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Biomedical subjects

R A Clift

Publications and source records attributed to R A Clift.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1996

Phase II study of high-dose busulfan, melphalan and thiotepa with autologous peripheral blood stem cell support in patients with malignant disease.

The purpose of this study was to determine the toxicities and potential effectiveness of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) followed by autologous peripheral blood stem cell (PBSC) infusion in patients with a variety of diseases. A phase II clinical trial of Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC infusion in 104 patients with breast cancer (n = 48), malignant lymphoma (n = 25), ovarian cancer (n = 13), multiple myeloma (n = 7) and other malignancies (n = 11) was performed. Sixty-two patients were treated in an academic medical center and 42 in a community cancer center. Grade 3-4 regimen-related toxicities occurred in 14% of patients, causing regimen-related mortality in six (6%) patients with an overall transplant-related mortality of 9%. Transplant-related deaths occurred in 6/62 patients (10%) treated in an academic medical center and in 3/42 (7%) treated in a community cancer center. Complete remissions (CR) were achieved in 1/17 (6%) patients with refractory stage IV breast cancer, 4/4 patients with responsive stage IV breast cancer, 6/13 (46%) with more-advanced lymphoma and 4/4 with less-advanced lymphoma. These patients are alive and disease-free a median of 712, 279, 461 and 404 days after transplant, respectively. Nineteen of 22 patients with stage II-III breast cancer remain alive and disease-free a median of 365 days after transplant. Complete remissions were also seen in 4/9 patients with ovarian cancer and 3/7 with multiple myeloma. The Bu/Mel/TT regimen followed by autologous PBSC infusion is associated with acceptable morbidity and mortality, appears to have significant activity in patients with breast cancer and is well tolerated in the adjuvant setting of stage II-III breast cancer. Bu/Mel/TT also appears to have significant activity in patients with lymphoma, multiple myeloma and possibly ovarian cancer. Further phase II-III studies are warranted in patients with these and other malignancies.

Adolescent↗
PubMed1996

High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: comparison of autologous bone marrow and peripheral blood stem cells.

Consecutive patients with non-Hodgkin's lymphoma (NHL, n = 133) or Hodgkin's disease (HD, n = 20) were treated with 12.0 Gy of fractionated total body irradiation, etoposide 60 mg/kg, and CY 100 mg/kg followed by infusion of autologous hematopoietic stem cells. Seventy-nine patients received purged (n = 62) or unpurged BM (n = 17), and 74 received unpurged PBSCs alone (n = 56) or with BM (n = 18). The median day for achieving a sustained granulocyte count of 0.5 x 10(9)/I was 14 range (7-66) for BM recipients and 10 (7-30) for PBSC +/- BM recipients (P = 0.03). A platelet count of 20 x 10(9)/I was achieved at a median of day 24 (6-145) in BM recipients and day 11 (range, 7-56) in PBSC +/- BM recipients (P = 0.007). The median number of platelet units transfused was 86 (0-1432) for BM recipients and 30 (6-786) for PBSC +/- BM recipients (P = 0.001). The median number of hospital days was 36 (10-88) for BM recipients and 27 (14-76) for PBSC +/- BM recipients (P = 0.0001). The unadjusted Kaplan-Meier (KM) estimates of survival, event-free survival (EFS) and relapse at 2 years were 0.57, 0.45 and 0.43 for patients receiving BM and 0.55, 0.36 and 0.59 for patients receiving PBSC +/- BM. After adjusting for confounding variables, the estimated relative risk (RR) of death from any cause was 0.92 (P = 0.75), of relapse was 1.25 (P = 0.39), of non-relapse mortality was 0.71 (P = 0.42) and of mortality and/or relapse was 1.17 (P = 0.48) for patients receiving PBSC +/- BM as compared to BM. For 46 patients with NHL receiving unpurged PBSC alone, the unadjusted KM estimate of relapse was 0.61 compared with 0.48 for 52 comparable patients receiving purged BM, while the RR for relapse for patients receiving unpurged PBSCs was 1.37 (P = 0.33) after adjusting for other significant covariates. These data confirm previous observations that patients who receive PBSC +/- BM have faster engraftment, fewer transfusions and shorter hospital stays than patients who receive only BM. There were no statistically significant differences between the two groups in survival, relapse, death from causes other than relapse and event-free survival.

