Hillard M. Lazarus

High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.

PURPOSE To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

Randomized, Multicenter, Open-Label Study of Pegfilgrastim Compared With Daily Filgrastim After Chemotherapy for Lymphoma

PURPOSE The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 x 10(9)/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed. PATIENTS AND METHODS An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 micro g/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 micro g/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkins or non-Hodgkins lymphoma. RESULTS The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 micro g/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle. CONCLUSION Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.

Autologous bone marrow transplant in acute myeloid leukemia in first remission.

PURPOSE The Eastern Cooperative Oncology Group conducted a prospective study of postremission high-dose chemotherapy and autologous bone marrow transplantation (autoBMT) in a group of uniformly treated adults with de novo acute myeloid leukemia (AML) to evaluate whether intensive, myeloablative therapy in first complete remission (CR) could improve the disease-free survival. PATIENTS AND METHODS After initial CR was induced by the combination of daunorubicin, cytarabine, and thioguanine, patients not eligible for allogeneic bone marrow transplantation (alloBMT) were offered autoBMT. Within a median of 2 months after CR, and without intervening postremission therapy, bone marrow was obtained, purged by exposure to 4-hydroperoxycyclophosphamide (4-HC), and cryopreserved. High-dose therapy consisted of oral busulfan over 4 days (16 mg/kg total) followed by intravenous (IV) cyclophosphamide 50 mg/kg daily for 4 days. The cryopreserved marrow was then reinfused. RESULTS Of the 39 patients scheduled for autoBMT, four relapsed before transplantation. Two of the 35 (6%) transplant patients died of transplant-related complications, and 11 (33%) relapsed a median of 8 months after marrow reinfusion. No relapse has occurred after 24 months posttransplant. With a median follow-up of 31 months, the median disease-free survival period for all 39 patients has not been reached; however, 54% +/- 16% of patients are projected to be alive and disease-free at 3 years. CONCLUSION Long-term, disease-free survival after autoBMT in AML seems to be better than the outcome after conventional-dose postremission therapy and rivals the results of alloBMT.

High-Dose Versus Standard Chemotherapy in Metastatic Breast Cancer: Comparison of Cancer and Leukemia Group B Trials With Data From the Autologous Blood and Marrow Transplant Registry

PURPOSE To assess survival of patients with metastatic breast cancer treated with high-dose chemotherapy (HDC) versus standard-dose chemotherapy (SDC). PATIENTS AND METHODS SDC in four Cancer and Leukemia Group B (CALGB) trials was compared with hematopoietic stem-cell support in patients from the Autologous Blood and Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. A total of 1,509 women were enrolled onto CALGB trials, and 1,188 women received HDC. No significant survival differences existed by CALGB trial or HDC regimen. Consideration was restricted to candidates for both SDC and HDC. The resulting sample included 635 SDC and 441 HDC patients. The outcome of interest was overall survival. RESULTS The HDC group displayed better performance status. The SDC group had slightly better survival in first year after treatment. The HDC group had lower hazard of death from years 1 to 4 and had somewhat higher probability of 5-year survival (adjusted probabilities [95% confidence intervals], 23% [17% to 29%] v 15% [11% to 19%], P =.03). CONCLUSION After controlling for known prognostic factors in this nonrandomized analysis of two large independent data sets, women receiving HDC versus SDC for metastatic breast cancer have a similar short-term probability of survival, and might have a modestly higher long-term probability of survival.

Phase I/II study of combined granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor administration for the mobilization of hematopoietic progenitor cells.

