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C D Buckner

Publications and source records attributed to C D Buckner.

At least 55 records · Page 3Linked to original sources
PubMed1997

Effect of different chemotherapy regimens on peripheral-blood stem-cell collections in patients with breast cancer receiving granulocyte colony-stimulating factor.

PURPOSE: To evaluate the effects of chemotherapy regimens on peripheral-blood stem-cell (PBSC) yields in patients with breast cancer who receive granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: One hundred patients with breast cancer received cyclophosphamide 4 g/m2 for dose (CY) (n = 10), CY and etoposide 600 mg/m2 (CE) (n = 13), CE and cisplatin 105 mg/m2 (CEP) (n = 19), or CY and paclitaxel 170 mg/m2 (n = 58), followed by G-CSF. PBSC collections were initiated when the WBC count recovered to greater than 1 x 10(9)/L. A multivariate analysis was undertaken to evaluate the effects of different chemotherapy regimens and patient variables on PBSC collections as measured by the yield of CD34+ cells. RESULTS: The medians of average daily CD34+ cell yields for patients who received paclitaxel plus CY, CE, and CEP with G-CSF were 12.9, 11.03, and 5.37 x 10(6)/kg, respectively, compared with 2.02 x 10(6)/kg in the reference group that received CY with G-CSF (P = < .0001, .002, and .09, respectively). On first-day collections, patients who received paclitaxel plus CY, CE, and CEP with G-CSF yielded medians of 11.07, 8.09, and 3.52 x 10(6) CD34+ cells/kg, respectively, compared with 0.90 x 10(6)/kg in the reference group that received CY with G-CSF (P = .0006, .02, and .09, respectively). The number of previous cycles of chemotherapy, previous radiotherapy, marrow involvement, and phase and stage of disease did not have statistically significant effects on CD34+ cell yield. CONCLUSION: Combination chemotherapy regimens were superior to single-agent CY for the mobilization of CD34+ cells.

Antigens, CD34↗
PubMed1997

Collection of peripheral blood stem cells following administration of paclitaxel, cyclophosphamide, and filgrastim in patients with breast and ovarian cancer.

PURPOSE: To determine the toxicities and efficacy of paclitaxel, cyclophosphamide (Cy), and recombinant human granulocyte-colony stimulating factor (filgrastim) administered for mobilization and collection of peripheral blood stem cells (PBSC) in patients with breast and ovarian cancer. METHODS: One hundred and forty-one patients with breast (n = 115) or ovarian cancer (n = 26) received paclitaxel 170 mg/m2 and Cy 2 gm/m2 (n = 42) or paclitaxel 200 mg/m2, Cy 3 gm/m2 (n = 99), and filgrastim (6 micrograms/kg/day) followed by collection of PBSC by apheresis. RESULTS: The 2 dose levels of paclitaxel and Cy tested were well tolerated. The median yield of CD34+ cells from all patients was 6.53 x 10(6)/kg (range, 0.11-51.76) collected with a median of 2 aphereses (range, 1-8). The target dose of 2.5 x 10(6) CD34+ cells/kg was achieved in 85% of patients. The mean daily collection of CD34+ cells was 5.46 x 10(6)/kg for patients receiving 200 mg/m2 of paclitaxel and 3 gm/m2 of Cy as compared to 2.77 for patients receiving the lower doses (p = 0.0005). Increasing the dose of paclitaxel and Cy did not significantly increase the fraction of patients achieving a target dose of 2.5 x 10(6) CD34+ cells/kg (87% vs 81%, p = 0.367) but did increase the fraction achieving a target of 5.0 x 10(6) CD34+ cells/kg (73% vs 45%, p = 0.002). The mean daily collection of CD34+ cells for patients who had received only 1 prior chemotherapy regimen was 6.59 x 10(6)/kg as compared to 3.47 for patients who had received more than 1 prior chemotherapy regimen (p < 0.0001). Prior radiation therapy (p = 0.003) and patient performance status (p = 0.047) were adverse risk factors for achieving a target dose of > or = 2.5 x 10(6) CD34+ cells/kg. CONCLUSIONS: The combination of paclitaxel, Cy, and filgrastim can be administered with acceptable toxicity, allowing collection of adequate quantities of PBSC from the majority of patients with breast and ovarian cancer. Increasing the doses of paclitaxel and Cy increased the number of CD34+ cells collected and decreased the number of apheresis procedures necessary to collect target cell doses. However, increasing drug doses did not increase the fraction of patients yielding the minimum CD34+ target dose of 2.5 x 10(6)/kg. Collection of PBSC early in the disease course is the best strategy to assure optimal CD34+ cell doses in all patients.