Adolescent↗
PubMed1995

Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment.

A retrospective study compared posttransplant engraftment parameters in 203 patients with myelofibrosis (MF) with those in a population of 203 matched controls without MF. There were no significant differences between these groups in the proportions of patients who died without achieving engraftment and in the disease-free survival distributions. Furthermore, comparisons between the two groups of patients reaching the respective endpoints showed no differences in the time distributions for reaching 0.5 or 1.0 x 10(9)/L granulocytes, but the time to platelet transfusion independence was 3 days longer in patients with MF. In further analysis, results for 33 patients with severe MF were compared with those of their respective controls. The proportions of patients with severe MF who died without reaching these engraftment endpoints and the disease-free survival distributions in the two groups were similar. Among patients who reached the respective engraftment endpoints, there was no statistically significant difference in the pace of granulocyte recovery. In patients with severe MF, there was a 7-day delay in the time to reach platelet transfusion independence and a 2-day delay in the time to reach red blood cell independence, but the differences were not statistically significant. The present results do not substantiate concerns raised by earlier studies. MF may delay the time to reach platelet independence by approximately 3 days and may increase platelet transfusion requirements, but no other perturbation of hematopoietic reconstitution was apparent.

Adolescent↗
PubMed1995

A retrospective analysis of the long-term effect of splenectomy on late infections, graft-versus-host disease, relapse, and survival after allogeneic marrow transplantation for chronic myelogenous leukemia.

The present study was performed as a retrospective analysis of the role of pretransplant splenectomy to determine the incidence of late bacterial infections, acute and chronic graft-versus-host disease (GVHD), relapse, and survival among 358 patients receiving HLA-identical marrow grafts for chronic myelogenous leukemia. Sixty-eight (19%) of the 358 patients had undergone splenectomy before transplantation. There was a trend towards more grade II-IV acute GVHD among splenectomized patients, but this was not significant in the multivariate analysis. The incidence of chronic GVHD was similar for splenectomized and nonsplenectomized patients. Late infectious complications did not significantly differ between splenectomized and control patients (rates per patient year were 0.16 and 0.14, respectively). The overall risk of leukemic relapse was significantly increased for splenectomized patients (56% v 32% for controls, P = .001) and control patients with splenomegaly (P < .0001). Splenectomy and splenomegaly remained significant and independent hazards for relapse in the multivariate analysis (hazard ratio [HR], 1.82, P = .029; and HR, 1.49, P = .002; respectively). Relapse was also increased in patients with advanced disease (HR, 2.95; P = .0001), in patients with T-cell-depleted marrow (HR, 4.51; P = .0001), and in the female donor and male recipient combination (HR, 1.74; P = .044). Patients with splenectomy had an increased overall mortality (HR, 1.18), but this was not statistically significant in the multivariate analysis. In summary, our study showed no significant influence of splenectomy on late posttransplant infections, acute or chronic GVHD, or overall survival. There was no evidence that splenectomy decreased recurrence of chronic myelogenous leukemia.

Abscess↗
PubMed1995

Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients.

We studied 346 patients after bone marrow transplantation (BMT) for chronic myeloid leukemia (CML) for the presence of the bcr-abl transcript detected by the polymerase chain reaction (PCR) to understand the frequency and implication of a positive test. A total of 634 samples of BM and/or peripheral blood were obtained for PCR analysis between 3 and 192 months after BMT. A positive PCR test at 3 months post-BMT was not statistically significantly associated with an increased risk of relapse compared with PCR-negative patients. However, a positive PCR assay at 6 months and beyond was highly associated with subsequent relapse. The Kaplan-Meier estimate of relapse for patients testing PCR-positive at 6 to 12 months was 42% versus 3% for PCR-negative patients (P < .0001). The Kaplan-Meier estimate of survival at 4 years for the PCR-positive patients was 74% compared with 83% for the PCR-negative group (P = .002). Multivariable analysis indicated that a PCR-positive result at 6 to 12 months post-BMT, the type of BMT donor (allogeneic matched donor v mismatched or unrelated), and the presence of acute GVHD were independent risk factors for subsequent relapse. The relative risk (RR) for relapse for patients PCR-positive at 6 to 12 months post-BMT was 26.1 (95% confidence interval, 8.9 to 76.1, P < .0001). The outcome of long-term patients (> 36 months post-BMT) who tested PCR-positive was much better, as 15 of 59 (25%) tested positive for bcr-abl, but only one patient relapsed. There was a 91% concordance between PCR tests of simultaneously obtained BM and peripheral blood. These analyses show that the PCR assay of the bcr-abl fusion transcript 6 to 12 months post-BMT is an independent predictor of subsequent relapse which provides an opportunity for early therapeutic intervention.

