High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group.

The optimum treatment of primary CNS lymphoma (PCNSL) is not yet determined. The objective of this study was to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) in patients with newly diagnosed PCNSL. Twenty-five patients received two courses of initial chemotherapy combining methotrexate, etoposide, carmustine and methylprednisolone, and one course of ifosfamide-cytarabine followed by peripheral stem cell collection. Seventeen responsive patients then received HDT using carmustine, etoposide, cytarabine and melphalan with autologous stem cell rescue. After ASCT for responding patients or after salvage therapy for non-responders, whole brain radiation therapy at a dose of 30 Gy was delivered. The objective response rate to the induction chemotherapy was 84%. Four of the 21 responding patients did not have ASCT because of toxicity or refusal. With a median follow-up time of 34 months, the projected event free survival rate is 46% at 4 years. Projected overall survival is 64% at 4 years. Sixteen patients are actually in continuous complete response. No evidence of late treatment-related toxicity was observed. This treatment approach appears feasible in newly diagnosed PCNSL with encouraging results.

Mediastinal tumor size and response to chemotherapy are the only prognostic factors in supradiaphragmatic Hodgkin's disease treated by ABVD plus radiotherapy: ten-year results of the Paris-Ouest-France 81/12 trial, including 262 patients.

PURPOSE: To identify prognostic factors in 262 patients with supradiaphragmatic Hodgkin's disease (HD), clinical stages (CS) I and II, prospectively treated between 1981 and 1988 according to the Paris-Ouest-France (POF) 81/12 protocol by three 1-month cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus methylprednisone (ABVD-MP) followed by subtotal nodal irradiation (RT). PATIENTS AND METHODS: The size of mediastinal tumor (MT) was measured in all patients: 66 did not have MT (NoMT); 105 had a small-size MT (SSMT), ie, mediastinal mass ratio (MMR) less than 0.33; 58 had a medium-size MT (MSMT), ie, MMR > or = 0.33 and less than 0.45; and 33 had a bulky MT (BuMT), ie, MMR > or = 0.45. All patients received three cycles (CS IA, one cycle only) of ABVD-MP; patients in partial remission (PR) or complete remission (CR) after chemotherapy (CT) received supradiaphragmatic RT (involved fields, 40 Gy; adjacent fields, 30 Gy) plus lumboaortic and splenic RT (30 Gy); patients not in CR or PR after CT received salvage CT. RESULTS: Two hundred seventeen patients (82.8%) entered CR after CT and 258 (98.5%) after RT. Ten-year freedom-from-progression (FFP) and survival rateswere 88.6% and 89.4%, respectively. According to univariate analysis, MT size and post-CT status were the only factors to influence both FFP and survival. For patients with NoMT or SSMT, those with MSMT, and those with BuMT, FFP rates were 94.1%, 87.0%, and 63.0% (P < .001), respectively, while corresponding survival rates were 92.6%, 87.2%, and 78.2% (P < .05). FFP rates were significantly different between the patients who achieved CR and those who did not achieve CR after CT: 94.6% versus 65.3% (P < .001); corresponding survival rates were 89.9% and 73.7% (P < .01). Multivariate analysis confirmed that MT size and post-CT status were the only two prognostic factors for FFP; for survival, the same two characteristics, as well as age (< 40 v > or = 40 years), significantly affected prognosis. We were thus able to identify three groups. The 33 patients (12.6%) with a BuMT had 10-year FFP and survival rates of 63.0% and 78.2%, respectively. Of 229 patients without BuMT, the 195 who attained CR after CT had an optimal prognosis (FFP, 96.6%; survival, 93.6%), while those who failed to achieve CR after CT had an intermediate prognosis (FFP, 68.8%; survival, 77.6%). CONCLUSION: These results demonstrate the independent impact on HD prognosis of tumor burden and post-CT status.

[Treatment of localized forms of Hodgkin's disease with 3 courses of chemotherapy (ABVD-MP) in combination with wide focal and prophylactic lumbo-splenic radiotherapy. The POF 81/12 protocol]. / Traitement des formes localisées de la maladie de Hodgkin par 3 cures de chimiothérapie (ABVD-MP) associées à une radiothérapie focale élargie et lombo-splénique prophylactique. Protocole POF 81/12.

