Publications (8)100.32 Total impact
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Article: Transplantation in Waldenstrom's macroglobulinemia--the French experience.
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ABSTRACT: Published data on transplantation in Waldenstrom's macroglobulinemia (WM) are still limited. We present a retrospective multicentric study of 27 WM patients who underwent 19 autologous (median age, 54 years) and 10 allogeneic (median age, 46 years) transplantations. Median time between diagnosis and transplantation was 36 months; 66% of patients had received three or more treatment lines and 72 % had chemosensitive disease. High-dose therapy (HDT) and autologous transplantation induced a 95% response rate (RR), including 10 major responses. With a median follow-up of 18 months, 12 patients are alive at 10 to 81 months and eight are free of disease progression at 10 to 34 months. The toxic mortality rate (TRM) was 6%. Allogeneic transplantation was preceded by HDT in nine patients and by a nonmyeloablative regimen in one patient. The RR was 80%, including seven major responses. With a median follow-up of 20.5 months, six patients are alive and free of progression at 3 to 76 months. Four patients died, all from toxicity, resulting in a TRM of 40%. HDT followed by autologous transplantation is feasible in WM, even in heavily pretreated patients, with some prolonged responses but a high relapse rate. Conversely, allogeneic transplantation is more toxic, but likely induces a graft-versus-WM effect and may, for some patients, result in long-term disease control.Seminars in Oncology 05/2003; 30(2):291-6. · 3.50 Impact Factor -
Article: Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease.
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ABSTRACT: Few reports are available on the treatment of patients with Waldenström macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5). The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P <.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group. There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents.Blood 12/2001; 98(9):2640-4. · 9.90 Impact Factor -
Article: Evaluating treatment strategies in advanced Waldenström macroglobulinemia: use of quality-adjusted survival analysis.
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ABSTRACT: A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubicin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemia in first relapse or with primarily resistant disease, was conducted on the behalf of the 'Groupe Coopératif Macroglobulinémie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of overall survival (OS), although a significant benefit in terms of time to disease progression and event-free survival (EFS) was noted. In this rare disorder, where few randomized trials have been conducted, we took advantage of this trial to assess treatment differences while integrating quality of life considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWiST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWiST and summed up giving the so-called Q-TWiST. No difference was found between randomized groups in terms of mean CT. Mean TOX in the two groups were similarly close except when considering alopecia as a relevant toxic event. By contrast, mean TWiST was 5.9 months longer in the FAMP group than in the CAP group (P = 0.006). Unsurprisingly, given the absence of difference in OS but the difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P = 0.047). As a result, benefit of FAMP in terms of average Q-TWiST only relied on the value of the utility coefficient attributed to REL (U(REL)), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely.Leukemia 10/2001; 15(9):1466-70. · 9.56 Impact Factor -
Article: Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients.
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ABSTRACT: To comparatively assess first-line treatment with fludarabine and 2 anthracycline-containing regimens, namely CAP (cyclophosphamide, doxorubicin plus prednisone) and ChOP (cyclophosphamide, vincristine, prednisone plus doxorubicin), in advanced stages of chronic lymphocytic leukemia (CLL), previously untreated patients with stage B or C CLL were randomly allocated to receive 6 monthly courses of either ChOP, CAP, or fludarabine (FAMP), stratified based on the Binet stages. End points were overall survival, treatment response, and tolerance. From June 1, 1990 to April 15, 1998, 938 patients (651 stage B and 287 stage C) were randomized in 73 centers. Compared to ChOP and FAMP, CAP induced lower overall remission rates (58.2%; ChOP, 71.5%; FAMP; 71.1%; P <.0001 for each), including lower clinical remission rates (CAP, 15.2%; ChOP, 29.6%; FAMP, 40.1%; P =.003). By contrast, median survival time did not differ significantly according to randomization (67, 70, and 69 months in the ChOP, CAP, and FAMP groups, respectively). Incidences of infections (< 5%) and autoimmune hemolytic anemia (< 2%) during the 6 courses were similar in the randomized groups, whereas fludarabine induced, compared to ChOP and CAP, more frequent protracted thrombocytopenia (P =.003) and less frequent nausea-vomiting (P =.003) and hair loss (P <.0001). For patients with stage B and C CLL first-line fludarabine and ChOP regimens both provided similar overall survival and close response rates, and better results than CAP. However, there was an increase in clinical remission rate and a trend toward a better tolerance of fludarabine over ChOP that may influence the choice between these regimens as front-line treatments in patients with CLL.Blood 10/2001; 98(8):2319-25. · 9.90 Impact Factor -
Article: Evaluating treatment strategies in chronic lymphocytic leukemia: use of quality-adjusted survival analysis.
