Emanuele Angelucci

Abstract: BACKGROUND: Transfusion-dependency affects the natural history of myelodysplastic syndromes. Secondary iron overload may concur to this effect. The relative impact of these factors on the outcome of patients with myelodysplastic syndrome receiving allogeneic stem-cell transplantation remains to be clarified. DESIGN AND METHODS: We retrospectively evaluated the prognostic effect of transfusion history and iron overload on the post-transplantation outcome of 357 patients with myelodysplastic syndrome reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry between 1997 and 2007. RESULTS: Transfusion-dependency was independently associated with reduced overall survival (hazard ratio=1.48, P=0.017) and increased non-relapse mortality (hazard ratio=1.68, P=0.024). The impact of transfusion-dependency was noted only in patients receiving myeloablative conditioning (overall survival: hazard ratio=1.76, P=0.003; non-relapse mortality: hazard ratio=1.70, P=0.02). There was an inverse relationship between transfusion burden and overall survival after transplantation (P=0.022); the outcome was significantly worse in subjects receiving more than 20 red cell units. In multivariate analysis, transfusion-dependency was found to be a risk factor for acute graft-versus-host disease (P=0.04). Among transfusion-dependent patients undergoing myeloablative allogeneic stem cell transplantation, pre-transplantation serum ferritin level had a significant effect on overall survival (P=0.01) and non-relapse mortality (P=0.03). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload. CONCLUSIONS: Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome.

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Abstract: Previous observational studies suggest that rituximab may be useful in the treatment of primary immune thrombocytopenia (ITP). This randomized trial investigated rituximab efficacy in previously untreated adult ITP patients with a platelet count of 20 x 10(9)/L or less. One hundred three patients were randomly assigned to receive 40 mg/d dexamethasone for 4 days with or without 375 mg/m(2) rituximab weekly for 4 weeks. Patients who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab. Sustained response (ie, platelet count > or = 50 x 10(9)/L at month 6 after treatment initiation), evaluable in 101 patients, was greater in patients treated with dexamethasone plus rituximab (n = 49) than in those treated with dexamethasone alone (n = 52; 63% vs 36%, P = .004, 95% confidence interval [95% CI], 0.079-0.455). Patients in the experimental arm showed increased incidences of grade 3 to 4 adverse events (10% vs 2%, P = .082, 95% CI, -0.010 to 0.175), but incidences of serious adverse events were similar in both arms (6% vs 2%, P = .284, 95% CI, -0.035 to 0.119). Dexamethasone plus rituximab was an effective salvage therapy in 56% of patients refractory to dexamethasone. The combination of dexamethasone and rituximab improved platelet counts compared with dexamethasone alone. Thus, combination therapy may represent an effective treatment option before splenectomy. This study is registered at http://clinicaltrials.gov as NCT00770562.

Abstract: Since 2002, date of publication of the previous Italian Society of Haematology (SIE) practice guidelines for management of myelodysplastic syndromes (MDS), novel disease-modifying treatments have been introduced and the SIE commissioned an update. After a comprehensive review of the medical literature published since January 2001, the Expert Panel formulated recommendations for the management of adult and paediatric MDS, graded according to the available evidence. The major updates are: first-line hypomethylating agents in patients with INT2-high-risk disease; controlled use of first-line lenalidomide in low-INT1 risk transfusion-dependent patients with 5q deletion; deferasirox in low-INT1 patients with a relevant transfusional load; first-line high-dose ESA in low-INT1 patients with Hb <10g/dl and endogenous EPO <500U/l; allogeneic HSCT first-line therapy for INT2- and high-risk patients <65 years without severe co morbidities.

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Abstract: Recently, management of limited stage diffuse large cell lymphoma (DLCL) is trending toward a low intensity chemotherapy approach. Since 1993 we have used a brief weekly (6 weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine, and Prednisone = ACOP-B) followed by involved field radiotherapy in 207 consecutive patients with well defined localized DLCL without age limit (median 57 years, range 18-85). Treatment was completed as designed in 183 of 207 patients (88%). One hundred and ninety-nine patients (96%) achieved complete remission. At a median follow-up of 66 months 170 patients are alive (82%), 168 of them free of disease. Twenty-nine patients experienced relapse after achieving a complete remission. Kaplan-Meier, risk of relapse was 24% after 13 years. Thirty (14.5%) patients have died, 14 (6.8%) due to lymphoma progression, one due to regimen toxicity and 15 (7.2%) from other causes while remaining in complete remission. The probability of overall survival and event free survival at 13 years was 78% (95% CI 70-87%) and 63% (95% CI 50-75), respectively. Crude rate of secondary malignancy was 5.26 /1000 person-years. The ACOP-B regimen plus involved field radiotherapy is well tolerated both short and long term and is an effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of the haemopoietic stem cells for which the only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to assess the long-term clinical and haematological results in 26 PNH patients who received HSCT in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median, 32 years). Twenty-three donors were HLA-identical (22 siblings and 1 unrelated) and 3 were HLA-mismatched (2 related and 1 unrelated). Fifteen patients received a myeloablative conditioning (MA) consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced-intensity conditioning (RIC) (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following MA or RIC respectively). As of October 31, 2009, 15 patients (11 in the MA group and 4 in the RIC group) are alive with complete haematological recovery and no evidence of PNH following a median follow-up of 131 months (range, 30 to 240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients, 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with MA. No thromboembolic event nor recurrence of PNH were reported following transplant. Our results confirm that most patients with PNH may be definitively cured with HSCT.

Abstract: PURPOSE: Epigenetic changes play a role and cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). We conducted a phase II multicenter study on the combination of the DNA-methyltransferase inhibitor 5-azacytidine (5-AZA) and the histone deacetylase inhibitor valproic acid (VPA) in patients with higher risk MDS. EXPERIMENTAL DESIGN: We enrolled 62 patients with MDS (refractory anemia with excess blasts, 39 patients; refractory anemia with excess blasts in transformation, 19 patients; and chronic myelomanocytic leukemia (CMML), 4 patients) and an International Prognostic Scoring System (IPSS) rating of Intermediate-2 (42 patients) or high (20 patients). VPA was given to reach a plasma concentration of >50 microg/mL, then 5-AZA was added s.c. at 75 mg/m(2) for 7 days in eight monthly cycles. RESULTS: The median overall survival was 14.4 months. At a median follow-up of 12 months (range, 0.7-21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed eight cycles, 30.7% obtained complete or partial remission, 15.4% had a major hematologic improvement, whereas 38.5% showed stable disease. Drug-related toxicity was mild. Favorable prognostic factors for survival were IPSS Intermediate-2 and plasma VPA of > or =50 microg/mL (log rank = 0.013 and 0.007, respectively). Analysis of polymorphisms important for the metabolism of the drugs used in the trial showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher VPA doses to achieve the target VPA plasma concentration of 50 microg/mL on day 1 of 5-AZA treatment (P = 0.0021). CONCLUSION: Our data show that the 5-AZA/VPA combination is active and safe in patients with MDS with a poor prognosis. Achievement of VPA therapeutic levels may indeed increase 5-AZA efficacy.

Abstract: BACKGROUND: We investigated the addition of rituximab to dose-dense and high-dose chemotherapy with autologous stem cell transplantation in patients with untreated poor-prognosis diffuse large B-cell lymphoma. DESIGN AND METHODS: Ninety-four young patients (age, 18-60) with stage III-IV diffuse large B-cell lymphoma at intermediate/high or high risk according to the age-adjusted International Prognostic Index were enrolled into a phase II trial. The treatment was as follows: four courses of bi-weekly rituximab-cyclophosphamide-epirubicin-vincristine-prednisone (R-MegaCEOP14), two courses of rituximab-mitoxantrone-cytarabine-dexamethasone (R-MAD) and carmustine-etoposide-cytarabine-melphalan (BEAM) with autologous stem cell transplantation. RESULTS: The complete response and toxic death rates were 82% and 5%, respectively. Failure-free survival and overall survival rates at 4 years were 73% and 80%, respectively. The outcomes of these patients were retrospectively compared to those of 41 patients with similar characteristics enrolled into a previous phase II trial of high-dose chemotherapy without rituximab. This historical group was treated with eight weekly infusions of methotrexate-doxorubicin-cyclophosphamide-vincristine-prednisone-bleomycin (MACOP-B), two courses of MAD and BEAM with autologous stem cell transplantation. The 4-year failure-free survival rates for the rituximab and historical groups were 73% versus 44%, respectively (p=0.001); the 4-year overall survival rates were 80% and 54%, respectively (p=0.002). A Cox's multivariable model was applied to adjust the effect of treatment for unbalanced or important prognostic factors: failure and death risks were significantly reduced in the rituximab group compared to the historical group, with an adjusted hazard ratio of 0.44 (p=0.01) for failure-free survival and 0.46 (p=0.02) for overall survival. CONCLUSIONS: These results suggest that the addition of rituximab to high-dose chemotherapy is effective and safe in diffuse large B-cell lymphoma with a poor-prognosis and such regimens need to be compared to dose-dense chemoimmunotherapy without autologous stem cell transplantation in randomized trials.

Abstract: New measures of iron accumulation in liver and heart (superconducting quantum inference device and magnetic resonance imaging), and oral iron chelators (deferiprone and deferasirox) are available for managing iron overload in thalassemia major. To assure appropriate use of these new health technologies, the Italian Society of Hematology appointed a panel of experts to produce clinical practice-guidelines for the management of iron overload in thalassemia major and related disorders. The analytical hierarchy process, a technique for multicriteria decision analysis, was applied to relevant key questions in order to identify the alternative strategies, generate explicit criteria for their evaluation, and check how well the alternatives fulfilled the criteria. The result of a comprehensive systematic review of articles released from 1990 to 2007 was used as a source of scientific evidence to compare the decisional options pairwise, and select the final recommendation. Every step in the model was developed from questionnaires and group discussion. The resulting recommendations advise about which examination to carry out in order to plan iron chelation therapy, when to start iron chelation, which iron chelator to choose in regularly transfused patients, how to monitor iron chelation therapy, and when and how to switch standard therapy.

