Transplantation of allogeneic peripheral blood stem cells.
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Adult↗
Biomedical subjects
W I Bensinger
Publications and source records attributed to W I Bensinger.
Busulfan, cyclophosphamide and fractionated total body irradiation for autologous or syngeneic marrow transplantation for acute and chronic myelogenous leukemia: phase I dose escalation of busulfan based on targeted plasma levels.
In a previous phase I study, it was concluded that tolerable doses of busulfan (BU), cyclophosphamide (CY) and total body irradiation (TBI) were 8 mg/kg, 60 mg/kg and 12.0 Gy, respectively, for autologous marrow transplant recipients. In an attempt to decrease the variability of BU steady-state concentration (Css) following oral dosing, a BU dose escalation study based on targeted plasma levels was performed in patients receiving autologous transplants for AML or syngeneic transplants for CML. In this study, the BU dose was adjusted up or down based on observed plasma concentration. All patients received a fixed dose of CY 60 mg/kg and TBI of 12 Gy. The first dose level evaluated was 8.6 mg/kg with a target BU Css of 511 ng/ml. Eight patients were entered at this level and the median BU Css achieved was 441 (range 253-566). One of eight patients developed grade 3-4 regimen-related toxicities (RRT). The oral dose of BU for dose level II was 10.6 mg/kg with a target Css of 632 ng/ml. Six patients were entered at this level and median BU Css achieved was 642 (range 566-674). One of six patients developed grade 3-4 RRT. The oral dose for dose level III was 12.6 mg/kg with a target BU Css of 754 ng/ml. Five patients with AML were entered at this dose level and the median plasma BU Css was 733 ng/ml (682-900). Two of five (40%) patients at dose level III developed grade 3-4 RRT which was considered excessive making dose level II the MTD. This study showed that targeted BU Css can reliably be achieved with a bias of -5.23% and mean absolute error of 11.3%. Overall, targeting made a -32.5% to 158.3% change 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 Css seen in other studies and appears to have allowed for an increase in oral dosing from 8 mg/kg to 10.6 mg/kg. Despite achieving higher and more uniform BU Css, there was no apparent effect on relapse or survival, although the number of patients evaluated was small.
Acute Disease↗
Microbial contamination of peripheral blood stem cell collections.
We prospectively evaluated microbiologic cultures for a series of 1263 peripheral blood stem cell harvests collected from 376 sequential patients. The incidence of microbial contamination was 0.23% of all samples, or 47% of samples from patients not receiving systemic antibiotics. This incidence of positive microbial cultures is less than that for cultures of bone marrow (3.8%) after harvesting and before further processing. Of the three positive cultures, two grew coagulase-negative Staphylococcus and the third, Streptococcus viridans. Two patients were reinfused with cultured-positive PBSC components, and neither exhibited the same organism in subsequent blood cultures. Although microbial contamination may occur during peripheral blood stem cell collection and cryopreservation, this report indicates that PBSC contamination does not play a conspicuous role in the infectious complications of PBSC transplantation.
Bacteriological Techniques↗
High-dose busulfan and cyclophosphamide followed by autologous transplantation in patients with advanced breast cancer.