Adult↗
PubMed1997

Methotrexate and cyclosporine for graft-vs.-host disease prevention: what length of therapy with cyclosporine?

One hundred three patients with leukemia, aplastic anemia, or myelodysplastic syndrome were treated by marrow transplantation from genotypically HLA-identical siblings (n = 92) or HLA haploidentical family members differing for one HLA antigen on the nonshared haplotype (n = 11). To prevent graft-vs.-host disease (GVHD), they were administered postgrafting immunosuppression with a short course of intermittent methotrexate with daily cyclosporine for no more than 11 days. Customarily, we have given cyclosporine for 180 days after transplant. In the current study, we asked whether cyclosporine could be stopped earlier without affecting the risk of chronic GVHD. By day 60, patients who never had acute GVHD, or whose acute GVHD had resolved, were randomized to have cyclosporine stopped (n = 52) or continued for the usual 180 days (n = 51). Results were analyzed with a median follow-up of 9.3 years after transplant, and showed that patients in whom cyclosporine was discontinued on day 60 had a significantly more rapid onset (p = 0.001), but not a significantly higher overall incidence of chronic GVHD than those in whom the drug was stopped on day 180 (43 vs. 54%; p = 0.26). Transplant-related mortality was comparable among patients without preceding acute GVHD, regardless of when cyclosporine was discontinued (11% for both study arms). However, transplant-related mortality appeared to increase among patients with preceding acute GVHD in whom cyclosporine was stopped by day 60 (38 vs. 17%). Results suggest that cyclosporine can safely be discontinued early in patients who never had evidence of acute GVHD, while those with preceding acute GVHD would benefit from a longer course of the drug. Because of the relatively small sample sizes, these results would best be treated as promising preliminary findings that should be confirmed in larger randomized studies.

Adult↗
PubMed1997

High-dose busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell transplantation in patients with aggressive lymphoma or relapsed Hodgkin's disease.

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy with busulfan (Bu), melphalan (Mel), and thiotepa (TT), and of autologous peripheral blood stem cell (PBSC) infusion in patients with aggressive non-Hodgkin's lymphoma (NHL) or relapsed Hodgkin's disease (HD). Forty patients, 23 with intermediate (n= 18) or high-grade (n=5) NHL and 17 with HD received Bu (12 mg/kg), Mel (100 mg/kg), TT (450-500 mg/m2) [corrected], and autologous PBSC infusion. Of 27 patients with more advanced disease, 16 had primary refractory disease, 8 were in refractory relapse, and 3 were in third remission. Of 13 patients with less advanced disease, 7 were in untreated or responding first relapse and 3 were in second remission, whereas 3 with high-grade NHL were in first remission. Twenty-nine patients (73%) had received prior radiotherapy (RT) prohibiting a total-body irradiation (TBI)-based conditioning regimen. The projected 2-year probabilities of survival, event-free survival, and relapse for all patients were 0.60, 0.46, and 0.31 (0.85, 0.85, and 0.15 for patients with less advanced disease and 0.48, 0.30, and 0.37 for patients with more advanced disease). The probability of nonrelapse mortality in the first 100 days was 0.17. Severe idiopathic pneumonia syndrome was not observed in any patients with less advanced disease and in only one patient with more advanced disease. A regimen of BuMelTT is well tolerated in patients with aggressive NHL or relapsed HD, and results obtained to date are at least equivalent to other published regimens, including TBI-based regimens. This regimen appears to be a particularly attractive alternative for patients who have already received dose-limiting RT and should be evaluated further in prospective, randomized studies.

Adolescent↗
PubMed1996

Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy.