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Abstract: Common polymorphisms in genes encoding for cytokines implicated in the inflammatory response and Th1/Th2 balance might play a role in the development and prognosis of chronic lymphocytic leukaemia (CLL). To test the hypothesis, we investigated 13 single nucleotide polymorphisms (SNPs) in nine of such genes in a population-based case-control study, conducted in the Italian region of Sardinia in 1999-2003. Forty incident CLL cases and 113 population controls were available for study. The following SNPs were selected: IL1A-889C > T, IL1RN 9589A > T, IL1B-31C > T, IL1B-511C > T, IL2-384T > G, IL6-174G > C, IL6-597G > A, IL10-1082A > G, IL10-3575T > A, TNF-308G > A, LTA- 91A > C, LTA 252A > G and CARD15 nt1007. After adjusting by age and gender, individuals homozygous for the IL1B-511T allele run a lower risk of CLL (OR = 0.1, 95% CI 0.0, 0.8, p = 0.032), while risk showed a 4.5-fold increase associated with the genotype homozygous for the IL6-174C allele (OR = 4.5; 95% CI 1.1, 19.3, p = 0.041). Individuals homozygous for the IL6-174C allele and carrying the homozygous IL1B-511C allele showed an 11-fold increase in CLL risk (OR = 11.4, 95% CI 1.9, 69.4, p = 0.008). None of the other interleukin SNPs evaluated showed any association with CLL risk. Large multicentre pooled studies are warranted, achieving the statistical power required to confirm whether IL6 and IL1B gene polymorphisms might play a role in CLL development and prognosis, as well as the null associations herein reported.

Abstract: Thalassemia associates anemia and iron overload, two opposite stimuli regulating hepcidin gene expression. We characterized hepatic hepcidin expression in 10 thalassemia major and 13 thalassemia intermedia patients. Hepcidin mRNA levels were decreased in the thalassemia intermedia group which presented both lower hemoglobin and higher plasma soluble transferrin receptor levels. There was no relationship between hepcidin mRNA levels and those of genes controlling iron metabolism, including HFE, hemojuvelin, transferrin receptor-2 and ferroportin. These results underline the role of erythropoietic activity on hepcidin decrease in thalassemic patients and suggest that mRNA modulations of other studied genes do not have a significant impact.

Abstract: We investigated lymphoma risk following hepatitis infection in a case-control study of 274 incident lymphoma cases, defined according to the WHO classification, and 336 population controls in Sardinia, Italy. Part of our study population (198 cases and 219 controls) was included in the EPILYMPH study of Hepatitis C virus (HCV) infection in relation to non-Hodgklin's lymphoma risk. Based on questionnaire information on whether and at what age a diagnosis of hepatitis was posed by a physician, systematic anti-HCV antibodies testing in cases and controls by enzyme-linked immunoassay, and HCV-RNA assessment by PCR analyses in positive samples, we investigated more in detail whether hepatitis non-C is also associated with lymphoma risk, and whether risk varies by clinical form of hepatitis (acute or chronic infection). After adjusting by age, gender, education, and area of birth whether from the study area or elsewhere in Italy, a previous generic diagnosis of hepatitis was associated with a significantly elevated lymphoma risk [odds ratio (OR) = 1.8; 95% CI 1.1, 2.8], which was equally increased for hepatitis B (OR = 1.8; 95% CI 0.9, 3.5), for HCV positive subjects overall (OR = 2.0; 95% CI 0.8, 4.8), and for hepatitis non-B non-C (OR = 1.6; 95% CI 0.7, 3.9). Once concurrent infection from other hepatitis viruses was excluded, acute or chronic hepatitis C was the only one showing a consistent risk increase in all lymphoma subtypes, but follicular lymphoma. Some indications of an excess risk of lymphoma were observed also for acute, but not chronic forms of hepatitis B and hepatitis non-B, non C. Self-limited hepatitis C did not show an association. No significant heterogeneity in the risk of major lymphoma subtype was observed. Our results confirm a role of either acute or chronic active HCV infection in lymphomagenesis. Further studies are warranted to test the hypothesis that acute infection from other hepatitis viruses might also increase lymphoma risk.

Abstract: BACKGROUND: In 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. PATIENTS AND METHODS: Patients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). RESULTS: Ninety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT) + RT] were 93% and 92% for ABVD and EVE arms, respectively (P = NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P < 0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P < 0.05). No differences in terms of overall survival (OS) were observed for the two study arms. CONCLUSIONS: In unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as initial treatment for HL.

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Abstract: In recent years, new conditioning regimens have been explored in patients not eligible for conventional transplant with the aim to reduce transplant-related mortality. In a phase II multicentric prospective trial, we investigated the safety and feasibility of the treosulfan-fludarabine combination prior to allogeneic hematopoietic stem cell transplant in patients with various hematological malignancies not eligible for conventional regimens because of previous intensive treatment, older age, and comorbidities. Forty-six consecutive patients, median age 48 years (range 17-69), were enrolled. Sixteen of them were in complete remission, and 20 had a HSCT comorbidity index > or = 1. Forty-four patients had regular and sustained engraftment, and 39 out of 40 evaluable patients developed complete chimerism. Nonhematological toxicity was limited. Risk of transplant-related mortality was 9% (95% CI, 2-17%) at day +100 and plotted at 15% (95% CI, 7-22%) after 7 months. The estimated overall survival and progression-free survival with a median follow-up of 20 months were 51% and 38%, respectively. The estimated 30 months progression-free survival for patients transplanted in remission was 56%. The treosulfan-fludarabine combination is a reduced-toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional transplant regimens. Longer follow-up and further prospective studies are necessary to evaluate this regimen.

Abstract: Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value </=6.3 ms). Only patients with severe hepatic iron overload (T2* <1.4 ms) showed cardiac T2* value indicative of dangerous myocardial iron deposition. Serum ferritin was not significantly correlated with cardiac T2* (p=0.24). Gradient echo T2* magnetic resonance imaging provides a rapid and reproducible method for detecting myocardial iron overload which developed after a heavy transfusion burden equal to or greater than 290 mL/kg of packed red blood cell units.

Abstract: This paper describes the trends in haematopoietic stem cell transplantation (HSCT) activity for children in Europe over the last three decades. We analysed 31,713 consecutive paediatric HSCTs reported by the European Group for Blood and Marrow Transplantation (EBMT) centres between 1970 and 2002. Data were taken from the EBMT registry and were compared according to period and centre category (paediatric or combined). Since 1996, there has been a significant increase in the number of HSCTs performed exclusively by paediatric centres, as well as in the number of alternative donor HSCTs, and in the use of peripheral blood stem cells (P<0.0001). The number of allogeneic HSCTs (allo-HSCTs) for acute lymphoblastic leukaemia, acute myeloblastic leukaemia and chronic myeloid leukaemia remained stable, whereas it increased for myelodysplastic syndromes and lymphomas, and decreased significantly for non-malignant diseases (P<0.0001). Multivariate analysis showed that younger age, human leukocyte antigen genoidentical donors, HSCT performed after 1996 and transplant centres performing more than 10 allo-HSCT/year were all associated with decreased transplant-related mortality (TRM) (P<0.0001). The number of autologus HSCTs (auto-HSCTs) for acute leukaemia decreased significantly, whereas it increased for solid tumours (P<0.0001). Multivariate analysis showed that both auto-HSCT performed before 1996 and paediatric solid tumours (P<0.0001) had higher TRM. Indications for paediatric HSCT have changed considerably during the last seven years. These changes provide tools for decision making in health-care planning and counselling.

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Abstract: The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and referred mainly to the pre-antivirals era. Today a rational approach to the problem of hepatitis B in these patients provides for: (a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), (b) the treatment with antivirals (therapy) of active carriers, (c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, (d) the biochemical and hepatitis B surface antigen (HBsAg) monitoring (or universal prophylaxis, in case of high risk immunosuppression) in subjects with markers of previous contact with HBV (HBsAg negative and anti-HBc positive), in order to prevent reverse seroconversion. Moreover it is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and in HBsAg negative recipients of anti-HBc positive grafts.

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Abstract: Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not receive chelation therapy due to short-life expectancy and the difficulties associated with the administration of the current reference standard chelator, deferoxamine. There have, however, been some reports of reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion requirement, ultimately resulting in long-lasting transfusion-free survival.

Abstract: BACKGROUND AND OBJECTIVES: The molecular analysis of minimal residual disease (MRD) may provide information on the risk of recurrence in patients with acute lymphoblastic leukemia (ALL). The aim of this study was to correlate the kinetics of MRD clearance after allogeneic transplantation with the clinical outcome of adults with ALL. DESIGN AND METHODS: MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) using probes derived from fusion chimeric genes (BCR/ABL and MLL/AF4) (n=22) or rearrangements of the T-cell receptor or immunoglobulin genes (n=21). Forty-three adult patients with ALL were studied to correlate the kinetics of MRD clearance before and after allogeneic hematopoietic stem cell transplantation. RESULTS: At 36 months, the overall survival of patients who underwent transplantation in hematologic remission (n= 37) was 80% for those who were PCR-negative before transplantation (n= 12) compared to 49% for PCR-positive patients (n= 25)(p=0.17). For the same patients the cumulative incidence of relapse was 0% and 46%, respectively (p=0.027). Moreover, the relapse rate of patients who were PCR-negative at day +100 after transplantation was remarkably low (7%) compared to that among patients who were PCR-positive (80%, p=0.0006). INTERPRETATION AND CONCLUSIONS: The kinetics of MRD clearance may help to identify patients at high risk of leukemia relapse after allogeneic stem cell transplantation. Patients not achieving an early molecular remission after transplantation require prompt and appropriate pre-emptive treatments such as infusions of donor lymphocytes or new experimental drugs.

Abstract: AIMS AND BACKGROUND: Evidence linking the glucose-6-phosphate dehydrogenase (G6PD) polymorphism and risk of non-Hodgkin's lymphoma is conflicting. Risk of non-Hodgkin's lymphoma was increased in subjects expressing the G6PD deficient phenotype, whereas subjects under medication with statins, a lipid-lowering class of drugs partially mimicking G6PD deficiency, seemed to enjoy a protective effect. METHODS: We conducted a case-control study on lymphoma risk associated with the self-reported G6PD deficient phenotype in 122 lymphoma male cases and 116 male controls in Sardinia, Italy. The association with the GdMed+ genotype, the most frequent variant expressing a deficient enzyme activity, was also tested in 49 male lymphoma cases and 31 controls. The WHO classification was used to identify lymphoma subentities. RESULTS: Neither self-reported G6PD deficient phenotype nor the GdMed+ genotype showed an association with lymphoma risk or its subentities. CONCLUSIONS: Our results do not confirm an association either positive or negative between the G6PD polymorphism and lymphoma risk.

