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
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).
References (29)
- et al.
Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission
Blood
(2000) - et al.
Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders
Blood
(2001) - et al.
Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive, chronic-phase chronic myeloid leukemia after failure of interferon-{alpha}
Blood
(2004) - et al.
Evolving concepts in the management of chronic myeloid leucemia:recommendations from an export panel on behalf of the European LeukemiaNet
Blood
(2006) - et al.
High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia
Blood
(2004) - et al.
Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations
Blood
(2004) - et al.
GIMEMA Working Party on Chronic Myeloid Leukemia. Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia
Blood
(2004) - et al.
Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment
Blood
(2003) - et al.
Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years
Blood
(2007) - et al.
Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome
Science
(1990)
Interferon alfa-2a compared with conventional chemotherapy for the treatment of chronic myeloid leukemia
N Engl J Med
Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea
Leukemia
Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa
J Clin Oncol
Complete cytogenetic and molecular responses to IFN-alpha based therapy for chronic myeloid leukemia are associated with excellent long-term prognosis
Cancer
Cited by (13)
Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor
2011, BloodCitation Excerpt :Recent evidence suggests that leukemic stem cells might undergo terminal differentiation in response to IFNα,12 a cytokine known to produce a curative effect in a small subset of patients (reviewed in Kujawski and Talpaz13). Although these results, along with reports on several cases of successful treatment with IFNα after a course of IM (or vice versa),14,15 provide new enthusiasm for the reintroduction of IFNα into the management of CML,13 the molecular mechanisms that underlie the rationale for combining Bcr-abl inhibitors and IFNα remain to be delineated. Cellular responses to IFNα are mediated by the cell surface type I IFN receptor that consists of the interferon-α/β receptor (IFNAR)1 and IFNAR2 chains.
Imatinib is receptive to a collaboration
2011, BloodDynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells
2011, BloodCitation Excerpt :Similarly, for the small number of patients who achieve CMR after administration of IFN-α therapy, ongoing immune surveillance may be important. This agent may represent an attractive therapeutic option because several recent clinical studies,15,41-43 as well as in vitro data,44 have suggested that IFN-α selectively impairs proliferation of primitive CML progenitors. Although the ability of allografts and IFN-α to cure CML remains incompletely understood, we believe that, based on our analyses, continuous TKI therapy has the potential to diminish the leukemic stem cell population at least in a subset of patients.
Interferon in chronic myeloid leukaemia: past and future
2009, Best Practice and Research: Clinical HaematologyCitation Excerpt :In some occasions IFN-α could be used as a first line therapy in order to reduce the tumor burden and then imatinib in order to obtain a complete molecular response. This was the case for 26 CML-CP patients who achieved CCyR for a median of 73 months (0–148) after a median period of IFN-α therapy of 88 months (15–202) [76]. 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 MMR was reached in 20 patients (77%), and BCR/ABL transcripts were undetectable in 13 (50%).
Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia
2008, BloodCitation Excerpt :For 7 HLA-A*02+ CML patients (Figure 5A), sufficient PBMCs were available to perform culture experiments. To assess disease stage in these patients we evaluated the percentage of circulating CD33+ and CD34+ cells36,37 and FISH analysis.31,32 Samples from patients 1, 2, and 5 lacked circulating CD33+ or CD34+ cells, and cytogeneic analysis showed 100% of Philadelphia (Ph)–negative metaphases.
Molecular monitoring in chronic myeloid leukemia (CML)
2015, Biochimica Clinica