High-dose melphalan and allogeneic peripheral blood stem cell transplantation for treatment of early relapse after allogeneic transplant.
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Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count >0.5 x 10(9)/l and to a platelet count >20 x 10(9)/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence. (+info)
Treatment of leukemic relapse following unrelated umbilical cord blood transplantation with interleukin-2: potential for augmenting graft-versus-leukemia and graft-versus-host effects with cytokines.
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In comparison to bone marrow, umbilical cord blood has decreased intrinsic immune responsiveness allowing transplantation across HLA barriers with lower rates of graft-versus-host disease. However, laboratory models have also suggested that cord blood may be extremely sensitive to stimulation by cytokines. We report an adult recipient of an ex vivo expanded, HLA-mismatched, unrelated cord blood transplant who experienced a late extramedullary relapse while still in hematologic remission. Despite demonstrating immune tolerance on minimal immunosuppressive agents, a brief course of intravenous interleukin-2 resulted in rapid, aggressive graft-versus-host and graft-versus-leukemia reactions. This case highlights the potential of cytokine immunomodulation following cord blood transplantation, but also suggests caution in stimulating these cells. (+info)
Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease.
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Although allogeneic transplantation can be curative for patients with sickle cell disease, the toxicity of conditioning regimens has precluded its use in adults with significant end-organ damage. Newer conditioning regimens have been developed that are less toxic and that may broaden the applicability of allogeneic transplantation in this disorder. We report two adults with end-stage sickle cell disease, who underwent allogeneic transplantation from an HLA-identical sibling donor after conditioning with fludarabine/melphalan and ATG. Both patients had been extensively transfused and one had multiple RBC antibodies. One of the patients also had end-stage renal disease, and was dialysis dependent. Engraftment occurred promptly in both patients. Both achieved 100% donor chimerism and both were free of pain crises after transplant. The first patient died of a respiratory failure related to chronic graft-versus-host disease (GVHD) on day 335 after transplantation. The second patient developed severe gastro-intestinal GVHD and TTP and died on day 147 after transplantation. Conditioning with fludarabine/melphalan and ATG followed by allogeneic stem cell transplantation resulted in prompt and reliable engraftment in adults with end-stage sickle cell disease. The incidence of severe GVHD was unacceptably high and may be related to the ethnicity of the patients or to the inflammatory state associated with pre-existing sickle cell disease. (+info)
Umbilical cord blood transplantation for Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI).
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Severe Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is usually fatal by early adulthood. Bone marrow transplantation is the only form of definitive enzyme replacement therapy available. A 5-year-old boy with Maroteaux-Lamy syndrome has successful recovery of bone marrow and enzymatic functions after umbilical cord blood transplant from his unaffected HLA-identical brother. Busulphan (16 mg/kg) and cyclophosphamide (200 mg/kg) were used as preparative chemotherapy with short methotrexate and long cyclosporin as prophylaxis against graft-versus-host disease (GVHD). A total of 6.08 x 10(7)/kg nucleated cells and 2.92 x 10(5)/kg CD34+ cells were transplanted with neutrophil engraftment achieved on day 26. There was no evidence of acute and chronic GVHD. Fifteen months after transplant, a normal level of N-acetylgalactosamine-4-sulphatase activity was achieved despite mixed chimerism. There was clinical improvement of hepatosplenomegaly, facial and skin features, joint mobility and resolution of suppurative middle ear effusion. He returned to school and continued to perform well in academic studies. We report here the first successful umbilical cord blood transplant as treatment of Maroteaux-Lamy syndrome. (+info)
Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.
