Fludarabine, Cyclophosphamide, and Mitoxantrone as Initial Therapy of Chronic Lymphocytic Leukemia: High Response Rate and Disease Eradication

Abstract

Purpose: Fludarabine, cyclophosphamide, and mitoxantrone (FCM) results in a high response rate in previously treated patients with chronic lymphocytic leukemia (CLL). The aim of this study was to investigate FCM as frontline therapy in CLL. Experimental Design: Sixty-nine patients under the age of 65 years with active CLL were treated. Patients received six cycles of fludarabine 25 mg/m 2 i.v. Â 3 days, cyclophosphamide 200 mg/m 2 i.v. Â 3 days, and mitoxantrone 6 mg/m 2 i.v. Â 1 day. Treatment outcome was correlated with clinical and biological variables. The clinical significance of eradicating minimal residual disease (MRD) was also analyzed. Results: The overall response, MRD-negative complete response (CR), MRD-positive CR, nodular partial response (PR), and PR rates were 90%, 26%, 38%, 14%, and 12%, respectively. Severe (grades 3 or 4) neutropenia developed in 10% of the patients. Major and minor infections were reported in 1% and 8% of cases, respectively. Median response duration was 37 months. Patients with del(17p) failed to attain CR. Patients achieving MRD-negative CR had a longer response duration and overall survival than patients with an inferior response. Low serum lactate dehydrogenase levels, low ZAP-70 expression, and mutated IgV H genes predicted longer response duration. Finally, both low ZAP-70 and CD38 expression in leukemic cells correlated with MRD-negativity achievement. Conclusion: FCM induces a high response rate, including MRD-negative CRs in untreated patients with active CLL. Treatment toxicity is acceptable. Both high ZAP-70 and increased CD38 expression predict failure to obtain MRD-negative response. Patients in whom MRD can be eradicated have longer response duration and overall survival than those with inferior response. These results indicate that FCM can be an ideal companion for chemoimmunotherapy of patients with CLL.

Normal levels of peripheral CD19+CD5+ CLL‐like cells: Toward a defined threshold for CLL follow‐up—A GEIL‐GOELAMS study

“…This point was emphasized with studies showing that eradication of the disease was associated with a longer survival and, conversely, that MRD positivity had a negative prognostic impact on CLL relapse and survival with various therapeutic approaches (17)(18)(19)(20)(21).…”

Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after rituximab-containing immunochemotherapy: a comparative analysis

“…Novel therapies that incorporate purine analogs and monoclonal antibodies (moabs) [1][2][3][4][5][6] recently improved response rates in chronic lymphocytic leukemia (CLL), so that up to 70% of patients now achieve a complete clinical remission according to the National Cancer Institute criteria. 7,8 Furthermore, consolidation strategies using stem cell transplantation [9][10][11][12] or therapeutic antibodies [13][14][15] were introduced in an effort to improve the quality and duration of remissions.…”

“…Consequently, minimal residual disease (MRD) assessments during and after therapy gained importance to individualize therapy 6,9,15,16 and to measure efficacy of novel therapeutic approaches. 4,5,17,18 Although exclusively qualitative and rather insensitive techniques for MRD assessments such as consensus primer IGH PCR 4,10,12,19 or CD19/CD5 dual staining by flow cytometry 5,20,21 are still being used, sensitive MRD quantification requires either specialized four-color flow cytometry (MRD flow) or allelespecific oligonucleotide primer IGH RQ-PCR (ASO IGH RQ-PCR). There is evidence that even qualitative MRD methods can provide prognostic information.…”

Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells

“…24 Clinically, CLL patients with cells carrying p53 gene mutations are more resistant to fludarabine regimens and have a shorter survival. [25][26][27] Nevertheless, other studies report that fludarabine can also induce apoptosis of CLL cells in vitro in a p53-independent manner. 28 Our study was focused on CLL cases bearing a wild type p53 genotype.…”