This study was conducted to evaluate the efficacy of high-dose busulfan (BU) and cyclophosphamide (CY) in patients undergoing autologous hematopoietic stem cell transplantation for metastatic breast cancer. Twenty-two patients with stage IV breast cancer underwent autologous marrow (n = 13), peripheral blood stem cell (PBSC) (n = 6) or marrow plus PBSC (n = 3) transplantation following BU (14-16 mg/kg) and CY (120-180 mg/kg). Of 22 patients, 18 had refractory relapse, one had primary refractory disease, two had responding relapse and one had no evidence of disease (NED) at the time of transplant. Eight patients had bone only disease, six had bone plus visceral disease, and eight had loco-regional recurrent disease. The median time for diagnosis to transplant was 1124 days (range 210-2582). Staging for evaluation of response was performed 4-6 months after transplantation. Six patients were not evaluable (NE) for response because of NED at transplant (n = 1) or early death due to transplant-related complications (n = 5) (one of RSV interstitial pneumonia, two of fungal infection and two of regimen-related toxicities) occurring at a median of 17 days (range 14-59) post-transplant. The patient who was NED at time of transplant is still NED on day 336 post-transplant. Seven of the 16 evaluable patients achieved a complete response (CR) (44%), five achieved a partial response (PR) (31%) and five had no response (NR), with an overall response rate of 75%. Five of 18 (28%) patients treated in refractory relapse, and both patients treated in responding relapse achieved a CR. Of the seven patients who achieved CR, three are alive and disease-free on days 204, 276 and 752 and three relapsed on days 209, 715 and 1127 post-transplant. One patient in CR died of aspergillus pneumonia on day 306 post-transplant. The median day to progression in five patients who achieved a PR after transplantation was 335 (range 144-507). The probabilities of survival and event-free survival (EFS) at 2 years was 0.22 and 0.15, respectively for all 22 patients. The probability of EFS at 2 years for the eight patients achieving CR (including one patient who was NED at transplant) was 0.33. The probabilities of overall survival at 2 years in patients who did and did not achieve a CR after transplantation was 0.63 and 0.14, respectively (P = 0.004). These data suggest that high-dose BU-CY followed by autologous stem cell transplantation is an effective regimen in patients with advanced breast cancer demonstrating that BU is an active agent in this disease and could be incorporated into treatment regimens requiring hematopoietic stem cell support.
Adult↗
Factors influencing collection of peripheral blood stem cells in patients with multiple myeloma.
This study was performed to determine the factors influencing the collection of autologous peripheral blood stem cells (PBSC) in patients with multiple myeloma (MM) who had disease which had progressed after an initial response or who had refractory disease. Fifty-seven patients with MM underwent PBSC collections following recombinant human granulocyte colony stimulating factor (G-CSF) alone (n = 19) (16 micrograms/kg/day), cyclophosphamide (CY) (4 gm/m2 x 1) with either G-CSF (10 micrograms/kg/day) (n = 7) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (500 micrograms/m2/day) (n = 7) or cyclophosphamide (4 gm/m2 x 1) and etoposide (200 mg/m2/day x 3) (CE) with G-CSF (10 micrograms/kg/day) (n = 24). The goal was to collect 5 x 10(6) CD34+ cells/kg. Fifty of 57 patients underwent autologous transplantation with PBSC alone (n = 39) or PBSC + marrow (n = 11). The median yield of CD34+ cells was 7 x 10(6)/kg (range 0-178.3). Thirty-nine of 57 patients (68%) achieved the target level of 5 x 10(6) CD34+ cells/kg in a median of three (range 1-8) collections. Eighteen (32%) patients yielded < 5 x 10(6) CD34+ cells/kg with the first collections. Thirteen of these 18 patients yielded < 2.5 x 10(6) and five yielded 2.5-4.95 x 10(6) CD34+ cells/kg. Of the 18 patients with less than optimal CD34+ cell yields, five with CD34+ yields of 2.5-4.95 x 10(6)/kg received PBSC alone at transplant, six underwent marrow storage to augment the PBSC dose and received PBSC plus marrow and seven patients underwent secondary collections. Of seven patients who underwent second (n = 5) or third (n = 2) cycles of PBSC collections using G-CSF 16 (n = 4) or 32 (n = 3) micrograms/kg/day, > 2.5 x 10(6) CD34+ cells/kg were collected in four patients. Two patients achieved < 0.18 CD34+ cells following three cycles of mobilization. In a linear regression model, an increased percentage of marrow involvement and prior radiotherapy (RT) were statistically significantly associated with a low CD34+ cell collection yield (P = 0.003, and 0.01, respectively). A mobilization regimen of CE plus G-CSF was associated with a significantly higher yield of CD34+ cells as compared to patients receiving G-CSF alone (P = 0.02). CY with G or GM-CSF was not significantly different than G-CSF alone (P = 0.49). Twenty-two of 24 (92%) patients receiving CE with G-CSF achieved a target level of 5 x 10(6) CD34+ cells/kg or more as compared to 11 of 19 (58%) patients receiving G-CSF alone (P = 0.01) and six of 14 (43%) patients receiving CY with G or GM-CSF (P = 0.001). These data suggest that percentage of marrow involvement, prior radiotherapy, and number of prior chemotherapy regimens are important predictors of PBSC yield in patients with MM. These data also suggest that CE plus G-CSF is superior to G-CSF alone or CY plus G/GM-CSF based on mean daily CD34+ cell collection yield. Higher doses of G-CSF (16-32 micrograms/kg/day) can result in adequate CD34+ cell collections in some secondary attempts in patients with MM failing an initial mobilization regimen.