Abstract: Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

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Abstract: In addition to the severe beta thalassemias, hematologists have begun to recognize the more severe forms of alpha thalassemia, namely hemoglobin (Hb) H disease and Hb H/Hb Constant Spring, as well as the beta compound heterozygote, beta thalassemia/HbE. Clinically, variably severe anemia becomes apparent in the first year accompanied by occasionally massive expansion of erythropoiesis. The most anemic patients require regular red blood cell transfusions to avoid death from cardiac failure. However, the inevitable iron accumulation leads to dysfunction, primarily involving the heart, liver, and endocrine system; thus, regularly transfused patients require iron chelation. A major discovery was that allogeneic bone marrow (stem cell) transplantation in severely affected subjects with both alpha and beta thalassemia could result in cure. Current work deals with specific complications, such as iron overload and endocrine, cardiopulmonary, thrombophilic, and osteopenic problems. The thalassemias are likely to benefit in the future from specific gene therapy. There are also important advances in genetic counseling based on results of early fetal diagnosis.

Abstract: BACKGROUND: The aim of the study was to evaluate the outcome of acute myeloid leukaemia (AML) in patients with a previous malignancy (sAML) treated with chemo- and/or radiotherapy, enrolled in conventional trials. PATIENTS AND METHODS: In a multicentre setting, a prospective non-concurrent analysis was performed on 2513 new AML patients, aged 12-78 years, consecutively enrolled in EORTC-GIMEMA trials between 1987 and 2001. Thirty-eight patients with sAML were identified and compared with a group of 114 de novo AML patients matched according to age, French-American-British criteria, white blood cell count at diagnosis, trial and time of diagnosis of AML. Induction treatment response, disease-free survival (DFS), duration and overall survival (OS) were evaluated in the two groups. RESULTS: Comparing the complete remission (CR) rate between 38 sAML patients and 114 de novo AML patients, selected according to the previously reported criteria, we observed no difference in the CR rates [25/38 (66%) versus 66/114 (58%); Pearson chi(2) 0.7393, P=0.390] as well as no differences while comparing the DFS and the OS between the two groups. CONCLUSION: The results of this study suggest that sAML patients are characterised by a good performance status permitting their recruitment in conventional trials without a previous myelodysplastic phase. Similar to de novo AML patients, sAML patients show good response to treatment and the possibility of cure.

Abstract: BACKGROUND AND OBJECTIVES: Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). DESIGN AND METHODS: Between 1996 and 2001, 130 DLCL patients, aged < or = 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. RESULTS: The complete remission rate was 59% in arm A and 70% in arm B (p = 0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio = 1.15, 95% confidence intervals = 0.72-1.84, p = 0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio = 1.67, 95% confidence interval = 0.98-2.85, p = 0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. INTERPRETATION AND CONCLUSIONS: HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy.

Abstract: PURPOSE: In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). PATIENTS AND METHODS: Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. RESULTS: The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. CONCLUSION: When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

Abstract: 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%.

Abstract: Hereditary haemochromatosis is an autosomal recessive disorder of iron regulation that results in abnormal intestinal iron absorption with progressive iron overloading of parenchymal cells. Two specific, single point mutations of the HFE gene (C282Y and H63D) have been described in haemochromatosis patients. Epidemiological studies have revealed a strict association between hereditary haemochromatosis and C282Y homozygosis or C282Y/H63D compound heterozygosis, suggesting that these mutations may provide a useful tool for diagnosis. However, recent investigations from southern Europe have reported lower allelic frequencies of the C282Y mutation among haemochromatosis patients, apparently depending on the geographical area of the population analysed. To assess the predictive value of the detection of the C282Y and H63D HFE mutations in our geographical area, we have evaluated their occurrence in 46 haemochromatosis patients from southern Italy. We found that only 19.6% of our patients were homozygous for the C282Y mutation and 21.7% were compound C282Y/H63D heterozygotes. Among the remaining 59%, approximately 40% did not display any of the known HFE mutations. We conclude that, in southern Italy, another genetic determinant/s must be responsible for many haemochromatosis cases and that a genetic screening for the C282Y and H63D HFE mutations is not sufficient for hereditary haemochromatosis diagnosis.

Abstract: The breast is a rare localization of primary non-Hodgkin's lymphoma. We review our 15 years' experience in 11 patients with primary breast lymphoma. Based on our experience and on literature data we support a management scheme with CHOP or CHOP-like combination chemotherapy followed by involved field radiotherapy.

Abstract: BACKGROUND: In advanced age the prognosis of Hodgkin's lymphoma (HL) is poor, but, as a consequence of the low incidence of HL in the elderly, prospective studies are lacking and the best treatment strategy is difficult to define. PATIENTS AND METHODS: One-hundred and five HL patients over 65 years of age were treated homogeneously with an original reduced-intensity regimen designed for HL in the elderly containing vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone and bleomycin (VEPEMB). Forty-eight early stage (IA-IIA) patients received three courses of VEPEMB followed by involved field irradiation. Fifty-seven advanced stage (IIB-IV) patients received six courses followed by radiotherapy limited to the areas of bulky disease. RESULTS: Mean age was 71 years (range 66-83). Co-morbidities were present in 39 patients (37%). A treatment plan modification for poor tolerance or toxicity was needed in 18 patients. Results were satisfactory, even if they were better in early rather than in advanced stage disease: complete response rate 98% versus 58% (P <0.01); 5-year failure-free survival 79% versus 34% (P <0.01). The results were affected by advanced stage, systemic symptoms and co-morbidity but they were not influenced by age itself. CONCLUSIONS: VEPEMB is an effective and low toxic regimen for HL in the elderly. Co-morbidity is a prognostic factor more important than age itself.

Abstract: The anemia in beta-thalassemia major is caused by a combination of hemolysis and ineffective erythropoiesis, with the latter being more important. Studies of the underlying cause of the hemolysis have indicated that oxidant injury to circulating red blood cells (RBCs) was of critical importance, with evidence of oxidant damage to RBC membrane proteins 4.1 and band 3. Therefore, it seemed reasonable that oxidant damage to thalassemic erythroid precursors would cause their accelerated apoptosis and ineffective erythropoiesis. However, direct analysis showed that the apoptotic programs turned on in thalassemics were not those triggered by oxidative damage but were dependent on activation of FAS/FAS-Ligand interaction. Thus, destruction of thalassemic erythroid precursors may involve different mechanisms from those that cause RBC hemolysis.

Abstract: BACKGROUND: Cirrhosis is a well-known complication of thalassemia major. In this context, it is a consequence of iron overload and hepatitis C virus infection and generally seems to be irreversible. OBJECTIVE: To determine whether cirrhosis in thalassemia major can be reversible. DESIGN: Retrospective study. SETTING: Bone Marrow Transplantation Unit and Pathology Service, Pesaro Hospital, Pesaro, Italy. PATIENTS: 6 patients who developed liver cirrhosis before or after their thalassemia was cured by bone marrow transplantation (age at transplantation, 11 to 25 years). After diagnosis of cirrhosis, the patients received iron depletion and antiviral therapies. MEASUREMENTS: Each liver biopsy specimen was coded. A liver pathologist and a member of the transplantation center with expertise in hepatopathology graded the specimens by using the Ishak staging and grading systems. Neither knew the patient's identity or the sequence of biopsy with regard to the time of treatment. RESULTS: After the patients received iron depletion and antiviral therapies, liver biopsy specimens showed impressive reduction in liver iron stores. In 4 patients, iron removal was complete. Serum aminotransferase levels decreased in all patients and normalized in 5; histologic inflammatory activity decreased in all patients and disappeared in 2. Follow-up biopsies showed regression of incomplete or definite cirrhosis in all patients; 3 patients had presented with portal fibrosis without bridging, and the others had portal fibrosis and portal-to-portal bridging. Several biopsies and the presence of many portal spaces confirmed the diagnosis of cirrhosis; follow-up biopsies confirmed regression of cirrhosis. CONCLUSION: In some patients in whom bone marrow transplantation has cured thalassemia, cirrhosis may be reversible after iron removal treatment.

Abstract: From April 1981 to February 2000, 105 patients with chronic myeloid leukemia (CML) underwent BMT from HLA-identical related donors at a single center. Eighty-eight patients were in chronic phase (CP), 11 patients in accelerated phase and six patients in blast crisis. Ten of these patients received a second BMT (BMT2). Comparison of BMT in CP with chemotherapy and/or alpha-IFN (n=70) was also made. Patients were given cyclophosphamide (CY) and single-dose TBI (CYTBI, n=38) or busulfan (BU) and CY (BUCY, n=67). Overall 54 patients are alive and 52 of them are disease-free with a median follow-up of 11.3 (range 1.1-19.4) years. Ten-year disease-free survival (DFS) in CP patients was better after BUCY, 61% (95% CI, 47-68%) than after CYTBI, 41% (95% CI, 23-61%) (P=0.07). For 88 patients who received a transplant in CP, results were significantly improved when BMT was performed within 1 year after diagnosis (P=0.02) or at an age < or = 25 years old (P=0.01). Ten-year survival in patients who received BMT in CP was better than in patients treated with chemotherapy (56% vs 10%; P=0.0001) or alpha-IFN-based treatment (33%; P=0.09) with survival curves crossing at 4.2 years and at 4 years, respectively. The probability of DFS after BMT2 was 60% (95% CI, 26-87%). CP patients who received BMT after CYTBI had a higher probability of relapse and transplant-related mortality than patients receiving BUCY (53% and 58% vs 9% and 34%; P=0.002 and P=0.08, respectively). All but six patients are currently on no medication and have resumed all activities without any limitation. These long-term results confirm that allogeneic BMT is the only curative approach for CML patients and should be offered to all patients with a suitable donor as soon after diagnosis as possible.

