Elsevier

Leukemia Research

Volume 32, Issue 2, February 2008, Pages 255-261
Leukemia Research

Imatinib mesylate therapy in chronic myeloid leukemia patients in stable complete cytogenic response after interferon-alpha results in a very high complete molecular response rate

https://doi.org/10.1016/j.leukres.2007.06.008Get rights and content

Abstract

To determine the impact on minimal residual disease by switching to imatinib chronic phase chronic myeloid leukaemia (CP-CML) patients responsive to interferon-alpha (IFNα), in stable complete cytogenetic response (CCR) but with persistent PCR positivity.

Twenty-six Philadelphia positive (Ph+) CML patients in stable CCR after IFNα but persistently positive at PCR analysis during this treatment, were given imatinib mesylate at standard dose.

At enrolment into the study, median IFN treatment and CCR duration were 88 months (range 15–202) and 73 months (range 10–148), respectively. Imatinib treatment resulted in a progressive and consistent decline of the residual disease as measured by quantitative PCR (RQ-PCR) in all but one of the 26 patients; at the end of follow-up, after a median of 32 months (range 21–49) of treatment, a major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%), and BCR/ABL transcripts were undetectable in 13 (50%). The achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response versus 18.97 for those who did not; p < 0.001), but not with other clinical/biological disease characteristics.

These results indicate that patients induced into CCR by IFN treatment represent a subset with very favourable prognosis, which can significantly improve molecular response with imatinib and further support investigative treatment schedules combining these two drugs.

Introduction

Chronic myeloid leukemia (CML) is a malignant hematopoietic disease whose molecular hallmark is the BCR/ABL gene rearrangement originating from a t(9;22) translocation. The BCR/ABL fusion product encodes for a deregulated tyrosine kinase (TK), which has a central role in the pathogenesis of the disease [1]. Until recently, interferon-α (IFN) was considered the gold standard for drug therapy of CML, as it yielded complete cytogenetic response (CCR) in 10–25% of patients with significant survival prolongation, particularly in low risk patients usually obtaining a higher response rate [2], [3]. However, even in best responding patients, the disease still remained detectable at a molecular level, and the majority of patients eventually relapsed [4], [5], [6], [7]. Only consistently negative RT-PCR patients appeared to remain 100% in CCR at 10 years follow-up [7].

The introduction of imatinib mesylate (STI571, Gleevec), a selective inhibitor of the BCR/ABL TK, has revolutionized the disease management, as it induces CCR in 50–90% of chronic phase (CP) CML patients, including those resistant or refractory to IFNα [8], [9]. Furthermore, molecular monitoring using quantitative PCR (RQ-PCR) has shown a consistent reduction of the transcript level in a high proportion of responder patients, and the degree of the molecular response strongly correlates with the probability of progression-free survival. A reduction of the BCR/ABL transcript level ≥3 log at 12 or 18 months predicts almost 100% long-term remission [8], [9], [10], [11], [12]. However, residual disease still remains detectable using PCR standard procedures in the majority of patients, and development of imatinib resistance is the main cause of therapy failure [11], [12], [13], [14], [15], [16], [17].

In this study, we administered standard dose imatinib to 26 CML patients in late CP, who were in stable CCR induced by IFN, but had persistent residual disease by molecular analysis. We monitored the level of BCR/ABL fusion transcript by RQ-PCR to assess the impact on residual disease of crossover from IFN to imatinib in this subset of IFN-responding patients and the possible correlations between response to imatinib and clinical-biological characteristics of patients at diagnosis and during follow-up.

Section snippets

Patients and study design

Twenty-six Ph+ CP-CML patients who had been diagnosed in our institutions between December 1985 and March 2000 entered this study. Inclusion criteria were: (a) having received an IFNα based treatment, (b) being in stable CCR defined as the absence of Ph+ mitoses in at least two consecutive analyses (6 months apart), and (c) being persistently positive at qualitative PCR analysis for the BCR/ABL transcript.

At presentation all patients were previously untreated and in first CP according to the

Pre-Imatinib features of patients

Clinical features of the 26 patients enrolled into the study are summarized in Table 2.

At diagnosis median age was 40 years (range 21–64), and baseline Sokal risk score was low in 18 patients and intermediate in the remaining 8, whereas no patient was in high risk category. Overall, median weekly dose of IFN received from the patients was 26 MU, the median duration of IFN treatment being 88 months (range 15–202). All the 26 patients had sustained CCR from a median of 73 months (range 10–148) at

Discussion

In the present study, we analysed the effect of switching to imatinib 26 CML patients with long term cytogenetic but not molecular response to IFN. The main reason for this therapeutical decision was to evaluate whether a stable cytogenetic response to IFN could be improved at the molecular level through the possible complementary actions of the two drugs.

We found that 77% of our patients treated with a standard dose of imatinib reached BCR/ABL levels <0.01 over a median follow-up period of 32

Acknowledgements

Supported by a grant from ROMAIL, Regione Campania, PRIN e FIRB (MIUR, Rome), Ministero della Salute (Rome).

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