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Tests and Treatment Responses In Chronic Phase CML A tool to assist health care professionals to communicate with their patients about the different types of tests used for the diagnosis of CML, monitoring response to TKI therapy and mutational analysis as outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). OVERVIEW Chronic myelogenous leukemia (CML) is the cancer of blood-forming cells in the bone marrow. CML is a slow growing cancer that causes an increase in the number of white blood cells. CML is caused by the reciprocal translocation between chromosomes 9 and 22. The BCR gene located on chromosome 22 and the ABL1 gene located on chromosome 9 join together to form the BCR-ABL1 fusion gene. This translocation also creates a longer chromosome 9 and a shorter chromosome 22, which is called the Philadelphia (Ph) chromosome. CML occurs in three different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy with small molecules that target the BCR-ABL1 protein is the standard of care for all patients with newly diagnosed chronic phase CML. TESTS Bone marrow cytogenetics detects and measures the number of cells in the bone marrow that contain the Ph chromosome. It is performed at diagnosis to establish the disease phase. Fluorescence in-situ hybridization (FISH) on a peripheral blood specimen using dual probes for the BCR and ABL genes can be used, if collection of bone marrow is not possible. Quantitative reverse transcriptase polymerase chain reaction (QPCR) is the most sensitive test that detects and measures the BCR-ABL1 gene in a peripheral blood specimen. QPCR should be done at diagnosis to establish the BCR-ABL1 transcript levels at baseline. BCR-ABL1 kinase domain mutational analysis detects new mutations in the BCR-ABL1 gene that may occur during treatment for CML. Mutational analysis helps to select an alternate TKI therapy when CML is not responding to a particular TKI therapy. TREATMENT RESPONSES Monitoring response to TKI therapy is one of the key management strategies of CML. Hematological response measures normalization of the blood counts, particularly white blood cell counts. Cytogenetic response measures the decrease in the number of bone marrow cells that have the Ph chromosome. Molecular response measures the decrease in the number of cells in the peripheral blood that contain the BCR-ABL1 gene. QPCR is the only test capable of monitoring molecular response to TKI therapy after the patient has achieved complete cytogenetic response (CCyR). QPCR should be performed in a lab that uses the International Scale (IS) that was established to standardize the measurement of molecular response across different laboratories. In the QPCR (IS), results are expressed as the ratio of BCR-ABL1 gene transcripts to the number of control gene transcripts (BCR, ABL1, or GUSB). Laboratories with no access to QPCR (IS) may establish their own standardized baseline, based on a large number of pre-treatment samples. Molecular response is then measured as the log-reduction of BCR-ABL1 transcripts from the standardized baseline (not a reduction from the actual baseline level in an individual patient). NCCN.org Page 1 of 4 TREATMENT RESPONSE CRITERIA Hematologic Response Cytogenetic Response Molecular Response NCCN.org Complete Hematologic Response (CHR) Peripheral blood counts and platelet counts completely normal; No blasts or immature cells in the peripheral blood and no signs or symptoms of disease including no enlarged spleen Complete Cytogenetic Response (CCyR) No Ph chromosome is detectable in bone marrow cytogenetics Partial Cytogenetic Response (PCyR) 1%–35% of cells have the Ph chromosome on bone marrow cytogenetics Major cytogenetic response (MCyR) 0%–35% of cells have the Ph chromosome on bone marrow cytogenetics Complete Molecular Response (CMR) No BCR-ABL1 transcripts are detectable in peripheral blood by QPCR using IS Early molecular response (EMR) BCR-ABL1 ≤10% by QPCR using IS at 3 or 6 months Major molecular response (MMR) BCR-ABL1 0.1% by QPCR using IS or at least a 3-log reduction in the BCR-ABL1 transcript levels from the standardized baseline (if QPCR using IS not available) Page 2 of 4 MONITORING RESPONSE TO TKI THERAPY AND MUTATIONAL ANALYSIS RESPONSE MILESTONES TEST TEST SAMPLE AT DIAGNOSIS ANYTIME DURING THERAPY BCR-ABL1/ABL1 ≤10% by QPCR using IS or PCyR on Bone Marrow Cytogenetics QPCR (IS) Peripheral Blood or Bone Marrow ü CCyR 3 MONTHS 6 MONTHS 12 MONTHS 18 MONTHS ü ü ü ü Every 3 months after initiation of TKI therapy until CCyR is achieved. Repeat QPCR (IS) in 1–3 months if there is 1-log increase in BCR-ABL1 transcript levels with a MMR Every 3 months for 3 years and every 3–6 months thereafter, after CCyR has been achieved: Bone marrow Cytogenetics BCR-ABL1 kinase domain mutation analysis NCCN.org Bone Marrow Peripheral Blood or Bone Marrow ü If QPCR using IS not available If there is no CCyR or MMR Any sign of loss of response (hematologic or cytogenetic relapse) BCR-ABL1/ABL1 >10% by QPCR using IS or Lack of PCyR on bone marrow cytogenetics If not in MMR and 1-log increase in BCR-ABL1 lack of CCyR at transcript levels without a MMR 12 months Less than a CCyR 1-log increase in BCR-ABL1 transcript levels and loss of MMR Disease progression to accelerated or blast phase Page 3 of 4 REFERENCES 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidlines®), Chronic Myelogenous Leukemia, Version 1.2015. 2. Radich JP. Monitoring response to tyrosine kinase inhibitor therapy, mutational analysis, and new treatment options in chronic myelogenous leukemia. J Natl Compr Canc Netw. 2013;11(5 Suppl):663-6. 3. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84. 4. Jabbour E, Branford S, Saglio G, et al. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Cancer. 2011;117(9):1800-11. Erratum in: Cancer. 2011;117(15):3535. 5. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37. This tool was produced in combination with a live and enduring educational activity. This activity is supported by an educational grant from Bristol-Myers Squibb. 275 Commerce Drive • Suite 300 Fort Washington, PA 19034 P: 215.690.0300 • F: 215.690.0280 NCCN.org – For Clinicians | NCCN.org/patients – For Patients NCCN.org Page 4 of 4 HEM-N-0333-0415