Abstract: BACKGROUND AND OBJECTIVES: beta-thalassemia is an important public health problem in the countries bordering the Mediterranean sea. One of the major consequences of this disorder, primarily (due to an ineffective erythropoiesis) or secondarily to blood transfusions (which are necessary for the patient's survival), is iron storage. Applying X-ray microanalysis we wanted to demonstrate the different sites of iron storage in subcellular compartments (mitochondria, cytosol, nucleus, rough endoplasmic reticulum and lipid droplets) and whether there were any other trace elements stored in liver cell. DESIGN AND METHODS: X-ray microanalysis was performed (at 100 kV in the STEM mode of a Hitachi H7000) on thin sections from specimens of liver biopsies from 6 patients affected by b-thalassemia, during follow-up after bone marrow transplantation. RESULTS: Spectra showed no correlation between iron peaks of lysosomes and hepatic iron concentration (HIC) or serum ferritin levels. Iron peaks were also detected in other subcellular compartments such as cisternae of rough endoplasmic reticulum, mitochondria and cytosol. No iron peaks were detected in lipid droplets and no significant iron peaks were found in the nuclei. Traces of copper were almost constantly found in lysosomes and cytosol. INTERPRETATION AND CONCLUSIONS: These results demonstrated iron storage within subcellular organelles other than lysosomes and highlighted a non-correlation between lysosomal iron peaks and HIC or serum ferritin levels. The presence of traces of copper in the lysosomes and in the cytosol may be correlated with the stronger hypothesis of links in the metabolism of the two elements (iron and copper), as ceruloplasmin is a ferroxidase copper-dependent protein. X-ray microanalysis may become a relevant tool in the localization of iron storage within hepatocytes in the evaluation of the effectiveness of bone marrow transplantation and iron chelation therapy. It also may provide some interesting information about iron metabolism in hepatocytes.

Abstract: BACKGROUND AND OBJECTIVES: In beta-thalassemia major (Cooley's anemia), ferrokinetic studies show that 60-80% of erythroid precursors die in the marrow or extramedullary sites. However, study of marrow aspirates does not reveal huge numbers of dead and dying erythroid precursors. We explored this apparent discrepancy with the hypothesis that enhanced phagocytosis of thalassemic erythroid precursors was a likely explanation. Prior studies had reported on an increase in thalassemic marrow macrophages and their enhanced state of activation. Therefore this study explored the characteristics of thalassemic erythroid precursors which might lead to enhanced susceptibility to phagocytosis. We have shown that enhanced erythroid apoptosis parallels the extent of ineffective erythropoeisis in thalassemic patients, and apoptotic cells are rapidly phagocytosed. Thus, increased apoptosis and perhaps other features of thalassemic erythroid precursors might be the cause of their enhanced phagocytic removal. DESIGN AND METHODS: Erythroid precursors were isolated from normal and beta-thalassemia major marrow, and incubated with uniform cultures of murine macrophages. The extent of phagocytosis was measured and then specific inhibitors were added to identify some of the messages effete erythroid precursors use to signal their condition to macrophages. RESULTS: Beta-thalassemia major erythroid precursors are phagocytosed twice as effectively as normal erythroid precursors. INTERPRETATION AND CONCLUSIONS: Experiments using inhibitors of phagocytosis showed that enhanced apoptosis is certainly responsible for part of the increased phagocytosis of thalassemic erythroid precursors. Interestingly, normal erythroid precursors are also subject to phagocytosis by qualitatively similar mechanisms.

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Abstract: To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 +/- 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

Abstract: We analyzed the results of a three or more drug combination as treatment for moderate or severe cGVHD developing after transplantation for thalassemia, in 45 patients with median age of 11 (range 2-26) years. Eighteen patients received a three drug regimen with cyclosporine (CsA), methylprednisolone (MP) and azathioprine (AZ) as first line therapy, 16 patients received this regimen as salvage therapy and 11 patients were given a four or five drug regimen with CsA, MP, AZ, cyclophosphamide (CY) and/or methotrexate (MTX) mainly as salvage therapy. The overall complete response (CR) rate was 77.3%, with 94% of CR in patients receiving the three drug regimen as first line, 88% in patients receiving it as salvage therapy and 36.6% in patients given the four or five drug regimen. The probability of CR in patients given the three drug regimen as first or salvage therapy or the four/five drug regimen was 89%, 53% and 30%, while the probability of survival was 89%, 65% and 58%, respectively. The incidence of treatment failure was low in our patients. Patients treated with the three drug regimen as first line therapy had less treatment-related complications than patients receiving this regimen as salvage therapy or patients given the four or five drug regimen. The main causes of treatment-related mortality (20%) were infectious complications. This retrospective study showed that a three or more drug combination is safe and effective for treatment of moderate or severe cGVHD at least in younger patients.

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Abstract: Patients undergoing bone marrow transplantation are profoundly immunosuppressed as a result of their intensive myeloablative chemotherapy and are at high risk for opportunistic fungal infections mainly caused by Candida spp and Aspergillus spp. Trichosporon beigelii (T beigelii) has emerged as a life-threatening opportunistic pathogen in granulocytopenic and immunocompromised hosts and there is a marked increase in cases reported in the literature. Response to antifungal agents is poor, mortality is high and immunological recovery is the most important factor for a favorable outcome in patients with trichosporonosis. We present three cases of T. beigelii infection in patients undergoing allogeneic bone marrow transplantation in our center and we review cases described in the literature.

Abstract: Twenty-six transplanted thalassemic patients out of 295 analyzed, showed the presence of persistent mixed chimerism, over a period of time varying between 2 and 11 years after BMT. Despite the presence of large numbers of residual host cells, these transplanted thalassemic patients no longer require red blood cell transfusions and have a functional graft, producing sufficient levels of hemoglobin A ranging from 8.3-14.7 g/dl. These ex-thalassemic patients with persistent mixed chimerism, although they did not achieve complete donor engraftment are no longer exposed to the risk of graft rejection. The mechanisms underlying this apparent state of tolerance or education in these patients are at the present time unknown. However, these observations may be useful for physicians involved in defining optimal strategies for clinical gene therapy, in utero hematopoietic stem cell transplantation and adoption of less toxic conditioning regimens in mini-transplantation.

Abstract: Twenty-nine patients with thalassemia and a median age of 6 years (range 1.1-33 years) were given a BMT from an alternative donor. Six of the 29 donors were HLA-phenotypically identical and two were mismatched relatives, 13 were mismatched siblings and eight were mismatched parents. Six patients received no antigen (relatives), 15 patients one antigen, five patients two antigen and three patients three antigen disparate grafts. Twenty-three patients were in class 2 or class 3, whereas six patients were in class 1. Thirteen patients were given BUCY, nine patients BUCY plus ALG, six patients BUCY plus TBI or TLI and one patient BUCY with prior cytoreductive-immunosuppressive treatment as conditioning. As GVHD prophylaxis four patients received MTX, 22 CsA + MTX + methylprednisolone (MP) and three patients CsA + MP. Thirteen of 29 patients (44.8%) had sustained engraftment. The probability of graft failure or rejection was 55%. There were no significant differences between antigen disparities and graft failure. The incidence of grade II-IV acute GVHD was 47.3% and chronic GVHD was 37.5%. The incidence of acute GVHD was higher in patients receiving one or two antigen disparate in the GVHD direction grafts (vs no antigen) (P EQ 0.04; odds ratio 10.8; 95% CI 1.5-115). The probability of overall and event-free survival was 65% and 21%, respectively, with median follow-up of 7.5 years (range 0.6-17 years) for surviving patients. The degree of HLA disparity between patient and donor did not have a significant effect on survival. The incidence of nonhematologic toxicity was low. Transplant-related mortality was 34%. GVHD (acute or chronic) was a major contributing cause of death (50%) followed by infections (30%). We conclude that at present, due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens.

Abstract: BACKGROUND: We report a young girl with thalassaemia who showed development and regression of multiple hepatic masses. RESULTS: The tumours, detected 3 years after allogeneic bone-marrow transplantation, showed progressive reduction in size and number following a phlebotomy program to treat iron overload. CONCLUSION: The detailed CT, MRI and histological findings are described.

Abstract: BACKGROUND AND METHODS: We tested the usefulness of measuring the hepatic iron concentration to evaluate total body iron stores in patients who had been cured of thalassemia major by bone marrow transplantation and who were undergoing phlebotomy treatment to remove excess iron. RESULTS: We began treatment with phlebotomy a mean (+/-SD) of 4.3+/-2.7 years after transplantation in 48 patients without hepatic cirrhosis. In the group of 25 patients with liver-biopsy samples that were at least 1.0 mg in dry weight, there was a significant correlation between the decrease in the hepatic iron concentration and total body iron stores (r=0.98, P<0.001). Assuming that the hepatic iron concentration is reduced to zero with complete removal of body iron stores during phlebotomy, the amount of total body iron stores (in milligrams per kilogram of body weight) is equivalent to 10.6 times the hepatic iron concentration (in milligrams per gram of liver, dry weight). With the use of this equation, we could reliably estimate total body iron stores as high as 250 mg per kilogram of body weight, with a standard error of less than 7.9. CONCLUSIONS: The hepatic iron concentration is a reliable indicator of total body iron stores in patients with thalassemia major. In patients with transfusion-related iron overload, repeated determinations of the hepatic iron concentration can provide a quantitative means of measuring the long-term iron balance.

Abstract: Beta-thalassemia major is characterized by ineffective erythropoiesis leading to severe anemia and extensive erythroid expansion. The ineffective erythropoiesis is in part due to accelerated apoptosis of the thalassemic erythroid precursors; however, the extent of apoptosis is surprisingly variable. To understand this variability as well as the fact that some patients undergoing allogeneic marrow transplantation are resistant to the myeloablative program, we attempted more quantitative analyses. Two groups of patients totaling 44 were studied, along with 25 healthy controls, and 7 patients with hemolysis and/or ineffective erythropoeisis. By 2 flow cytometric methods, thalassemic erythroid precursors underwent apoptosis at a rate that was 3 to 4 times normal. Because thalassemic marrow has between 5- to 6-fold more erythroid precursors than healthy marrow, this translated into an absolute increase in erythroid precursor apoptosis of about 15-fold above our healthy controls. In searching for the causes of the variability in thalassemic erythroid precursor apoptosis, we discovered tight direct correlations between the relative and absolute extent of apoptosis and the extent of erythroid expansion as measured either by the absolute number of marrow erythroid precursors or by serum soluble transferrin receptor levels. These results could mean that the most extreme rates of erythroid proliferation lend themselves to cellular errors that turn on apoptotic programs. Alternatively, extreme rates of erythroid hyperplasia and apoptosis might be characteristic of more severely affected patients. Lastly, extreme erythroid hyperplasia could generate such numbers of apoptotic erythroid precursors that marrow macrophages are overwhelmed, leaving more apoptotic cells in the sample.