Sixteen patients with advanced hematologic malignancies were transplanted with HLA-identical allogeneic peripheral blood stem cells (PBSCs) that were selected for CD34+ cells by an avidin-biotin immunoadsorption technique. The median age of patients was 48 years (range, 37 to 67). Patients received 12.0 or 13.2 Gy of total body irradiation followed by 120 mg/kg of cyclophosphamide. Normal donors received 16 mg/kg of granulocyte-colony stimulating factor on days 1 to 6 followed by PBSC harvests on days 4 to 7. PBSC harvests were processed each day on a single avidin-blotin column containing an antibody to the CD34 antigen and processed cells were infused without cryopreservation daily for 4 consecutive days. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine alone for 5 patients and CSA plus methotrexate for 11 patients. A median of 18.64 (6.74 to 34.97) x 10(8) CD34+ cells/kg patient body weight were collected from each donor. A median of 8.96 (2.62 to 17.34) x 10(8) CD34+ cells/kg patient body weight were recovered after avidin-biotin adsorption which represented a median CD34+ cell yield of 53% (18% to 77%) with a median purity of 62% (34% to 82%). There was a reduction in CD3+ cells from a median of 557.26 (227.73 to 677.77) x 106/kg to 0.73 x 10(4)/kg (0.40 to 3.65), in CD4+ cells from 351.72 (194.47 to 520.11) x 10(6)/kg to 0.40 (0.15 to 1.03) x 10(4)/kg and in CD8+ cells from 169.74 (53.34 to 325.83) x 10(6)/ kg to 0.32 (0.12 to 2.71) x 10(4)/kg representing a median 2.8 (2.19 to 3.14) log reduction in T cells. One patient died of infection on day 3 posttransplant and was unevaluable for recovery of neutrophils. The median day to recovery of 500 neutrophils/mL was 15 (8 to 26) in the remaining 15 patients. Six of 16 patients falled to achieve a platelet count of 20,000/mL before death on days 3 to 97 of transplant-related complications. The median day to achieving platelets of 20,000 mL in the remaining 10 patients was 11 (7 to 31). Eight of 16 patients (50%) died between 3 and 97 days posttransplant, 7 of transplant-related causes, and 1 of progressive disease. Grade 2-4 acute GVHD occurred in 12 out of 14 (86%) and grades 3-4 in 6 out of 14 (43%) evaluable patients. Six of 8 evaluable patients developed clinical chronic GVHD and 1 developed subclinical chronic GVHD. Bone marrow and/or peripheral blood chimerism studies in 12 evaluable patients showed 97% to 100% donor type in 11 patients with 1 patient in relapse showing 40% donor cells 60 to 90 days posttransplant. Four of 16 patients (25%) are alive and disease-free 312 to 576 days after transplant. There were no episodes of graft failure or rejection. This study shows that allogeneic transplantation using CD34+ selected PBSC results in prompt and sustained engraftment. CD34+ selection, as employed in this preliminary study, however, resulted in an apparently higher rate of acute and chronic GVHD. However, The sample size is quite small and precludes a more definitive conclusion regarding GVHD.

Adult↗
PubMed1996

Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome.

Between September 1987 and December 1994, 80 patients with multiple myeloma (MM) received high-dose busulfan and cyclophosphamide without (n = 57) or with modified total body irradiation (n = 23) followed by marrow from allogeneic donors. At transplant, 71% of the patients had disease that was refractory to chemotherapy. Thirty-five patients died of transplant-related causes within 100 days and 11 deaths occurred later. The actuarial probabilities of survival and progression-free survival were .24 +/- 0.17 and .20 +/- 0.10 at 4.5 years. Complete remissions were obtained in 36% of patients who had actuarial probabilities of survival and event-free survival of .50 +/- 0.21 and .43 +/- 0.17 at 4.5 years. In a multivariate analysis, adverse risk factors for outcome endpoints included: transplantation greater than 1 year from diagnosis; beta-2 microglobulin > 2.5 at transplant; female patients transplanted from male donors; patients who had received greater than eight cycles of chemotherapy before transplant and Durie stage 3 disease at the time of transplant. These results indicate that allografting for patients with MM can result in long-term disease-free survival for a minority of patients. Efforts to reduce transplant-related mortality should focus on earlier transplantation, less toxic treatment regimens, better supportive care, and improved prevention and treatment of graft-versus-host disease (GVHD).

Adult↗
PubMed1996

Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation.

