RAPID REVIEW

Strategies for Monitoring Tyrosine Kinase Inhibitor Response in Chronic Phase CML and the Role of Second-Line Inhibitors in Disease Management

Guest Discussant: Robert G. Fenton, MD, PhD, Clinical Associate Professor, Clinical Research Committee Member, University of Maryland, Marlene and Stewart Greenbaum Cancer Center. Dr. Fenton reports no financial relationships relevant to this field of study.

The seven-year update of IRIS (a phase-3 International Randomized Study of Interferon and STI571), which randomized chronic-phase CML (CP-CML) patients to IFNa/AraC or imatinib (400 mg/d), showed an 81% EFS and 86% OS for imantinib.1 It is now standard practice for CP-CML patients to receive imatinib (400 mg/d) and, while the drug is highly effective, more wide-scale use of imatinib has shown that 30% of patients will fail this treatment, either due to intolerance (< 5% of patients) or failure to obtain an adequate response.2 Recognizing when imatinib has failed is important, since there are therapeutic options available that can overcome imatinib resistance. The monitoring of patients receiving imatinib, and the determination of which patients are eligible for second-line tyrosine kinase inhibitor (TKI) treatment, are discussed here.

1. Monitoring the response to imatinib. Prior to treatment, bone marrow (BM) should be sent for cytogenetics and quantitative reverse transcription-PCR (QT-PCR) using the International Standard (IS) as control for Bcr-Abl expression levels. Bone marrow assays should be repeated at 3, 6, 12, and 18 months to determine the degree of cytogenetic and molecular response of the patient. Peripheral blood provides data on hematologic response. Critical landmarks of response include the following:

Complete Hematologic Response (CHR): Optimally, a CHR is attained by three months, and if it is not attained by six months, the patient has primary resistance to imatinib, and mutation screening should be performed to educate the choice of a second-line treatment (dasatinib or nilotinib).

Cytogenetic Response: As determined by FISH or metaphase analysis, a Major Cytogenetic Response (MCyR; defined as 1-35% Ph + cells) should be observed at six months of treatment; patients who do not meet this landmark often harbor secondary mutations in Bcr-Abl that decrease the affinity of imatinib for the kinase and confer clinical resistance.3 A MCyR must be present by one year, or it is unlikely that a Complete Cytogenetic Response (CCyR), an important marker of long-term DFS, will occur. Optimally, a CCyR will occur by one year, and must be obtained by 18 months or other treatments should be considered.

Molecular Response: QT-PCR can accurately determine the number of Bcr-Abl transcripts at a dilution of one tumor cell in 105 normal cells. For patients who have attained a CCyR at 12 months, Bcr-Abl QT-PCR will be < 1% of IS. By 18 months, a Major Molecular Response (MMR), defined as < 0.1% of IS, should be achieved. This represents a three-log reduction in Bcr-Abl expression, and is significantly correlated with long-term PFS. In one study, of the 70 patients who achieved an imatinib-induced MMR in the first two years of treatment, only one lost this response.4 Analysis of the IRIS molecular data showed that patients with MMR at 18 months had an EFS of 95%, compared with 86%, 62%, and 58% for patients with Bcr-Abl of 0.1%-1% of IS; 1%-10% IS; and > 10% IS.5 Attaining a MMR is the most important indicator of long-term PFS on first- or second-line therapy.

2. Resistance to imatinib: For patients who have achieved a CCyR, disease status can be monitored by performing QT-PCR on peripheral blood cells. If Bcr-Abl levels begin to rise, and this is confirmed in subsequent assays over the next few months, BM cytogenetics should be assayed for reappearance of the Philadelphia chromosome and any other new cytogenetic abnormalities that would suggest clonal evolution. If loss of response is confirmed, the patient should be queried about imatinib compliance, and a trough serum imatinib level should be obtained. BM should be sent for PCR amplification and sequencing to determine if a secondary mutation in Bcr-Abl is present to account for imatinib resistance.6 This latter data will help to inform decision as to which second-line drug to select. A similar evaluation is performed on patients who are refractory to first-line therapy with imatinib.

