Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapy.

A total of 30-50% of early breast cancer (EBC) patients considered as high risk using standard prognostic factors develop metastatic recurrence despite standard adjuvant systemic treatment. A means to better predict clinical outcome is needed to optimize and individualize therapeutic decisions. To identify a protein signature correlating with metastatic relapse, we performed surface-enhanced laser desorption/ionization-time of flight mass spectrometry profiling of early postoperative serum from 81 high-risk EBC patients. Denatured and fractionated serum samples were incubated with IMAC30 and CM10 ProteinChip arrays. Several protein peaks were differentially expressed according to clinical outcome. By combining partial least squares and logistic regression methods, we built a multiprotein model that correctly predicted outcome in 83% of patients. The 5-year metastasis-free survival in 'good prognosis' and 'poor prognosis' patients as defined using the multiprotein index were strikingly different (83 and 22%, respectively; P<0.0001, log-rank test). In a multivariate Cox regression including conventional pathological factors and multiprotein index, the latter retained the strongest independent prognostic significance for metastatic relapse. Major components of the multiprotein index included haptoglobin, C3a complement fraction, transferrin, apolipoprotein C1 and apolipoprotein A1. Therefore, postoperative serum protein pattern may have an important prognostic value in high-risk EBC.

A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma.

The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2-3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- s.d.) were 65 +/- 16 and 63 +/- 15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86 +/- 14 and 82 +/- 15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.

Autografting for chronic granulocytic leukemia in transformation.

Forty-five patients were treated for chronic granulocytic leukemia (CGL) in transformation by intensive chemotherapy (23 patients) or radiochemotherapy (22 patients) followed by autologous transplantation of bone marrow (17 patients) or blood-derived hematopoietic stem cells (28 patients). Hematopoiesis was reestablished in most evaluable patients and was significantly more rapid in previously splenectomized patients or in those receiving more than 10 X 10(8) nucleated cells/kg. However, partial or complete failure of engraftment was observed in 11 patients, in most cases after autografting with marrow cells. The median survival of all patients was 4.5 months. The major cause of death was the rapid recurrence of the blast cells not eradicated by the conditioning regimen. However, 4 of the 11 patients treated during the accelerated phase are still alive in the chronic phase, 17, 23, 35, and 54 months after autografting. These results and the restoration of hematopoiesis without the Philadelphia chromosome in 5 patients suggest that autografting could be used in CGL before the onset of the blast crisis.

Modified chemotherapy with carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) and autologous bone marrow transplantation in 24 poor-risk patients with acute lymphoblastic leukemia.

Twenty-four poor-risk patients with acute lymphoblastic leukemia received a modified regimen of carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) followed by autologous bone marrow transplantation (ABMT). Nineteen patients were in second or subsequent complete remission (CR) when treated with this regimen; 3 died early, 2 died of pneumonia in CR, 11 relapsed within 3 months (median), and 3 remain in CR with no maintenance therapy 14-24 months after ABMT. Of the 5 patients with measurable disease who were treated, 3 had CR and 1 remains in CR without maintenance therapy more than 28 months after ABMT. The toxicity of this regimen was acceptable, but late pulmonary toxic effects remain a major concern. These results are poor in terms of efficacy, and new effective methods of eradicating acute lymphoblastic leukemia in patients with poor prognosis should be investigated.

Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission.

Twenty-seven patients ranging in age from 15 to 36 years participated in a pilot study, and underwent allogeneic bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL) in first complete remission (CR) in four French centers. All patients were grafted from human leukocyte antigen/mixed leukocyte culture (HLA/MLC) identical sibling after conditioning regimen consisting of cyclophosphamide and total body irradiation (TBI). Sixteen patients are alive in persistent first remission, with a median follow-up of 56 months (range, 41 to 82 months). The 6-year Kaplan-Meier probability of disease-free survival (DFS) is 59%. Only three patients relapsed (5, 7, and 7 months after transplantation). These interesting results have led us to propose, in accord with a French multicentric protocol, allogeneic BMT for adults under 40 years of age during the first CR of ALL.

Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia.

PURPOSE: Optimal postremission therapy remains controversial in adult patients with acute lymphoblastic leukemia (ALL). In a large multicentric trial (LALA87), we compared allogeneic bone marrow transplantation (BMT) with other postremission therapies (chemotherapy or autologous transplantation) using the result of the human leukocyte antigen (HLA) typing as a random allocation. PATIENTS AND METHODS: Patient eligibility requirements were as follows: (1) inclusion in LALA87 trial, (2) complete response to induction or salvage therapy, (3) age 15 to 40 years, and (4) at least one potential sibling donor. Patients with an HLA-identical sibling were assigned to the BMT group, while patients without a sibling donor constituted the control group. Allogeneic transplantation was scheduled for patients in the BMT group; in the control group, patients were randomly allocated to receive chemotherapy or autologous transplantation. RESULTS: Of 284 eligible points, 257 entered the study: 116 were allocated to the BMT group and 141 to the control group. The 5-year survival rates were not statistically significantly different between the two groups. When only patients with high-risk ALL were considered (those with [1] Philadelphia chromosome [Ph1] ALL, [2] null or undifferentiated ALL, or [3] c-ALL with either age greater than 35 years or WBC count > 30 x 10(9)/L or time to achieve complete remission > 4 weeks), overall survival (P = .03) and disease-free-survival (P = .01) were better for the BMT group compared with the control group (5-year overall survival rates, 44% v 20%; 5-year disease-free survival rates, 39% v 14%). CONCLUSION: Allogeneic transplantation does not improve survival in patients with standard-risk ALL and should be recommended only for patients with adverse prognostic factors.