Allogeneic peripheral blood stem cell (PBSC) transplants from HLA-identical siblings were performed in 37 patients with advanced hematologic malignancies. Outcomes were compared to a historical group of 37 similar patients with advanced hematologic malignancies receiving bone marrow (BM) transplants from HLA-identical donors. The PBSC group and historical BM group were well matched for diagnosis, disease stage, age, and graft-versus-host disease (GVHD) prophylaxis. Patients received PBSC transplants between 1993 to 1995 while BM patients were treated between 1989 to 1994. Engraftment, measured by the time to reach a peripheral neutrophil count > 500/L and platelet count > 20,000/microL without transfusions, occurred on days 14 and 11 in the patients transplanted with PBSC compared to days 16 and 15 in the patients receiving BM (P = .00063, .00014). The PBSC group required a median of 8 U of red blood cells and 24 U of platelets compared to 17 U of red blood cells and 118 U of platelets for BM transplant recipients (P = .0005, .0001). The estimated risks of developing grades 2 to 4 acute GVHD were 37% for the PBSC group and 56% for the BM group (P = .18), while the estimated risks of grades 3 to 4 acute GVHD were 14% for the PBSC group and 33% for the BM group, P = .05). Chronic GVHD occurred in 7 of 18 evaluable patients receiving PBSC and 6 of 23 evaluable patients receiving BM, P = .5. The estimated risks of transplant-related mortality at 200 days were 27% versus 45% (P = .33) relapse were 70% versus 53% (P = .27) and of overall survival were 50% and 41% (P = .39) for patients transplanted with PBSC or BM, respectively. This retrospective comparison suggests that compared to marrow transplantation from HLA-identical donors, allogeneic PBSC transplantation from HLA-identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of acute or chronic GVHD.

Adult↗
PubMed1996

Tumor-specific aneuploidy not detected in CD19+ B-lymphoid cells from myeloma patients in a multidimensional flow cytometric analysis.

Aneuploidy and lg light chain restriction were used as separate, independent tumor specific markers to study 26 patients with multiple myeloma to determine whether bone marrow B cells, as defined by CD19 expression, are clonally related to myeloma plasma cells. Specimens were characterized using multidimensional flow cytometry to identify the presence of clonality in both the B lymphoid and plasma cell populations using both surface and cytoplasmic staining with antibodies specific for kappa or lambda lg light chain In none of the patients with multiple myeloma were CD19+ cells found to be clonally restricted to kappa or lambda. The monoclonal plasma cells (MPC) were found to be uniformly negative for CD10, CD19, and CD34, while the CD19+ B lymphoid cells present within the samples expressed normal intensities and relationships of these antigens, which allowed them to serve as internal positive controls. Combined analysis of call surface antigen expression and DNA content allowed plasma cell populations to be characterized for aneuploidy without interference from normal bone marrow cells. The MPC, detected on the basis of bright CD38 expression (CD38+2), demonstrated DNA aneuploidy in 65% of cases (DNA index range of 0.9 to 1.3). These aneuploid DNA distributions had typical cell cycle profiles (including G1,S and G2+M) expected of a proliferating population. In all cases, DNA aneuploidy was confined almost entirely to the CD38+2, CD19- malignant plasma cells, while cells expressing CD19 were diploid. These results support the concept that myeloma is a disease process mediated by self-replicating, late compartments of B-cell ontogeny.

ADP-ribosyl Cyclase↗
PubMed1996

Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation.

Patients successfully treated with a marrow transplant often have concerns about fertility and pregnancy. This study was performed to determine pregnancy outcome among patients who had received high-dose chemotherapy alone or with total-body irradiation (TBI) and marrow transplantation for aplastic anemia or hematologic malignancy. Records of 1,326 postpubertal and 196 prepubertal patients currently more than 12 years of age after marrow transplant in Seattle from August 1971 to January 1992 were reviewed to determine the patients with normal gonadal function and pregnancies. Among 708 postpubertal women, 110 recovered normal ovarian function and 32 became pregnant. In addition, nine formerly prepubertal girls with normal gonadal function became pregnant. Among 618 postpubertal men, 157 recovered testicular function and partners of 33 became pregnant. An additional two formerly prepubertal men had partners who became pregnant. Forty-one female patients and partners of 35 male patients had 146 pregnancies after transplant. All 76 patients responded to a questionnaire requesting pregnancy history, outcome, infant birth weight, and congenital anomalies information for all clinically recognized pregnancies. There were 115 live births among 146 (79%) pregnancies. Spontaneous abortion terminated four of 56 (7%) pregnancies for 28 female cyclophosphamide (CY) recipients and six of 16 (37%) pregnancies for 13 TBI recipients (P = .02). Partners of 28 male CY recipients had four of 62 (6.4%) pregnancies terminate with spontaneous abortion, but there were no spontaneous abortions among eight pregnancies of five TBI recipients' partners. Preterm delivery occurred for eight of 44 (18%) and five of eight (63%) live births for 24 CY and eight TBI female recipients (P = .01). This 25% incidence among all female patient pregnancies is higher than the expected incidence of 8% to 10% (P = .0001). The 13 preterm deliveries resulted in 10 low birth weight ([LBW] 1.8 to 2.24 kg) and three very low birth weight ([VLBW] < or = 1.36 kg) infants, for an overall incidence of 25%, which is higher than the expected incidence of 6.5% for the general population (P = .0001). Twelve of the 13 premature infants survive. Congenital anomalies were seen among two of 52 (3.8%) live-born infants of female and six of 63 (9.5%) live-born infants of male patients, which is not different from the 13% of single congenital anomalies reported for the general population. These data demonstrate that clinically recognized pregnancies among women who have received a marrow transplant incorporating TBI are likely to be accompanied by an increased risk of spontaneous abortion. Pregnancies among all women who received a marrow transplant are likely to be accompanied by preterm labor and delivery of LBW or VLBW babies who do not seem to be at an increased risk of congenital anomalies. However, determination of possible adverse effects of parental exposure to high-dose alkylating agents with or without TBI on children born posttransplant requires longer, additional follow-up.