Adolescent↗
PubMed1995

High-dose cyclophosphamide, carmustine, and etoposide followed by allogeneic bone marrow transplantation in patients with lymphoid malignancies who had received prior dose-limiting radiation therapy.

PURPOSE: To evaluate a high-dose chemotherapy regimen without total-body irradiation (TBI) followed by allogeneic (allo) bone marrow transplantation (BMT) in patients with lymphoid malignancies who had received prior dose-limiting radiotherapy. PATIENTS AND METHODS: Fifty-six patients with non-Hodgkin's lymphoma (NHL, n = 26), Hodgkin's disease (HD, n = 17), or acute lymphoblastic leukemia (ALL, n = 13) with a history of previous radiation therapy were treated with cyclophosphamide (7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2; CBV) followed by allo BMT. RESULTS: Nine of 56 patients are alive and disease-free a median of 1,091 (range, 512 to 1,784) days post-transplant. The probabilities of transplant-related mortality, relapse, and event-free survival at 2 years for the entire group of 56 patients were .62, .59, and .17, respectively. Patients who received 600 mg/m2 of carmustine had a higher incidence of grade 3 or 4 regimen-related toxicities (RRTs) (14 of 22) than did patients who received 300 mg/m2 (12 of 33; P < .04), whereas there was no difference in relapse (.34 and .53, respectively, P = .73). Fourteen of 16 patients who received allo BMT for advanced disease (n = 12) or less-advanced disease (n = 4) but who were also eligible for auto BMT relapsed (n = 4) or died of transplant-related complications (n = 10). CONCLUSIONS: Allo BMT following a high-dose CBV regimen resulted in long-term disease-free survival in 17% of patients with lymphoid malignancies who had received prior dose-limiting radiotherapy. A high incidence of transplant-related complications, especially fatal idiopathic pneumonia syndrome (IPS) and a high relapse rate limited success. Morbidity and mortality associated with carmustine 600 mg/m2 were high and were not associated with a decrease in relapse. The number of patients in this study eligible for either allo or auto BMT was limited and precluded meaningful analysis of relative effectiveness.

Adolescent↗
PubMed1995

Phase II study of busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for allogeneic bone marrow transplantation in patients with advanced myeloid malignancies.

A previous phase I dose escalation study determined that the maximum tolerated doses of busulfan and cyclophosphamide that could be combined with 12.0 Gy of total body irradiation were 7 mg/kg and 50 mg/kg, respectively. A phase II study of these three agents was carried out in 56 patients with advanced myeloid malignancies receiving allogeneic bone marrow transplants from HLA-identical donors. Cyclosporine with methotrexate or with prednisone was administered for prophylaxis against graft-versus-host disease. Grade 3 (n = 8) and 4 (n = 3) regimen-related toxicity occurred in 20% of patients, which was the maximum predicted from the phase I study. The 2-year actuarial probabilities of non-relapse mortality and relapse were 0.52 and 0.55, respectively. Fourteen patients survive, 12 in remission, 581-1761 days post-transplant. The actuarial probabilities of disease-free survival for patients with recurrent acute myeloid leukemia and advanced chronic myeloid leukemia at 2 years were 20% and 23%, respectively. When compared with our historical experience in patients receiving other treatment regimens, there was no apparent improvement in disease-free survival.

Adolescent↗
PubMed1994

Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia.

