Alain Delmer

Imatinib plus Peginterferon Alfa-2a in Chronic Myeloid Leukemia

BACKGROUND Imatinib (400 mg daily) is considered the best initial therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. However, only a minority of patients treated with imatinib have a complete molecular remission. METHODS We randomly assigned 636 patients with untreated chronic-phase CML to receive imatinib alone at a dose of 400 mg daily, imatinib (400 mg daily) plus cytarabine (20 mg per square meter of body-surface area per day on days 15 through 28 of each 28-day cycle) or pegylated interferon (peginterferon) alfa-2a (90 μg weekly), or imatinib alone at a dose of 600 mg daily. Molecular and cytogenetic responses, time to treatment failure, overall and event-free survival, and adverse events were assessed. An analysis of molecular response at 12 months was planned. A superior molecular response was defined as a decrease in the ratio of transcripts of the tyrosine kinase gene BCR-ABL to transcripts of ABL of 0.01% or less, corresponding to a reduction of 4 log(10) units or more from the baseline level, as assessed by means of a real-time quantitative polymerase-chain-reaction assay. RESULTS At 12 months, the rates of cytogenetic response were similar among the four groups. The rate of a superior molecular response was significantly higher among patients receiving imatinib and peginterferon alfa-2a (30%) than among patients receiving 400 mg of imatinib alone (14%) (P=0.001). The rate was significantly higher among patients treated for more than 12 months than among those treated for 12 months or less. Gastrointestinal events were more frequent among patients receiving cytarabine, whereas rash and depression were more frequent among patients receiving peginterferon alfa-2a. CONCLUSIONS As compared with other treatments, the addition of peginterferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT00219739.).

CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte.

Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase 2 trial using cytarabine and rituximab as induction regimen before autologous stem cell transplantation. Patients younger than 66 years with stage 3 or 4 MCL were included. Treatment consisted of 3 courses of CHOP(21) with rituximab at the third one and 3 of R-DHAP. Responding patients were eligible for autologous stem cell transplantation with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, Performance Status > 16%, lactate dehydrogenase > 1N 38%, Mantle Cell Lymphoma International Prognostic Index (low 55%, intermediate 38%, high 13%). The overall response rate was 93% after (R)-CHOP and 95% after R-DHAP. Although uncommon after (R)-CHOP (12%), 57% of patients were in complete response after R-DHAP. With median follow-up of 67 months, median event-free survival is 83 months, and median overall survival is not reached. Five-year overall survival is 75%. Comparison with a previous study without rituximab shows improvement of outcome (median event-free survival, 51 vs 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with rituximab and cytarabine-based regimens is safe and effective in MCL patients. This regimen is currently compared with R-CHOP(21) induction in a multicentric European protocol.

Nodular, Lymphocyte-Predominant Hodgkin Lymphoma A Long-Term Study and Analysis of Transformation to Diffuse Large B-Cell Lymphoma in a Cohort of 164 Patients From the Adult Lymphoma Study Group

Nodular, lymphocyte‐predominant Hodgkin lymphoma (NLPHL) represents a rare entity.

Primary digestive tract lymphoma : a prospective multicentric study of 91 patients

BACKGROUND The optimal management of primary gastrointestinal lymphoma including the use of surgery remains unsettled. This prospective study aimed to determine the prognostic factors of primary gastrointestinal lymphoma and to evaluate a therapeutic strategy based on surgical tumor reduction, followed by chemotherapy adapted to the histological type of tumor and tumor removal or nonremoval. METHODS Ninety-one patients were included (mean age, 50.4 years) with mainly gastric (61%) or several digestive tract organ (18%) involved sites in clinical stages IE (43%), IIE (27%), and IV (30%). Three therapeutic groups were defined: group I, patients with low-grade lymphoma (n = 28); group II, patients with high-grade lymphoma who had complete tumor removal (n = 24); and group III, patients with high-grade lymphoma who had only partial or no tumor removal (n = 39). Each group underwent adapted chemotherapy. RESULTS The respective overall 5-year survival rates for groups I, II, and III were 81% +/- 6%, 100%, and 56% +/- 8%, respectively (P < 0.0001). By Cox multivariate analysis, the prognostic factors of survival were age under 65 (P < 0.05), gastric localization (P < 0.05), stage IE (P < 0.001), and radical or incomplete surgery (P < 0.01). CONCLUSIONS Combined radical surgery and chemotherapy according to histological grading is associated with prolonged remission in patients with primary digestive tract lymphoma. Moreover, compared with chemotherapy alone, incomplete resection of tumor is associated with increased survival of high-grade lymphomas.

