Effect of CD34(+) cell dose on resource utilization in patients after high-dose chemotherapy with peripheral-blood stem-cell support.

PURPOSE: The mean time to neutrophil and platelet recovery for patients receiving high-dose chemotherapy (HDC) supported with peripheral-blood stem cells (PBSCs) is related to the dose of CD34(+) cells infused. The effect of cell dose on resource utilization after transplantation has not been previously reported. MATERIALS AND METHODS: We assessed CD34(+) cell dose and resource utilization for 1,317 patients undergoing transplantation with PBSCs from April 1991 to June 1997. PBSCs were collected after mobilization with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). Daily measurement of the CD34(+) content of the PBSC collection was performed by a central laboratory using a single CD34(+) analysis technique. Resource utilization included engraftment parameters, length of stay, and transfusion requirements for 100 days posttransplantation. Analysis included descriptive statistics and multiple regression. RESULTS: Mean patient age was 47 years, and 86% of patients were female. Median cell dose was 3.6 x 10(6)/kg and 13.2 x 10(6)/kg for patients receiving less than 5.0 x 10(6) CD34(+) cells/kg and 5.0 x 10(6) or more CD34(+) cells/kg, respectively. Patients receiving less than 5. 0 x 10(6) CD34(+) cells/kg were more likely to have metastatic breast cancer or non-Hodgkin's lymphoma and required more platelet and RBC transfusions, 3.3 more hospital days, and increased antibiotic and antifungal use. In univariate analysis, the cost of care was $41,516 (+/-$20,876 SD) and $32,382 (+/-$16,353 SD) for patients with less than 5.0 x 10(6) CD34(+) cells/kg and 5.0 x 10(6) or more CD34(+) cells/kg, respectively. In multivariate analysis, patients with less than 5.0 x 10(6) CD34(+) cells/kg had an increase in costs of $5,062 (+/- $1,262 SE). CONCLUSION: Infusion of more than 5.0 x 10(6) CD34(+) cells/kg was associated with a reduction in resource utilization. Achieving a target of 5.0 x 10(6) CD34(+) cells/kg should have important clinical and economic benefits for patients.

Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells.

PURPOSE: The purpose of this study was to compare the effects of filgrastim, sargramostim, or sequential sargramostim and filgrastim on CD34(+) cell yields and morbidity after myelosuppressive mobilization chemotherapy (MC). PATIENTS AND METHODS: One hundred fifty-six patients were randomized to receive filgrastim (n = 51), sargramostim (n = 52), or sargramostim for 5 days followed by filgrastim (n = 53) after MC with either cyclophosphamide and etoposide (n = 75) or paclitaxel and cyclophosphamide (n = 81). RESULTS: Compared with those who received sargramostim, patients who received filgrastim had faster recovery of an absolute neutrophil count of 0.5 x 10(9)/L or greater (a median of 11 v 14 days; P =. 0001), with fewer patients requiring RBC transfusions (P =.008), fewer patients with fever (18% v 52%; P = 0.001), fewer hospital admissions (20% v 42%; P =.013), and less intravenous antibiotic therapy (24% v 69%; P =.001). Patients who received filgrastim yielded more CD34(+) cells (median, 7.1 v 2.0 x 10(6)/kg/apheresis; P =.0001), and a higher fraction achieved 2.5 x 10(6) (94% v 78%; P =.021) and 5 x 10(6) (88% v 53%; P =.001) or more CD34(+) cells/kg with fewer aphereses (median, 2 v 3; P =.002) and fewer days of growth-factor treatment (median, 12 v 14; P =.0001). There were no major differences in outcomes between the filgrastim alone and the sequential regimens. After high-dose chemotherapy, patients who had peripheral-blood stem cells (PBSCs) mobilized with filgrastim or the sequential regimen received higher numbers of CD34(+) cells and had faster platelet recovery (P =.015), with fewer patients (P =.014) receiving fewer platelet transfusions (P =.001) than patients receiving sargramostim-mobilized PBSCs. CONCLUSION: It was concluded that filgrastim alone or sequential sargramostim and filgrastim were superior to sargramostim alone for the mobilization of CD34(+) cells and reduction of toxicities after MC.