Adult↗
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↗
Autologous transplantation with peripheral blood stem cells collected after granulocyte colony-stimulating factor in patients with acute myelogenous leukemia.
The use of peripheral blood stem cells (PBSC) with or without bone marrow (BM) in patients with acute myelogenous leukemia (AML) undergoing autologous transplantation in untreated first relapse (Rel1) or in second remission (CR2) was evaluated in a phase II study. Twenty-three patients with AML in untreated Rel1 (n = 8) and CR2 (n = 15) underwent autologous transplant using PBSC with (n = 19) or without (n = 4) BM. Six patients received busulfan (BU) and cyclophosphamide (CY) and 17 received BU, CY and total body irradiation prior to transplant. The median number of CD34+ cells infused was 4.81 x 10(6)/kg (range 0.04-15). Fifteen of 23 patients received post-transplant interleukin-2 (IL-2) at a median of 43 days (range 11-93) in an attempt to decrease relapses. The median day of recovery of granulocytes to 0.5 x 10(9)/I was 12 (range 8-27) and platelets to 20 x 10(9)/I was 15 (range 8-103). Patients received a median of 4 units (range 0-20) of red blood cells and 29 units (range 4-252) of platelets. The probability of 100 day non-relapse mortality was 0.14. The probabilities of survival and relapse at 2 years were 0.24 and 0.65, respectively. The probabilities of relapse in patients receiving (n = 15) and not receiving (n = 8) interleukin-2 (IL-2) were 0.59 and 0.74, respectively (P = 0.1). Overall, seven of 23 (30%) patients are alive and continuously disease-free at a median of 483 days (range 113-835) post-transplant. These data demonstrate that the infusion of PBSC collected after rhG-CSF corrected engraftment problems previously observed with autologous BM transplants in patients with AML but was associated with a high relapse rate.
Acute Disease↗
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↗
Syngeneic marrow transplantation in patients with multiple myeloma.
Eleven patients with advanced multiple myeloma (MM) received syngeneic marrow (n = 10) or peripheral blood stem cell (n = 1) transplants following cyclophosphamide (CY) and total body irradiation (TBI) (n = 8), busulfan (Bu) and CY (n = 1), Bu, CY and TBI (n = 1) or Bu, melphalan and thiotepa (n = 1). At the time of transplant one patient had stage II and 10 patients had stage III disease. Four patients had refractory disease, two had chemotherapy sensitive disease and five had progressed after an initial response to chemotherapy. The median time from diagnosis to transplant was 353 days (range 176-6118). After transplant, the median time to achieve granulocytes of 0.5 x 10(9)/l and platelets of 20 x 10(9)/l was 12 days (range 9-20) and 12 days (9-27), respectively. One patient died of interstitial pneumonia syndrome on day 32 and one died of veno-occlusive disease of the liver on day 44 post-transplant, and these were unevaluable for response. Five of nine evaluable patients achieved a complete response (CR), three a partial response, and one patient had no response. Three patients who did not achieve CR died of progressive disease 106, 142 and 321 days post-transplant. Of five patients who achieved a CR, three relapsed on days 539, 737 and 1706 and died on days 1759, 1596 and 1736, respectively; one patient died of myelodysplastic syndrome on day 1407 without evidence of MM and one patient is alive and disease-free 3297 days after transplant. One of the two long-term survivors has a persistent monoclonal protein in the blood 15 years post-transplant. These data show that high-dose therapy and infusion of normal syngeneic marrow cells can cure a small fraction of patients with MM. However, the majority of patients did not achieve durable CR, demonstrating the need for improved transplant conditioning regimens, earlier transplant or additional post-transplant treatment strategies when syngeneic transplants are performed.
