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Biomedical subjects

R A Clift

Publications and source records attributed to R A Clift.

At least 19 recordsLinked to original sources
PubMed2001

Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies.

In the early 1990s, 4 randomized studies compared conditioning regimens before transplantation for leukemia with either cyclophosphamide (CY) and total-body irradiation (TBI), or busulfan (Bu) and CY. This study analyzed the long-term outcomes for 316 patients with chronic myeloid leukemia (CML) and 172 patients with acute myeloid leukemia (AML) who participated in these 4 trials, now with a mean follow-up of more than 7 years. Among patients with CML, no statistically significant difference in survival or disease-free survival emerged from testing the 2 regimens. The projected 10-year survival estimates were 65% and 63% with Bu-CY versus CY-TBI, respectively. Among patients with AML, the projected 10-year survival estimates were 51% and 63% (95% CI, 52%-74%) with Bu-CY versus CY-TBI, respectively. At last follow-up, most surviving patients had unimpaired health and had returned to work, regardless of the conditioning regimen. Late complications were analyzed after adjustment for patient age and for acute and chronic graft-versus-host disease (GVHD). CML patients who received CY-TBI had an increased risk of cataract formation, and patients treated with Bu-CY had an increased risk of irreversible alopecia. Chronic GVHD was the primary risk factor for late pulmonary disease and avascular osteonecrosis. Thus, Bu-CY and CY-TBI provided similar probabilities of cure for patients with CML. In patients with AML, a nonsignificant 10% lower survival rate was observed after Bu-CY. Late complications occurred equally after both conditioning regimens (except for increased risk of cataract after CY-TBI and of alopecia with Bu-CY).

Adolescent↗
PubMed1999

Bone marrow transplantation in adult thalassemic patients.

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.

Adolescent↗
PubMed1998

Unrelated and HLA-nonidentical related donor marrow transplantation for thalassemia and leukemia. A combined report from the Seattle Marrow Transplant Team and the International Bone Marrow Transplant Registry.

Allogeneic marrow transplantation is curative therapy for thalassemia, but fewer than 30% of patients have an HLA-identical sibling marrow donor. Selection of alternative donors of hematopoietic stem cells (unrelated individuals or HLA-nonidentical family members) has been aided by establishment of world-wide donor registries now exceeding 3.6 million volunteers and by DNA-based HLA typing to more closely match potential donors. Coupled with improved methods to control graft-versus-host disease and prevent fungal and cytomegalovirus infection, remarkable progress has been made in alternative donor transplantation. For patients 50 years of age or younger, with recently diagnosed chronic myelogenous leukemia (CML) in chronic phase, 1- and 5-year survivals after HLA-A, B, DRB1 identical unrelated marrow transplantation in Seattle are 82% and 74%, respectively. These results are essentially identical to outcome in similar patients given HLA-matched sibling allografts. However, the world-wide number of alternative donor transplants for thalassemia remains limited to date: 4 unrelated and 60 HLA-nonidentical related transplants have been reported to the IBMTR since 1969 with actuarial overall survival of 75%. Using the paradigm of CML, it is likely that access to curative therapy of thalassemia will improve with optimal HLA typing and donor selection early in the course of disease.

Bone Marrow Transplantation↗
PubMed1998

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS: Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS: The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS: Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.

Adolescent↗
PubMed1997

Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (C(SS)BU) during the dosing interval were measured for each patient. The mean C(SS)BU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with C(SS)BU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with C(SS)BU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). C(SS)BU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with C(SS)BU above and below the median (P = .33). There was no statistically significant association of C(SS)BU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly C(SS)BU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Adult↗
PubMed1997

Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy.

The purpose of this report is to describe the results of stem cell transplantation as initial treatment for secondary acute myeloid leukemia (AML). Forty-six patients (median age 42 years) with secondary AML (17 therapy-related, 29 myelodysplasia-related) who had not received remission induction chemotherapy underwent allogeneic (n = 43) or syngeneic (n = 3) transplantation. The 5-year actuarial disease-free survival was 24.4%, and the cumulative incidences of relapse and nonrelapse mortality were 31.3% and 44.3%, respectively. Lower peripheral blood blast count was associated with a lower risk of relapse (P = .05) and shorter time from AML diagnosis to transplant was associated with a lower risk of nonrelapse mortality (P = .02) and improved disease-free survival (P = .026). Patients with therapy-related secondary AML tended to have lower disease-free survival (P = .16) and a higher relapse rate (P = .16) than patients whose leukemia was not therapy-related. The results of these 46 previously untreated patients were compared to 20 patients (median age 36 years, 12 therapy-related, 8 myelodysplasia-related) transplanted with chemotherapy-sensitive disease after induction chemotherapy (first complete remission [n = 6], second complete remission [n = 3], first untreated relapse [n = 11]). We found no statistically significant difference in outcome between these 2 groups of patients. These results suggest that prompt transplantation should be considered after diagnosis of secondary AML or, if possible, high-risk myelodysplasia, particularly in patients with low peripheral blast counts. Innovative transplant strategies are needed to reduce the high risks of relapse and nonrelapse mortality seen in this patient population.

Adolescent↗
PubMed1997

Allografting for chronic myeloid leukaemia.