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.

High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma.

PURPOSE: To evaluate a high-dose treatment regimen of fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide (Cy) followed by autologous stem-cell transplantation (ASCT) in patients with malignant lymphoma. PATIENTS AND METHODS: Fifty-three patients with non-Hodgkin's lymphoma (NHL; n = 43) or Hodgkin's disease (HD; n = 10) received 12.0 Gy of fractionated TBI, etoposide 60 mg/kg, and Cy 100 mg/kg followed by infusion of autologous hematopoietic stem cells. RESULTS: Thirty-one of 53 patients are alive a median of 643 (range, 177 to 1,144) days after transplant. The 2 year Kaplan-Meier (K-M) estimates of survival, event-free survival (EFS), and relapse for all 53 patients were 54%, 45%, and 43%, respectively. Sixteen of 24 patients with less advanced disease and 10 of 29 patients with more advanced disease survive free of disease for K-M estimates of EFS of 61% and 31%, respectively (P = .006). The K-M estimates of relapse were 34% for patients with less advanced disease and 53% (P = .05) for patients with more advanced disease. The K-M estimates of dying from causes other than relapse were 8% in patients with less versus 25% in patients with more advanced disease (P = .09). CONCLUSION: These data indicate that approximately 60% of patients transplanted early after failure of initial therapy for malignant lymphoma are projected to be disease-free more than 2 years after treatment with fractionated TBI, etoposide, and Cy and infusion of autologous hematopoietic stem cells. The transplant-related mortality rate is low and relapse is the main cause of treatment failure in patients with less advanced disease. For patients with more advanced disease, the K-M estimates of both transplant-related deaths (25%) and relapse (53%) remain major problems.

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

PURPOSE: To evaluate high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) in patients with lymphoid malignancy who had received prior radiation therapy. PATIENTS AND METHODS: Fifty-seven patients with non-Hodgkin's lymphoma (NHL; n = 23), Hodgkin's disease (HD, n = 32), or acute lymphoblastic leukemia (ALL; n = 2) with a history of previous radiation therapy were treated with cyclophosphamide (Cy; 7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2) (CBV) followed by ABMT. RESULTS: The projected 2-year probabilities of survival, event-free survival (EFS), and relapse were .31, .24, and .76, respectively. For patients with intermediate- and high-grade lymphoma and HD the probabilities were .27, .10, and .14 for EFS and .57, .90, and .77 for relapse. The probability of nonrelapse mortality in the first 100 days post-ABMT was 33%. Idiopathic pneumonia syndrome (IPS) was observed in no patients who received carmustine 300 mg/m2 and 23% of patients who received carmustine 600 mg/m2 (P = .05). Eight-three percent of patients who received mediastinal radiation therapy less than 3 months before transplant developed IPS, compared with 13% who received radiation therapy more than 3 months before transplant (P = .001). CONCLUSION: ABMT following high-dose CBV resulted in long-term disease-free survival in 25% of patients with lymphoid malignancies who had previously received dose-limiting radiation therapy. Fatal IPS and a high relapse rate were major factors limiting successful outcome following ABMT. The morbidity and mortality rates associated with the administration of carmustine 600 mg/m2 were prohibitively high, especially in patients who received mediastinal radiation immediately before ABMT, and were not associated with a decrease in post-ABMT relapse.

Multicenter phase II study to evaluate a 28-day regimen of oral fluorouracil plus eniluracil in the treatment of patients with previously untreated metastatic colorectal cancer.

PURPOSE: To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m(2) or 1.15 mg/m(2) twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity. RESULTS: Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m(2) and 1.15 mg/m(2), respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m(2)-dose group was similar to the 1.00 mg/m(2)-dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m(2)-dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia. CONCLUSION: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.

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.

Immunocytochemical analysis of tumor cells in pre- and post-culture peripheral blood progenitor cell collections from breast cancer patients.