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BACKGROUND: Since allogeneic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematologic cancers, we sought to induce analogous graft-versus-tumor effects in patients with metastatic renal-cell carcinoma by means of nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. METHODS: Nineteen consecutive patients with refractory metastatic renal-cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of a peripheral-blood stem-cell allograft from an HLA-identical sibling or a sibling with a mismatch of a single HLA antigen. Cyclosporine, used to prevent graft-versus-host disease, was withdrawn early in patients with mixed T-cell chimerism or disease progression. Patients with no response received up to three infusions of donor lymphocytes. RESULTS: At the time of the last follow-up, 9 of the 19 patients were alive 287 to 831 days after transplantation (median follow-up, 402 days). Two had died of transplantation-related causes, and eight from progressive disease. In 10 patients (53 percent) metastatic disease regressed; 3 had a complete response, and 7 had a partial response. The patients who had a complete response remained in remission 27, 25, and 16 months after transplantation. Regression of metastases was delayed, occurring a median of 129 days after transplantation, and often followed the withdrawal of cyclosporine and the establishment of complete donor-T-cell chimerism. These results are consistent with a graft-versus-tumor effect. CONCLUSIONS: Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy. (+info)
In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation.
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A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m(2) on days -7 to -3; and melphalan, 140 mg/m(2) on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor-mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD. (+info)
Phenotype of the engrafting stem cell in mice.
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The present data on engraftment into non-myeloablated mice strongly suggest that engraftment is determined by host-donor ratios as opposed to opening space. Theoretically, if the ratios of donor to host stem cells could be altered, especially without causing toxicity to the host animal, then the phenotypic readout could be increased in a clinically applicable manner. To research this further, we investigated low-dose irradiation (100 cGy) for its effects on marrow, spleen and peripheral blood counts, as well as engrafting stem cell levels. We found a transient but significant depression in the white blood cell and platelet counts in the peripheral blood which returned to normal by two weeks, with no apparent deleterious effect on the animals. However, the same irradiation dose after two months impaired marrow repopulation and reduced engraftment potential to less than 20% capacity. These results suggested that we could obtain much higher phenotypic readouts after engraftment with this model; thus, we assessed the engraftment of 40 million male BALB/c marrow cells into female hosts exposed to 100 cGy at two, five and eight months after cell infusion. The resultant high levels of chimerism, reaching 100% in many cases, strongly suggest that the key to engraftment in these models is host-donor stem cell ratios. One important issue relative to the above finding is whether cytokine-stimulated proliferating stem cells have irreversibly lost engraftment capacity or whether changes in the engraftment capacity are of a plastic nature, possibly related to cell cycle transit. A number of experiments following engraftment have shown that the engraftment defect is reversible and can be repeatedly lost and regained during the initial portions of a cytokine-stimulated culture. The above results suggest that, at least at the more primitive stem cell level, hematopoietic stem cell regulation may in part be based on a cell cycle model rather than a hierarchical system. (+info)
T lymphocytes determine the development of xeno GVHD and of human hemopoiesis in NOD/SCID mice following human umbilical cord blood transplantation.
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Over the past decade the human-immunodeficient mouse chimera has become a well-established in vivo model for studying the human immune system and/or hemopoiesis. Under certain experimental conditions and depending on the composition of the human cell graft, the recipient mice may develop a fatal disease, designated as discordant xenogenic graft-versus-host-disease (GVHD), which differs in target tissues and histopathology from allogenic GVHD. Experimental evidence is presented that immunodeficient mice are equally susceptible to allogenic GVHD as normal immunocompetent mice. Whole human cord blood and distinct cellular subpopulations from a single cord blood harvest were transplanted in NOD/severe combined immunodeficient mice and the repopulation of human cells was monitored over time. Depending on the ratio of lymphocytes to hemopoietic stem cells, proliferation of human T cells, hemopoiesis or a combination of the two is observed in widely varying proportions. When the graft contains a preponderance of lymphocytes, fatal protracted discordant xenogenic GVHD develops. Mice receiving purified CD34 cells survived up to 207 days in good health with more than 95% human cells in the bone marrow. In those mice all lineages (B and T lymphocytes, monocytes, granulocytes, erythrocytes and thrombocytes) were demonstrated in the bone marrow and peripheral blood. (+info)