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Fludarabine was associated with a good response and was well tolerated in patients with follicular lymphoma in phase II trials and this treatment may be associated with less adverse events than treatment with CHVP plus interferon in elderly patients.One hundred thirty-one patients older than 59 years with a follicular lymphoma and poor prognosis were randomized between the association of CHVP (12 cycles in 18 months) plus interferon (5 MU TIW for 18 months) or fludarabine alone (25 mg/m2/d x 5 days for 6 cycles, then 20 mg/m2/day for 6 further cycles for 18 months). Poor prognosis was defined by the presence of a large tumor mass, poor performance status, the presence of B symptoms, above normal LDH level, oror = 3 mg/l beta-microglobulin level.Patients treated with CHVP plus interferon had a higher response to treatment, a longer time to progression and a longer survival than those treated with fludarabine alone (P0.05 for all analyses). With a median follow-up of 29 months, the 2-year failure-free survival was 63% for the CHVP-plus-interferon arm compared to 49% for the fludarabine arm and the two-year survival was 77% and 62%, respectively. This benefit was confirmed in a multivariate analysis including initial prognostic parameters. Fludarabine alone was associated with less neutropenia than CHVP plus interferon. Interferon was decreased or stopped in 39% of the patients because of severe fatigue.CHVP plus interferon over 18 months was associated with a better outcome, even though the combination of interferon plus chemotherapy was less well tolerated than fludarabine.

To determine the prognostic factors and outcome of first-line induction failure Hodgkin's 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.We retrospectively analyzed data relating to 86 Hodgkin's 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.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).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.

To further delineate the cytokine involvement in human acute graft-versus-host disease (GVHD), we analyzed cytokine expression in peripheral blood mononuclear cells (PBMC) from patients who developed acute GVHD after allogeneic bone marrow transplantation and from those who did not.We used a highly quantitative and sensitive polymerase chain reaction assay based on the coamplification of an internal standard, with the cDNA derived from the mRNA of interest. Results are expressed in copy numbers, after normalization to a fixed amount of actin, allowing comparison between different samples. After a myeloablative regimen, 22 patients with hematological diseases received an unmanipulated allograft from a matched sibling. They were subsequently submitted to prophylactic immunosuppression. We examined the transcription of genes encoding cytokines in PBMC and skin biopsies. We selected T helper 1 (interferon ([IFN]gamma, interleukin [IL]-2), T helper 2 (IL-4, IL-10), and inflammatory (IL-1, IL-6) cytokines.Four weeks after bone marrow transplantation, the bulk of the PBMC population exhibited an increased expression of IL-1 and IL-6, with no major difference between GVHD+ and GVHD- patients. In addition, although IL-2 expression was not detected, increased levels of IFNgamma mRNA were observed in allografted patients, with higher levels in GVHD+ patients. In skin biopsies sampled at the beginning of GVHD, although low expression of IL-1 and IL-6 could be observed, neither type 1 (IL-2, IFNgamma) nor type 2 (IL-4, IL-10) cytokines could be detected.These studies suggest that the occurrence of human GVHD does not seem to be clearly associated with a T helper 1-type cytokine pattern.

Allogeneic BMT for patients with acute myeloid leukemia (AML) is presently a reference therapy. The indications for this therapy mainly rely upon prognostic factors, and their importance is constantly reassessed. To examine the impact of time from diagnosis to transplant on survival and leukemia-free survival (LFS), we analyzed 109 patients from the database of the SFGM comprising patients who had all 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 conditioned with cyclophosphamide (CY) and total body irradiation (TBI) (CYTBI), and methotrexate (MTX) + cyclosporin A (CsA) were used as graft-versus-host disease (GVHD) prophylaxis. Patient characteristics were: age = 33 +/- 9, M/F = 64/45, white blood cell count (WBC) at diagnosis = 27 +/- 42 x 10(9)/l, FAB distribution: M1 and M2 = 55; M3 = 15, M4 and M5 = 33, M0, M6 and M7 = 6. Karyotyping was carried out for 64 patients: 32 had a normal karyotype, 16 had good prognosis abnormalities (t(8;21), t(15;17), inv 16) and 16 patients had other abnormalities. Eleven patients needed two courses of induction to achieve CR. Time between diagnosis and BMT was 120 (64-287) days. Forty-nine patients developed gradeor = 2 acute GVHD (actuarial probability = 46%). With a median follow-up of 50 months (27-100), 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 three independent factors: time to transplant (120 days vsor = 120 days), acute GVHD (grade 2-4 vs grade 0-1) and age (33 vsor = 33). LFS is only influenced by the first two of these factors. The favorable impact of a shorter time from diagnosis to transplant should lead to performing the transplant as early 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 begin immediately and transplant be performed as soon as possible.