Randomized, controlled, dose-range study of Ro 25-8315 given before and after a high-dose combination chemotherapy regimen in patients with metastatic or recurrent breast cancer patients.

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of three different dose levels of pegylated granulocyte colony-stimulating factor (Ro 25-8315) on progenitor cell mobilization and hematologic recovery in cancer patients. PATIENTS AND METHODS: Breast cancer patients (n = 36) were randomly assigned to receive before (part I) and after (part II) chemotherapy either a single-dose injection of Ro 25-8315 (20 microg/kg, n = 9; 60 microg/kg, n = 9; 100 microg/kg, n = 10) or a standard daily dose of filgrastim (part I, 10 microg/kg/d; part II, 5 microg/kg/d) (control group, n = 8). RESULTS: Overall, Ro 25-8315 was well tolerated. In part I, more progenitor cell mobilization was observed with Ro 25-8315 100 microg/kg. The peak of circulating CD34(+) cells was obtained at day +5 in the four groups, and the absolute neutrophil count (ANC) returned to less than 20 x 10(9)/L by day +15. In part II, high levels of circulating CD34(+) cells (> 20 cells/microL) were obtained in all four groups. The chemotherapy-induced neutropenia (< 1 x 10(9)/L) was similar in the four groups. Ro 25-8315 100 microg/kg was more effective than filgrastim in reducing the number of patients with an ANC less than 0.5 x 10(9)/L on day +12 after chemotherapy. CONCLUSION: A single injection of Ro 25-8315 100 microg/kg might be the optimal dose for steady-state peripheral-blood progenitor cell mobilization. A single injection of 20, 60, or 100 microg/kg could be as efficient as daily administration of filgrastim to correct chemotherapy-induced cytopenia. The optimal dose of Ro 25-8315 should be determined according to the planned chemotherapy regimen.

Intensive sequential chemotherapy with repeated blood stem-cell support for untreated poor-prognosis non-Hodgkin's lymphoma.

PURPOSE: To demonstrate the feasibility and efficacy of six ambulatory high-dose sequential chemotherapy courses that include three intensified cycles supported by stem-cell infusion in high-risk and high-intermediate-risk untreated non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: A pilot nonrandomized study included 20 untreated patients aged less than 60 years with aggressive histologically identified NHL and two or three adverse-prognosis criteria (International Index). Patients received an ambulatory regimen with high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF) and repeated peripheral-blood stem-cell (PBSC) infusion. The median age was 39 years (range, 20 to 59), with 13 men and seven women. Chemotherapy consisted of one cycle every 21 days for a total of six cycles. The first three cycles (A1, A2, and A3) consisted of cyclophosphamide (Cy) 3,000 mg/m2, doxorubicin (Doxo) 75 mg/m2, and vincristine 2 mg (plus corticosteroids). The last three cycles (B4, B5, and B6) consisted of the same drug combination plus etoposide 300 mg/m2 and cisplatin 100 mg/m2. For an expected duration of 18 weeks, the projected dose-intensity was 25 mg/m2/wk for Doxo and 1,000 mg/m2/wk for Cy. G-CSF 300 micrograms was administered from day 6 following each cycle until neutrophil reconstitution. Two aphereses were performed at approximately day 13 after each A cycle, and PBSCs were injected at day 4 of each B cycle. Radiotherapy on tumor masses > or = 5 cm was scheduled after completion of the last cycle. RESULTS: The median duration of grade 4 neutropenia was 1 day (range, 0 to 7) for each A cycle and 4 days (range, 1 to 10) for each B cycle (P = .02). The median duration of grade 4 thrombopenia was 0 days (range, 0 to 8) for each A cycle and 6 days (range, 1 to 21) for each B cycle (P < .001). Hospitalization for febrile neutropenia was required for 18% and 44% of patients during cycles A and B, respectively (P < .01). Only three patients did not complete the protocol: one due to emergency surgery after cycle B4, one who died after cycle B5 from interstitial pneumonia, and one with delayed hematologic reconstitution after cycle B4. Chemotherapy delivery was optimal (median actual relative dose-intensity, 97%; range, 66 to 100). The median total dose administered over 18 weeks was 18,000 mg Cy (range, 12,000 to 18,000), 450 mg Doxo (range, 300 to 450), 900 mg etoposide (range, 300 to 900), and 300 mg cisplatin (range, 100 to 300). Evaluation of response after six courses showed 13 complete remissions ([CRs] 65%), four partial remissions (PRs), two nonresponses (NRs), and one toxic death. With a median follow-up period of 25 months (range, 16 to 43), 15 patients are alive, with 12 in continuous first CR; five patients relapsed (four of four PRs and one of 13 CRs). Two-year survival and failure-free survival (FFS) rates are 73% and 56%, respectively. The disease-free survival (DFS) rate for the CRs is 86%. CONCLUSION: PBSC support contributes to the feasibility of first-line, very-high-dose, ambulatory chemotherapy delivery in poor-risk NHL and is associated with a high rate of remission and FFS.