Chlorambucil in Indolent Chronic Lymphocytic Leukemia

Dighiero, Guillaume; Maloum, Karim; Desablens, B; Cazin, Bruno; Navarro, Maurice; Leblay, R; Leporrier, M; Jaubert, J.; Lepeu, G.; Dreyfus, Brigitte; Binet, Jacques‐Louis; Travade, Philippe

doi:10.1056/nejm199805213382104

Cited by 391 publications

(129 citation statements)

References 24 publications

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“…Although there is no benefit at present in treating early stage CLL 25 it is possible that curative therapies will be feasible in the future. A very high quality response (disease not detectable by 'clonotypic' PCR) is an initial step toward treatment strategies designed to eliminate minimal residual disease.…”

Section: Discussionmentioning

confidence: 99%

Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy

Glenn

Maslak

et al. 2000

Leukemia

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Fludarabine is the most active agent in the treatment of chronic lymphocytic leukemia (CLL). Despite this activity only a minority of patients treated with fludarabine achieve a complete response. We evaluated a new treatment program of sequential therapy with fludarabine followed by high-dose cyclophosphamide in previously untreated patients with CLL. This report details the results in 25 patients with previously untreated CLL. Patients received fludarabine (25 mg/m 2 /day ؋ 5 days every 4 weeks for six cycles) as induction followed by consolidation with high-dose cyclophosphamide at one of three dose levels 1.5 g/m 2 , 2.25 g/m 2 , or 3 g/m 2 administered every 2 weeks for three doses. High-dose cyclophosphamide was given with G-CSF support (5 g/kg/day days 3-12). Complete response (CR) required a normal physical examination, normal CBC, a normal bone marrow evaluation including no residual lymphoid nodules on biopsy. A nodular response was defined as a complete response with the exception of an occasional residual nodule seen on bone marrow biopsy. Flow cytometric analysis for CD5:CD19 dual staining and / clonal excess was performed in all patients as a sensitive measure of minimal residual disease (MRD). Selected patients had patient/tumor-specific oligonucleotides generated that were subsequently used in a polymerase chain reaction as an extremely sensitive measure of MRD. There were no treatment-related deaths and no patient encountered unacceptable toxicity. After completion of this sequential regimen 76% (95% confidence interval: 59-93%) of patients had a major response: eight (32%) achieved a CR, four (16%) a nodular response, seven (28%) a PR, and six patients (24%) failed. Four patients withdrew from study during induction with fludarabine and did not receive at least one cycle of cyclophosphamide. Of the 21 patients who received consolidation with cyclophosphamide 10 (48%) had an improved quality of response when compared to that achieved with fludarabine. Two patients (8%) had no disease detectable by flow cytometry ('flow cytometric' CR) after six cycles of fludarabine. This improved to nine patients (36%) after high-dose cyclophosphamide. Following consolidation with high-dose cyclophosphamide three patients (12%) tested negative by PCR. All of these patients had morphologic evidence of residual disease after six cycles of fludarabine. Consolidation with high-dose cyclophosphamide increased the fraction of patients achieving a nodular response or CR three-fold (16% to 48%). This appears to be clinically relevant because with a median follow-up of 52 (range 34-78) months the projected 6-year survival for patients achieving a CR or NR is 91% compared to 41% for all others (P = 0.012). We conclude that sequential therapy with fludarabine followed by high-dose cyclophosphamide in previously untreated patients with CLL is safe and can improve the quality of response in a large proportion of patients compared to therapy with fludarabine alone. Leukemia (2000) 14, 1577-1582.

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Section: Discussionmentioning

confidence: 99%

Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy

Glenn

Maslak

et al. 2000

Leukemia

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“…Furthermore, there were six cases of acute leukemia in the group of 422 patients treated with chlorambucil as initial or secondary treatment, but no such cases among those patients who were never treated with this agent. 10 Similar conclusions were drawn from the studies performed by the IGCI CLL Cooperative Group, 15 and the Cancer and Leukemia group B, 16 which compared patients with B-CLL who received early treatment with chlorambucil to a group of B-CLL patients with deferred therapy in relation to the time of progression of the disease.…”

Section: Indications For Chemotherapymentioning

confidence: 57%

“…Several randomized trials indicate that initiation of chlorambucil-related therapy during the indolent phase of CLL does not prolong the survival time of CLL patients. 10,[15][16][17] Dighiero and Binet note that approximately one-third of CLL patients never require treatment and die from causes unrelated to this disease. 4 Only one-third have aggressive disease at diagnosis and should be immediately treated.…”

Section: Indications For Chemotherapymentioning

confidence: 99%

“…10 In the first study, patients were randomized either to a group treated daily with oral chlorambucil or to a group which did not receive treatment. In this study there was a survival advantage for the untreated group.…”

Section: Indications For Chemotherapymentioning

confidence: 99%

“…4 For many years alkylating agents, especially chlorambucil with or without steroids, have been considered the drugs of choice for the first line of treatment for CLL 5,6 and many hematologists still believe that such an approach should be considered as the gold standard. [7][8][9][10] More recently, renewed interest in CLL therapy has been created by the introduction of novel nucleoside analogues (NA), particularly fludarabine (FAMP) and cladribine (2-chlorodeoxyadenosine, 2-CdA), as well as combined chemotherapy. [11][12][13][14][15][16][17][18] The place of alkylating agents and NA in the management of CLL patients at the beginning of the new millennium, based on the results of randomized clinical trials, is the subject of this review.…”

Section: Introductionmentioning

confidence: 99%

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Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia

Robak

Kasznicki

2002

Leukemia

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Elevated serum levels of soluble CD44 can identify a subgroup of patients with early B-cell chronic lymphocytic leukemia who are at high risk of disease progression

Molica

Vitelli

Levato

et al. 2001

Cancer

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Chlorambucil in Indolent Chronic Lymphocytic Leukemia

Abstract: 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.

Cited by 391 publications

References 24 publications

Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy

Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy

Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia

Elevated serum levels of soluble CD44 can identify a subgroup of patients with early B-cell chronic lymphocytic leukemia who are at high risk of disease progression

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