We examined peripheral blood progenitor cell (PBPC) collections and CD(34+)-selected fractions cultured in PIXY321, a fusion protein comprising analog interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) domains, for the presence of contaminating tumor cells from 14 patients with advanced-stage breast cancer. Five of the 14 (36%) pre-culture PBPC specimens contained immunocyto-chemically (ICC)-detectable tumor cells using two different cocktails of monoclonal antibodies (mAbs). After 10 days in culture with PIXY321, the CD(34+)-selected fractions showed a median 23.6-fold expansion of hematopoietic cells. No ICC-positive tumor cells were detected in any post-culture specimens. We conclude that in vitro expansion of CD(34+)-selected PBPCs with PIXY321 can expand hematopoietic cell populations apparently without risk of expanding contaminating breast cancer cell populations.

A randomized study of etoposide and carboplatin with or without paclitaxel in the treatment of small cell lung cancer.

Small cell lung cancer accounts for 20% to 25% of all lung cancer cases and is initially responsive to combination chemotherapy. However, the majority of patients relapse, and at that point their disease is highly resistant to chemotherapy. The combination of etoposide with either cisplatin or carboplatin is regarded as the standard of care for these patients. Previous studies have documented the activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) at doses of 135 to 250 mg/m2 administered over 1, 3, or 24 hours as either a single agent or in combination with etoposide and a platinum compound. Studies adding paclitaxel to etoposide/carboplatin (EP) have demonstrated complete responses in both limited and extensive disease, but all have been in single-arm phase II studies. Preliminary data also suggest the possibility of a dose-response curve for the combination. We recently began a randomized phase II/III comparison of the standard EP to EP plus paclitaxel for newly diagnosed patients with limited or extensive small cell lung cancer. Carboplatin in this study is dosed according to area under the concentration-time curve as calculated by the Calvert formula. The study compares EP (carboplatin area under the concentration-time curve of 6 intravenously [IV] over 30 to 60 minutes on day 1, with etoposide 120 mg/m2 IV days 1 to 3) versus EP plus paclitaxel (paclitaxel 200 mg/m2 IV 1-hour infusion on day 1, carboplatin area under the concentration-time curve of 6 IV over 30 to 60 minutes on day 1, and etoposide 50/100 mg orally on alternating days 1 to 10). The design, inclusion criteria, and staging of patients in this study will be presented with initial accrual and patient characteristics. Randomized studies of this type are essential if the true role of this new combination is to be fully evaluated.

High-dose chemotherapy and autologous peripheral blood progenitor cell transplant for the treatment of Hodgkin's disease.

This paper evaluates a comprehensive strategy of chemotherapy mobilization of peripheral blood progenitor cells (PBPCs) followed by high-dose chemotherapy for the treatment of refractory or relapsed Hodgkin's disease (HD). Patients with relapsed or refractory HD were enrolled to receive cyclophosphamide, etoposide +/- cisplatin (CE +/- P) and rhG-CSF mobilization of PBPCs. Patients achieving < or = 2.5 x 10(6) CD34+ cells/kg following initial mobilization were eligible to receive a second course of CE +/- P. Unmanipulated PBPCs alone were infused following administration of high-dose carmustine, etoposide, cytarabine arabinoside and cyclophosphamide (BEAC). Thirty-eight consecutive patients with relapsed or refractory HD were initially enrolled to receive CE +/- P. Analysis was performed on an intent-to-treat basis. A median of 6.4 x 10(6) CD34+ cells/kg (range 0.66-62.3) were collected with a median of 3 (range 2-9) leukaphereses. Twenty-eight of 38 (74%) patients achieved > or = 2.5 x 10(6) CD34+ cells/kg. Analysis of variables potentially effecting mobilization of CD34+ cells revealed that only the amount of prior chemotherapy statistically influenced collecting CD34+ cells (P = 0.005). Two of six patients undergoing a second mobilization procedure achieved > or = 2.5 x 10(6) CD34+ cells/kg for a total of 30 patients eligible to proceed with high-dose BEAC. The 3-year Kaplan-Meier estimate of overall survival (OS) and progression-free survival (PFS) for all 38 patients is 65 and 53%, respectively. The 3-year OS and PFS for the 28 patients receiving BEAC is 77 and 64% respectively vs 33 and 30% for the 10 patients not receiving BEAC. The strategy of CE +/- P and BEAC was well tolerated with a 100-day treatment-related mortality of 3.6%. All patients experienced rapid and sustained hematologic recovery with PBPCs alone. The median time to an ANC > or = 5 x 10(9)/1 and platelet transfusion independence was 10 days. Although development of better strategies to mobilize PBPCs may benefit additional patients, currently the best strategy to collect PBPCs is early before patients have received extensive chemotherapy treatment. Collection of PBPCs immediately following initial relapse or induction failure using CE +/- P for PBPC mobilization allows sufficient PBPCs to be collected in greater than 90% of patients. Treatment of refractory or relapsed HD utilizing a strategy of CE +/- P PBPC mobilization for hematopoietic reconstitution following high-dose BEAC is associated with acceptable toxicity and rapid engraftment. A 3-year PFS greater than 60% can be achieved in the community hospital setting.

