Strategies in the Management of Secondary Resistance and in Chronic Phase CML

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Mark L. Heaney, MD, PhD
Associate Clinical Professor of Medicine
Columbia University Medical Center
New York, New York

This is the case of a patient with secondary resistance to imatinib. The patient is a 24-year-old previously healthy African American woman who initially presented in June 2007 with a 2-month history of headaches and weight loss.

On physical examination, she was noted to have splenomegaly with a spleen tip palpable 10 cm below the left costal margin. Laboratory evaluation found a WBC of 492, hemoglobin 8.8, and platelets 505,000. The differential cell count showed 93% neutrophils and 5% eosinophils. A bone marrow examination revealed a hypercellular marrow with an increased myeloid/erythroid ratio. Cytogenetics showed the 9;22 chromosome translocation, and quantitative and molecular genetics showed a BCR-ABL level of 12.5%.

The diagnosis of chronic myeloid leukemia was made, and the patient began treatment with imatinib 400 mg orally daily after a short course of hydroxyurea. The patient had a good clinical response achieving a complete hematologic remission in July 2007 and a major molecular remission or MR3 in November 2007. The patient maintained the response until March 2008 when she became pregnant. Imatinib was discontinued, and the patient was followed closely. Because of rising white blood cell count, hydroxyurea was initiated at 24 weeks of pregnancy in August 2008. The patient delivered a healthy boy at 28 weeks of pregnancy in September 2008, and imatinib was resumed shortly thereafter. The patient continued to be followed closely and relocated to the New York area in the winter of 2009.

During follow up in March 2009, she was noted to have a WBC of 16.3, hemoglobin 12.9, and platelets 176,000. Peripheral blood fluorescence in situ hybridization showed that 47% of the cells had translocation 9;22 consistent with recurrent chronic phase CML. The patient subsequently presented to our institution, and a bone marrow examination found translocation 9;22 in 2 of 20 metaphases but an additional translocation of 3;6 in 18 of 20 metaphases. Molecular genetic analysis showed a BCR-ABL level of 27.9% and also found a 35-nucleotide insertion mutation between axons 8 and 9 that is associated with resistance to imatinib.

The patient began treatment with nilotinib 400 mg orally every 12 hours. She achieved a complete hematologic response in May 2009 and a complete cytogenetic response in August 2009. There was evidence of ongoing response achieving a major molecular response in February 2010 and by June 2010 had achieved an MR4.

This patient illustrates an example of secondary resistance to initial treatment with a tyrosine-kinase inhibitor. National Comprehensive Cancer Network recommends molecular monitoring of the patients every 3 months for 3 years after a complete cytogenetic response has been achieved. They also recommend close monitoring if a 1-log rise in BCR-ABL transcript levels is observed. Loss of response is defined by a hematologic relapse, a cytogenetic relapse, or a 1-log rise in BCR-ABL transcript levels in the setting of a loss of major molecular response or MR3. In the case of the patient presented, there was evidence of hematologic relapse in addition to evidence of clonal evolution manifested by the acquisition of translocation 3;6 and the 35-nucleotide insertion between axons 8 and 9.

Secondary resistance is usually the result of an inherent change in the CML clone. It can be related to mutations in the ABL kinase domain that results in resistance to initial tyrosine-kinase inhibitor. Other mechanisms of resistance have also been documented which include amplification of the Philadelphia chromosome or other mechanisms that lead to increased expression of BCR-ABL. In addition, reduced levels of cellular transporters allowing for decreased intracellular concentrations of agents such as imatinib including the Oct-1 protein have been shown to lead to resistance as have increased levels of proteins causing export of imatinib such as MDR1.

It is important to remember that other factors besides inherent leukemia cell resistance can lead to treatment failure; for example, poor intestinal absorption due to conditions such as Crohn's disease or drug-drug interactions that lead to increased metabolism of tyrosine-kinase inhibitors can lead to treatment failure. It is also important to recognize that incomplete adherence to the treatment regimen is an important cause of treatment failure and should always be evaluated in the setting of loss of response.

As a result, loss of response in a patient with chronic myeloid leukemia should prompt a careful history to ascertain patient compliance or use of drugs or foods that could interfere with TKI absorption or increase TKI metabolism leading to lower plasma levels. In addition, a bone marrow examination to assess clonal evolution and the acquisition of mutations in BCR-ABL should be performed.

This information will greatly help in the selection of treatment and can help to resolve whether there has been the acquisition of an inherent resistance mutation or a failure due to incomplete adherence. This information can also be used in the selection of a second generation or third generation tyrosine-kinase inhibitor as the appropriate next treatment. For example, the acquisition of the T315I mutation might prompt the use of imatinib as the next treatment while other second-generation tyrosine-kinase inhibitors including dasatinib, nilotinib, and bosutinib each have distinct pharmacologic sensitivities to a different ABL1 kinase mutations, together with knowledge of a patient’s ability to be compliant with treatment recommendations will help to identify the next best treatment for the patient.

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Last modified: September 13, 2013
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