 months were 71%. With a maximum follow-up of 2471 days, none of the patient experienced hematologic or clinical relapse. In one patient reappearance of host cells was documented 180 days post-transplant which disappeared 277 days post-transplant and the patient is in complete hematological and cytogenetic remission 5 years after the transplant. The probability of transplant-related mortality was 29% while the probability of moderate to severe acute graft-versus-host disease was 38%. This study indicates that busulfan and cyclophosphamide are a good conditioning regimen for marrow transplantation in patients with chronic myeloid leukemia in chronic phase.