Lymphocyte content in peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor.

The effects of rhG-CSF on peripheral blood lymphocytes and lymphocyte populations in the apheresis product has been determined in 13 individuals (11 autografts and 2 normal donors) who had peripheral blood mononuclear cells (PBMCs) collected on days 3, 4, and 5 of administration of rhG-CSF 16 micrograms/kg/day x 5 days. The absolute number of CD34+ cells increased 9 and 25-fold from pretreatment levels after 4 and 5 days of rhG-CSF, respectively. All patients demonstrated an increase in CD3, CD4, CD8, CD19 and CD20 lymphocytes after 3 days of rhG-CSF with T lymphocytes increasing 1.5-2.0 times baseline by day 3 or rhG-CSF administration. All lymphocyte phenotypes returned to below pretreatment levels on days 4 and 5 of rhG-CSF administration. The ratio of CD4/CD8 lymphocytes was not affected by rhG-CSF. Collection of PBMCs on 3 consecutive days yielded a mean of 8.77 x 10(8) CD34 cells, 14.03 x 10(10) total nucleated cells and 3.17 x 10(10) CD3 lymphocytes. These data suggest that rhG-CSF mobilized PBMCs have approximately one log more T cells than marrow and the effect of rhG-CSF on the quantity and phenotype of lymphocytes is minimal. Strategies for coping with an increased incidence of GVHD, if it occurs, could include the utilization of both methotrexate and cyclosporine as immunoprophylaxis, selective T cell depletion or CD34 positive selection.

A randomized trial of once vs twice daily administration of intravenous granisetron with dexamethosone in patients receiving high-dose cyclophosphamide, thiotepa and carboplatin.

The purpose of this study was to determine the optimal schedule of i.v. granisetron and dexamethosone for control of nausea and emesis in patients receiving high-dose chemotherapy (HDC). Seventy patients with breast cancer received high-dose cyclophosphamide, thiotepa and carboplatin (CTCb) for 3 consecutive days. All 70 received dexamethasone 12 mg i.v. and granisetron 1 mg i.v. prior to infusion of CTCb and were randomized to receive placebo (n = 37) or an additional identical dose of granisetron (n = 33) 12 h later. Beginning on day 2 of chemotherapy administration, 55 patients evaluable later self-administered a cocktail of diphenhydramine (benadryl), lorazepam (ativan) and dexamethasone (BAD). Fourteen of 37 patients (38%) receiving granisetron once a day and 15/33 (44%) receiving it twice a day had a complete response during the first 24 h following the first doses of chemotherapy (P = 0.52). In the 55 evaluable patients receiving BAD, 18 of 29 (62%) in the once daily group and 14/26 (54%) in the twice daily group required additional medications (P = 0.54). The median time to first emetic episode was 20 h (range 6.6-79.5) for patients receiving once a day and 21.4 hours (range 5.8-105.3) for patients receiving twice a day granisetron (P = 0.48). Five patients in the once daily and seven patients in the twice daily group had complete control of nausea and emesis throughout the study period (P = 0.37). It was concluded that there were no statistically significant differences in nausea and emetic control between dexamethasone with once daily or twice daily i.v. granisetron administration in patients receiving high-dose CTCb.

Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim.

Myelosuppressive chemotherapy is frequently used for mobilization of autologous CD34(+) progenitor cells into the peripheral blood for subsequent collection and support of high-dose chemotherapy. The administration of myelosuppressive chemotherapy is typically followed by a myeloid growth factor and is associated with variable CD34 cell yields and morbidity. The two most commonly used myeloid growth factors for facilitation of CD34 cell harvests are granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We performed a randomized phase III clinical trial comparing G-CSF, GM-CSF, and sequential administration of GM-CSF and G-CSF following administration of myelosuppressive chemotherapy. We evaluated CD34 yields, morbidity, and cost-effectiveness of the three cytokine schedules. One hundred and fifty-six patients with multiple myeloma, breast cancer, or lymphoma received cyclophosphamide with either paclitaxel or etoposide and were randomized to receive G-CSF 6 microg/kg/day s.c., GM-CSF 250 microg/m(2)/day s.c., or GM-CSF for 6 days followed by G-CSF until completion of the stem cell harvest. Compared with patients who received GM-CSF, patients who received G-CSF had faster recovery of absolute neutrophil count to 0.5 x 10(9) per liter (median of 11 vs14 days, P = 0.0001) with fewer patients requiring red blood cell transfusions (P= 0.008); fewer patients with fever (18% vs 52%, P = 0.001); fewer hospital admissions (20% vs 42%, P = 0.13); and less intravenous antibiotic therapy (24% vs 59%, P = 0.001). Patients who received G-CSF also yielded more CD34 cells (median 7.1 vs 2.0 x 10(6) kg per apheresis, P = 0.0001) and a higher percentage achieved 2.5 x 10(6) CD34 cells per kilogram (94% vs 78%, P = 0.21) and 5 x 10(6) CD34 cells per kilogram (88% vs 53%, P = 0.01) or more CD34 cells per kilogram with fewer aphereses (median 2 vs 3, P = 0.002) and fewer days of growth factor treatment (median 12 vs 14, P = 0.0001). There were no significant differences in outcomes between groups receiving G-CSF alone and the sequential regimen. After high-dose chemotherapy, patients who had peripheral blood stem cells mobilized with G-CSF or the sequential regimen received higher numbers of CD34 cells and had faster platelet recovery with fewer patients requiring platelet transfusions than patients receiving peripheral blood stem cells mobilized by GM-CSF. In summary, G-CSF alone is superior to GM-CSF alone for the mobilization of CD34(+) cells and reduction of toxicities following myelosuppressive chemotherapy. An economic analysis evaluating the cost-effectiveness of these three effective schedules is ongoing at the time of this writing.

Rapid engraftment after autologous transplantation utilizing marrow and recombinant granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in patients with acute myelogenous leukemia.

