Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group.
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Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%, P =.01) and hemorrhagic cystitis (32% v 10%, P =.003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the busulfan-treated group versus 47% in the TBI group (P =.05). Death from GVHD was more common in the busulfan group (22% v 3%, P <.001). Obstructive bronchiolitis occurred in 26% of the busulfan patients but in only 5% of the TBI patients (P <.01). Complete alopecia developed in 8 busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group (P <.001). Cataracts occurred in 5 busulfan-treated patients and 16 TBI patients (P =.02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively (P =.004). Leukemia-free survival (LFS) in patients with early disease was 68% in busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the busulfan group versus 49% in the TBI group (P <.01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively. (+info)
Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens.
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Allogeneic bone marrow transplantation (BMT) is a common treatment of hematologic malignancies. Recurrence of the underlying malignancy is a major cause of treatment failure. Donor-derived cytotoxic T lymphocytes (CTLs) specific for patients' minor histocompatibility antigens (mHags) play an important role in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivities. mHags HA-1 and HA-2 induce HLA-A*0201-restricted CTLs in vivo and are exclusively expressed on hematopoietic cells, including leukemic cells and leukemic precursors, but not on fibroblasts, keratinocytes, or liver cells. The chemical nature of the mHags HA-1 and HA-2 is known. We investigated the feasibility of ex vivo generation of mHag HA-1- and HA-2-specific CTLs from unprimed mHag HA-1- and/or HA-2-negative healthy blood donors. HA-1 and HA-2 synthetic peptide-pulsed dendritic cells (DCs) were used as antigen-presenting cells (APC) to stimulate autologous unprimed CD8(+) T cells. The ex vivo-generated HA-1- and HA-2-specific CTLs efficiently lyse leukemic cells derived from acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) patients. No lytic reactivity was detected against nonhematopoietic cells. Sufficient numbers of the CTLs can be obtained for the adoptive immunotherapy purposes. In conclusion, we present a feasible, novel therapy for the treatment for relapsed leukemia after BMT with a low risk of GVHD. (+info)
Bone marrow transplantation for severe aplastic anemia: the Barcelona Hospital Clinic experience.
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BACKGROUND AND OBJECTIVE: The outcome of patients with severe aplastic anemia (SAA) has improved considerably over the last decades. Bone marrow transplantation (BMT) is the treatment of choice in young patients who have an HLA-identical sibling donor. This study analyzes the outcome and factors related to survival in patients with SAA receiving BMT in our institution. DESIGN AND METHODS: Between March 1978 and December 1996, 49 consecutive patients received an HLA-identical sibling marrow transplant for SAA. Median age was 21 years (range, 4 to 47) and 15 (31%) were women. Median interval from diagnosis to transplant was 2.6 months (range, 0.5 to 159). Between 1978 and 1982 all patients were conditioned with cyclophosphamide (CY) alone and received methotrexate (MTX) until day 102 as graft-versus-host disease (GvHD) prophylaxis. From 1983 most patients received CY and thoraco-abdominal irradiation (TAI) as the conditioning regimen and cyclosporin A (CSA) as GvHD prophylaxis. RESULTS: Survival probability at 10 years was 55 +/- 7% with a median follow-up for the surviving patients of 8.5 years. The incidences of graft failure, grade II to IV acute GvHD, and chronic GvHD were 21%, 39.5% and 31%, respectively. In multivariate analysis three factors adversely influenced survival: a) age > or = 30 years (p = 0.05); b) > or = 10 transfusion units pre-BMT (p = 0.008); and c) use of long course MTX for GvHD prophylaxis (p = 0.01). One case of squamous-cell carcinoma occurred in a TAI-treated patient 13 years post-transplantation. INTERPRETATION AND CONCLUSIONS: BMT is effective in young patients with SAA who have an HLA-identical sibling donor, particularly if minimally transfused pre-transplant. The introduction of TAI and CSA to our preparative regimen has led to a remarkably increased survival. (+info)
Treatment of multiple myeloma.