Multiple lymphomatous polyposis of the gastrointestinal tract: Prospective clinicopathologic study of 31 cases

BACKGROUND & AIMS Multiple lymphomatous polyposis (MLP) is an uncommon type of gastrointestinal lymphoma. The aim of this study was to analyze the clinicopathologic features and outcome of a large series of patients. METHODS From 1984 to 1995, 31 patients were enrolled prospectively. Exhaustive staging and immunohistochemical analysis were performed. The first 10 patients were treated with cyclophosphamide-vincristine-prednisolone (COP) and the subsequent 21 with doxorubicin-teniposide-cyclophosphamide-prednisolone (AVmCP). Eleven patients were treated with high-dose radiochemotherapy and stem cell autotransplantation because of partial response or relapse. RESULTS Advanced age and multiple polyps involving several gastrointestinal segments characterized initial clinical presentation. The typical tumor cell phenotype (pan-B+, CD5+, and CD10-) along with Bcl-1 rearrangement indicated that MLP is the gastrointestinal counterpart of mantle cell lymphoma. After COP treatment, only 3 patients achieved partial remissions, whereas 80% of patients after AVmCP treatment achieved complete or good partial remission. High-dose radiochemotherapy changed partial into complete remission in 80% of cases. None of the initial 10 patients survived for 3 years, but the expected 5-year survival rate was 59% in patients receiving the anthracycline-containing regimen (P < 0.0001). CONCLUSIONS MLP is a distinct entity among gastrointestinal lymphomas. An anthracycline-containing multidrug regimen and high-dose radiochemotherapy supported by autotransplantation seem to improve its poor prognosis.

Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study.

Mantle cell lymphoma (MCL) is a distinct clinico-pathological entity with a poor prognosis. We have conducted a prospective study in patients with MCL to evaluate a therapeutic strategy in which CHOP polychemotherapy was followed by DHAP if CHOP failed to induce complete remission. Responding patients then proceeded to an intensification therapy with autologous peripheral blood stem cell transplantation (APBSCT). Twenty-eight consecutive patients with newly diagnosed aggressive MCL were included. After four cycles of CHOP regimen, two complete responses (CR) were obtained (7%) and 14 (50%), five (18%) and seven (25%) patients achieved partial (PR), minor (MR) and no response, respectively (one patient died from septic complications during CHOP induction). The two patients in CR after CHOP underwent intensification with TBI, high-dose cyclophosphamide–etoposide and APBSCT. The other twenty-five patients received DHAP and in this group a response rate of 92% (21 CR (84%), two PR (8%)) was observed. Two patients had progressive disease. The twenty-three responding patients received high-dose therapy (TAM8 regimen: TBI–cytarabine–melphalan) followed by APBSCT. One of the two partial responding patients achieved CR after TAM8. After a median follow-up of 47.6 months (range, 14–70), seven patients have relapsed. Our data confirm that: (1) CHOP regimen induces a low CR rate in MCL; (2) CHOP plus DHAP appears to be much more efficient and allows a large proportion of patients to proceed to high-dose therapy in CR; (3) consolidation therapy including TBI and high-dose Arac-C followed by APBSCT may improve event-free survival.

Angioimmunoblastic-Like T-Cell Non Hodgkin's Lymphoma: Outcome After Chemotherapy in 33 Patients and Review of the Literature