We conducted a randomized trial with ceftazidine alone or associated with amikacin or vancomycin to investigate the efficacy of the daily 3 g dosage of ceftazidime and the efficacy of monotherapy with ceftazidime and to determine if vancomycin should be added empirically.Patient inclusion criteria were: age over 10 years, therapeutically-induced neutropenia and fever for at least three hours above 38.5 degrees C in absence of a clear non-infectious aetiology. Patients were randomized into three groups: group C, ceftazidime alone 3 g/day; group CA, ceftazidime 3 g/day plus amikacin 15 mg/kg/day; or group C, ceftazidime 3 g/day plus vancomycin 1.5 g/day.Results from one hundred and two episodes of fever were analyzed. The underlying diseases were haematological malignancies (89 patients) and solid tumours (13 patients). The median duration of neutropenia (0.5 x 10(9) PMN/L) was 18 days and the minimum duration of 7 days. The main criterion for the analysis of efficacy was the onset of a major infectious event, i.e. death related to documented or suspected infection and any infectious event considered life-threatening or hindering future treatment of the underlying disease. Eight (22%) patients in group C developed major infectious events compared with four (13%) in group CA and none in group CV (p0.01). Major infectious events were mainly due to Gram-positive organisms, particularly Streptococcus species.We conclude that: 1) ceftazidime alone and in association with amikacin is effective in preventing Gram-negative major infectious events; and 2) vancomycin should not be added only when a Gram-positive infection is documented, but used empirically.

Four out of 23 consecutive patients treated with high-dose Ara-C for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during Ara-C infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose Ara-C may be associated with cytokine release.

The prognosis of Burkitt's lymphoma is generally considered to be poor, particularly in the advanced stages of the disease. Although recent chemotherapy protocols have given high rates of cure in children, there are few such reports concerning adults. We therefore conducted a retrospective analysis of the results for treatment of 46 adults in the Institut Gustave Roussy (IGR) between 1978 and 1987, in order to establish an effective treatment strategy for use in a prospective trial. The median age of the patients was 31 years and the majority were Caucasians of European origin. The clinical symptoms and course of the disease were similar to those in the pediatric situation and corresponded to the so-called non endemic forms observed in Europe and the United States. Presentation was generally extra-nodal, usually with abdominal manifestations. As a rule, the disease progressed rapidly and showed a high affinity for the central nervous system in the absence of specific prophylaxis, despite systemic therapy with highly active agents, particularly in the advanced stages. According to Murphy's classification, there were 6 stage I, 11 stage II, 19 stage III and 10 stage IV patients (3 of whom had CNS involvement). Treatment was heterogenous, although all the patients received polychemotherapy including anthracyclins. The best results were obtained from eleven patients treated according to the French Multicenter Protocols for pediatric Burkitt's lymphoma (LMB-84 and LMB-86). Kaplan-Meier 5-year relapse free survival rate among the 46 patients was 42% (stage I: 83%; stage II: 67%; stage III: 30%; stage IV: 30%). In order to standardize our therapeutic approach, we started a prospective study in 1988 using the unmodified pediatric protocol for our adult patients.

Prolymphocytic leukemia is an entity characterized by morphologic, immunologic, clinical and behavioral features which allows its keeping apart from chronic lymphoid leukemia. Careful analysis of blood smear is the main step for its diagnosis. Our purpose is to remind this particular chronic lymphoproliferative syndrome which requires energetic initial treatment. Prolymphocytic leukemia de novo as well as a possible transformation of chronic lymphoid leukemia to prolymphocytic leukemia are discussed.

In recent years, the prognosis of non-seminomatous germ-cell tumors has been greatly improved by the use of novel chemotherapeutic regimens including platinum derivatives. However, the prognosis remains poor for a certain proportion of these patients. We have therefore developed an intensive chemotherapy protocol (PEC) followed by bone marrow autografting: cisplatin (40 mg/m2/day x 5 d), etoposide (350 mg/m2/day x 5 d), cyclophosphamide (1,600 mg/m2/day x 4 d). Forty-four poor-prognosis patients were thus treated. The results can be stratified into 3 categories, as follows: I: 12 refractory patients: 3 CR, 6 PR, 2 failures, 1 unevaluable. Median survival was short (7 months, range 2-16 months); II: 6 patients with sensitive relapse: 5 CR, 1 unevaluable. Four patients remained in CR at 42, 45, 46 and 48 months; III: 26 patients who received PEC as consolidation therapy in the first CR-PR after courses of conventional chemotherapy and who were selected at the time of diagnosis on the basis of factors of poor prognosis: 16 CR, 3 PR, 7 unevaluable. Two-year disease-free survival (Kaplan-Meier) is 60%. The median duration of neutropenia (less than 0.5 x 10(9)/l) was 15 d (range 6-37) and that of thrombocytopenia (less than 20 x 10(9)/l), 13 d (range 3-32). The most significant non-hematologic toxicity was of the gastrointestinal tract; in particular severe mucositis. Four iatrogenic deaths occurred (2 candidiasis, 1 aspergillosis and 1 hemorrhage). Pharmacokinetic studies were used to determine the optimum time for reinfusing the marrow and provided information on the mechanism of the mucositis. In conclusion, PEC protocol showed a high efficacy with 94% response rate (68.5% CR) among the 35 evaluable pts. Patients refractory to conventional treatment did not appear to benefit from this intensive chemotherapy. However, it appears that it may be useful for patients with relapses sensitive to salvage therapy. Encouraging results were obtained with the PEC protocol administered as early consolidation for patients with identifiable risk factors at diagnosis. A multicenter, randomized trial is currently underway in France to compare this approach with standard conventional chemotherapy.

