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There is a substantial incidence of graft failure in patients with thalassemia after myeloablative conditioning regimens especially in class 3 patients in whom its incidence could be as high as 8–38.5%. Most patients with graft failure have recurrence of thalassemic marrow. Historically, results of second transplants for thalassemia were poor because of a high rejection rate and/or increased TRM. Sixteen patients with thalassemia recurrence following rejection of the first graft and with a median age of 9 years (range, 4–20) were given second transplants using BM (n=7) or PBSC (n=9) after preparation with a new treatment protocol. All but two patients received stem cells from the same donor. The median interval between two transplants was 28 months (range, 8–204). The sustained engraftment rate was high (94%) with only one patient having primary graft failure. The probability of overall survival, event-free survival, TRM and graft failure were 79, 79, 16 and 6%, respectively. There were three transplant-related deaths. Thirteen patients are alive with Lansky/Karnofsky score of 100. This intensified treatment protocol was well tolerated with no significant increase in toxicity. The excellent results obtained with this new preparative regimen allow us to recommend it for second transplantation for patients with thalassemia recurrence.Bone Marrow Transplantation (2008) 42, 397–404; doi:10.1038/bmt.2008.175; published online 23 June 2008 [ABSTRACT FROM AUTHOR]

Presents a study that showed the fate of chronic myeloid leukemia patients treated with bone marrow transplantation (BMT) or non-BMT approaches at a center. Definitions of disease stage and relapse; Definition of transplant-related mortality; Comparison between the characteristics of the transplant and non-transplant groups.

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. Bone Marrow Transplantation (2001) 27, 45–51. [ABSTRACT FROM AUTHOR]

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... [ABSTRACT FROM AUTHOR]

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. Bone Marrow Transplantation (2000) 25, 745–749. [ABSTRACT FROM AUTHOR]

Despite conventional and new therapies for the treatment of chronic GVHD (cGVHD), this syndrome continues to account for significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. With the expanded use of allogeneic peripheral blood stem cell transplantation, matched unrelated as well as mismatched related donors there is an increased incidence of cGVHD that poses a new clinical challenge. Over the past 10 years some new agents have been used, particularly, as a salvage therapy for the treatment of cGVHD. Many of the new agents discussed in this paper may have a role in the future as a therapy for cGVHD. Randomized clinical trials must be performed earlier in the course of cGVHD to establish the efficacy of these new drugs. Bone Marrow Transplantation (2000) 25 , 689–696. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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 FROM AUTHOR]

This study investigates the effect of fetal liver transplantation in reconstituting hemopoiesis in supralethally irradiated rats. Different cell doses of fetuses at the embryonic age of 15 and 18 days were compared to equivalent cell doses of adult bone marrow cells. Although the frequency of engraftment ranged between 75 and 100% in all the groups of animals studied, the survival rate at 30 days after TBI did not show any significant difference between the fetal liver and the bone marrow treated recipients. The bone marrow transplants performed in littermate rats almost doubled the percentage of survivors at 30 days and showed a cell dose relationship suggesting that, in the closed colony of random-bred rats used, the mortality after bone marrow and fetal liver transplants was mainly due to graft-versus-host-disease. Antibiotic prophylaxis and treatment during the experiment did not modify the results in a separate group of fetal liver and bone marrow transplanted rats. In the rat model system used in this set of experiments fetal liver did not reveal any advantage over bone marrow transplantation. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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 β-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 FROM AUTHOR]

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 FROM AUTHOR]

To obtain further insight into gonadal function, a series of 50 prepubertal patients with β-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 17β-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 FROM AUTHOR]

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 FROM AUTHOR]