New approach to bone marrow transplantation in thalassemia.
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Biomedical subjects
Publications and source records attributed to M Galimberti.
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The authors report their experience on allogeneic bone marrow transplant in an HIV seropositive thalassemic child. Before transplant a treatment with Azidothymidine was performed with the aim of reducing the viral load. Engraftment took place but, later, an explosive upsurge of viral disease occurred with encephalitis, positivation of the P24 antigen, proliferation of opportunistic infections and an increase of the IgG level. Furthermore the failure of CD4+ cell recovery was also observed. This case underlines that bone marrow transplantation can have a successful engraftment in HIV seropositive patients, but this doesn't modify the course of the infection.
Cardiac and vascular toxicity of recombinant interleukin-2 (rIL-2) was evaluated by in vitro and in vivo experiments in rats. Using isolated spontaneously beating atria, no changes were detected in heart rate or myocardial contractility in response to rIL-2 treatment at concentrations ranging from 0.1-100 U/ml. Daily sc administration of rIL-2 for 7 consecutive days (at doses of 2.3 X 10(4) to 1.15 X 10(6) U/ml) produced a prolongation of the QaT interval and significant modifications in serum electrolyte concentrations. Ex vivo contractility of atria excised at the end of rIL-2 treatment showed no deterioration in myocardial contractility with increasing dosage. rIL-2, at concentrations of 0.1-1000 U/ml, did not induce any modification of perfusion pressure in isolated rat tail artery but produced a significant displacement to the left of the dose-response curves for norepinephrine compared to basal conditions. The relative potencies were not dose-dependent. Our results indicate that rIL-2 does not exert a direct cardiotoxic effect, and suggest an indirect action on vascular smooth muscle, i.e., an aspecific modulation of vascular response to mediators.
Ten patients treated with combination chemotherapy regimen containing Cisplatin, Bleomycin and Etoposide (PEB) were submitted to Holter monitoring during the first cycle of treatment. No modifications of heart rate, ST-T segment were observed and only a slight increase of incidence of sopraventricular ectopic beats was recorded. One patient developed a transient second degree atrio-ventricular block in the first day during episodes of vomiting. These data suggest that combination chemotherapy with PEB, at least during the first cycle of treatment, has no significant arrhythmogenic effect.
Thirty patients with malignant hematological disease underwent allogeneic bone marrow transplantation following Busulphan (Bu) and Cyclophosphamide (Cy). The diseases were chronic myelogenous leukemia, acute lymphoblastic and non lymphoblastic leukemia, myelofibrosis and multiple myeloma in complete remission and in relapse. A sustained disease-free survival (DFS) was achieved in 0/5 acute leukemia patients transplanted in relapse, in 5/7 acute leukemia patients transplanted in remission (600-1550 days) and in 6/9 CML patients transplanted in the chronic phase of the disease (500-950 days). A sustained DFS was also achieved in one 2nd BMT for relapsed CML. The data suggest that the Bu-Cy protocol combines high tumor ablative capability with toxicity comparable to previously described conditioning regimens for allogeneic BMT, particularly in diseases involving a great expansion of the bone marrow.
Thirty children aged one to 15 years with acute lymphoblastic leukemia and acute nonlymphoblastic leukemia were transplanted from HLA matched donors using two different preparative regimens: 18 patients were prepared with cyclophosphamide and Total Body Irradiation while 12 patients received Busulphan and Cyclophosphamide. 15 patients survive 7 to 74 months after transplant. Although for the second group of patients a longer follow-up is needed in order to evaluate eradication of the disease and long-term toxicity, the combination chemotherapy alone results in improving survival (71% versus 28%) and decreasing relapse rate (30% versus 56%) compared with the group of patients who received the chemoradiotherapy regimen. Also the incidence of Interstitial Pneumonia has been lower in the group receiving chemotherapy alone. We conclude that this protocol is generally well tolerated in young patients, without increasing secondary toxicity.
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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.
Thalassemia major is a progressive disease. Modern therapy with transfusions and iron chelation has greatly improved both the quality and length of thalassemics life. Nevertheless, progressive overload of iron in the organs, hepatitis and other infections acquired randomly imply the risk of mortality that increases with age. Bone marrow transplant from an HLA identical donor (a possibility for about 45%) represents the only form of radical cure of the disease. With the classification of the classes of risk we know today that a thalassemic child has a chance to die from transplant 3 to 100 with probability of being cured 94%. Thalassemics that receive the transplant at a more advanced stage of complications of the disease have a major risk of death due to the transplant of class 2 (14% probability of death due to the transplant against 83% chance of being cured). Class 43 patients have 9 chances out of 100 to die of transplant and 60% probability of being cured of thalassemia.
BACKGROUND: Since juvenile chronic myeloid leukemia (JCML) represents no more than 2% of leukemia in children, clinical and investigative experience of this disorder has been limited. In order to evaluate the diagnostic criteria currently applied, to provide centralized facilities for blood culture and to collect data on treatment, and to propose a uniform treatment protocol in our country, a National Registry for JCML was recently established in the "Associazione Italiana di Ematologia Oncologia Pediatrica" (AIEOP). PATIENTS: Out of the 24 cases reported from 9/35 centres, 22 were considered sufficiently documented and were enrolled in the Registry. Clonogenic assay on marrow and peripheral blood cells was performed in all available cases. RESULTS: Common features were non-specific clinical (fever, splenomegaly, hepatomegaly, lymphadenomegaly) and hematologic alterations (anemia, thrombocytopenia, leukocytosis usually < 50 x 10(9)/l, monocytosis, circulating immature granulocytes, increased HbF, normal karyotype). In 11 out of 11 cases, in vitro blood cultures showed the spontaneous growth of CFU-C in the absence of any exogenous source of colony-stimulating activity. Twelve of the 22 patients (55%) are alive (probability of survival 47.7%); most patients were treated according to an acute myeloid leukemia-directed schedule; 5/7 children treated with interferon were alive with disease after a median time of 29 months from diagnosis (range 8-95 months); 4/5 children who underwent bone marrow transplantation were alive in complete remission 10, 24, 42 and 118 months, after the diagnosis. Age < 1 year at presentation was the most significant prognostic factor in terms of probability of survival (80% vs 28%; p = 0.0024). CONCLUSIONS: JCML must be considered in young children for whom acute leukemia has been suspected but ruled out; in vitro cultures should be considered mandatory to confirm the diagnosis. Age less than one year at the presentation was associated with prolonged survival. Only bone marrow transplantation was followed by prolonged disease-free survival, whereas intensive chemotherapy seemed not very effective and potentially associated with life-threatening complications. Interferon therapy appears to be a promising alternative to chemotherapy while the value of unrelated marrow donor is explored.