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BACKGROUND AND OBJECTIVE: Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies. The standard treatment with intermittent courses of melphalan and prednisone (MP) was introduced more than 30 years ago and, since then there has been little improvement in event-free and overall survival (EFS & OS). The aim of this article is to review: 1) the role of initial chemotherapy (ChT), maintenance treatment with alpha-interferon and salvage ChT, 2) the results of high-dose therapy (HDT) followed by allogeneic or autologous stem cell transplantation (allo-SCT and auto-SCT), and 3) the most important supportive measures. EVIDENCE AND INFORMATION SOURCES: The authors of this review have been actively working and contributing with original investigations on the treatment of MM during the last 15 years. In addition, the most relevant articles and recent abstracts published in journals covered by the Science Citation Index and Medline are also reviewed. STATE OF THE ART AND PERSPECTIVES: The importance of avoiding ChT in asymptomatic patients (smoldering MM) is emphasized. The criteria and patterns of response are reviewed. MP is still the standard initial ChT with a response rate of 50-60% and an OS of 2-3 years. Combination ChT usually increases the response rate but does not significantly influence survival when compared with MP. Exposure to melphalan should be avoided in patients in whom HDT followed by auto-SCT is planned, in order to not preclude the stem cell collection. The median response duration to initial ChT is 18 months. Interferon maintenance usually prolongs response duration but in most studies does not significantly influence survival (a large meta-analysis by the Myeloma Trialists' Collaborative Group in Oxford is being finished). In alkylating-resistant patients, the best rescue regimens are VBAD or VAD. In patients already resistant to VBAD or VAD and in those in whom these treatments are not feasible we recommend a conservative approach with alternate day prednisone and pulse cyclophosphamide. While HDT followed by autotransplantation is not recommended for patients with resistant relapse, patients with primary refractory disease seem to benefit from early myeloablative therapy. Although results from large randomized trials are still pending in order to establish whether early HDT intensification followed by auto-SCT is superior to continuing standard ChT in responding patients, the favorable experience with autotransplantation of the French Myeloma Intergroup supports this approach. However, although the complete response rate is higher with intensive therapy, the median duration of response is relatively short (median, 16 to 36 months), with no survival plateau. There are several ongoing trials comparing conventional ChT with HDT/autoSCT in order to identify the patients who are likely to benefit from one or another approach. With allo-SCT there is a transplant-related mortality ranging from 30 to 50% and also a high relapse rate in patients achieving CR. However, 10 to 20% of patients undergoing allo-SCT are long-term survivors (> 5 years) with no evidence of disease and, consequently, probably cured. The use of allogeneic peripheral blood stem cells (PBSC) in order to speed the engraftment and also the use of partially T-cell depleted PBSC which can decrease the incidence of graft-versus-host disease are promising approaches. In the setting of allo-SCT, donor lymphocyte infusion is an encouraging strategy in order to treat or prevent relapses. Finally, important supportive measures such as the treatment of anemia with erythropoietin, the management of renal failure and the use of bisphosphonates are reviewed. (+info)
Management of human cytomegalovirus infection and disease after allogeneic bone marrow transplantation.
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BACKGROUND AND OBJECTIVE: Human cytomegalovirus (HCMV) infection and disease remain a major cause of morbidity and mortality after bone marrow transplantation. HCMV disease, especially pneumonitis, may be treated with ganciclovir and immunoglobulin but even so the outcome is poor with mortality rates of 30-70%. It is therefore imperative to treat HCMV infection before it develops into disease. The aim of this article is to describe the main strategies used to prevent HCMV infection and to improve the survival after CMV disease in bone marrow transplant recipients. INFORMATION SOURCES: In the present review, we examined personal papers in this field and articles published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: Major advances have been made in preventing HCMV infection and disease through two different approaches, both of which reduce HCMV induced morbidity and mortality: In pre-emptive therapy, patients are given ganciclovir when HCMV infection is first identified and this is continued 3-4 months after transplantation; in prophylactic therapy ganciclovir is given to all patients at risk of HCMV disease from engraftment up to 3-4 months post transplantation. Each strategy has advantages and disadvantages and there is no evidence for the superiority of one over the other since the overall survival is the same and the incidence of death from HCMV disease is similar. PERSPECTIVES: The use of more sensitive tests such as HCMV PCR or antigenemia may improve the outcome but probably will not eradicate all HCMV disease. Future possible strategies could include adoptive transfer of CD8+ HCMV-specific cytotoxic T lymphocytes clones derived from the donor marrow or boosting donor or patient immunity using subunit anti-HCMV vaccines such as gB or pp65. (+info)
Recombinant human granulocyte-macrophage colony-stimulating factor accelerates engraftment kinetics after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia.
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BACKGROUND AND OBJECTIVE: The use of recombinant human granulocyte-macrophage stimulating factor (rhGM-CSF) has been shown to be well-tolerated and to reduce post-transplantation morbidity in adults undergoing HLA-identical allogeneic bone marrow transplantation (BMT). There is however, limited experience in children. DESIGN AND METHODS: We performed a prospective, comparative multicenter trial using rhGM-CSF after allogeneic BMT in children with acute lymphoblastic leukemia (ALL). The study comprised 24 patients with ALL who received rhGM-CSF and 22 patients with ALL who did not receive rhGM-CSF. There were no statistically significant differences in the demographic characteristics between the rhGM-CSF-treated and untreated groups. rhGM-CSF was given at a dose of 10 micrograms/kg/day infusion over 4 hours from day +1 until +28 or until the absolute neutrophil count (ANC) was > or = 1 x 10(9)/L. All patients received HLA-identical sibling marrow and cyclosporine alone for graft-versus-host disease (GvHD) prophylaxis. The number of cells infused was similar in both groups. A software program (Statview 4.0, Abacus Concept, Inc., Berkeley, CA, USA) was used for statistical analysis. RESULTS: The median of days to achieve ANC > or = 0.5 x 10(9)/L was shorter in the rhGM-CSF-treated patients (14 days vs 18.5 days; p < 0.0001). Patients who received rhGM-CSF had a lower incidence of grade III-IV mucositis. The duration of hospital stay was significantly shorter in patients who received rhGM-CSF (31 days vs 45 days; p < 0.005). No differences in GvHD severity, relapse or survival were observed. At the dose and schedule used in the present study, rhGM-CSF was well-tolerated and no side effects were observed. INTERPRETATIONS AND CONCLUSIONS: rhGM-CSF at a dose of 10 micrograms/kg/day in children with ALL undergoing allogeneic BMT is well tolerated, accelerates neutrophil and platelet engraftment, reduces the intensity and severity of mucositis and permits a more rapid discharge from hospital. (+info)
Polymorphisms for the size of heterochromatic regions allow sex-independent quantification of post-BMT chimerism targeting metaphase and interphase cells.