This study was performed to determine whether peripheral blood stem cells (PBSCs) mobilized with recombinant granulocyte-colony stimulating factor (rhG-CSF) increase the tempo of granulocyte and platelet recovery when added to marrow in patients with acute myelogenous leukemia (AML) undergoing autologous bone marrow transplantation (BMT). Twenty six patients with AML had bone marrow harvested in first (n = 16) or second (n = 10) complete remission (CR) and cryopreserved. Patients received rhG-CSF alone (n = 20) or rhG-CSF following chemotherapy (n = 6). PBSCs were collected from 24 of the 26 patients a median of 7 (range 3-2130) days after marrow harvest. Two patients presumed to be in second CR did not have PBSCs collected because of early relapse. Fourteen patients in first CR (n = 3), second CR (n = 8) or first relapse (n = 3) proceeded to autologous BMT utilizing marrow + rhG-CSF-mobilized PBSCs. Engraftment parameters were compared with a historical group of 158 patients with AML who had received purged (n = 67) or unpurged (n = 91) autologous BMT without PBSCs. The median number of peripheral blood total nucleated and CD34+ cells collected from 24 patients was 19.55 x 10(8)/kg (range 1.83-54.83) and 5.59 x 10(6)/kg (1.23-34.79), respectively. All patients transplanted achieved a granulocyte level of > 0.5 x 10(9)/l with a median of 13 days (range 11-27 days) and platelets to 20 x 10(9)/l median 14 days (range 9-83 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment-related mortality in 1000 consecutive patients receiving high-dose chemotherapy and peripheral blood progenitor cell transplantation in community cancer centers.

High-dose chemotherapy (HDC) with autologous peripheral blood progenitor cell (PBPC) is being increasingly utilized as a therapeutic modality for patients with chemotherapy-sensitive disease. Several published HDC regimens have become relatively widely used. The purpose of this analysis was to determine treatment-related mortality (TRM) following administration of five different HDC regimens in community cancer centers. A retrospective evaluation of 1000 consecutive patients with leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, sarcoma, ovarian cancer, or breast cancer who received one of five published HDC regimens followed by PBPC infusion over a 5-year period in community cancer centers was performed to determine TRM. Fifty-nine patients (5.9%) died within 100 days of PBPC infusion. Twenty-five patients (2.5%) died predominantly of causes related to disease progression. Thirty-four patients (3.4%) died of TRM, 15 patients (1.5%) died from infection and 19 (1.9%) died from regimen-related toxicities (RRT). In a logistic model, increasing age (P = 0.001) and lower numbers of CD34+ cells/kg (P = 0.003) were associated with an increased risk of 100-day TRM. High-dose cyclophosphamide, thiotepa, and carboplatin was associated with a lower risk of mortality than other regimens (P = 0.0001). High-dose chemotherapy and autologous PBPC support can be performed in community cancer centers with relative safety. Patient age, the type of preparative regimen and the number of CD34+ cells infused were important determinates of mortality.

Phase I study of high-dose busulfan, melphalan and thiotepa with autologous stem cell support in patients with refractory malignancies.

The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m2 followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m2 and escalating doses of thiotepa 450-550 mg/m2 followed by infusion of cryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m2 and thiotepa 500 mg/m2. Two of three patients receiving thiotepa 550 mg/m2 experienced grade 3 colitis. Twenty patients were enrolled at the maximum tolerated dose and the incidence of grade 3-4 regimen-related toxicity and mortality was 10% and 5%, respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepatic toxicity and 20% experienced grade 1-2 skin toxicity. The median time to achieve a granulocyte count of 0.5 x 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1-26 days). Five of ten patients with stage 4 refractory breast cancer achieved a complete and two a partial remission with a complete response rate of 50% and a overall response rate of 70%. In conclusion, busulfan, melphalan and thiotepa can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignancies are warranted.

A phase I-II study of high-dose melphalan, mitoxantrone and carboplatin with peripheral blood stem cell support in patients with advanced ovarian or breast carcinoma.

The purpose of this study was to develop a high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) regimen for treatment of patients with ovarian carcinoma that could be administered in an outpatient setting. Fourteen patients with advanced ovarian (n = 9) or breast (n = 5) carcinoma, who had failed conventional chemotherapy, were entered into a dose-escalation trial to determine the maximum tolerated dose (MTD) of carboplatin that could be administered with fixed doses of melphalan (160 mg/m2) and mitoxantrone (50 mg/m2). Twenty-five additional patients were included in a phase II trial at the MTD. Two of two patients had grade 4 severe regimen-related toxicities (RRT), one fatal, at a dose level of 1600 mg/m2. Two of 29 patients (6.9%) treated at the MTD (carboplatin, 1400 mg/m2) died of RRT. All three patients who died of toxicity had a calculated AUC for carboplatin >30 mg/ml/min. Thirty-one patients with ovarian cancer who had failed chemotherapy were treated, 24 at the MTD. Fourteen of 20 patients (70%) with ovarian carcinoma with evaluable disease achieved a CR and seven (35%) are alive disease-free a median of 20 months (range, 7-26). Five of seven patients with ovarian cancer who had failed chemotherapy but were rendered clinically disease-free following surgery survive without progression a median of 13 months (range, 9-19). Eight of 16 (50%) platinum-resistant and 4/12 (33%) platinum-sensitive patients with ovarian cancer survive disease-free.