PURPOSE To study the toxicity and efficacy of combined granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration for mobilization of hematopoietic progenitor cells (HPCs). MATERIALS AND METHODS Cohorts of a minimum of five patients each were treated subcutaneously as follows: G-CSF 5 micrograms/kg on days 1 to 12 and GM-CSF at .5, 1, or 5 micrograms/kg on days 7 to 12 (cohorts 1, 2, and 3); GM-CSF 5 micrograms/kg on days 1 to 12 and G-CSF 5 micrograms/kg on days 7 to 12 (cohort 4); and G-CSF and GM-CSF 5 micrograms/kg each on days 1 to 12 (cohort 5). Ten-liter aphereses were performed on days 1 (baseline, pre-CSF), 5, 7, 11, and 13. Colony assays for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) were performed on each harvest. RESULTS The principal toxicities were myalgias, bone pain, fever, nausea, and mild thrombocytopenia, but none was dose-limiting. Four days of treatment with either G-CSF or GM-CSF resulted in dramatic and sustained increases in the numbers of CFU-GM per kilogram collected per harvest that represented 35.6 +/- 8.9- and 33.7 +/- 13.0-fold increases over baseline, respectively. This increment was attributable both to increased numbers of mononuclear cells collected per 10-L apheresis and to increased concentrations of progenitors within each collection. The administration of G-CSF to patients already receiving GM-CSF (cohort 4) caused the HPC content to surge to nearly 80-fold the baseline (P = .024); the reverse sequence, ie, the addition of GM-CSF to G-CSF, was less effective. The CFU-GM content of the baseline aphereses correlated with the maximal mobilization achieved (r = .74, P = .001). CONCLUSION Combined G-CSF and GM-CSF administration effectively and predictably mobilizes HPCs and facilitates apheresis.

Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients ( > 55 to 70 years of age) with acute myelogenous leukemia

PURPOSE Considerable morbidity and mortality and costs occur during induction therapy for acute myeloid leukemia (AML). Colony-stimulating factors (CSFs) can shorten neutropenia, and may lower costs. We performed a cost-minimization analysis of granulocyte macrophage colony stimulating factor (GM-CSF) for AML patients > 55 to 70 years of age during an Eastern Cooperative Oncology Group Study. PATIENTS AND METHODS Clinical data were from a randomized double-blind phase III trial of 117 AML patients. Estimates of costs were from financial accounts from seven participating institutions. Costs were reported from the third party payor perspective. Analyses were conducted utilizing a decision analytic model. The primary source of event probabilities was in-hospital care with or without an active infection. Sensitivity analyses were also reported. RESULTS When compared to AML patients who received placebo. GM-CSF patients had fewer grade 4-5 infections (9.6% versus 36.2%, P = 0.002) and grade 3-5 infections (52% versus 70%. P = 0.07) and

High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Ovarian Cancer: An Autologous Blood and Marrow Transplant Registry Report

2.310 in savings. Sensitivity analyses indicated that similar cost estimates applied over a range of clinical and economic assumptions. CONCLUSIONS This analysis can serve as a template for cooperative group cost analyses. Cooperation on study methodologies may allow for results that are relevant to both clinicians and policy makers.

Treatment of primary resistant or relapsed multiple myeloma with high-dose chemoradiotherapy, hematopoietic stem cell rescue, and granulocyte-macrophage colony-stimulating factor