Abstract: One hundred seven adult patients with thalassemia aged from 17 through 35 years and transplanted from HLA-identical siblings between November 1988 and September 1996 were evaluated on December 31, 1997. The outcome experience of 20 consecutive patients transplanted between November 13, 1988 and January 10, 1991 and reported in September 1992 is updated after 5 additional years. The experience on 87 patients transplanted between May 1991 and September 1996 is described and evaluated as of the end of December 1997. Of 107 patients, 69 survive between 1.5 and 9 years after transplantation. Sixty-six of these patients do not have thalassemia and are identified as ex-thalassemic after bone marrow transplantation. The youngest survivor is 20 years old, 6 are older than 30 years, and the oldest is 37 years of age. Patients with chronic active hepatitis at the time of transplant were significantly more likely to die than patients without (P =.05; relative risk, 2.05). Marrow transplantation is a valid treatment option for older patients with thalassemia who have suitable donors and show deterioration with conventional therapy.

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Abstract: In transfused patients with aplastic anemia, incidence of graft rejection remains significant. Seventeen transfused patients with severe aplastic anemia received BMT from HLA-identical sibling donors after conditioning with cyclophosphamide (CY, 50 mg/kg/day for 4 days) plus total lymphoid irradiation (TLI, 750 cGy in a single dose). For graft-versus-host disease (GVHD) prophylaxis one patient received methotrexate, five patients received CsA and 11 received CsA in association with methylprednisolone. All patients had sustained engraftment. The actuarial survival of patients was 76% with a median follow-up for surviving patients of 11 years (range 0.3-14.5 years). The incidence of grade II-III acute GVHD was 24%, and chronic GVHD 35%. Median Karnofsky score of surviving patients is 100 (range 90-100). Only one patient developed interstitial pneumonia. None of the patients has developed a malignancy after BMT. The role of limited field irradiation in development of malignant neoplasms after BMT for aplastic anemia is discussed. We conclude that a conditioning regimen using CY + TLI in sensitized aplastic anemia patients results in a high survival rate on long-term follow-up.

Abstract: Thirty-two thalassemic patients with a median age of 7.7 years (range 3.4-26 years) were given a second HLA-identical related marrow transplant (BMT2) for graft failure. Four patients were in class 1 and 28 patients in classes 2 and 3. Twenty-one patients had full thalassemia recurrence (first group) and 11 patients had aplastic marrows (second group) either with or without residual donor marrow cells after the first BMT (BMT1). As conditioning regimen for BMT2 all but five patients received BUCY or CY in association with total lymphoid irradiation (TLI) and/or anti-lymphocyte globulin (ALG), whereas nine patients received a new preparative regimen with hydroxyurea, azathioprine, fludarabine before conditioning with BUCY. Twenty one of 31 evaluable patients (67.7%) had initial, and 16 (51.6%) had sustained engraftment. Ten patients (32.3%) failed to engraft. Overall and event-free survival for the entire group of patients were 49% and 33%, respectively, with a median follow-up of 4 years (range 0.6-14 years) for surviving patients. Event-free survival was higher in the second group of patients compared with the first group (41% vs 29%). The second group of patients appeared to have less graft failure compared with the first group (30% vs 63%; P = 0.1). Transplant-related mortality was 28%. A linear stepwise regression analysis revealed that occurrence of graft failure within 60 days after BMT1 (P = 0.04) and absence of residual donor marrow cells (P = 0.009) predicted for graft failure following BMT2, whereas the occurrence of graft failure after 60 days (P = 0.03) had a positive influence on survival following BMT2. The incidence of grade >/=2 acute GVHD was low (14%). Eight of nine patients who received the new preparative regimen are alive, four without thalassemia. This study shows that BMT2 can be an effective therapy for a proportion of patients with poor survival expectancies despite conventional treatment.

Abstract: We report a right atrial myxoma which suddenly developed in a thalassemic patient after allogeneic bone marrow transplantation. The tumor was first detected by echocardiography on day +47 after transplant and the patient underwent surgical removal of the myxoma on day +103. The post-operative course was uneventful, and at more than 3 years from the event, he is alive and well, cured from his congenital disease, with no detectable intra-cardiac tumor. The onset of the myxoma in the early post-transplant period and the extremely high velocity of growth suggest a possible relationship of this condition with the immunosuppressive status.

Abstract: 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.

Abstract: Iron-induced cardiac disease is the primary cause of death in transfused patients with thalassaemia major. The beneficial effects of deferoxamine mesylate on clinical cardiac disease have been well described but the impact of therapy on subclinical cardiac dysfunction is unknown. To assess the reversibility of subclinical cardiac dysfunction we studied the cardiac status during iron depletion treatment (phlebotomy) in iron overloaded patients, cured of thalassaemia by marrow transplantation, without clinical manifestation of heart failure but with alteration in both left ventricular diastolic function and in contractility property. 32 patients were studied and demonstrated a slight but significant impairment in the morphology and function if compared with matched normal controls. 17 of these patients were submitted to sequential echocardiographic evaluations during the phlebotomy programme. Following completion of the programme, normalization of the indices of contractility and normalization of diastolic function were observed. This study indicates that transplanted thalassaemia patients with subclinical left ventricular diastolic dysfunction and impaired left ventricular contractility may reverse these processes with an effective regimen of iron reduction such as phlebotomy.

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) 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."

Abstract: A case of Kaposi's sarcoma (KS) in an allogenic BMT recipient is reported. A 26-year-old man underwent allogeneic bone marrow transplantation for microdrepanocytosis. He received prolonged immunosuppressive therapy for mild chronic GVHD. Two years after BMT he developed KS localized to the skin. The KS improved rapidly and outcome was complete remission after cessation of immunosuppression.

Abstract: 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.

Abstract: PURPOSE: To evaluate the role of allogeneic bone marrow transplantation (BMT) in children with chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Forty-three children with CMML given BMT and reported to the European Working Group on Myelodysplastic Syndrome in Childhood (EWOG-MDS) data base were evaluated. In 25 cases, the donor was a human leukocyte antigen (HLA)-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 a matched unrelated donor (MUD). Conditioning regimens consisted of total-body irradiation (TBI) and chemotherapy in 22 patients, whereas busulfan (Bu) with other cytotoxic drugs was used in the remaining patients. RESULTS: Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. There was a significant difference in the incidences of chronic graft-versus-host disease (GVHD) between children transplanted from compatible/one-antigen-mismatched relatives and from alternative donors (23% and 87%, respectively; P < .005). Probabilities of transplant-related mortality for children given BMT from HLA-identical/one-antigen-disparate relatives or from MUD/ mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%, whereas the 5-year event-free survival (EFS) rate was 31%. The EFS rate for children given BMT from an HLA-identical sibling or one-antigen-disparate relative was 38%. In this latter group, patients who received Bu had a better EFS compared with those given TBI (62% v 11%, P < .01). CONCLUSION: Children with CMML and an HLA-compatible relative should be transplanted as early as possible. Improvement of donor selection, GVHD prophylaxis, and supportive care are needed to ameliorate results of BMT from alternative donors.

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Abstract: 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.

Abstract: To evaluate the usefulness of magnetic resonance imaging for the quantitative determination of hepatic iron, we examined 43 patients with thalassemia major and assessed the influence of pathologic changes in the liver on the precision of estimates of the hepatic iron concentration. Tissue signal intensities were measured from magnetic resonance T1-weighted images derived from gradient-echo (GE) pulse sequences and the ratio of the signal intensity of liver to muscle calculated. By excluding patients (n = 9) having a signal intensity ratio (SIR) less than or equal to 0.2, a linear relationship with hepatic iron was found and subsequent analyses were limited to these 34 patients. In 27 patients with hepatic fibrosis, an overall correlation of -0.848 was found between hepatic iron and SIR. By contrast, in the seven patients with no fibrosis, the correlation coefficient (-0.993) was significantly greater (P < .0001). Despite the differences in correlation, the regression line between hepatic iron and SIR for the patients with no fibrosis did not differ significantly with respect to either slope or intercept from that of the patients with fibrosis. Thus, the presence of fibrosis did not seem to affect the pattern of the relationship between hepatic iron and the SIR, but rather to increase the variability of the relationship. Clinically, the presence of fibrosis makes estimates of hepatic iron derived from magnetic resonance imaging so variable as to be of little practical use in the management of transfusional iron overload.

Abstract: We analyzed plasma pharmacokinetics of busulfan in 64 children and young adults (age 2.8-26; median 11 years) with homozygous beta-thalassemia transplanted with bone marrow from HLA-identical sibling donors. A uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg in 12 divided doses, and cyclophosphamide 120 or 200 mg/kg. Three sets of parameters were examined in this homogenous patient population: (1) factors that affect the plasma kinetics of busulfan, such as age and pre-transplant liver status defined by liver function tests, ferritin levels and liver biopsy; (2) busulfan-related toxicity: occurrence of veno-occlusive disease, seizures and idiopathic interstitial pneumonitis; and (3) the relationship between busulfan exposure and transplant outcome: engraftment delay or rejection, aplasia, occurrence of mixed chimeras and mortality. Kinetic analysis of first and 10th dose (using area under the curve (AUC), maximum and minimum concentration) as comparable, showing no sign of accumulation or decline in busulfan plasma levels over time. Age and liver status did not influence busulfan metabolism. No relationship was found between busulfan exposure and toxicities or transplant outcome. We conclude that busulfan monitoring is not predictive in children and young adults with homozygous beta-thalassemia receiving busulfan and high-dose cyclophosphamide along with histocompatable sibling donor marrow.

Abstract: 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.

Abstract: The life threatening anemia in beta-thalassemia major (Cooley's anemia) is characterized by profound intramedullary lysis, the cause of which is incompletely understood. Using marrow obtained from beta thalassemia major patients undergoing allogeneic bone marrow transplantation in Pesaro Italy, it became possible to directly study the mechanism of the intramedullary hemolysis. Based on our previous studies, we hypothesized that the unmatched alpha globin chains would interfere with normal assembly of erythroid precursor membrane proteins. Patient and control erythroid precursors were reacted with monospecific polyclonal rabbit antibodies directed against spectrin, band 3, and band 4.1 and with a monoclonal anti-alpha globin chain antibody. Using laser confocal fluorescence microscopy, normal erythroid precursors show no alpha globin chain accumulation and exhibited uniformly smooth rim fluorescence of the three membrane proteins. In some thalassemic precursors, spectrin appeared to interact with large alpha globin accumulations, and in many of these cells the spectin appeared clumped and discontinuous. Band 4.1 interacted strongly with accumulations of alpha globin in thalassemic precursors to produce bizarrely clumped zones of abnormal band 4.1 distribution. Band 3 was incorporated smoothly into thalassemic erythroblast membranes. However, the proerythroblasts and basophilic erythroblasts were significantly deficient in band 3. Thus, accumulations of alpha globin in beta-thalassemia major colocalized with and disrupt band 4.1 and spectrin assembly into the membrane. The cause of deficient band 3 incorporation into thalassemic proerythroblast membranes remains unknown. These profound membrane alterations would likely contribute to the intramedullary lysis seen in Cooley's anemia.