High-dose chemotherapy with BUCY or BEAC and unpurged peripheral blood stem cell infusion in patients with low-grade non-Hodgkin's lymphoma.

Forty-nine patients with low-grade non-Hodgkin's lymphoma (NHL) received high-dose chemotherapy (HDC) with busulfan and cyclophosphamide (BUCY) or carmustine, etoposide, cytarabine and CY (BEAC) followed by unpurged autologous peripheral blood stem (PBSC) infusion. All patients had failed initial chemotherapy or progressed after an initial remission. Peripheral blood stem cells were mobilized with CY alone (n = 1), CY, etoposide (n = 19), or CY, etoposide and cisplatin (n = 29) followed by granulocyte colony-stimulating factor. Twenty-two patients received BU, 16 mg/kg, and CY, 120 mg/kg. Twenty-seven patients received carmustine 300 mg/m2, etoposide 600 mg/m2, cytarabine 600 mg/m2, and CY 140 mg/kg. Four patients (8%) died of non-relapse causes, two (9%) in the BUCY group and two (7%) in the BEAC group. Twenty-seven patients (55%) relapsed or progressed at a median of 9.4 months (2-38) from PBSC infusion. Ten patients who relapsed are alive a median of 31 months (range, 6-47) after relapse. The probabilities of relapse at 3.6 years for patients receiving BUCY or BEAC were 0.57 and 0.70, respectively (P = 0.92). Twenty-seven patients (55%) are alive at a median of 3.6 years (range, 1-5). The probabilities of survival at 3.6 years for patients receiving BUCY or BEAC were 0.58 and 0.55, respectively (P = 0.72). The probabilities of EFS at 3.6 years for patients receiving BUCY or BEAC were 0.36 and 0.28, respectively (P = 0.82). It was concluded that BUCY is an active regimen for the treatment of patients with low-grade NHL.

Mobilization of peripheral blood stem cells with docetaxel and cyclophosphamide (CY) in patients with metastatic breast cancer: a randomized trial of 3 vs 4 g/m2 of CY.

The purpose of this study was to develop a regimen of docetaxel, cyclophosphamide (CY) and filgrastim for mobilization of peripheral blood stem cells (PBSC) in patients with metastatic breast cancer (n = 66). A phase I trial of CY 2, 3 or 4 g/m2 with docetaxel 100 mg/m2, in consecutive cohorts of four patients each, did not reveal any dose-limiting toxicities and subsequent patients were randomized to receive 3 or 4 g/m2 of CY. The median yield of CD34+ cells from all patients was 11.06x10(6)/kg (range, 0.03-84.77) from a median of two aphereses (range, 1-7); 6.52x10(6) CD34+ cells/kg/apheresis (range, 0.01-52.07). Target CD34+ cell doses > or =2.5 and > or =5.0x10(6)/kg were achieved in 89% and 79%, respectively. There were no statistically significant differences in CD34+ cell yields or target CD34+ cell doses achieved following 3 or 4 g/m2 of CY. Patients with only one prior chemotherapy regimen yielded a median of 12.82x10(6) CD34+ cells/kg/apheresis compared to 5.85 for those receiving > or =2 regimens (P = 0.03). It was concluded that the combination of docetaxel, 100 mg/m2, CY 3 g/m2 without mesna could be administered with acceptable toxicity with collection of adequate quantities of PBSC from the majority of patients.