Adult↗
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

Optimization of peripheral blood stem cell mobilization.

Peripheral blood stem cells (PBSC) are increasingly utilized in lieu of marrow for hematopoietic support due to the ease of collection and the rapid kinetics of recovery relative to bone marrow (BM). Neutrophil and platelet recovery times after PBSC transplantation average less than 8-12 days after infusion in contrast to the usual two to four weeks experienced after BM transplantation. This has simplified autologous transplantation and made it safer because patients require fewer days of antibiotic and blood component support and are discharged earlier from the hospital. The administration of hematopoietic growth factors during recovery from high-dose chemotherapy increases the number of circulating hematopoietic progenitor cells to levels as much as 1,000-fold greater than levels normally found in blood and 10-50 times greater than with chemotherapy alone. More recently, it has been shown that adequate numbers of PBSC can be collected using growth factors alone without prior chemotherapy. Although not yet universally accepted, the CD34+ cells content of PBSC appears to be the single most powerful predictor of recovery kinetics in patients receiving myeloablative therapy and PBSC infusion. Infusion of > 5 x 10(6) CD34+ cells/kg is associated with a rapid engraftment of neutrophils and platelets, although successful engraftment has also been reported with the infusion of 2.5-5 x 10(6) CD34+ cells/kg. By measuring the CD34 or colony forming units-granulocyte-macrophage (CFU-GM) content of PBSC collections, mobilization chemotherapy and cytokine regimens, age, marrow disease, prior radiation and prior chemotherapy treatment have been found to be important factors influencing the numbers of stem cells collected. The current challenge for clinical investigators is to improve methods of identifying patients who will fail to mobilize sufficient numbers of PBSC prior to collection and to utilize new strategies for stem cell mobilization. The relative ease of collection and the rapid engraftment after myeloablative therapy suggest that PBSC will likely supplant marrow for both allogeneic and autologous transplantation in the next five years.

Antigens, CD34↗
PubMed1996

Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS-related acute myeloid leukaemia.

Allogeneic marrow transplantation using related marrow donors for myelodysplasia (MDS) and acute myeloid leukaemia (AML) arising from MDS results in 35-56% actuarial disease-free survival. Because the use of unrelated donors has not been well-characterized, we report on the outcome of 52 patients with MDS or MDS-related AML consecutively treated between 1987 and 1993 with unrelated donor marrow transplantation. The median age was 33 (range 1-53) years. 33 patients received chemotherapy and total body irradiation and the remainder busulfan and cyclophosphamide. The donors were phenotypically identical at the HLA-A, B and Dw/DRB1 loci in 34 cases and mismatched for one HLA locus in 17 cases and two loci in one case. Marrow was non-T-cell depleted and methotrexate with cyclosporine or FK506 was used for postgrafting immunosuppression. The 2-year disease-free survival, relapse, and non-relapse mortality rates were 38%, 28% and 48%, respectively. One patient who relapsed survives disease-free after withdrawal of immunosuppressive therapy. 16/19 survivors have a performance status of 90-100%. Patients with MDS in transformation or with AML had a significantly higher risk of relapse than patients with less advanced disease (P = 0.0014). Increased non-relapse mortality was significantly associated with higher age, longer disease duration before transplant, lower neutrophil count on admission and, unexpectedly, being seronegative for cytomegalovirus. We conclude that the outcome with transplantation using unrelated donors is similar to reported results using related donors and that a meaningful proportion of eligible patients with an otherwise incurable disease may be cured with this treatment. However, mortality from the transplant procedure is high and future studies should focus on reducing toxicity.