The records were reviewed of 58 patients receiving transplants in Seattle with unmanipulated marrow from HLA-identical siblings during the accelerated phase (AP) of chronic myeloid leukemia. Variables examined for association with survival and relapse included the interval from diagnosis to transplant, the reasons for categorization as AP, age, regimen, and cytomegalovirus serology. Four patients relapsed. The 4-year probabilities of survival, relapse-free survival, nonrelapse mortality, and relapse were 0.49, 0.43, 0.51, and 0.12, respectively. After completion of the stepwise multivariate analysis, age less than 38 years and categorization as AP solely on the basis of chromosomal abnormalities emerged as being independently significantly associated with improved survival. The 4-year probability of survival for the 16 patients categorized as AP because of chromosomal abnormalities and receiving transplant less than 1 year from diagnosis was 0.74. The low probability of relapse in these patients suggests that more aggressive preparative regimens are not indicated for patients receiving transplants in AP because of the increased risk of transplant-related mortality.

Acute Disease↗
PubMed1994

Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.

A prospective randomized study was conducted comparing two conditioning regimens for the treatment of patients with chronic myeloid leukemia in chronic phase by marrow transplantation from HLA identical siblings. Sixty-nine patients received 60 mg/kg of cyclophosphamide on each of 2 successive days followed by 6 fractions of total body irradiation each of 2.0 Gy (CY-TBI), and 73 patients received 16 mg/kg of busulfan delivered over 4 days followed by 60 mg/kg CY on each of 2 successive days (BU-CY). There was no significant difference between the CY-TBI and the BU-CY groups in the 3-year probabilities of survival (0.80 for both), relapse (0.13 for both), or event-free survival (CY-TBI, 0.68; BU-CY, 0.71) or in speed of engraftment or incidence of venocclusive disease of the liver. The 4-year probabilities of survival and event-free survival for patients transplanted within 1 year of diagnosis were 0.86 and 0.72, respectively, for each group. Significantly more patients in the CY-TBI group experienced major creatinine elevations. There was significantly more acute graft-versus-host disease in the CY-TBI group. Fever days, positive blood cultures, hospitalizations, and inpatient hospital days were significantly more common in the CY-TBI group than in the BU-CY group. In conclusion, the BU-CY regimen was better tolerated than, and associated with survival and relapse probabilities that compare favorably with, the CY-TBI regimen.

Adolescent↗
PubMed1994

Effect of graft-versus-host disease prophylaxis on relapse in patients transplanted for acute myeloid leukemia.

Between November 1978 and September 1988, 184 patients with acute myeloid leukemia in first remission received marrow transplants from HLA-identical siblings after conditioning with 120 mg/kg of cyclophosphamide and 12.0 Gy fractionated total body irradiation. Patients received either cyclosporine (CYA, n = 59), methotrexate (MTX, n = 82), or MTX + CYA (n = 43 as graft-versus-host disease (GVHD) prophylaxis. The probabilities of grades II-IV acute GVHD after CYA, MTX or MTX+CYA were 0.43, 0.48 and 0.28, respectively (p = 0.06). The probability of non-relapse mortality was 0.53, 0.50 and 0.42 at 4 years in patients treated with CYA, MTX, or MTX + CYA, respectively. The probability of relapse was 0.24 in patients receiving CYA, 0.24 in patients receiving MTX and 0.44 in patients receiving MTX + CYA (p = 0.02). The probability of survival at 4 years was 0.54 with CYA, 0.51 with MTX and 0.45 with MTX + CYA. A multivariate analysis of risk factors for relapse examined age, WBC at diagnosis, blast count at diagnosis, percentage of marrow blasts, FAB subtype, the number of remission induction courses to achieve a remission, maintenance therapy, consolidation therapy, marrow cell dose, donor-recipient sex, GVHD prophylaxis regimen and isolation and decontamination in laminar airflow rooms. GVHD prophylaxis with MTX + CYA was independently significantly associated with an increased risk of relapse (relative risk 2.25, p = 0.01). Acute GVHD was associated with increased non-relapse mortality (RR = 3.58, p < 0.0001). The administration of MTX + CYA did not adversely affect survival because patients receiving this regimen experienced less mortality from causes other than relapse when compared with patients receiving either CYA or MTX alone.

