Knowledge that the hybrid BCR–ABL oncoprotein is responsible for the development and progression of Ph-positive chronic myeloid leukemia (CML) has provided an excellent opportunity to dissect how this protein alters hematopoietic cell dynamics and has become a paradigm for the investigation of molecular mechanisms. The tyrosine kinase encoded by the Src-homology (SH)1 domain of the ABL component of BCR–ABL is undoubtedly the most crucial for oncogenic transformation Citation[1]. Owing to its essential role in the leukemogenicity, the SH1 domain of BCR–ABL is an obvious molecular target. Subsequent efforts have focused on the rational design of synthetic compounds with chemical structures that are able to compete with either adenosine triphosphate (ATP) or a substrate for occupancy of the binding site in the kinase domain. The most successful synthetic ATP-binding inhibitor that has been developed to date is the 2-phenylaminopyrimidine, imatinib mesylate (IM), formely known as STI571 (Glivec® or Gleevec®) Citation[2]. Combined preclinical data suggested that IM might have value as a therapeutic agent and the first clinical trials with this drug were initiated in 1998. Prior to this, treatment options for CML had been limited. Allogeneic stem cell transplantation (AlloSCT), although potentially curative, remains limited by suitable donor availability and transplant-associated mortality and morbidities. Interferon (IFN)-α induces complete cytogenetic responses (CCyR) at rates of 5–20% in early chronic-phase disease but is associated with important toxicities and, most importantly, with a reduction in efficacy with increasing duration of chronic-phase disease Citation[3,4]. Imatinib selectively inhibits BCR–ABL by occupying the ABL domain ATP-binding site and it maintains the protein in an active conformation Citation[5]. Presently, thousands of patients have been treated worldwide and the success forecasted from those initial data has been largely achieved. However, there remain problems associated with the clinical use of IM for the treatment of CML.
Results of imatinib in patients with chronic-phase chronic myeloid leukemia (IRIS Study)
The patients in this trial were randomly assigned to receive IM at a dose of 400 mg orally per day or subcutaneous IFN-α at a daily target dose of 5 million U/m2 body surface area, plus 10-day cycles of cytarabine (AraC) at a daily dose of 20 mg/m2 every month Citation[6]. Patients were allowed to cross over to the other treatment group if they did not achieve either a complete hematologic response (CHR) after 6 months of therapy, a major cytogenetic response (MCyR) after 12 months, or if they had a relapse or an increase in white blood cells or could not tolerate treatment. With a median of 60 months follow-up, 69% of patients in the IM group and 3% in the group given IFN-α with AraC continued with their initially assigned treatment. Of the patients receiving IFN-α with AraC, 65% had crossed over to IM, whereas 3% in the IM group had switched to the alternative treatment. Grade 3 or 4 adverse events related to IM occurred in 6% of patients; most of these have been observed in the first 2 years and consisted of neutropenia, thrombocytopenia, anemia, elevated liver enzymes and fluid retention.
Complete hematologic remission was obtained in 96% of patients at 12 months and 98% at 60 months. The estimated rates of MCyR and CCyR at 12 months were 85 and 69%, respectively. With a median follow-up of 60 months, the best observed rate of MCyR was 89% and the best rate of CCyR was 82%. Of the 382 patients who still received IM at 60 months, 368 (96%) had a CCyR. In patients who were deemed to be low risk, the rate of CCyR was 89%; the rate among patients at intermediate risk was 82% and for those at high risk the rate was 69% (p ≤ 0.001). The estimated annual rate of treatment failure after the start of IM therapy was 3.3% in the first year, 7.5% in the second year, 4.8% in the third year, 1.5% in the fourth year and 0.9% in the fifth year. The Sokal score was not associated with disease progression in patients who had a CCyR; moreover, the patients who had a CCyR and a reduction of at least 3 log in levels of BCR–ABL transcripts in bone marrow cells after 18 months of treatment had an estimated rate of survival without progression of CML of 100%.