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BACKGROUND AND OBJECTIVE: Fully quantitative cytological techniques for the analysis of hemopoietic chimerism are very limited and largely restricted to sex-chromosome detection after sex-mismatched bone marrow transplants (BMTs). The aim of the present investigation was to assess the usefulness of autosomal polymorphisms for the size of heterochromatic regions in the identification of donor and recipient cells and therefore in the quantification of the hemopoietic chimerism after sex-matched BMT. DESIGN AND METHODS: Hemopoietic chimerism was followed up in 3 transplanted patients targeting a polymorphism for the size of the pericentromeric heterochromatin (PCH) of chromosome 9, uncovered by restriction endonuclease (RE) in situ digestion (REISD) with the RE Sau3A, to differentiate donor and recipient cells on conventional bone marrow chromosome preparations. RESULTS: The polymorphism for the size of the PCH of chromosome 9 allowed differentiation of donor and recipient cells targeting both metaphase and interphase nuclei. The misidentification error for the polymorphism for the size of HPC of chromosome 9 was estimated as 1% for metaphases and 6-11% for interphases. The 3 cases studied showed complete chimerism in the first post-BMT sample analyzed, which was maintained in 2 of them. One patient relapsed and showed transient mixed chimerism. One month later, this patient achieved a second complete remission, showing complete chimerism again. In this patient, who received a sex-mismatched BMT, chimerism was also quantified by sex-chromosome identification using established methods, such as conventional cytogenetics and FISH, and the results obtained were similar to those rendered by Sau3A-REISD. INTERPRETATION AND CONCLUSIONS: The polymorphism for the size of the PCH of chromosome 9 uncovered by Sau3A-REISD allows accurate quantification of the hemopoietic chimerism after sex-matched BMT. (+info)
Prevention of graft-versus-host disease in high risk patients by depletion of CD4+ and reduction of CD8+ lymphocytes in the marrow graft.
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From March 1994 to September 1997, 30 patients with hematological malignancies (12 ANLL, 10 CML, four ALL and four multiple myeloma) received HLA-identical allogeneic bone marrow transplants with the marrow graft selectively depleted of CD4+ lymphocytes and the CD8+ cell content adjusted to 1x10(6)/kg. Total depletion of CD4+ and partial depletion of CD8+ lymphocytes was carried out by an immunomagnetical method. All patients were considered as having high risk for developing GVHD by at least one of the following criteria: patient age >35 years; donor age >35 years; donor multiparity or marrow from an unrelated donor. Twenty-four cases received marrow from an identical sibling and six from an unrelated donor. In order to assess the role of methotrexate (MTX) in addition to cyclosporin A (CsA) after transplant, patients were randomly assigned to received either CsA alone (n = 15) or CsA plus a short course of MTX (n = 15). No case of primary graft failure was observed, but two patients developed late graft failure. Six patients presented grade II acute GVHD and no case of severe III-IV GVHD was seen. The actuarial probability of developing grade II-IV acute GVHD was 25.9+/-9.6% for the entire population. Patients receiving post-transplant CsA + MTX had significantly less probability of acute GVHD than those receiving CsA exclusively (6.7+/-6.4% vs. 50.5+/-17.8%, P = 0.03) and the schedule of post-transplant immunosuppression was the only factor associated with the incidence of acute GVHD in a multivariate analysis. The actuarial incidence of chronic GVHD for the entire population was 31.8+/-12.5, and there was no significant difference between both groups with additional prophylaxis. Four patients with CML and three with ANLL relapsed: the actuarial probability of remaining in complete remission for all patients was 53.6+/-17.3%. For patients with acute leukemia, the probability of remaining in complete remission did not differ significantly between those transplanted in first complete remission and those receiving a transplant in more advanced phases of the disease (87.5+/-11.6% vs. 72.9+/-16.5%; P = 0.44). The incidence of mixed chimerism assessed by PCR was 34%. Nineteen patients are alive between 2 and 43 months post-transplant, the probability of overall survival being 57.8+/-10.4%. Our data indicate that this method of selective T cell depletion is very effective in preventing acute GVHD in high risk patients, particularly when used in combination with post-transplant CsA + MTX. (+info)