Adult↗
Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: a Phase I/II trial.
PURPOSE: To define the maximum tolerated dose (MTD) of unshielded total body irradiation (TBI) delivered from dual 60C sources at an exposure rate of 0.08 Gy/min and given in thrice daily fractions of 1.2 Gy in patients with advanced lymphoid malignancies. METHODS AND MATERIALS: Forty-four patients with a median age of 28 (range 6-48) years were entered into a Phase I/II study. All patients received cyclophosphamide (CY), 120 mg/kg administered over 2 days before TBI. Marrow from human leukocyte antigen (HLA) identical siblings was infused following the last dose of TBI. An escalation-deescalation schema designed to not exceed an incidence of 25% of Grade 3-4 regimen-related toxicities (RRTs) was used. The first dose level tested was 13.2 Gy followed by 14.4 Gy. RESULTS: None of the four patients at the dose level of 13.2 Gy developed Grade 3-4 RRT. Two of the first eight patients receiving 14.4 Gy developed Grade 3-4 RRT, establishing this as the MTD. An additional 32 patients were evaluated at the 14.4 Gy level to confirm these initial observations. Of 40 patients receiving 14.4 Gy, 13 (32.5%) developed Grade 3-4 RRTs; 46% in adults and 12% in children. The primary dose limiting toxicity was Grade 3-4 hepatic toxicity, which occurred in 12.5% of patients. Noninfectious Grade 3-4 interstitial pneumonia syndrome occurred in 5% of patients. The actuarial probabilities of event-free survival, relapse, and nonrelapse mortality at 2 years were 0.10, 0.81, and 0.47, respectively, for patients who received 14.4 Gy of TBI. CONCLUSIONS: The outcome for patients receiving 14.4 Gy of TBI was not different from previous studies of other CY and TBI regimens in patients with advanced lymphoid malignancies. These data showed that the incidence of Grade 3-4 RRTs in adults was greater than the 25% maximum set as the goal of this study, suggesting that 13.2 Gy is a more appropriate dose of TBI for adults, while 14.4 Gy is an appropriate dose for children.
Adolescent↗
Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor.
The idiotype of myeloma immunoglobulin can be used as a unique tumour-specific antigen. We tested the hypothesis that tumour antigen-specific immunity can be transferred from bone-marrow-transplant donor to recipient. We immunised a healthy sibling donor with myeloma immunoglobulin from the plasma of the recipient, conjugated to an immunogenic carrier protein and emulsified in an adjuvant, before marrow transplantation. Detection of a lymphoproliferative response, a parallel response in the carrier protein, recovery of a recipient CD4+ T-cell line with unique specificity for myeloma idiotype, and demonstration by in-situ hybridisation that the cell line was of donor origin, proved that a myeloma idiotype-specific T-cell response was successfully transferred to the recipient. Donor immunisation with myeloma idiotype may represent a new strategy for enhancing the specific anti-tumour effect of allogeneic marrow grafts.
Adult↗
Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor.
Peripheral blood stem cells (PBSCs) are widely used in autologous transplantation because of ease of collection and rapid hematopoietic reconstitution. However, PBSCs have rarely been used for allogeneic transplantation because of concerns about donor toxicities from cytokine administration and the theoretical increased risk of graft-versus-host-disease (GVHD) from the large number of T cells infused. Eight patients with advanced malignancies received allogeneic PBSC transplants from genotypically HLA-identical sibling donors. All donors received 5 days of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 16 micrograms/kg/day) subcutaneously and were leukapheresed for 2 days. After treatment of the patient with total body irradiation and cyclophosphamide (n = 7) or etoposide, thiotepa, and cyclophosphamide (n = 1), PBSCs were infused immediately after collection and without modification. All patients received cyclosporine and either methotrexate (n = 6) or prednisone (n = 2) for GVHD prophylaxis, rhG-CSF was well tolerated with mild bone pain requiring acetaminophen occurring in two donors. All patients engrafted and in seven hematopoietic recovery was rapid, with 500 neutrophils/microL achieved by day 18 and 20,000 platelets/microL by day 12. Complete donor engraftment was documented by Y chromosome analysis in all four sex-mismatched donor-recipient pairs tested and by DNA analysis in two sex-matched pairs. One patient died on day 18 of veno-occlusive disease of the liver with engraftment but before chromosome analysis could be performed (results are pending in 1 patient). A second patient died of fungal infection 78 days after transplant. Grade 2 acute GVHD occurred in two patients and grade 3 GVHD occurred in one patient. One patient is 301 days from transplant in remission with chronic GVHD; the remaining five patients are alive and disease free 67 to 112 days after transplantation. Preliminary results indicate that allogeneic PBSCs mobilized by rhG-CSF can provide rapid hematologic recovery without an appreciably greater incidence of acute GVHD than would be expected with marrow. Further follow-up is required to determine the incidence of chronic GVHD and any potential beneficial effects on relapse after transplant.