A phase-2 study randomized patients who failed first-line imatinib at 400 or 600 mg/d to either high-dose imatinib (800 mg/d) or dasatinib (140 mg/d). Dasatinib-treated patients had a significantly higher percentage of MCyR, CCyR, and MMR, with pleural effusions and cytopenias being the main toxicities.7 Dasatinib and nilotinib have demonstrated similar phase-2 efficacy in imatinib-resistant patients. For dasatinib-resistant patients, approximately 90% achieved CHR, 60% MCyR, and 40% a CCyR; for imatinib-intolerant patients, the corresponding numbers were 90%, 80%, and 75%. It appears that 70 mg BID and 100 mg qd are equally efficacious, although the latter is less toxic.8 In one study of second-line dasatinib, 86% of patients with MMR at 12 months remained in CCyR at 24 months, while only 64% without a MMR were in CCyR (p = .0006).9 Nilotinib induces 90% CHR and 30%-40% CHR in imatinib-resistant patients with toxicities, including thrombocytopenia, neutropenia, elevated serum lipase and glucose levels, hypophosphatemia, and prolonged QT interval.10 Most patients who were intolerant of imatinib tolerated either dasatinib or nilotinib in the second line. No less than half of imatinib-resistant patients achieve a CCyR on second-line therapy. For patients without a CCyR allogeneic stem-cell transplant should be considered if a suitable donor is available.

4. Imatinib resistance due to Bcr-Abl mutations: Mutations in Bcr-Abl that decrease the affinity of imatinib for the ATP-binding site of the kinase are an important cause of imatinib resistance. In some cases, these mutations are present at low levels prior to treatment, and are selectively amplified during therapy, and in other cases mutations arise during therapy. Studies show that second-line responses to either nilotinib or dasatinib correlate with the affinity of mutant Bcr-Abl for either agent.11 For instance, patients whose mutant Bcr-Abl has a high affinity for nilotinib (IC50, 150 nM) had a greater chance of attaining a CCyR than those with low-affinity mutations.12 Patients whose BM cells were shown to have mutant Bcr-Abl prior to treatment with imatinib were more likely to fail or have a suboptimal response (e.g., no CCyR at 12 or 18 months).13 The number of different Bcr-Abl mutations discovered to date is over 30, and for most of these, it is not clear if the IC50 for imatinib, nilotinib, or dasatinib, as determined by in vitro cell-bases assays, correlates with clinical response or resistance in vivo, and how serum levels of imatinib in a given patient with a specific mutation will alter clinical outcome.14 However, clinically useful data is accumulating: Nilotinib is ineffective against Y253H and E255V/K mutations, while dasatinib has activity and desatinib is inactive against F317L.12 Hence, mutation analysis of Bcr-Abl mutations in patients with primary resistance to imatinib, or with progressive disease after an initial response, can provide important information for second-line therapy. Of importance, the T315I mutation is resistant to all three kinase inhibitors, and these patients should be considered for interferon, allogeneic SCT, or novel therapies. If in chronic phase, such patients continue to have an indolent course, so multiple therapies may be attempted in a deliberate manner.15

References

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2. de Lavallage H, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia in chronic phase: Incidence of sustained responses in an intention to treat analysis. J Clin Oncol. 2008;26:3358-3363.

3. Brandford S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276-283.

4. Hughes TP, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood. 2008;112:3965-3973.

5. Branford S, et al. Desirable performance characteristics for Bcr-Abl measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood. 2008;112:3330-3338.

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8. Shah NP, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and — intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26:3204-3212.

9. Hochhaus A, et al. Dasatinib-associated major molecular responses are rapidly achieved in patients with chronic myeloid leukemia in chronic phase (CMML-CP) following resistance, suboptimal response, or intolerance on imatinib (abstract). Blood. 2008;112:1095.

10. Hazarika M, et al. Tasigna for chronic and accelerated phase Philadelphia chromosomepositive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res. 2008;14:5325-5331.

11. Shah NP, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401.

12. von Bubnoff N, et al. Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood. 2006;108:1328-1333.

13. Khorashad JS, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008;2016:4806-4813.

14. Bixby D, Talpaz M. Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. ASH Educational Program Book. 2009;:461-476.

15. Jabbour E, et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood. 2008;112:53-55.