Abstract: We report a thalassemia patient suffering from congenital transposition of the great arteries, surgically corrected according to Mustard technique at the age of 4 months, who underwent bone marrow transplantation. Despite a syncopal episode occurring during the first day after marrow infusion the transplant was successful. Thirty-two months later, normalization of hematologic parameters was observed together with a substantial improvement in cardiac function.

Abstract: Thalassemia patients can be categorized as class 1 (minimal liver damage and iron overload), class 3 (extensive liver damage from iron overload), and class 2 (intermediate). These categories are prognostic for treatment outcome after marrow transplantation. Class 3 patients have more transplant-related mortality than other patients. This study examines transplantation outcome for class 3 patients. Records were reviewed of 215 patients in class 3 who received transplants in Pesaro from HLA-identical related donors between May 1, 1984 and May 1, 1994. The influence of pretransplant, peritransplant, and posttransplant variables on survival, relapse, and transplant-related mortality was examined by product-limit and proportional-hazards multivariate analysis. Age and conditioning regimen were influential on survival, and regimens with less than 200 mg/kg cyclosporine (CY) were associated with 5-year survival probabilities of .74 and .63 patients younger than 17 years and older patients, respectively. Transfusion history and regimen were influential on rejection with 5 year probabilities of .53 and .24 in patients who received less than or greater than 100 red blood cell transfusions before transplantation and regimens containing less than 200 mg/kg CY. Results of transplantation for patients with advanced thalassemia treatment have improved with the introduction of conditioning regimens with less CY. This has been associated with an increase in rejection (particularly in patients who have received < 100 red blood cell transfusions before transplant). Efforts at reducing the rejection rate by modifying the conditioning regimen should be concentrated on younger patients who have received a small number of transfusions. Patients with thalassemia who have HLA-identical family members should be transplanted before they are in class 3.

Abstract: 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.

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Abstract: 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.

Abstract: Patients with beta thalassemia major present with severe anemia and need continuous transfusion therapy. The consequent iron overload leads to hemochromatosis. Initial cardiac involvement can be present in thalassemic patients without clinical manifestations of heart failure. The purpose of this study was to assess the contractile reserve of the left ventricle in patients with normal baseline two-dimensional (2-D) echocardiographic findings using low dose dobutamine echocardiography. The underlying hypothesis was that, at an early stage, structural impairment of the myocardial wall due to myocardial iron deposits and/or secondary fibrotic changes could be so subtle so as not to impair resting systolic function, but is severe enough to blunt or even exhaust the contractile response to inotropic stimulation. Twenty-four consecutive patients (13 men and 11 women; ages 18 +/- 3.8 years) with beta thalassemia major undergoing evaluation for bone marrow transplantation entered the study. By selection, all were asymptomatic, without clinical signs of cardiac failure, and had normal regional and global systolic function at baseline echocardiographic study. A control group of 16 age and sex matched subjects was also studied. All underwent baseline, 2-D, and Doppler study, as well as dobutamine stress (up to 5 &mgr;g/kg per min) 2-D echocardiographic study. Patients and controls showed comparable values of indexes of global (ejection fraction: 0.64 +/- 0.06 vs 0.65 +/- 0.05, P = NS) and regional (systolic thickening of posterior wall: 90 +/- 34 vs 91 +/- 34%, P = NS) function at baseline. Left ventricular diastolic filling was evaluated with Doppler echocardiography. Peak flow velocity in early diastole was increased in thalassemic patients compared to controls (114 +/- 16 vs 96 +/- 18 cm/sec, P < 0.01), and flow velocity deceleration time was reduced (139 +/- 17 vs 157 +/- 20 msec, P < 0.01). At peak dobutamine, thalassemic patients showed a blunted contractile response compared to controls for indexes of both global (ejection fraction: 0.62 +/- 0.06 vs 0.69 +/- 0.05, P < 0.01) and regional (% systolic thickening of posterior wall: 91 +/- 36 vs 130 +/- 39%, P < 0.01) function. When individual patient analysis was performed, echocardiographic parameters were beyond the 95% confidence limits obtained from normal controls in 5 (21%) of the 24 study patients by one or more Doppler diastolic indexes, in 6 (25%) by indexes of contractile reserve, and in 11 (46%) by one of either diastolic function or contractile reserve indexes. These data demonstrate that the "iron heart" of asymptomatic thalassemic patients is a weak heart. Even if the regional and global systolic functions are similar to normals under resting conditions, the application of an inotropic challenge unmasks the weakness of these hearts, which can be identified at an earlier stage of their natural history through the blunted contractile response following the infusion of low dose dobutamine. The information on contractile reserve is not redundant, but rather incremental and in addition to that provided by Doppler echocardiographic indexes, which may be abnormal in these patients. (ECHOCARDIOGRAPHY, Volume 13, September 1996)

Abstract: We report the reliability and safety of percutaneous liver biopsy in the evaluation of hepatic iron loading and histology in patients with homozygous beta-thalassaemia prior to and in serial biopsies following allogeneic bone marrow transplantation for this disorder. 501 thalassaemic patients aged 11 +/- 4.5 years (range 1-32 years) underwent 1184 consecutive percutaneous liver biopsies without ultrasound guidance. Overall, 81% of biopsies were evaluable for histological examination and grading of iron. The adequacy of liver biopsy specimens increased with patient age: evaluable specimens were obtained in 73% of patients < 5 years of age and in 86% of samples in patients aged > 15 years. The degree of iron overload and fibrosis in each biopsy was reported separately by at least two pathologists who did not know the clinical status of each patient. In 103 biopsies, iron grade by light microscopy corresponded to an iron concentration varying between a mean of 32.46 +/- 14 mumol/g dry weight liver tissue for iron stores graded by light microscopy as absent to 417.6 +/- 150 mumol/g dry weight liver tissue for stores graded as severe. The fibrosis score of multiple samples of liver obtained at autopsy within 100 d of the percutaneous biopsy in 41 patients who died following BMT correlated perfectly with that of the first sample in > 60% biopsies; in most of the discordant cases fibrosis had been underestimated in the percutaneous biopsy. Liver biopsy demonstrated evidence of chronic hepatitis in 30% of patients with normal transaminase and in 57% of patients with transaminase within twice the normal range. Liver biopsy was complicated in six patients (0.5%) by haemoperitoneum, periocholecystic haematoma, kidney haematoma, or bile peritonitis; no complication was fatal. These data demonstrate that percutaneous liver biopsy provides reliable information regarding liver iron and histology in homozygous beta-thalassaemia with an extremely low risk of complications.

Abstract: We treated 18 heavily iron-loaded patients who had become ex-thalassaemics after bone marrow transplantation with subcutaneous desferrioxamine therapy for 5-20 months. As determined using serum ferritin concentration, transferrin saturation and stainable liver iron obtained in follow-up biopsies, marked decreases in body iron stores were observed with this regimen. Moreover, the liver function tests demonstrate a trend to normalization in all cases. Local skin reactions to desferrioxamine were the only toxicities observed. We conclude that pharmacological iron chelation is a safe and effective therapy in the reduction of iron deposits in this clinical situation; it therefore represents a valid alternative to phlebotomy in selected patients.

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Abstract: 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.

Abstract: Use of the mother as mismatched marrow donor was assessed in 19 children with advanced leukemia. Patients were homogeneous for HLA incompatibility, age, donor, and conditioning regimen, and stage of disease. All received busulfan and cytoxan, combined with unmodified donor marrow, ALG given before and after transplant, and short MTX and cyclosporine as GVHD prophylaxis. Survival, LFS, and relapse respectively were 26, 26, and 33%. Incidence of overall and severe acute GVHD was 58 and 32%, respectively. Four patients had failure of engraftment, and two of these are alive with autologous reconstitution in complete remission. Probability of rejection was 21%. Results of haploidentical transplants were compared with those of children with advanced leukemia treated at the same institution, who received marrow from HLA-identical siblings. The probability of long-term leukemia-free survival was similar in the two groups. We thus propose using the mother as an alternative marrow donor in children with advanced leukemia.

Abstract: We analyzed the success of suprapubic cystotomy in patients with severe hemorrhagic cystitis after bone marrow transplantation. Seventy-three out of 963 patients developed severe hemorrhagic cystitis which resulted in urinary tract obstruction after high-dose cytoreductive therapy. Eleven patients (15%) failed medical treatment and required emergency suprapubic cystotomy. Three of these patients died of other complications prior to resolution of HC. Of the remaining 8 patients who underwent surgery, 4 are alive. The mortality rate was significantly higher in patients who required surgery than in those who responded to medical therapy. Patients whose HC required surgery also had a greater transfusion requirement than those who responded to medical therapy. We conclude that surgical treatment of severe HC should be undertaken only after failure of medical therapy.

Abstract: PURPOSE: We reviewed the results of transplanting allogeneic marrow from HLA-identical donors in patients with beta-thalassemia. Among the 484 consecutive patients who have received transplants since 1981, survival and disease-free survival rates leveled off at approximately 1 year after transplantation, at 82 and 75%, respectively. PATIENTS AND METHODS: Clinical characteristics of patients before transplant have been studied to determine their impact on survival, disease-free survival, and graft rejection. By multivariate analysis, portal fibrosis, hepatomegaly, and a history of inadequate chelation therapy were identified as risk factors. The patients were then divided into three classes of risk. RESULTS: The rate of prolonged disease-free survival was 98% and 87% for class 1 and class 2 patients. This rate of disease-free survival is 70% with the use of our last conditioning protocol for class 3 patients. Older patients (17-32 years) have a 79% probability of prolonged disease-free survival. CONCLUSIONS: We conclude that for patients with thalassemia major, transplantation of bone marrow from a human leukocyte antigen-identical donor offers a high probability of disease-free survival, particularly for those patients in early stages of their disease.

Abstract: 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.

Abstract: We report a case of acute cardiac tamponade without concurrent myocardial disease occurring in a thalassemia patient early after bone marrow transplantation. The pericardial effusion was preceded by an episode of junctional tachycardia. Repeated evaluation by echocardiography was done shortly after the patient developed the arrhythmia and permitted a detailed, timed observation of the event and description of the symptoms.