Advanced-stage epithelial ovarian cancer is often chemosensitive but is not usually curable with conventional-dose therapies (1). New paclitaxelplatinum chemotherapy combinations have improved expected survival of patients with advanced disease. However, these regimens do not increase rates of pathologic complete remission and seem unlikely to cure substantially more patients than standard cyclophosphamide regimens (2). The prognosis of women with advanced ovarian cancer remains poor. Although clinical trials of double-dose chemotherapy in advanced ovarian cancer do not indicate increased cure rates, considerable in vitro and in vivo data support the importance of dose intensity in treating ovarian cancer, including trials of high-dose cisplatin delivered intraperitoneally (3-7). Ovarian cancer shares many features with hematologic malignant conditions, which benefit from dose-intensive therapy. Such features include almost universal initial chemosensitivity and occasional cures with conventional therapy despite large tumor bulk (1, 2). A favorable doseresponse curve is also seen for various agents, and many drug combinations exhibit synergy in vitro (3-6). Consequently, there is considerable interest in using high-dose therapy with autologous hematopoietic stem-cell support (autotransplantation) for ovarian cancer. Although conventional salvage therapy for ovarian cancer produces responses in 15% to 25% of women with platinum-sensitive disease (8-12), early trials of autotransplantation report response rates as high as 75% for drug-resistant tumors (13-15). However, duration of response is short (on average, 6 to 7 months) in patients who receive transplants for refractory disease. Recent studies of transplantation focus on patients with relapsed chemosensitive disease. Stiff and colleagues (16) reported a median progression-free survival of 19 months and a median survival of 29 months in 20 women with relapsed platinum-sensitive tumors and minimal tumor burden (maximal diameter<1 cm). These results are particularly encouraging because these women had received a median of two previous conventional chemotherapy regimens. Past studies of conventional therapy in this setting indicate median survivals of only 16 to 20 months (8-12). In a recent study, Legros and coworkers (17) report a 5-year survival rate of 60% in 53 patients who received autotransplants after completing induction therapy for advanced ovarian cancer. Because 5-year survival rates of 20% to 30% are common in unselected groups of women with advanced-stage disease who were receiving standard platinum-based chemotherapy (1, 2), the study by Legros and colleagues suggests that autotransplantation may be beneficial during first remission. Although early studies of autotransplantation for advanced ovarian cancer are encouraging, most reported series are small, especially those that focus on patients with minimal previous therapy. No randomized trials have been reported, and although several are under way, accrual is slow. To better assess the effectiveness of high-dose chemotherapy and autotransplantation, we analyzed 421 women who were reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) from 1989 to 1996. We determined progression-free survival and survival for the group as a whole and identified prognostic factors related to outcome of transplantation. Methods Autologous Blood and Marrow Transplant Registry The ABMTR is a voluntary organization of more than 200 institutions, located primarily in the United States, Canada, and Central and South America, that perform autotransplantation. Participating centers report data on consecutive autotransplantations to a statistical center at the Medical College of Wisconsin, Milwaukee. The ABMTR defines autotransplantation as treatment with a dose of chemotherapy that is high enough to warrant autologous bone marrowderived or blood-derived hematopoietic stem-cell support. The treating institution decides whether a particular regimen requires such support. The ABMTR began collecting data in 1992. Data were collected retrospectively for persons receiving autotransplants between 1989 and 1992 and prospectively thereafter. Participating centers register consecutive autotransplantations for all diseases. According to data collected in the Centers for Disease Control and Prevention National Hospital Discharge Surveys (18, 19), approximately 50% of autotransplantations in North America are registered with the ABMTR. Participating centers are required to register all consecutive transplantations, and compliance is monitored by on-site audits. Computerized error checks, physician review of submitted data, and on-site audits of participating centers ensure data quality. The ABMTR research program, which includes collection and analysis of transplantation data, has been approved by the institutional review board of the Medical College of Wisconsin. The ABMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, pretransplantation disease stage and responsiveness to chemotherapy, date of diagnosis, graft type (bone marrowderived or blood-derived stem cells), high-dose conditioning regimen, post-transplantation disease progression and survival, development of a new malignant condition, and cause of death. Information on progression or death is requested every 6 months. All ABMTR centers contribute registration data. Transplantation centers that have the required data management support collect research data for consecutive registered patients on comprehensive report forms. Submitted information encompasses pre- and post-transplantation clinical information, such as tumor size and pathologic characteristics, sites of disease, all treatments for ovarian cancer, bulk of disease at transplantation, clinical status (including cardiac, pulmonary, renal, and liver function), doses of high-dose therapy, blood or marrow graft treatment, and sites of post-transplantation progression. Demographic characteristics and survival rates in women with ovarian cancer are similar in the registration and research databases. Patients Registration data were collected on all patients with ovarian cancer who were treated in participating centers between 1 January 1989 and 31 December 1996. Fifty-seven North American transplantation centers submitted comprehensive research data for 421 of all 513 eligible registered patients. According to our analysis, the study group of 421 patients and the 92 patients for whom only registration data were available did not differ significantly in demographic features and survival rates. We focused on the 421 women for whom comprehensive data were available, including 100 patients from Loyola University in Maywood, Illinois, who were previously described in a less extensive analysis (20). Median follow-up of survivors was 29 months (range, 3 to 82 months). Statistical Methods To compare patient and treatment characteristics, we used the chi-square test for categorical variables and the KruskalWallis test for continuous variables. Probabilities of 100-day mortality (death in the first 100 days from any cause), progression-free survival, and overall survival were calculated by using the KaplanMeier product-limit estimate. Treatment-related death (death without progression) was calculated by using the cumulative incidence estimate (21). A pointwise test was used for univariate comparisons. Variables were tested in univariate analyses for their association with death and treatment failure (the inverse of progression-free survival) by using Cox proportional-hazards regression; these analyses also examined whether the proportional hazards assumption was met for each covariate, using the time-dependent covariate method. Variables considered were age (above or below the median), Karnofsky performance status (<90% vs. 90%), disease stage and histologic characteristics at diagnosis, response to initial therapy, number of previous chemotherapy regimens, pretransplantation remission state, pretransplantation bulk of disease, chemosensitivity, platinum sensitivity, interval between diagnosis and transplantation, high-dose regimens, graft type (bone marrow or blood stem cells), and year of transplantation. For the final multivariate model, forward stepwise selection was used to select variables; a P value less than 0.05 was considered statistically significant. First-order interactions of variables in the final model were also checked. Using a time-dependent covariate approach, we checked all variables to ensure that the assumption of the Cox model was valid. A score test (22) was used to determine whether any center-specific effects required adjustment. Chemosensitivity was defined as partial response (>50% decrease in the size of measurable disease) or complete response to the last chemotherapy regimen given in the 6 months before transplantation. Platinum sensitivity was defined as a partial or greater response to the last platinum-based chemotherapy regimen given in the 6 months before transplantation or an unmaintained remission after the completion of platinum-based therapy 6 or more months before transplantation. Patients with optimal debulking were defined as those who had tumors less than 1 cm in maximal diameter after initial surgery. Progression of disease after transplantation was defined as clinical or radiographic evidence of new or progressive disease or a CA 125 value greater than 50 IU/mL and increasing. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Patient characteristics are shown in Tables 1 and 2. More than 80% of women had stage III or IV disease at diagnosis, which is somewhat higher than the percentage observed in unselected surveys of ovarian cancer. However, histologic characteristics, grade, type

