J. L. Pico

Comparison of High-Dose Therapy and Autologous Stem-Cell Transplantation With Conventional Therapy for Hodgkin's Disease Induction Failure: A Case-Control Study

PURPOSE To determine the prognostic factors and outcome of first-line induction failure Hodgkins disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients. PATIENTS AND METHODS We retrospectively analyzed data relating to 86 Hodgkins disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases. RESULTS Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P < .001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058). CONCLUSION Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.

Pharmacokinetics of high-dose busulfan in children

SummaryThe pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4–14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803±228 ng/ml was achieved at 92–255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119±54 ml/min per m2, with an apparent distribution volume of 27.10±11.50 l/m2. A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25–7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5–1.4).

Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Société Française de Greffe de Moëlle (SFGM)

Increasing numbers of patients are surviving after allogeneic bone marrow transplantation and are therefore at risk for developing late complications. Among these complications, avascular necrosis of bone has been reported, but only two single‐centre studies included sufficient patients to enable analysis of the risk factors for developing avascular necrosis. In this multicentre retrospective study the aim was to assess risk factors for this complication in a large number of patients.

Early intensified chemotherapy with autologous bone marrow transplantation in first line treatment of poor risk non-seminomatous germ cell tumours : preliminary results of a French randomized trial. Discussion

UNLABELLED For 30 months we have treated 115 non-pretreated non-seminomatous germ cell tumour (NSGCT) patients with poor risk characteristics. Patients were allocated randomly to either arm A: NCI regimen with vinblastine, etoposide (E), bleomycin and double dose cisplatin (P2) (PVeBV) 3 or 4 cycles Q3W, or arm B: modified PVeBV protocol (bleomycin in continuous infusion) Q4W than a cycle of high-dose E + cyclophosphamide + P2 (PEC) and autologous bone marrow transplantation (ABMT). 114 patients are evaluable: 81 testicular, 18 mediastinal and 15 retroperitoneal primaries. RESULTS Arm A 57 patients: 7 patients did not complete the treatment. There were 15 failures, 9 PR, 33 CR. Seven patients relapsed. The 2-year survival is 82%. Arm B 57 patients: 16 patients did not complete the treatment. There were 26 failures, 7 PR and 24 CR. Nine patients relapsed. The 2-year survival is 60%. Both CR rates and survival are not statistically different. This trial fails to show any benefit of early intensified chemotherapy + ABMT to increase the CR and survival rates in poor risk NSGCT.

Pharmacokinetics of high-dose melphalan in children and adults

SummaryMelphalan pharmacokinetics were studied in 20 children with stage IV neuroblastomas or Ewings sarcomas and in 10 adults with AML, ALL, or small cell lung carcinomas, after IV administration of high doses (140 mg/m2 with furosemide-induced diuresis and 180 mg/m2 without induced diuresis) and high fluid intake (3000 ml/m2/day).Unchanged melphalan was assayed in plasma and cereorospinal fluid by means of a high-performance liquid chromatographic procedure. The elimination half-life (t1/280 min) allows autologous bone marrow transplantation 24 h after the drug administration. In some children we were able to detect melphalan in cerebrospinal fluid samples.

Long-term survivors after salvage high dose chemotherapy with bone marrow rescue in refractory germ cell cancer

Between April 1984 and May 1985, 17 heavily pretreated patients with relapsing or refractory germ cell tumours were treated with cisplatin 40 mg/m2/day, days 1-5; etoposide 350 mg/m2/day, days 1-5; cyclophosphamide 1600 mg/m2/day, days 2-5 and autologous bone marrow transplantation on day 8 as consolidation of conventional salvage chemotherapy. None of the 11 refractory patients and 4 of the 6 responders to prior salvage treatment are long-term survivors at 68, 72, 74 and 74 months. Mean aplasia duration was 17 days and there were 7 documented episodes of septicaemia in 17 febrile patients. 1 patient died of treatment. Among the 4 survivors, 2 patients have a sustained grade II invalidating neuropathy. We conclude that this regimen is not recommended as salvage therapy in refractory patients but may be a useful consolidation treatment in patients responding to conventional salvage chemotherapy.