Molecular response in newly diagnosed chronic myeloid leukemia patients treated with 800 mg imatinib daily (RIGHT Trial)
A total of 115 patients entered a multicenter study conducted in academic and community practices across the USA using 800 mg daily of IM as initial therapy in patients with newly diagnosed CML Citation[7]. The patients were followed for both molecular and cytogenetic responses for up to 18 months. As of June 27, 2006, 89 patients were still on the study or had reached the end of the study. Peripheral blood sampling using PCR showed that the kinetics of major molecular response (MMR) (defined as ≥3 log reduction in BCR–ABL/ABL for these patients) was rapid, with 50 out of 115 patients (44%) on treatment achieving a MMR by 6 months. This differs from the previous IRIS study, in which IM 400 mg daily resulted in 21% MMR at the 6-month time point. At 12 months, the MMR rate remained at 44% with 50 out of 115 patients showing at least a 3 log reduction. Tolerability of the higher dose of IM did not differ significantly in this study; the most frequent adverse events included myelosuppression, rash, fatigue and musculoskeletal symptoms. The authors conclude that IM 800 mg daily results in more rapid reduction in tumor burden than 400 mg daily. Of course, further follow-up will be needed to determine if the rapid reduction in CML cells implied by the kinetic response to 800 mg IM will reduce later rates of progression over time.
Imatinib resistance
Relatively rare cases of primary hematological IM resistance are described in the literature and secondary resistance is reported in a low number of chronic-phase CML patients. The mechanisms of secondary resistance have largely been described Citation[8]. Selection for cells that present BCR–ABL kinase domain point mutations represent the common mechanism of acquired resistance to IM in 50–90% of cases. Some mutations confer only a mild degree of resistance and dose escalation may re-induce remission in some cases; moreover, novel BCR–ABL inhibitors might be effective in mutation-driven resistance. In approximately 10% of resistant patients, the mechanism is due to overproduction of BCR–ABL through genomic amplification or the acquisition of additional Ph chromosomes. There are few BCR–ABL-independent mechanisms of IM resistance Citation[9]. Those mechanisms can explain primary resistance or the reason why 30–50% of blast-phase patients do not respond to IM.
Several biological and clinical studies have reported Src gene activation in IM-resistant patients. Clonal evolution, MDR-1 gene overexpression and altered nuclear transport and drug efflux may explain other cases of IM resistance Citation[10].
Treatment guidelines
The European Leukemia Network appointed a panel of experts to review the current situation and to discuss how the treatment of CML could be managed in the imatinib era Citation[11]. They provided an update of the results achieved to date with IFN-α, allografting (AlloSCT), autografting and IM treatment approaches. The superiority of IFN-α with or without AraC over hydroxyurea had already been demonstrated. The superiority of 400 mg IM over IFN-α with or without AraC has also been documented. Conventional AlloSCT is a recognized procedure that allows the achievement of long-lasting molecular remissions or cures in approximately 50% of eligible patients. The long-term outcome of IM treatment cannot yet be assessed owing to too short patient follow-up. AlloSCT holds the promise of cure but with a high toxicity and mortality rate. Imatinib 400 mg daily is the preferred and recommended initial treatment in all CML patients at diagnosis; however, in patients with high disease risk and a low European Bone Marrow Transplant (EBMT) risk score, the choice between IM and AlloSCT should be discussed. It should be underlined that even patients with such characteristics should receive a trial with IM since early response to the drug can reinforce or weaken the indication for AlloSCT.
In case of resistance, the first choice should be a dose escalation of IM to 600 or 800 mg daily. AlloSCT could be offered to patients with low or intermediate EBMT risk score. Novel tyrosine kinase inhibitors and targeted agents are already under evaluation in preclinical and clinical trials.
Conclusion
Increasing understanding of the pathogenesis of CML and the introduction of IM has marked a major advance in CML treatment. It is currently recommended that IM therapy be continued indefinitely. The discontinuation of IM, even in patients with undetectable levels of BCR–ABL transcripts, may result in relapse Citation[12]; the presence of quiescent nonproliferating leukemic stem cells insensitive to the drug might explain this phenomenon Citation[13]. Despite this, mathematical studies have showed a general potential of IM to induce a complete eradication of the neoplastic clone Citation[14].
Our understanding of the major mechanisms of IM resistance has led to the clinical development of novel BCR–ABL inhibitors. Nilotinib (AMN107), an aminopyrimidine that is a structural derivative of IM, binds the ABL kinase domain in the inactive conformation with a 25-fold increase in potency and has activity against many IM-resistant point mutations, except T315I. Dasatinib (BMS-354825) is a thiazolecarboxamide that is structurally unrelated to IM. It binds to the ABL kinase domain in the active conformation and also inhibits Src family kinases. It is 300-fold more potent than IM and inhibits most point mutations, except T315I Citation[15].
MK-0457 is a novel kinase inhibitor that can also be effective for the T315I point mutation. It is an aurora kinase inhibitor and shows antiproliferative activity against a variety of tumor cells other than leukemia Citation[16].
There is hope that IM and second-generation kinase inhibitors can make CML a curable disease.
Related Research Data
References
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