Abstract: Among 450 thalassemic patients treated in the Hematologic Department, 50 patients who were disease-free 4-6 years after allogeneic bone marrow transplantation were sequentially studied by liver biopsy. The patients received marrow from siblings who were genotypically HLA identical at A, B, C and DR loci. For evaluation of siderosis and associated lesions, each patient underwent liver biopsy before, and again 6 months and yearly for 4 to 6 years after bone marrow transplant. Spontaneous reversibility of liver iron overload, once the need for transfusions ceased when a functioning graft had been established, was observed in the youngest patients, aged 1-8 years, whereas iron excess remained at the end of follow-up in many patients aged 9-15 years. Hypotheses about the mechanism of the iron decrease are discussed. Several cases also obtained improvement of associated pathologies such as hepatitis, probably through modifications in the mechanisms controlling their immunological status.

Abstract: The presence of anti-HCV antibodies has been examined in a group of 256 consecutive thalassemic patients who received blood transfusions in several countries around the world. Overall 60% were found to be anti-HCV positive. A higher incidence of anti-HCV antibodies was noted in Italian patients with respect to patients living in Eastern countries, and in southern Italy with respect to northern Italy. Because these patients received a large portion of their transfusions before the anti-HCV test became available, these data indicate a higher anti-HCV seroprevalence among Italian blood donors and confirm published data indicating a higher seroprevalence in southern Italy. The anti-seropositivity correlated highly with serum transaminase elevation and with histological diagnoses of chronic active hepatitis.

Abstract: Ninety-eight patients with homozygous-beta thalassemia who had undergone allogeneic bone marrow transplantation (BMT) between May 1990 and March 1992 were tested for hepatitis C antibodies (anti-HCV) before and after BMT. Anti-HCV positivity was detected in 50 of the 98 patients (51%) before BMT. Seroconversion was demonstrated in seven of the 40 evaluable seronegative patients. In four cases it was probably due to the different sensitivity of first and second generation ELISA. Of the 46 evaluable seropositive patients 4 had transient and 5 persistent negativity for HCV antibodies after BMT. The high prevalence of anti-HCV positivity in thalassemic patients is related to the continuous requirement for blood transfusions. We found a strong correlation between biochemical and histological evidence of liver damage and anti-HCV positive status in multi-transfused patients. In our experience HCV hepatitis does not influence the outcome of BMT.

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Abstract: In patients with Thalassaemia Major the iron overload with alteration both of systolic and diastolic properties of left and right ventricles finally leads to symptoms of cardiac failure and is the most frequent cause of death in these patients. In the majority of asymptomatic thalassemic patients with normal myocardial mass it is possible to demonstrate an alteration of the diastolic function both with echocardiographic study and with radionuclide angiography (subclinical cardiac disease). We have also demonstrated in "ex thalassemics" with stable and heavy iron overload in the subclinical cardiac disease phase a subnormal systolic function and a slight impairment of the contractility state. Therefore our purpose was to evaluate cardiac performance emphasising the contractility properties of the left ventricle during moderate inotropic stimulation with dobutamine in thalassemic patients in subclinical cardiac disease. We are now also using this test to evaluate cardiac performance in adults thalassemic patients as a screening for marrow transplantation procedure. Dobutamine is a sympathomimetic drug (beta 1 agonist) that increases myocardial contractility and at high doses also systolic arterial blood pressure and heart rate. The half-life is extremely short and at low doses the drug has no major side effects. Continuous intravenous dobutamine infusion is largely used in the therapeutic field to treat cardiac failure and it is reported to be a very efficacious and safe therapeutic agent. Recently dobutamine stress echocardiography was reported to be an accurate non-invasive diagnostic technique for detecting cardiac dysfunction in adults with coronary artery disease (Dobutamine is used for this purpose at high dose to increase the myocardial oxygen consumption).(ABSTRACT TRUNCATED AT 250 WORDS)

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Abstract: In patients with thalassemia major iron overload leads to symptoms of cardiac failure and it is the most frequent cause of death. A sub group of asymptomatic thalassemic patients (Th Pts) who underwent bone marrow transplantation (BMT) and who presented persistently high serum ferritin level and heavy haemosiderosis were subjected to cardiological study to evaluate possible iron-related cardiac disease. We report here preliminary results obtained from the Echocardiographic studies carried out at baseline and at eight months follow-up in a group of ex-thalassemic after transplant who underwent phlebotomy in the attempt to reduce the iron overload.

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Abstract: To obtain further insight into gonadal function, a series of 50 prepubertal patients with beta-thalassaemia major (24 boys and 26 girls) aged from 12.6 to 18 years (mean 15 years) who had received a bone marrow transplantation (BMT) during childhood or the peripubertal period, at the age of 3.6-14.5 years (mean 10.8 years), were periodically re-evaluated at intervals of 6-12 months. The last evaluation was done 1-9 years (mean 4.2 years) after BMT. At each examination we measured height, pubertal stage, plasma gonadotrophins (LH and FSH) before and after the GnRH stimulation test (i.v.), sex steroids (total and free testosterone in males, and 17 beta-oestradiol in females), serum ferritin and bone age. Fourty percent of patients entered or passed through puberty normally despite clinical and hormonal evidence of gonadal dysfunction in most of them. A correlation was not found between the pubertal stage and age at BMT, and no statistical difference between patients who did not enter into puberty and patients with spontaneous pubertal development was found in serum ferritin levels. Our data confirm that gonads in male and female thalassaemic patients are exposed to the cytotoxic effects of the preparative transplant regime with alkylating agents. In some patients absence of pubertal development was due to gonadotrophin insufficiency, probably secondary to previous iron overload. These findings emphasize the need for a vigilant long-term follow up study of thalassaemic patients who have had BMT.

Abstract: After successful bone-marrow transplantation (BMT) in thalassaemia, the individual acquires the pattern of globin synthesis of the donor. We call such an individual "ex-thalassaemic after BMT", a term that underscores the cure of the genetic defect but maintenance of residual signs of organ damage due to iron overload and dysfunction acquired during the pretransplant years. We have analysed the extent and fate of tissue iron overload in 151 ex-thalassaemic patients after BMT, according to the risk factors of hepatomegaly, hepatic portal fibrosis, and inadequate chelation therapy. Serum ferritin concentrations decreased and unbound iron binding capacity (UIBC) increased slowly during the years after the transplant. When analysed according to risk group (assigned at the time of the transplant), ferritin and UIBC returned within the normal ranges in only the low-risk group (without hepatomegaly or portal fibrosis, and with adequate chelation pre-BMT). Ferritin and UIBC were still abnormal 7 years after the transplant in the moderate-risk group (those with one or two risk factors) and highly abnormal in the high-risk group (all three risk factors) indicating persistence of, respectively, moderate and severe iron overload at the time of transplant. In ex-thalassaemic patients who were studied before and yearly after the transplant the extent of haemosiderosis, as judged by staining of liver biopsy samples, decreased during the years after transplant. The degree of iron deposition and rate of post-BMT linear growth seem to influence rate of post-BMT decrease in tissue iron overload in different risk groups at the time of BMT.

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Abstract: BACKGROUND: Patients with homozygous beta-thalassemia, who have a good prognosis during treatment with conventional therapy, appear to have an especially high probability of hematologic cure with bone marrow transplantation, although the morbidity and mortality associated with such treatment are not established. METHODS: The records of all patients with thalassemia who received bone marrow transplants from HLA-identical donors in Pesaro, Italy, were examined from October 1982 through May 1992. Detailed evaluation of the outcome was conducted in the 89 patients identified as being in class 1 according to the Pesaro classification, in which hepatomegaly, portal fibrosis, and the inadequacy of iron chelation therapy are considered independent risk factors, and the patients are classified as being in class 1 if none of these factors are present, class 2 if one or two of the factors are present, and class 3 if all three factors are present. Sixty-four of the patients had been prepared for transplantation with a drug regimen in current use that includes busulfan and cyclophosphamide followed by cyclosporine as prophylaxis against acute graft-versus-host disease (protocol 6). RESULTS: There were seven deaths, all within 101 days of transplantation. Two of the 64 patients treated according to protocol 6 died. The probabilities of survival, rejection-free survival, death from causes unrelated to rejection, and rejection were 0.92, 0.85, 0.06, and 0.08, respectively, in the total group and 0.97, 0.93, 0.03, and 0.04 in the 64 patients treated according to protocol 6. Preliminary evidence suggests that there was useful unloading of tissue iron deposits. CONCLUSIONS: The high probability of cure with little early or late morbidity and mortality suggests that patients with class 1 thalassemia who have HLA-identical donors available should be treated by bone marrow transplantation. However, this was not a controlled trial, so we cannot directly compare the outcome with that of conventional treatment.

Abstract: The profound and life-threatening anemia in patients with Cooley's anemia is ascribed primarily to intramedullary hemolysis (ineffective erythropoiesis), the cause of which is obscure. Based on prior morphologic data showing nuclear abnormalities, we hypothesized that accelerated apoptosis could occur in these erythroid precursors. The highly successful bone marrow (BM) transplantation program for patients with Cooley's anemia provided us with a unique opportunity to test this hypothesis. We obtained pretransplantation BM aspiration samples from patients undergoing BM transplantation in Pesaro, Italy and from their allogeneic donors. The erythroid precursors were isolated using ficoll sedimentation and then panning selecting fro CD45- cells. Cytospin and Giemsa staining showed that the separation provided greater than 90% erythroblasts. Five million of these erythroblasts were lysed and their DNA was isolated. There were obvious ladder patterns of DNA breakdown products in beta-thalassemia major samples, with less occurring in beta-thalassemia trait. Normal individuals showed only a slight smear of breakdown of DNA. These results indicate there is enhanced apoptosis in the erythroblasts in the BMs of Cooley's anemia patients. This finding might partially explain why most of these erythroblasts never survive to become mature erythrocytes.

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Abstract: Early trials of allogeneic bone marrow transplantation (BMT) for homozygous beta-thalassemia and the analyses of results of transplantation in patients less than 16 years old have allowed us to identify three 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 three criteria were adverse constituted class 3, patients with none of the adverse criteria constituted class one and patients with one or various association 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 two Protocols for BMT to whom the patients are assigned on the base of the class they belong to at the time of BMT and independently on the age of the patient. For class 1, class 2 and for class 3 the probabilities of survival and of event-free-survival are respectively of 98% and 94%, 87% and 84%, 100% and 67%. For those patients that were older than 16 years at the time of the transplant, the probabilities of survival are 82% and the probabilities of event-free survival are 79%. Bone marrow transplantation is a new form of radical treatment of thalassemia in those patients with an HLA identical donor.

