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      Feasibility of Non-TBI Conditioning with Busulfan and Fludarabine for Allogeneic Stem Cell Transplantation in Lymphoid Malignancy

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          Abstract

          Background/Aims

          This retrospective study evaluated the transplantation outcomes of patients with adult lymphoid malignancies who received chemotherapy-based conditioning with busulfan and fludarabine (BuFlu) and busulfan and cyclophosphamide (BuCy2).

          Methods

          Thirty-eight patients (34 with acute lymphoblastic leukemia and 4 with lymphoblastic lymphoma) were included in the current study. The conditioning regimen was BuCy2 for 14 patients and BuFlu for the remaining 24 patients. Eight and 13 patients were high risk disease in the BuCy2 and BuFlu groups, respectively.

          Results

          The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 56.5% and 55.2% and that of extensive chronic GVHD 17.0% and 55.6% (p = 0.018) for the BuFlu and BuCy2 groups, respectively. The 3-year relapse rate was 27.8% and 31.4% and 3-year overall survival 34.3% and 46.8% for the BuFlu and BuCy2 groups, respectively. Treatment-related mortality (TRM) was significantly lower in the BuFlu group (16.9%) than in the BuCy2 group (57.1%, p = 0.010). In multivariate analyses, the BuFlu regimen was identified as an independent favorable risk factor for TRM (hazard ratio [HR], 0.036; p = 0.017) and extensive chronic GVHD (HR, 0.168; p = 0.034).

          Conclusions

          Our BuFlu regimen would appear to be an acceptable conditioning option for lymphoid malignancies, including high-risk diseases. It was safely administered with a lower TRM rate than BuCy2 conditioning.

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          Most cited references28

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          In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).

          An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P < or = .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.
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            Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients.

            (1980)
            This study of chronic graft-versus-host disease (GVHD) describes the clinical, pathologic and laboratory features, and the causes of morbidity and mortality in 20 patients who received allogeneic marrow transplants from HLA identical sibling donors. Chronic GVHD is a pleiotrophic syndrome with variability in the time of onset, organ systems involved and rate of progression. The clinical-pathologic features resemble an overlap of several collagen vascular diseases with frequent involvement of the skin, liver, eyes, mouth, upper respiratory tract, esophagus and less frequent involvement of the serosal surfaces, lower gastrointestinal tract and skeletal muscles. Major causes of morbidity are scleroderma with contractures and ulceration, dry eyes and mouth, pulmonary insufficiency and wasting. Chronic GVHD has features of immune dysregulation with elevated levels of eosinophils, circulating autoantibodies, hypergammaglobulinemia and plasmacytosis of viscera and lymph nodes. In this study, three patients had limited chronic GVHD with relatively favorable prognosis characterized by localized skin involvement and/or hepatic disease without chronic aggressive histology. Most patients, however, had extensive disease with a progressive course. Survival was largely determined by the presence or absence of serious recurrent bacterial infections. The over-all severity of disease was best assessed by using the Karnofsky performance rating.
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              Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO).

              One hundred nine patients with hematologic malignancies, undergoing bone marrow transplants (BMT) from unrelated donors, were randomized in 2 consecutive trials to receive or not to receive antithymocyte globulin (ATG) in the conditioning regimen, as follows: (A) 54 patients (median age, 28 years; 39% with advanced disease) were randomized to no ATG (n = 25) versus 7.5 mg/kg rabbit ATG (Thymoglobulin; Sangstat, Lyon, France) (n = 29); (B) 55 patients (median age, 31 years, 71% with advanced disease) were randomized to no ATG (n = 28) versus 15 mg/kg rabbit ATG (n = 27). Grade III-IV graft-versus-host disease (GVHD) was diagnosed in 36% versus 41% (P =.8) in the first and in 50% versus 11% (P =.001) in the second trial. Transplant-related mortality (TRM), relapse, and actuarial 3-year survival rates were comparable in both trials. In fact, despite the reduction of GVHD in the second trial, a higher risk for lethal infections (30% vs 7%; P =.02) was seen in the arm given 15 mg/kg ATG. Extensive chronic GVHD developed overall more frequently in patients given no ATG (62% vs 39%; P =.04), as confirmed by multivariate analysis (P =.03). Time to 50 x 10(9)/L platelets was comparable in the first trial (21 vs 24 days; P =.3) and delayed in the ATG arm in the second trial (23 vs 38 days; P =.02). These trials suggest that (1) 15 mg/kg ATG before BMT significantly reduces the risk for grade III-IV acute GVHD, (2) this does not translate to a reduction in TRM because of the increased risk for infections, and (3) though survival is unchanged, extensive chronic GVHD is significantly reduced in patients receiving ATG.
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                Author and article information

                Journal
                Korean J Intern Med
                KJIM
                The Korean Journal of Internal Medicine
                The Korean Association of Internal Medicine
                1226-3303
                2005-6648
                March 2012
                28 February 2012
                : 27
                : 1
                : 72-83
                Affiliations
                [1 ]Department of Hematology/Oncology, Kyungpook National University Hospital, Daegu, Korea.
                [2 ]Department of Laboratory Medicine, Kyungpook National University Hospital, Daegu, Korea.
                Author notes
                Correspondence to Sang Kyun Sohn, M.D. Department of Hematology/Oncology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Korea. Tel: 82-53-420-5587, Fax: 82-53-426-2046, sksohn@ 123456knu.ac.kr
                Article
                10.3904/kjim.2012.27.1.72
                3295992
                22403503
                3c524125-ef99-4142-98ec-dbecebe53074
                Copyright © 2012 The Korean Association of Internal Medicine

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 June 2011
                : 24 August 2011
                : 16 November 2011
                Categories
                Original Article

                Internal medicine
                busulfan,drug therapy,precursor cell lymphoblastic leukemia-lymphoma,fludarabine

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