We analyzed 33 patients with AILD T-NHL in a retrospective multicentric study. The median age was 62 yr (35-84 yr) (19 patients over 60 yr). Advanced disease (n = 31) and B-symptoms were consistently found (n = 29) and 20 patients had bone marrow involvement. The main laboratory abnormalities were: anemia (n = 13), hypereosinophilia (n = 13), lymphopenia (n = 14), hypergammaglobulinemia (n = 17), elevated lactate dehydrogenase (LDH) level (n = 24). First-line therapy was chemotherapy (ChT) alone (n = 25) or ChT after steroids (n = 8). Most patients received a CHOP-like regimen for a median number of 6 cycles and 3 patients received interferon alpha (IFN alpha) as consolidation after chemotherapy. With a median follow-up of 46 mo, 60% achieved a complete response but the outcome was poor with a relapse rate at 56%, a median survival referring to the total population was of 36 mo (2-108+ mo) and an overall survival at 5 yr of 36%. Two patients received high-dose chemotherapy (with total body irradiation) and autologous progenitor-cell transplantation for chemosensitive relapse and were free of disease at, respectively, 76 and 24 mo+. In conclusion AILD T-NHL still has a poor prognosis compared to other NHL. The role of intensive therapy and IFN alpha still remains to be evaluated.

Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial

A French and Belgian multicenter phase 3 trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia. Of 178 patients enrolled in the study, 165 were randomly assigned to receive 6 courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (FCR; 375 mg/m(2) in cycle one, 500 mg/m(2) in all subsequent cycles) or alemtuzumab (FCCam; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; 8 patients died in the FCCam group, 3 from lymphoma and 5 from in-fection. Overall response rates were 91% with FCR and 90% with FCCam (P = .79). Complete remission rates were 33.75% with FCR and 19.2% with FCCam (P = .04). Three-year progression-free survival was 82.6% with FCR and 72.5% with FCCam (P = .21). Three-year overall survival was similar between the 2 arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P = .27). These results indicate that the FCCam regimen for the treatment of advanced chronic lymphocytic leukemia was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. This study is registered with www.clinicaltrials.gov as number NCT00564512.

Fludarabine plus cyclophosphamide in Waldenström's macroglobulinemia: results in 49 patients.

Fludarabine (FDR) therapy gives a response rate of about 30% in previously treated patients with Waldenströms macroglobulinemia (WM). The combination of FDR and cyclophosphamide (Cy) has been shown to be effective in chronic lymphoproliferative disorders. We administered the combination of FDR (30 mg/m2 i.v. D1–D3) and Cy (300 mg/m2 i.v. D1–D3) to 49 patients. Median age was 64 years. The median hemoglobin, albumin, beta 2 microglobulin and immunoglobulin M (IgM) levels were 9.9 g/100 ml, 39.6 g/l, 3 mg/l and 24.7 g/l, respectively. In all, 14 patients (29%) had not previously been treated. FDR/Cy was administered every 4 weeks for a median of four cycles. In all, 38 patients (77.6%) had partial responses, nine had stable disease and two had progressive disease. After a median of follow-up of 25 months, six patients relapsed and two patients developed large-cell lymphoma. The median time to treatment failure was 27 months. The main toxicity was hematological. In all, 12 patients died, four from progression, one from large-cell lymphoma, three from infection and four from a second malignancy. Two factors negatively influenced overall and event-free survival, age >65 years and IgM <40 g/l. The FDR/Cy combination, therefore, gives a high response rate in WM, even in previously treated patients with factors of poor prognosis.

Splenic marginal zone lymphoma with or without plasmacytic differentiation

We report a series of 31 cases of splenic marginal zone lymphomas with an enlarged spleen and a multimicronodular macroscopic pattern. Two groups, A and B, were distinguished based on the presence (A) or absence (B) of a lymphoplasmacytic component with monoclonal immunoglobulin expression in the cytoplasm. There were no differences between the groups as far as age, sex, spleen weight, and progression. The only difference was the presence in group A of a monoclonal serum component and autoimmune disorders, particularly autoimmune hemolytic anemia. In most cases in which a liver and/or bone marrow biopsy was performed, lymphomatous infiltration was detected. Seven cases had a seric monoclonal IgM of 5 g/L or more and liver or bone marrow infiltration, corresponding to the definition of Waldenströms macroglobulinemia. Lymphoma cells had a monocytoid, centrocytoid and, in group A, lymphoplasmacytic morphology. The lymphomatous cells were positive for CD20, CD45 RA, and bcl-2. They expressed IgD in 9 cases, partially in 6, and were negative for IgD in 9 of the 24 cases studied. Progression seems to be slow, with a long survival. Three patients presented with transformation into a large B-cell lymphoma, which was responsible for death in two patients.