Abstract: Published work suggests that cardiac tamponade occurs only occasionally after bone-marrow transplantation (BMT) but the worrying number of cases encountered in the transplant programme in Pesaro, Italy, has led to an analysis of this complication. Cardiac tamponade occurred in 8 (2%) of 400 consecutive thalassaemic patients during conditioning for or within a month of BMT. 6 cases were fatal; these represented 9% of all causes of death and 29% of those occurring between start of conditioning regimen and 30 days post transplant. The syndrome was characterised by sudden onset of circulatory shock and cardiac arrest. The only effective treatment was immediate fluid removal. The absence of myocardial lesions and the complete resolution of the syndrome after pericardiocentesis suggest that the pericardial membranes played the main part in the pathogenesis of the syndrome. Since irradiation was not part of the conditioning regimen and since 3 of the affected patients had bacteraemia, the triggering factor for the syndrome could have been the drugs used for conditioning, acting alone or together with bacteraemia and trauma. The frequency with which we encountered the syndrome, and the similarity among our patients in clinical picture, and in characteristics of the effusion, indicate that cardiac tamponade occurring in thalassaemic patients after start of chemotherapy as conditioning for BMT is a specific syndrome requiring rapid treatment.

Abstract: Early trials of allogeneic marrow transplantation for homozygous thalassemia were disappointing in patients older than 16, with four of six patients dying early of graft-versus-host disease-related complications, one patient dying at 9 months of infection due to graft failure, and one dying at 6 years of recurrent thalassemia. Three classes of risk could be identified in analyses of results of transplantation in younger patients using the criteria of degree of hepatomegaly, the presence or absence of portal fibrosis, and a history of adequate or inadequate chelation therapy. Patients for whom all three criteria were adverse constituted a very high risk group (class 3) for marrow transplantation. On the basis of these analyses, a conditioning regimen was designed that yielded superior results for class 3 patients under 17 years of age. Most patients older than 16 years presenting for transplantation have disease characteristics that place them in class 3 and, because of the improved results with the new class 3 regimen in younger patients, a study was designed to treat patients older than 16 years using treatment regimens assigned on the basis of disease class. Twenty patients were treated using this protocol and, with a minimum follow-up of 9 months, there have been three early deaths, one patient has recurrent thalassemia, and 16 patients are alive disease-free. The actuarial probabilities of survival, disease-free survival, and rejection are 0.85, 0.80, and 0.05, respectively, with a survival plateau extending from 6 months to 3 years. Marrow transplantation is a reasonable option for adults with progressive thalassemia who have suitable donors.

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Abstract: We report a case of IgG lambda type multiple myeloma treated by allogeneic bone marrow transplantation. After transplant the monoclonal protein persisted for 2 years with no other sign of disease. Thereafter the monoclonal protein was no longer detectable and the patient was considered to be in complete remission for the next 4 years.

Abstract: Since 1983, 350 patients aged 1 to 19 years with beta-homozygous thalassemia were given infusions of HLA-identical marrow after high doses of busulphan and cyclophosphamide. Survival and event-free survival leveled off about 1 year after bone marrow transplantation at 82% and 75%, respectively. In 172 consecutive patients who were treated with our current regimen since June 1985, a multivariate analysis demonstrated that portal fibrosis, hepatomegaly, and a history of inadequate chelation therapy were significantly associated with reduced probabilities of survival and event-free survival. The patients were divided into three classes on the basis of the presence of hepatomegaly, portal fibrosis, and inadequate chelation therapy. Class 1 had none of the factors and class 3 had all three factors; class 2 had different associations of two out of the three factors. For class 1 patients, the 3-year probabilities of survival and event-free survival were 97% and 94%, respectively. For class 2 patients, the probabilities were 86% and 83%, and for class 3 patients, 58% and 52%. Bone marrow transplantation from HLA-identical donors is followed by a high probability of event-free survival in thalassemic patients, particularly if they belong to class 1.

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Abstract: We reviewed the results of transplantation of allogeneic marrow from HLA-identical donors in patients with beta-thalassemia who were less than 16 years old. Among the 222 consecutive patients who had received transplants since 1983, survival and event-free-survival curves leveled off about one year after transplantation, at 82 and 75 percent, respectively. Pretransplantation clinical characteristics were examined for their impact on survival, event-free survival, and the recurrence of thalassemia in the 116 consecutive patients who were treated with our current regimen, in use since June 1985. In a multivariate analysis, portal fibrosis and either the presence of hepatomegaly or a history of inadequate chelation therapy were significantly associated with reduced probabilities of survival and event-free survival. The patients were divided into three classes on the basis of the presence of hepatomegaly or portal fibrosis (class 1 had neither factor, class 2 had one, and class 3 had both). For class 1 patients the three-year probabilities of survival, event-free survival, and recurrence were 94, 94, and 0 percent, respectively. For class 2 patients the probabilities were 80, 77, and 9 percent, and for class 3 patients 61, 53, and 16 percent. We conclude that for patients under 16 years of age, transplantation of bone marrow from an HLA-identical donor offers a high probability of complication-free survival, particularly if they do not have hepatomegaly or portal fibrosis.

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Abstract: We report the incidence of cytomegalovirus (CMV) seroconversion, infections and mortality in 169 consecutive thalassemic patients transplanted in Pesaro. We observed a 44% incidence of early seroconversion and a 52% incidence of late seroconversion. No relationship was found between seroconversion and acute or chronic graft-versus-host disease (GVHD) or rejection. The donor status did not influence the incidence of seroconversion, GVHD and rejection. Only three patients died of CMV infection (1.7%); in each case CMV disease was the final cause of death in patients with severe acute GVHD.

Abstract: 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.

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Abstract: Thirty children aged 1-15 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 (TBI) while 12 patients received busulphan and cyclophosphamide. Fifteen patients survived 7 to 74 months after transplant. The association of busulphan and cyclophosphamide is a well-tolerated preparation for bone marrow transplant in children with eradicating and immunosuppressive efficacy comparable to that of the well-experienced TBI-cyclophosphamide association.

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Abstract: 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.

Abstract: The authors report a case of non Hodgkin lymphoma which, given its particular course and histomorphological features, can be classified as angiotropic large-cell lymphoma (i.e. proliferating angioendotheliomatosis). The most important characteristic is that the kidney was the target organ in this case, an observation rarely reported in the literature.

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Abstract: This study compares the efficacy of 2 posttransplant immunosuppressive regimens for prevention of graft-versus-host disease (GVHD). Forty-four patients, ages 8-15 years, with homozygous beta thalassemia received marrow allografts from HLA-identical siblings following an ablative regimen of busulfan and cyclophosphamide. Twenty-two patients received cyclosporine (CsA) alone and 22 received cyclosporine, cyclophosphamide, and methotrexate for prophylaxis against GVHD. Two who received CsA alone have died (1 of graft rejection and 1 of acute GVHD) as did 4 patients who received 3 drugs (1 of rejection, 1 of acute GVHD, 1 of infection and cardiac failure before engraftment, and 1 of acute respiratory failure before engraftment). One patient in each group rejected the transplant and survives with thalassemia. The probability of developing acute GVHD was 41% for the CsA group and 15% for the 3-drug group (P = less than 0.05). Patients receiving CsA alone had a probability of event-free survival of 86% compared to 77% in the group receiving 3 drugs (P = 0.40) with a followup of 209-706 days. Although the study showed a decrease in the incidence of GVHD in recipients of the more intensive prophylactic regimen, this study was terminated since it was apparent that even if larger numbers of patients were studied it would be difficult to demonstrate a significant survival advantage with the use of this drug regimen.

Abstract: The authors report the results of 113 patients who underwent bone marrow transplant for acute nonlymphoblastic leukemia, acute lymphoblastic leukemia and chronic myeloid leukemia in complete remission and relapse after different conditioning regimens.

Abstract: In a study of the outcome of marrow transplantation in patients with advanced thalassemia, 40 patients with homozygous beta-thalassemia who were 8 to 15 years of age (median, 10) received HLA-identical allogeneic marrow after treatment with busulfan and cyclophosphamide. Twenty-eight of the 40 patients were alive and free of disease 260 to 939 days after transplantation, and 2 patients were alive with thalassemia 372 and 1133 days after transplantation. The actuarial probabilities of survival and of disease-free survival at two years were 75 percent and 69 percent, respectively. Ten patients (25 percent) died. Three died of cardiac failure, interstitial pneumonitis, or septicemia within 14 days of transplantation. Three died of infectious complications associated with acute graft-versus-host disease at 46 to 97 days, and two died of infectious complications of chronic graft-versus-host disease at 249 and 290 days. Two patients had transplant rejection and died with marrow aplasia 115 and 192 days after transplantation. One patient had rejection after four months and while the marrow was aplastic underwent a successful second transplantation; the patient was alive without thalassemia 624 days after the first transplantation. The actuarial probability of grade 2 or higher acute graft-versus-host disease in the 32 patients with initial sustained engraftment was 35 percent. Three patients had chronic graft-versus-host disease, which was fatal in two and still active on day 710 in the third. We conclude that bone marrow transplantation can potentially save patients with advanced thalassemia from an otherwise inexorable progression to death from the complications of blood transfusions. The ultimate outcome in this group of patients must await a longer follow-up.

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Abstract: 30 patients with homozygous beta-thalassaemia aged 6 months to 7 years received allogeneic marrow transplants following busulphan (Bu) and cyclophosphamide (Cy). Post-transplant immunosuppression was with methotrexate (MTX) or MTX and Cy. The first 6 patients received 16 mg/kg Bu and 200 mg/kg Cy. 3 died of transplant-related complications and 3 survived without thalassaemia 701-762 days after transplantation. The subsequent 24 patients received 14 mg/kg Bu and 200 mg/kg Cy. 1 died on day 28 without engraftment and 23 survived 64-624 days after transplantation. 19 of the 23 surviving patients are without thalassaemia while 4 patients with initial engraftment became thalassaemic again in 32-46 days and survived 253-624 days after transplantation. The latest death was 50 days after transplantation. The probability of developing grade 2 or greater acute graft versus host disease (GVHD) in patients with sustained engraftment was 23%. 5 patients had chronic GVHD which is still active and causing disability in 3 patients 358, 456, and 477 days after transplantation. The actuarial survival was 86% and the actuarial disease-free survival was 73%.