Acute Disease↗
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

Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients.

PURPOSE: The pharmacokinetics of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (HCY) were studied in 14 patients being prepared for bone marrow transplantation with either busulfan (BU)/CY (n = 7) or CY/total-body irradiation (TBI) (n = 7) to determine whether exposure to CY and its proximate toxic metabolite HCY is modulated by other agents used in the preparative regimen. PATIENTS AND METHODS: HCY was assayed by a new method that stabilized the metabolite at bedside. In BU/CY patients (who also received phenytoin), CY clearance was 112% greater (P = .0014), half-life 54% less (P = .0027), peak HCY concentration in plasma/CY dose 113% greater (P = .0006), and the ratio of area under the plasma concentration-time curves (AUCs) of HCY to CY 166% greater (P = .0116) than in CY/TBI patients. The ratio of the AUC of HCY/CY dose was 48% greater in BU/CY patients than in CY/TBI patients when one CY/TBI patient with an apparent impaired ability to eliminate HCY was excluded from analysis. In CY/TBI patients, there was an inverse correlation between the AUC of HCY and that of CY (R2 = .740, P = .028). Also, the ratio of the AUC of HCY/CY dose was correlated with the average concentration of BU at steady-state (Css, Bu) (R2 = .646, P = 0.29). Variability in CY and HCY pharmacokinetics among the 14 patients overall was pronounced, with the highest variability (15-fold) observed in the ratio of the AUC of HCY to that of CY. CONCLUSION: Prior administration of BU and/or phenytoin significantly alters exposure to CY and HCY. Interpatient variability in HCY exposure at a given CY dose is substantial.

Adult↗
PubMed1996

Busulfan, cyclophosphamide and fractionated total body irradiation for allogeneic marrow transplantation in advanced acute and chronic myelogenous leukemia: phase I dose escalation of busulfan based on targeted plasma levels.

A previous phase I study determined that the maximum tolerated dose (MTD) of busulfan (BU) that could be given with a fixed dose of cyclophosphamide (CY) of 50 mg/kg and total body irradiation (TBI) dose of 12.0 Gy was 7 mg/kg. A phase II study was carried out in patients with advanced myeloid malignancies receiving allogeneic transplants without improvement in outcome as compared to historical controls. In that study, steady-state concentration (Css) of BU in 13 patients receiving a fixed dose of BU varied from 209 to 735 ng/ml. In an attempt to decrease the variability of the Css of BU, a study of targeting specific plasma concentrations was performed. In this study, BU dose was adjusted up or down based on first dose pharmacokinetics. The first dose level evaluated was 7.5 mg/kg with a target BU plasma level of 460 ng/ml. Six patients were entered at this level and the median BU plasma concentration achieved was 410 (range 390-533). One of six patients developed grade 3-4 regimen-related toxicities (RRT). Dose level II was a target of 559 ng/ml with a starting oral dose of BU of 9.6 mg/kg. Twelve patients were entered at this level and median plasma BU level was 548 (range 427-689). Three of 12 (25%) patients developed grade 3-4 RRTs and this was considered to be the MTD. The actuarial probability of grade II-IV acute GVHD was 0.70. Eight of 21 evaluable patients (38%) developed chronic GVHD. Of 18 patients who died, seven died of relapse at a median of 160 days (range 65-353) and 11 (61%) died of causes other than relapse at a median of 152 days (range 18-570). The actuarial probabilities of DFS, relapse and relapse-free mortality at 2 years in all patients were 0.13, 0.50 and 0.75, respectively. This study showed that targeted BU plasma levels within 10% of target can reliably be achieved with a bias of -2.07% and mean absolute error of 7.47%. Overall, targeting made a -31.8% to 100% in plasma BU Css as compared to expected BU Css based on first dose pharmacokinetics if targeting were not performed in this study. Thus targeting avoided much of the variability in BU concentrations seen in other studies. When compared with our previous phase II experience in same group of patients receiving same regimen, dose escalation of BU based on targeted plasma levels did not improve the outcome.

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