Marrow transplantation from human leukocyte antigen (HLA) matched related donors offers a high probability of prolonged treatment-free survival for patients with chronic myeloid leukaemia in chronic phase. Delay, patient and donor gender, patient age and previous palliation with busulphan predict outcome in this setting. Because of the median age at diagnosis and the genetics of the HLA system, transplants from HLA-matched related donors are available to less than 15% of newly diagnosed patients. Alternative donors include relatives with minor degrees of incompatibility and HLA-compatible unrelated volunteers. The probability of finding suitable unrelated donors has increased with the development of a network of registries now containing more than 3.6 million donors worldwide. Survival prospects will be improved by transplantation earlier in the course of the disease, better-matched donors and the discovery of new approaches for the prevention of graft-versus-host disease and opportunistic infections.

Bone Marrow Transplantation↗
PubMed1996

Marrow transplantation for patients with thalassemia: results in class 3 patients.

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.

Adolescent↗
PubMed1996

Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors.

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3-year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.

Actuarial Analysis↗
PubMed1996

Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony stimulating factor.

Recombinant G-CSF has been given to over 150 normal donors for the collection of allogeneic or syngeneic peripheral blood stem cells (PBSC). G-CSF was found to be well-tolerated with mild-moderate bone pain, edema and mild thrombocytopenia being the observed side effects. To date, approximately 90 unmodified primary PBSC transplants from HLA-identical related donors have been performed with engraftment that is, in general, considerably more rapid than marrow. Acute graft-versus-host-disease (GVHD), grades II-IV occurred in 47% of patients and grades III-IV in 17%. Despite the infusion of one to two logs more T cells, these results are not remarkably different than would be expected with marrow transplantation. There have also been successful reports of using G-CSF mobilized allogeneic PBSC following second transplants for graft rejection or relapse. Allogeneic PBSC have been infused without reconditioning for correction of graft failure and unmodified or CD34 selected PBSC have also been given with marrow to augment the dose of hematopoietic cells. Further studies are needed to define the role of allogeneic PBSC for transplantation, refine PBSC mobilization and collection techniques and to evaluate the long-term effects of cytokines in normal donors.

Animals↗
PubMed1996

Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors.

PURPOSE: To determine if an intensive preparative regimen of busulfan (BU), cyclophosphamide (CY), and total-body irradiation (TBI) could improve outcome after marrow transplantation for advanced morphology myelodysplasia (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML]) compared with that obtained with conventional CY/TBI and to analyze prognostic factors for transplantation for myelodysplasia. PATIENTS AND METHODS: A phase II study was conducted of 31 patients (median age, 41 years) treated with BU (7 mg/kg), CY (50 mg/kg), TBI (12 Gy), and human leukocyte antigen (HLA)-matched (n = 23) or -mismatched (n = 2) related or unrelated donor (n = 6) marrow transplantation. Results were compared with 44 historical control patients treated with CY (120 mg/kg) and TBI. RESULTS: The 3-year actuarial disease-free survival (DFS) rate was similar for the BU/CY/TBI group and the CY/TBI group (23% v 30%, P = .6), but there were trends toward lower relapse rates (28% v 54%, P = .27) and higher nonrelapse mortality rates (68% v 36%, P = .12) among the current patients compared with historical controls. Multivariate analysis showed that a normal karyotype pretransplant and the use of methotrexate as part of posttransplant immunosuppression were associated with improved survival and reduced nonrelapse mortality. Univariate analysis showed significant differences in relapse rates based on marrow source (57% for HLA genotypically matched marrow v 18% for all others, P = .04) and on disease morphology (66% for RAEB-T v 38% for RAEB and CMML, P = .05). CONCLUSION: Patients with advanced morphology myelodysplasia tolerated the intensified BU/CY/TBI preparative regimen and reduced posttransplant immunosuppression poorly. Novel transplant procedures are needed to reduce relapse rates without increasing nonrelapse mortality rates. In addition, transplantation before progression to RAEB-T, if possible, may reduce the risk of relapse.

Adolescent↗
PubMed1996

High-dose therapy followed by autologous hematopoietic stem-cell infusion for patients with multiple myeloma.

PURPOSE: To evaluate the outcome of patients with multiple myeloma (MM) who received high-dose therapy followed by autologous bone marrow (BM) or peripheral-blood stem-cell (PBSC) infusion. PATIENTS AND METHODS: Sixty-three consecutive patients with MM received autologous BM (n = 13) or PBSC with or without BM (n = 50) following regimens that contained busulfan (Bu) and cyclophosphamide (Cy) (n = 18), modified total-body irradiation (TBI) followed by Bu and Cy (n = 36), or Bu, melphalan, and thiotepa (n = 9). Two thirds of the patients had resistant disease and 69% had received more than 6 months of previous chemotherapy. RESULTS AND CONCLUSION: Recovery of peripheral-blood cell counts was more rapid in patients who received PBSC with or without BM than in patients who received BM alone. Sixteen of 63 patients (25%) died of complications of treatment within 100 days. Nineteen (40%) of 48 assessable patients achieved a complete response (CR), 23 (48%) had a partial response (PR), and six (12%) had no response. The probabilities of survival and survival without relapse or progression for all 63 patients at 3.0 years were .43 and .21, respectively. The probability of relapse or progression at 3 years was .69, and 17 patients (27%) have died of progressive MM. The probabilities of survival and relapse-free survival at 3 years for the 19 patients who achieved a CR were .42 and .17, respectively. In the multivariate analysis, beta2-microglobulin levels more than 2.5 micrograms/mL, more than two regimens of prior therapy and eight cycles of treatment, time to transplant longer than 3 years from diagnosis, and prior radiation were associated with adverse outcomes. Additional strategies, such as intervention earlier in the disease course, improved treatment regimens, sequential high-dose treatments, and posttransplant therapies may improve outcome of selected patients with MM.

Adult↗