Vindesine is a derivative of vinblastine and of vincristine. A high proportion of remissions were obtained in acute lymphoid leukaemia (6 complete and 1 incomplete remissions in 15 patients), in blastic crisis of chronic myeloid leukaemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. Permanent 48 h i.v. infusion may include a remission where i.v. pusch of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukaemia.

Two non randomized therapeutic trials have been conducted in oat cell carcinoma of the lung with limited disease. The first protocol combined chemotherapy (adriamycin, cyclophosphamide, VM 26, procarbazine) with mediastinal and supra-clavicular radiotherapy in classical fractionation (40 grays in 4 weeks). The second combined a more intensive chemotherapy (adriamycin, VP 16, methotrexate, cyclophosphamide) with an alternating radiotherapy (3 series of 15 grays). All patients received prophylactic brain irradiation. Preliminary results show a 9 month survival rate of 34 per cent and 62.5 per cent respectively. In addition, all patients in the second protocol presented a complete response at the end of the induction treatment. These preliminary data encourage proceeding with this kind of combined treatment.

Sixty three patients with limited small cell lung carcinoma were entered into a pilot study alternating monthly cycles of combination chemotherapy (doxorubicin, VP16213, cyclophosphamide and methotrexate (group A) or cis platinum (group B) with 3 courses of mediastinal radiotherapy. The total mediastinal dose was 45 Gy for the first 28 patients (group A) and 55 Gy for the remaining 35 (group B). The complete response rate was 86% in group A (median survival 14 months) and 91% in group B (median survival 20 months). Local control at two years was 61% in group A and 82% in group B, while relapse-free 2 year survival rates were 32% and 37% respectively. The acceptable toxicity and high response rate of this combined modality therapy lead us to further research in maintenance therapy.

Dose-effect relationships of high-dose melphalan were evaluated in 37 patients with measurable relapsed or refractory acute leukemias. Thirteen patients (Group 1) received 70-100 mg/m2 of melphalan without marrow rescue and 24 patients (Group 2) received 140-180 mg/m2 of melphalan followed by marrow transplantation. Patients in both groups were comparable with respect to age, sex, diagnosis, and status of the leukemia. The complete remission rate was 23% in Group 1 versus 75% in Group 2 (P less than 0.01). Hematological recovery of remission patients was not statistically different in either group. Nonhematological toxicity was comparable in the two dose ranges examined. These results demonstrate the existence of a dose-response effect of high-dose melphalan regimens in relapsed acute leukemias, without marked increases in nonhematological toxicity with these doses.

Angio-lymphoblastic lymphadenopathies are a newly described haematological entity, though not rare, characterised by a histological triad (vascular neogenesis, highly polymorphic or predominantly immunoblastic cellular proliferation and the presence of acidophilic protein deposits), a clinical syndrome consisting essentially of voluminous disseminated lymphadenopathy and hepatosplenomegaly and abnormal laboratory findings dominated by a polyclonal dysproteinaemia. This disorder, the first four French cases of which are described here, does not appear to be malignant in its early stages and is sensitive to corticosteroid therapy at that time. Secondary sarcomatous transformation is possible.

Vindesine, an analog of vinblastine and vincristine, has been submitted to a phase II trial, the results of which are judged in terms of remission induction. A high proportion of remissions were obtained in acute lymphoid leukemia and blastic crisis of chronic myeloid leukemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. A continuous 48-hour iv infusion may induce a remission where an iv push of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukemia.

The ability of human irradiated bone marrow to provide suitable environment for migrating stem cells has been studied in four patients. These had received chemotherapy plus doses of 40 Gy to thoracic vertebrae and sternum, followed by autologous bone marrow transplantation. The erythropoietic activity in the non-irradiated areas was increased but it was low in irradiated areas at 3.5 weeks and undetectable at 6 months after autotransplantation. This shows that no nidation of migrating stem cells actively contributed to bone marrow regeneration after 40 Gy and suggests the existence of environmental lesions. No extramedullary erythropoiesis and no bone marrow extension were found in these patients. Four patients who had received doses of 20 Gy to extended bone marrow volume were submitted to ferrokinetic studies from one to 18 years after radiotherapy. In non-irradiated areas the erythropoietic activity was within the normal range. In irradiated areas, it was significantly lower than in the non-irradiated areas and was intermediate between the erythropoietic activity in the sacrum of six healthy control subjects and in the irradiated areas of the four autografted patients. Bone marrow extension was found in these patients. This study suggests that bone marrow recovery after irradiation might not be an all-or-none phenomenon. It would be of interest to better document the dose-effect relationship.