Adult↗
Transplantation of allogeneic peripheral blood stem cells.
Recombinant G-CSF has been given to over 150 normal donors for the collection of allogeneic or syngeneic peripheral blood stem cells (PBSCs). 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 100 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 44% of patients and grades III-IV in 16%. From a small number of evaluable patients surviving for more than 100 days, it appears the incidence of chronic GVHD is approximately 50%. Despite the infusion of one to two logs more T cells, these results are not remarkably different than would be expected with marrow transplantation. Further studies are needed to define the role of allogeneic PBSCs for transplantation, to refine PBSC mobilization and collection techniques, and to evaluate the long-term effects of cytokines in normal donors.
Hematopoietic Stem Cell Transplantation↗
Optimization of peripheral blood stem cell collection.
Peripheral blood stem cells are increasingly used in lieu of marrow for hematopoietic support because of ease of collection and the rapid kinetics of recovery relative to bone marrow transplantation. More recently, it has been shown that adequate numbers of peripheral blood stem cells can be collected using growth factors alone without prior chemotherapy. By measuring CD34 or granulocyte-macrophage colony-forming unit content of peripheral blood stem cell collections, mobilization technique, age, marrow disease, prior radiation, and prior chemotherapy regimens have been found to be important factors influencing the numbers of stem cells collected. However, interpatient variation in CD34 collections remains high and there are subgroups of heavily pretreated patients who will fail to mobilize sufficient numbers of stem cells to ensure rapid engraftment. The current challenge for clinical investigations is to improve methods for identifying such patients prior to collection and utilize new strategies for stem cell mobilization. The relative ease of collection and the rapid engraftment after myeloablative therapy suggest that peripheral blood stem cells will likely supplant marrow for both allogeneic and autologous transplantation in the next 5 years.
Antineoplastic Agents↗
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↗
Peripheral-blood stem-cell collections after paclitaxel, cyclophosphamide, and recombinant human granulocyte colony-stimulating factor in patients with breast and ovarian cancer.
PURPOSE: Here we evaluate Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and cyclophosphamide (CY) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) for mobilization of peripheral-blood stem cells (PBSCs) for autologous stem-cell transplantation in patients with breast and ovarian cancer. PATIENTS AND METHODS: PBSCs were collected from 17 patients with breast (n = 11), ovarian (n = 5), and gastric (n = 1) cancer after administration of Taxol (170 mg/m2 x 1) and CY (4 g/m2 x 1) followed by rhG-CSF (10 micrograms/kg/d). PBSC collections after Taxol and CY were compared with PBSC collections from nine patients with stage IV breast (n = 8) or stage III ovarian (n = 1) cancer who had received CY (4 g/m2 x 1) followed by rhG-CSF (16 micrograms/kg/d) for mobilization. RESULTS: Mean WBC and platelet counts on the first day of apheresis were 6.3 x 10(9)/L (range, 1.9 to 22.1) and 35 x 10(9)/L (range, 19 to 77), respectively. The median numbers of CD34+ cells, peripheral-blood mononuclear cells (PBMNC), and peripheral-blood total nucleated cells (PBTNC) collected were 13.02 x 10(6)/kg (range, 5.4 to 57.8; mean, 16.02), 6.86 x 10(8)/kg (range, 1.9 to 51.2), and 17.41 x 10(8)/kg (range, 2.4 to 106.6), respectively. In the comparison group, the median yield of CD34+ cells was 6.39 x 10(6)/kg (range, 0.2 to 28; mean, 10.01; P = .01). The mean daily yield of CD34+ cells/kg/collection was 3.5 (range, 0.8 to 28.9) after Taxol and CY, as compared with 1.3 (range, 0.1 to 7.0) for patients who received CY alone (P = .01). All patients who received CY and Taxol reached a target level of 5 x 10(6) CD34+ cells/kg, as compared with five of nine patients (55.5%) who received CY alone (P = .03). CONCLUSION: These data suggest that Taxol and CY followed by rhG-CSF mobilizes PBSCs in patients with advanced breast and ovarian cancer more effectively than this regimen without Taxol.