Adolescent↗
PubMed1994

Marrow transplants from unrelated donors.

It is now possible to access more than 1 million HLA-A, B typed volunteers willing to donate marrow. A preliminary search through the U.S. NMDP provides direct computerized access to the HLA-A, B, DR phenotypes of more than 186,000 registered donors. Fifty-one percent of preliminary searches yield at least one HLA-A, B, DR match, but a disproportional number of successful searches benefit primarily patients of Caucasian origin. Substantially greater recruitment among different racial and ethnic groups must occur if non-Caucasians are to have a better chance of finding an HLA-matched donor. Improved cooperation between registries and transplant networks in different countries remains an important goal. The optimal application of URD transplants may not be possible until an efficient and reliable worldwide marrow donor program has been established. DNA typing and matching for HLA alleles improves the timeliness of the donor search process and the precision of donor selection. HLA mismatching increases the probability and severity of GVHD, but minor mismatches for one HLA-A, B, or D/DRB1 locus does not appear to decrease survival. Although the risk of GVHD in URD transplants remains high and survival currently is not as favorable as HLA identical sibling transplants, better supportive care and GVHD control are providing a gradual improvement in the long-term disease-free survival of URD transplants.

Bone Marrow Transplantation↗
PubMed1993

A randomized controlled trial of pentoxifylline for the prevention of regimen-related toxicities in patients undergoing allogeneic marrow transplantation.

This study evaluated the effect of pentoxifylline (PTX) on the incidence of regimen-related toxicity in patients receiving allogeneic marrow transplants from related donors. All patients received a regimen of methotrexate and cyclosporine as prophylaxis against acute graft-versus-host disease (GVHD). Patients were randomized to receive PTX or a placebo for 70 days and the outcome was examined in a blinded fashion. Forty-four patients were evaluate in each study arm. PTX had no significant effect on engraftment, the incidence of GVHD, venocclusive disease of the liver, infection, the need for oxygen, posttransplant survival, or the duration of hospitalization. Patients receiving PTX were significantly more likely to develop major elevations of serum creatinine levels. PTX was poorly tolerated and induced significantly more vomiting than the placebo. PTX as administered in this randomized study was associated with significant toxicity and offered no benefit in reducing transplant-related morbidity or mortality.

Adolescent↗
PubMed1993

Marrow transplantation in patients with thalassemia responsive to iron chelation therapy.

BACKGROUND: Patients with homozygous beta-thalassemia, who have a good prognosis during treatment with conventional therapy, appear to have an especially high probability of hematologic cure with bone marrow transplantation, although the morbidity and mortality associated with such treatment are not established. METHODS: The records of all patients with thalassemia who received bone marrow transplants from HLA-identical donors in Pesaro, Italy, were examined from October 1982 through May 1992. Detailed evaluation of the outcome was conducted in the 89 patients identified as being in class 1 according to the Pesaro classification, in which hepatomegaly, portal fibrosis, and the inadequacy of iron chelation therapy are considered independent risk factors, and the patients are classified as being in class 1 if none of these factors are present, class 2 if one or two of the factors are present, and class 3 if all three factors are present. Sixty-four of the patients had been prepared for transplantation with a drug regimen in current use that includes busulfan and cyclophosphamide followed by cyclosporine as prophylaxis against acute graft-versus-host disease (protocol 6). RESULTS: There were seven deaths, all within 101 days of transplantation. Two of the 64 patients treated according to protocol 6 died. The probabilities of survival, rejection-free survival, death from causes unrelated to rejection, and rejection were 0.92, 0.85, 0.06, and 0.08, respectively, in the total group and 0.97, 0.93, 0.03, and 0.04 in the 64 patients treated according to protocol 6. Preliminary evidence suggests that there was useful unloading of tissue iron deposits. CONCLUSIONS: The high probability of cure with little early or late morbidity and mortality suggests that patients with class 1 thalassemia who have HLA-identical donors available should be treated by bone marrow transplantation. However, this was not a controlled trial, so we cannot directly compare the outcome with that of conventional treatment.

Adolescent↗