Effect of postremission chemotherapy before human leukocyte antigen–identical sibling transplantation for acute myelogenous leukemia in first complete remission

In this prospective, multicenter, phase 2 study, multiple myeloma (MM) patients with primary resistant disease or recurrent chemosensitive disease, in chemoresistant relapse, or in second or subsequent remission were treated with high-dose chemoradiotherapy followed by autologous peripheral blood stem cell (PBSC) rescue. PBSCs were collected using granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg per day subcutaneously for 3 days. Patients underwent high-dose chemoradiotherapy consisting of melphalan (140 mg/m2 x 1 day), cyclophosphamide (60 mg/kg per day x 2 days), methylprednisolone (2 g/d x 7 days), and total body radiation (150 cGy bid x 3 days) followed by peripheral blood stem cell reinfusion (> or = 1.2 x 10(9) mononucleated cells per kg) and GM-CSF support (5 microg/kg per day) and were evaluated for response, survival, and toxicity. Thirty-six patients, median age 53.4 years, completed the study. The mean pretransplantation cumulative melphalan dose was 464 +/- 72 mg. Excluding the 3 patients (8.3%) who failed to engraft, the median times to engraftment and platelet recovery were 10 days (range, 8-39 days) and 17 days (range, 7-67 days), respectively. Four patients (11.1%) died of complications related to the regimen (main causes of death, sepsis and acute respiratory distress syndrome) within the first 100 days. Twenty-two patients (61.1%) achieved complete response (CR), 8 (22.2%) partial response, and 2 (5.5%) no response. Two patients developed myelodysplastic syndrome after achieving CR. For all 36 patients, the probability of overall survival at 5 years was 27.3%. Median survival was 31 months (range, 0.3-81 months) in all patients and 42 months (range, 3.4-81 months) in those with CR. The probabilities of overall and disease-free survival at 5 years for the 22 patients who achieved CR were 43.6% and 15.7%, respectively. This high-dose chemotherapy regimen coupled with PBSC rescue is associated with a high CR rate and is capable of inducing long-term survival in a subset of heavily pretreated patients with primary resistant or recurrent MM.