Between October 10, 1981 and December 31, 1987, we used the Hodgkin POF 81/12 protocol to treat 235 patients aged from 5 to 65 years (mean 30 years) with localized Hodgkin's disease clinically classified as stage IA (n = 6), stage IIA (n = 128) and stage IIB (n = 53). A contiguous lesion was present in 22 cases and a mediastinal lesion in 170 cases. The patients received 3 monthly courses of ABVD-MP (doxorubicin 25, bleomycin 10, vinblastine 6, dacarbazine 375 and methylprednisolone 120 mg per sq.m intravenously on days 1 and 15), except for stage IA non-mediastinal patients who received only one course. Thereafter, in the absence of failure (lack of changes or progression under chemotherapy), a 40 Gy wide focal irradiation and a 30 Gy prophylactic lumbo-splenic irradiation were performed. Complete remission (CR) was obtained in 229 patients, and the 6 failures (4 after ABVD-MP, 2 after radiotherapy) were treated with specific programmes. On December 1, 1988 (median survival 42 months, range 12-86 months) we had recorded 9 relapses (after 9 to 51 months) and 7 deaths (2 failures, 2 relapses and 3 patients in CR: ovarian carcinoma, road accident, exploratory pleural puncture). The current actuarial relapse and survival rates at 7 years are 5 and 94 respectively. Two unfavourable forms of the disease were identified: infra-diaphragmatic with massive lumbo-aortic lesions (5 cases: 1 failure, 1 relapse) and supra-diaphragmatic with a mediastinum/chest ratio of 0,45 or more (30 cases: 5 failures, 5 relapses). In the 200 patients devoid of these 2 risk factors the results obtained were: CR 100 percent, only 2 relapses and survival at 7 years 98 percent.

Autologous stem cell transplantation for anaplastic large-cell lymphomas: results of a prospective trial.

Autologous stem cell transplantation (ASCT) in the front line treatment of non-Hodgkin's lymphoma (NHL) remains controversial. Anaplastic large-cell lymphoma (ALCL) is known to have its own clinical and biological features. The outcome of ALCL patients treated with high-dose chemotherapy and ASCT as part of their first-line therapy was analysed in 202 intermediate or high-grade NHL patients in a prospective randomized trial. First-line chemotherapy comprised two alternating anthracycline-containing regimens. Responding patients were autografted after a BEAM (BCNU, cytarabine, etoposide and melphalan) regimen. Patients with bulky or residual masses were irradiated. Fifteen patients with ALCL were identified by morphological and immunological features (CD30 was expressed in 14 out of 15 patients, three patients expressed B-cell markers, five patients expressed T-cell markers and seven patients did not express cell markers). Anaplastic lymphoma kinase (ALK) expression was confirmed in seven cases. The median age was 39 years with a predominant male sex ratio (2.75). Thirteen patients were stage >/= III and six presented with two or more adverse prognostic factors. According to the international age-adjusted prognostic index, the expected complete remission (CR), event-free survival (EFS) and overall survival (OS) rates were 69%, 71% and 69%. Two deaths were observed (one due to interstitial pneumonitis, one due to pulmonary carcinoma). All patients entered CR, no relapse occurred and EFS and survival reached 87% with a follow-up of more than 5 years. These results differ significantly from those observed in the other 176 lymphoma patients: event-free survival was only 53 +/- 5% and OS reached 60 +/- 4% with a median follow-up of 56 months (P = 0.006). Intensified chemotherapy with autologous stem cell support appeared effective in the treatment of ALCL, offering patients the real chance of a cure.

Ovarian transposition by laparoscopy before radiotherapy in the treatment of Hodgkin's disease.

