Marie Recine, MS
Hamilton, New Jersey
Based on "Newly Diagnosed Chronic-Phase CML: Challenges of Identifying Non-Adherence to Therapy," Thomas G. Martin III, MD
This case study will discuss the monitoring of a patient with newly diagnosed chronic-phase chronic myeloid leukemia (CML) and the challenge of determining the cause of a rising BCR-ABL transcript level following achievement of a major molecular response (MMR).
Our patient is a 27-year-old male who presents with fatigue, early satiety, and right upper quadrant pain. He has no prior medical history.
A physical exam reveals an enlarged spleen that is palpable 8 centimeters below the costal margin.
Results of a complete blood count reveal leukocytosis (WBC = 145 x 109/L), anemia (Hgb = 11.7 g/dL), and normal platelet count (215 x 109/L). The differential shows 55% mature granulocytes, 20% immature granulocytes, 12% monocytes, 8% eosinophils, 7% lymphocytes, and 2% blasts.
A complete metabolic panel shows elevated uric acid (8.3 mg/dL) and lactate dehydrogenase (LDH; 390 mg/dL). All other tests, including liver function tests, are normal.
A bone marrow aspirate shows a hypercellular marrow with left-shifted granulocyte maturation, < 5% blasts, and mild-to-moderate fibrosis. Cytogenetic analysis reveals the presence of a 3-way translocation (karyotype, 46,Y t(X; 9; 22)), which is confirmed by fluorescence in situ hybridization (FISH; 114/200 events). Quantitative polymerase chain reaction (PCR) identifies the presence of the p210 fusion transcript and provides a BCR-ABL to ABL ratio of 17.056, standardized according to the International Scale (IS).
The patient is started on imatinib (400 mg orally/day). He experienced intermittent mild nausea, which was relieved with prochlorperazine, but experienced no rash or other adverse effects.
The patient responded well to imatinib. At one month, the patient achieved a complete hematologic response (WBC = 4.9 x 10 109/L; platelets = 182 x 109/L), although hemoglobin remained low (10.3 g/dL).
At 3 months, complete hematologic response was confirmed, and quantitative PCR indicated a declining transcript level (BCR-ABL/ABL ratio [IS] = 1.1).
At 6 months, the patient had achieved a complete cytogenetic response, as indicated by the absence of Ph+ metaphases. Quantitative PCR monitoring indicated a continued decline in transcript levels (BCR-ABL/ABL ratio [IS] = 0.21).
By 9 months, the patient had achieved an MMR, with a BCR-ABL/ABL ratio (IS) of 0.035.
At 12 months, the patient's transcript levels began to rise slightly (BCR-ABL/ABL ratio [IS] = 0.082), although he remained at the level of an MMR.
By 15 months, his transcript levels continued to rise (BCR-ABL/ABL ratio [IS] = 0.65) and the patient lost the MMR.
According to NCCN guidelines,1 quantitative PCR should be repeated in 1 to 3 months if there is a 1-log increase in BCR-ABL transcripts with an MMR. In addition, they recommend that BCR-ABL kinase domain mutation analysis should be performed if there is any sign of loss of response, defined as a 1-log increase in BCR-ABL transcripts and loss of MMR, which may indicate development of resistance.
An increase in transcript levels can also be due to poor compliance.2 However, there is no consensus on the lower limit of a fold rise that should prompt an evaluation of mutation analysis or compliance. Fold rise is a product of the velocity of the rise and the measurement interval, but are not considered in current monitoring guidelines. It has been shown that a short BCR-ABL doubling time in a patient in chronic-phase CML can indicate non-compliance.2
In this patient's case, mutational analysis was performed and no mutations were detected. However, an additional quantitative PCR measurement performed two weeks later indicated a short doubling time (10 days), suggesting non-compliance. Upon further questioning, the patient admitted taking a number of medication holidays lasting approximately one week each.
The patient was counseled regarding the importance of being compliant and the risk of relapse with non-compliance. A repeat quantitative PCR performed at 18 months indicated declining transcript levels (BCR-ABL/ABL ratio [IS] = 0.075) and re-achievement of MMR.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. Version 4.2013. February 25, 2013.
- Branford S, Yeung DT, Prime JA. BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management. Blood. 2012;119(18):4264-4271.