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ABSTRACT: To assess comparatively, in terms of quality-adjusted survival, three front-line treatments in patients with stage B- or C-chronic lymphocytic leukemia (CLL). To describe better and compare the survival after randomization of patients from the CLL90 trial that randomly compared ChOP (cyclophosphamide, doxorubicin, oncovin, prednisone), CAP (cyclophosphamide, doxorubicin, prednisone) and fludarabine in advanced CLL, we performed a quality-adjusted survival analysis. This consisted of defining four clinical states (toxicity, treatment free of toxicity, no treatment nor symptoms, relapse), then summing up the average times spent in each state weighted by utility coefficients that reflect relative value according to quality of life. The resulting quality-adjusted time without symptoms or toxicity (Q-TWIST) was compared between randomized groups, and sensitivity (threshold) analyses to the choice of utility coefficients was performed. Over 73 months after randomization, the fludarabine group gained a mean of 45 days of toxicity-free survival at CAP, and 61 days over ChOP. The mean TWIST was 27.05 months with CAP, 31.5 months with ChOP and 32.95 months with fludarabine. The threshold analyses showed that, whatever the utility weights, the mean Q-TWIST was always greater with ChOP or fludarabine as compared to CAP. Fludarabine was consistently a better treatment than ChOP, except in the unlikely case of high utility weights attributed to toxicity and low utility weights attributed to treatment. Nevertheless, from a clinical point of view, differences between ChOP and fludarabine were moderate or event slight (mean difference in TWIST of 1.45 months). We conclude that patients with advanced CLL have a moderate benefit in terms of Q-TWIST when treated with fludarabine over ChOP. These two treatments are always superior to CAP.Journal of Clinical Epidemiology 08/2001; 54(7):747-54. · 4.27 Impact Factor -
Article: Detection of minimal residual disease in B chronic lymphocytic leukemia (CLL).
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ABSTRACT: In the absence of specific chromosomal translocations the best method for detecting minimal residual disease (MRD) in B cell malignancies is based on the uniqueness of immunoglobulin (Ig) genes rearrangement. We here report a very sensitive method for assessing MRD in complete hematological remission (CHR) chronic lymphocytic leukemia (CLL) patients as defined by the international workshop on CLL (IWCLL). Twelve CLL patients in CHR and complete phenotypic remission (CPR) were included in the study. Eight of them received Fludarabine (FDR), one was treated by Chop regimen, and the remaining 3 were rescued by polychemotherapy followed by autologous bone marrow transplantation (ABMT). DNA extracted from peripheral blood lymphocytes (PBL) of each patient was amplified with VH family specific and framework 3 primers in 5' and a consensus JH primer in 3', before treatment and sequentially after the CPR completion. When no clonal rearrangement could be detected by this assay, the CDR3 sequence specific probe of the clone was used as the 3' primer, associated to the VH family specific primer in 5'. PCR products were analyzed by classical procedures in agarose and/or acrylamide gels. Mixtures of leukemic cells and normal PBL showed detection of a single leukemic cell among more than 10(5) normal cells. Four out of the 12 patients achieved molecular remission (MR) when employing CDR3 amplification. All 3 autografted patients were in MR, whereas only one out of the 9 patients treated by chemotherapy alone achieved MR. When using a clone specific probe, a clonal signal was observed in all cases but one (ABMT). Results presented here confirm that MR may be achieved in a few cases of B-CLL. Further studies are needed to determine the exact relationship between MRD and clinical outcome.Hematology and Cell Therapy 03/1999; 41(1):13-8. -
Article: Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia.
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ABSTRACT: To determine whether chlorambucil treatment benefits patients with indolent chronic lymphocytic leukemia (CLL), we conducted two randomized trials in 1535 patients with previously untreated stage A CLL. In the first trial, 609 patients were randomly assigned to receive either daily chlorambucil or no treatment; in the second trial, 926 patients were randomly assigned to receive either intermittent chlorambucil plus prednisone or no treatment. Median follow-up for the first and second trials exceeded 11 and 6 years, respectively. The end points were overall survival, response to treatment, and disease progression. Treatment of indolent CLL did not increase survival in either trial. In the treated group, as compared with the untreated group, the relative risk of death was 1.14 (95 percent confidence interval, 0.92 to 1.41; P=0.23) in the first trial and 0.96 (95 percent confidence interval, 0.75 to 1.23; P=0.74) in the second trial, with 76 percent and 69 percent of patients, respectively, having a response to therapy. Although chlorambucil slowed disease progression, there was no effect on overall survival. In the untreated group in the first trial, 49 percent of patients did not have progression to more advanced disease and did not need therapy after follow-up of more than 11 years; however, 27 percent of patients with stage A CLL died of causes related to the disease. Chlorambucil does not prolong survival in patients with stage A CLL. Since deferring therapy until the disease progresses to stage B or C does not compromise survival, treatment of indolent CLL is unnecessary.New England Journal of Medicine 06/1998; 338(21):1506-14. · 53.30 Impact Factor -
Article: Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations.
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ABSTRACT: T-cell prolymphocytic leukemia (T-PLL), a rare form of mature T-cell leukemias, and ataxia telangiectasia clonal proliferation, a related condition occurring in patients suffering from ataxia telangiectasia, have been associated to translocations involving the 14q32.1 or Xq28 regions, where are located the TCL1 and MTCP1 putative oncogenes, respectively. The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with these T-cell proliferations. Alternative splicing generates type A and B transcripts that potentially encode two entirely distinct proteins; type A transcripts code for a small mitochondrial protein, p8MTCP1, and type B transcripts, containing an additional open reading frame, may code for 107 amino-acid protein, p13MTCP1. The recently cloned TCL1 gene, also involved in translocations and inversions associated with T-cell proliferations, codes for a 14-kD protein that displays significant homology with p13MTCP1. We have generated rabbit antisera against this putative p13MTCP1 protein and screened for expression of p13MTCP1 normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations using a sensitive Western blot assay. We also investigated the MTCP1 locus configuration by Southern blot analysis. The p13MTCP1 protein was detected in the three T-cell proliferations with MTCP1 rearrangements because of t(X;14) translocations, but neither in normal resting and activated lymphocytes nor in the other T-cell leukemias. Our data support the hypothesis that p13MTCP1 and p14TCL1 form a new protein family that plays a key role in the pathogenesis of T-PLL and related conditions.Blood 04/1996; 87(5):1923-7. · 9.90 Impact Factor
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