Adult↗
Influence of total nucleated cell dose from marrow harvests on outcome in patients with acute myelogenous leukemia undergoing autologous transplantation.
This retrospective study was conducted to determine whether the total number of nucleated cells (TNC)/kg collected at marrow harvest was associated with outcome in 151 patients with acute myelogenous leukemia (AML) who received an autologous purged (n = 67) or non-purged (n = 84) marrow transplant. At the time of transplant 33 patients were in first complete remission (CR), 47 in second CR, 54 in first relapse and 17 beyond second CR. Ninety patients received busulfan (BU) 16 mg/kg and cyclophosphamide (CY) 120 or 200 mg/kg, 51 patients received CY 120 mg/kg and total body irradiation (TBI) 12-15.75 Gy and 10 patients received BU 8 mg/kg, CY 60 mg/kg and TBI 12 Gy as conditioning regimens. Patients whose marrow harvest yielded < 2 x 10(8) TNC/kg did not undergo purging with 4-hydroperoxycyclophosphamide (4HC). This group of patients (n = 28) had a 100 day mortality of 50% and only 54% achieved a granulocyte levels of > 0.5 x 10(9)/l and 29% achieved platelet transfusion independence. Patients whose marrow harvest yielded 2-4 x 10(8) TNC/kg and did not undergo marrow purging had a 20% mortality by day 100, 91% recovered granulocytes to > 0.5 x 10(9)/l and 61% became platelet independent. Patients whose marrow harvest yielded 2-4 x 10(8) TNC/kg and underwent marrow purging with 4HC had a 50% mortality by day 100 and 58% achieved a granulocyte levels of > 0.5 x 10(9)/l and 42% became platelet transfusion independent.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics.
We have determined the relationships between busulfan average concentration at steady-state and (1) rejection of graft, and (2) regimen-related toxicity, and have evaluated the dependence of busulfan clearance/F on body size and age. Patients received 16-30 mg/kg of busulfan followed by cyclophosphamide in doses of 120, 150, 174, or 200 mg/kg or 8 g/m2 in preparation for autologous, syngeneic or allogeneic grafts varying in compatibility from HLA-matched siblings to HLA-partially-matched unrelated donors. In a multivariate Cox time-to-rejection analysis, only busulfan concentration remained a significant determinant of rejection, P = 0.0154. An average concentration of busulfan at steady-state of at least 200 ng/ml was needed to avoid rejection of a matched-sibling graft, while 600 ng/ml was needed to avoid rejection of HLA-partially-matched related or HLA-matched unrelated donor grafts. The toxicity of the cytoreductive regimen correlated with busulfan average concentration at steady-state (rs = 0.717). Busulfan clearance/F expressed relative to body weight, ideal body weight or surface area declined with age during the first decade of life. Over the entire span of age, the coefficient of variation in clearance/F for all ages was similar when clearance/F was expressed in absolute terms (ml/min) and when adjusted for body surface area; the coefficient of variation was greater for clearance/F when expressed relative to total or ideal body weight. We conclude that busulfan concentration in plasma is an important determinant of graft survival and regimen-related toxicity, and that the variability of busulfan pharmacokinetics with age precludes the use of a fixed dose for all ages and indications.
Adolescent↗