BACKGROUND: The use of inverted Y irradiation in the treatment of Hodgkin's disease with pelvic lymph node involvement can cause iatrogenic early menopause in young women as a result of ovarian exposure to radiation. Ovarian transposition protects the ovaries by removing them from the irradiation field. This surgical procedure, initially performed by laparotomy, can now be done by laparoscopy. METHODS: During the period July 1994 to April 1996, laparoscopic ovarian transposition was performed on 4 young women with Hodgkin's disease 1 week before inverted Y radiotherapy. The surgical procedure, complications, length of hospitalization, and hormonal, clinical, and biologic results were evaluated. RESULTS: The mean duration of hospitalization was 4 days, and there were no postoperative complications. Iatrogenic menopause did not occur in any of the patients during the mean follow-up period of 20.75 months (range, 6-35 months; median, 20 months). CONCLUSIONS: Laparoscopy offers many advantages over laparotomy for ovarian transposition. This procedure, which can be performed without opening the abdominal wall, is highly efficient, requires only a short period of hospitalization, and leads to few postoperative complications. Laparoscopy is an attractive alternative to laparotomy for ovarian transposition in young women with advanced Hodgkin's disease who require pelvic radiotherapy.

Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response.

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.

Ten-year results of a strategy combining three cycles of ABVD and high-dose extended irradiation for treating Hodgkin's disease at advanced stages.

BACKGROUND: The treatment of Hodgkin's disease (HD) at advanced stages relies mainly upon multi-agent chemotherapies (CT), while the role of radiation therapy has not been definitely identified. The aim of this report is to analyze the 10-year results of a prospective study including 133 patients with HD clinical stages (CS) IIIA to IVB treated by three monthly courses of ABVD (adriamycin, bleomycin, vinblastin, and dacarbazine) followed by high-dose subtotal or total lymphoid irradiation [(S)TLI]. PATIENTS AND METHODS: From 1 October 1981 to 30 September 1988, 133 adult patients with HD CS IIIA (45), IIIB (33), IVA (seven) and IVB (48) were entered in the non-randomized multicentric prospective trial POF81/34. The number of involved nodal areas (NINA), and the number of visceral sites (NVIS) involved were registered in all patients; patients with bulky mediastinal tumor (BuMT) (mediastinal mass ratio > or = 0.45) were also identified. All patients received three monthly cycles of ABVD. Patients in complete remission (CR) or partial remission (PR) after completion of CT received a (S)TLI including the spleen (involved sites 40 Gy, non-involved 30 Gy); initially involved lung(s) and liver received 18 and 20 Gy, respectively; and patients not in CR or PR after CT or RT received salvage treatments. Univariate and multivariate analyses were performed to identify the factors contributing significantly to the prognosis; initial characteristics, as well as status after the three cycles of CT, were entered in the model. RESULTS: Of the 133 patients, 74 (55.6%) entered in CR after CT and 116 (87.2%) after completion of radiation therapy. Ten-year freedom from progression (FFP), freedom from tumor mortality (FFTM) and survival rates were 70.4%, 78.9% and 70.6%, respectively. According to univariate analysis the NVIS (< or = one vs. > or = two) was the only initial factor simultaneously influencing 10-year FFP (73.9% vs. 38.2%) FFTM (82.5 vs. 34.1%) and survival (73.5% vs. 17.3%) rates; on the other hand, the NINA (< or = four vs. > or = five) influenced FFP (81.4% vs. 60.7%) and FFTM rates (87.3% vs. 71.4%) while symptoms (A vs. B) influenced FFP (80.7% vs. 63.3%) and survival (82.8% vs, 61.2%) rates. Finally, age (< 40 vs. > or = 40) influenced survival rate only (79.2% vs. 50%). According to multivariate analysis, NVIS and NINA had an independent impact on FFP and FFTM, while survival was modified by the NVIS and age. The post-CT status (CR vs. no CR) had a major impact on FFP (85.3% vs. 64.9%) FFTM (92.1% vs. 63.3%) as well as on survival (78.6% vs. 54.7%) rates in both univariate and multivariate analyses. Complications of therapy were mainly due to RT: 11 patients acquired second malignancies, six developed lung fibrosis or severe pulmonary infections, three developed intestinal obstructions and six developed angina pectoris or carotid stenosis. CONCLUSIONS: Tumor burden (identified by the number of involved nodal areas and the number of visceral sites) and the response to initial CT were the two independent factors influencing the outcome of this group of 133 patients with HD, CSIII and IV treated by three cycles of ABVD followed by high-dose [(S)TLI].