VIP (etoposide, ifosfamide and cisplatinum) as a salvage intensification program in relapsed or refractory Hodgkin's disease

Forty-two patients with refractory (15 patients) or relapsed (27 patients) Hodgkin’s disease (HD) were included in a prospective single center study evaluating the efficacy of a regimen VIP combining etoposide 75 mg/m2/day days 1–5, ifosfamide 1.2 g/m2/day days 1–5 and cisplatinum 20 mg/m2/day days 1–5, one course every 4 weeks as salvage therapy in patients with refractory or relapsed Hodgkin’s disease, potentially eligible for high-dose chemotherapy with reinjection of hematopoietic stem cells (HSC). If patients were considered chemosensitive after two courses of VIP, high-dose chemotherapy followed by the reinjection of HSC was planned. After two courses of VIP, 67% achieved an objective response including 38% complete responses. Overall, 28 patients went on to high-dose therapy with reinjection of HSC, and 46% of grafted patients are in a sustained complete remission. When the overall patient population is considered, 33% are in complete remission (CR) with a median follow-up of 37 months. A CR of less than 12 months and refractory disease were associated with a poor survival. These results showed that the VIP regimen is effective in relapsed or refractory HD and allows high-dose therapy to be given in the case of most responding patients. However, results in patients with refractory disease or a first complete remission of less than 12 months need to be further improved.

Scoring system for the prediction of successful peripheral blood stem cell (PBSC) collection in non-Hodgkin's lymphoma (NHL): application in clinical practice.

Fifty-six patients with chemosensitive NHL were studied to assess factors affecting mobilization and peripheral blood stem cell (PBSC) collection: all were mobilized with high-dose cyclophosphamide and etoposide and G-CSF 5 μg/kg/day. None of them had bone marrow involvement at the time of mobilization or a history of extended field irradiation. Previous chemotherapy regimens were divided into two groups: moderately myelotoxic chemotherapy (MMC) and highly myelotoxic chemotherapy (HMC). The adequacy of the PBSC harvest was not associated with age, gender, a past history of bone marrow involvement or disease status. In contrast, the number of MMC cycles (n(MMC)) and the number of HMC cycles (n(HMC)) were both significant (P = 0.009 and P = 0.0004, respectively) and were used to compute a score predictive of a successful PBSC harvest: SCORE = n(MMC) + 4 n(HMC). The estimated successful PBSC collection rate was greater than 80% in patients with a score ranging from 0 to 15 and dropped rapidly to below 20% in patients with a score exceeding 25. This scoring system may help to determine the timing of PBSC mobilization in patients with a score below 15 and suggests that new PBSC mobilization procedures should be investigated in other patients. Bone Marrow Transplantation (2000) 25, 495–499.

Early Allogeneic Transplantation Favorably Influences the Outcome of Adult Patients Suffering from Acute Myeloid Leukemia

Allogeneic BMT for patients with acute myeloid leukemia (AML) is presently a reference therapy. The indications for this therapy may likely rely upon prognostic factors, and their importance are constantly investigated. To examine the impact of time from diagnosis to transplant on survival and Leukemia Free Survival (LFS), we analyzed 109 patients from the data base of the SFGM, patients who all had received an HLA-identical allogeneic BMT for a diagnosis of AML in First Complete Remission (CR1) between January 1987 and December 1992. All patients were prepared with cyclophosphamide (Cy) and Total Body Irradiation (TBI) (Cy — TBI), and Methotrexate (MTX) + Cyclosporine A (CSA) was used as Graft-vs.-Host Disease (GVHD) prophylaxis. Eleven patients needed 2 courses of induction to achieve CR. Time between diagnosis and BMT was 120 (64–287) days. Forty nine patients developed a grade 2 acute GVHD (Actuarial probability = 46%). With a median follow-up of 52 months (30–100), the 5 year probabilities for transplant related mortality (TRM), relapse, overall survival and LFS are respectively 25, 26, 59%, and 55%. A multivariate analysis showed that survival is adversely influenced by 3 independent factors: time to transplant (>120 days vs.≤120 days), acute GVHD (grade 2–4 vs. grade 0–1) and age (>33 vs.≤33). LFS is influenced by only the first two of these factors. The favorable impact of less time from diagnosis to transplant should lead to proceeding to the transplant as soon as possible. Practically speaking, this means that when such therapy is chosen for a patient with CR1 AML, the search for an allogeneic donor should be immediately investigated and transplant performed as soon as possible.

A Pilot Study of Autologous Bone Marrow Transplantation Followed by Recombinant Interleukin-2 in Malignant Lymphomas

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkins disease (HD) (11 patients) and non Hodgkins lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.