Chronic myelogenous leukemia (CML) is a slowprogressing

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1 At a Glance Practical Implications p e148 Author Information p e151 Full text and PDF Web exclusive Patterns of Specific Testing for Patients With Chronic Myelogenous Leukemia Original Research Allison M. Bell, PharmD, MSc, BCPS; Kristin M. Richards, PhD; Christopher R. Frei, PharmD, MSc, BCPS; and Jim M. Koeller, MS Chronic myelogenous leukemia (CML) is a slowprogressing form of leukemia characterized by increased and unregulated growth of myeloid cells in the bone marrow. CML occurs in 3 phases: chronic phase (during which most patients are diagnosed), accelerated phase (a transitional phase), and blast-crisis phase. Blastcrisis phase is the terminal phase of CML, often occurring within 3 to 5 years post diagnosis. 1 In 2009, the National Cancer Institute estimated that 5050 patients would be diagnosed with CML in the United States each year. 2 This disease has a widespread age range; the median age at diagnosis is 67 years, and the median age at death is 73 years. This disease is more prevalent in men. CML is characterized by identification (cytogenetically or via molecular methodology) of the chromosomal translocation (9:22) referred to as the Philadelphia chromosome (Ph+). This translocation results in the head-tail fusion of the break point cluster region (BCR) (chromosome 22 at band 11) and the Abelson murine leukemia (ABL) gene (chromosome 9 at band q34). 3 The product of this translocated gene plays a central role in the development of CML. Studies have shown that the fusion gene product, BCR-ABL, deregulates tyrosine kinase activity, which is thought to be integral to the development of CML. 4 CML is often suspected in patients with an irregular complete blood count (CBC), when granulocytes, basophils, and eosinophils are increased. CML is diagnosed by detecting the Ph+ chromosome in blood or bone marrow. 1 Detection is generally accomplished through routine cytogenetics (normal karyotyping). If bone marrow collection is not possible, then cytogenetic determination may be achieved via fluorescent in situ hybridization (FISH), which measures the percent of Ph+ metaphases. BCR-ABL transcripts can be measured by conventional qualitative reverse-transcriptase polymerase chain reaction (RT-PCR). RT-PCR generates a positive or negative reading. A real-time quantitative polymerase chain reaction (Q-PCR) can report the actual number of mrna transcripts. Although the Q-PCR test is highly sensitive and specific, it is also expensive; thus, Q-PCR is generally not obtained unless ABSTRACT Objectives: We assessed chemotherapy use in patients with chronic myelogenous leukemia (CML) to determine how use of CML-specific tests impacted drug selection and modification. We compared real-world data with National Comprehensive Cancer Network (NCCN) guideline recommendations. Study Design: This was a longitudinal, retrospective analysis of a commercial insurer database. Methods: Patients with at least 2 claims associated with CML between July 1, 2006, and June 30, 2008, were included. Time from diagnosis to first chemotherapy treatment was measured. We identified the use of karyotyping/fluorescent in situ hybridization (FISH), reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative polymerase chain reaction (Q-PCR), and kinase domain mutation analysis and compared use with NCCN recommendations. Results: Sixty patients with a CML diagnosis had specialty tests and received drug therapy. Median age was 55 years and 57% of patients were male. For 48 patients, the median time from diagnosis to therapy initiation was 3.7 months. Twelve patients had no CML-specific tests drawn prior to initiation. Forty-eight patients (80%) had CML-specific tests drawn every 3 months during drug therapy; however, 12 patients had at least one 3-month period with no labs. Overall, 85% received Q-PCR, 13% received RT-PCR, 2% received FISH, and no patients had karyotyping or mutation analysis. Imatinib was the initial chemotherapy in 87% of patients. Every patient who received a second-line drug (n = 9) had labs within 30 days of drug change. Conclusions: It appears that use of CML-specific molecular tests met 2008 NCCN guidelines. PCR testing was carried our prior to chemotherapy change; however, the use of mutation analysis was not identified. Educational efforts to promote the use of karyotyping/fish analysis and to use molecular tests with appropriate frequency should be considered. Am J Pharm Benefits. 2015;7(6):e147-e152 Vol. 7, No. 6 The American Journal of Pharmacy Benefits e147

2 n Bell Richards Frei Koeller PRACTICAL IMPLICATIONS We assessed specialty testing in patients with chronic myelogenous leukemia (CML) to determine guideline concordance and impact on chemotherapy selection/modification. Patients were selected from a commercial insurer database. It appears that use met National Comprehensive Cancer Network guidelines. n Sixty patients with CML had specialty tests and received chemotherapy. n Forty-eight patients had CML-specific tests drawn every 3 months during therapy. n Quantitative polymerase chain reaction was the most commonly used specialty test. patients are Ph+ negative by cytogenetic testing or have a low level of FISH positivity. Conventional cytogenetics is a microscopic examination of genetic material that screens for Ph+ cells among a minimum of 20 metaphase samples. A complete cytogenetic response (CCR) is defined by the absence (0%) of Ph+ chromosomes; CCR may be a possible surrogate marker for survival. 5,6 Molecular responses are primarily measured using the Q-PCR test. A complete molecular response is the absence of BCR-ABL mrna transcripts. In 2001, imatinib was the first selective inhibitor of the BCR-ABL tyrosine kinase approved by the FDA. However, despite high complete response rates, resistance to imatinib occurred in up to 37% of patients treated over a 6-year period. 7 It was also reported that 13% to 14% of patients discontinued imatinib therapy due to resistance or intolerance in the same period. 7,8 For those who remain on imatinib therapy, some continue to test positive for the BCR-ABL gene mutation. 9 Clinical evidence suggests the importance of achieving early cytogenetic and molecular response for optimal long-term outcomes. 10 The molecular basis of CML is heterogeneous, with some patients initially resistant or rapidly acquiring resistance to imatinib. Physiological changes in the patient or molecular changes in the BCR-ABL kinase domain (KD) may lead to imatinib resistance. More than 100 different point mutations in this domain can result in resistance. 11 Ernst and colleagues found that 53 of 95 patients (55.8%) with imatinib resistance in various disease stages had detectable mutations; 22 different mutations were seen within these individuals. Patients responses to dose increases were poor. 12 While not all point mutations may confer imatinib resistance, disease progression is associated with improperly treated resistance. 12 The BCR-ABL mutation T315I is of particular concern, since it mediates resistance to other tyrosine kinase inhibitors (TKIs), including dasatinib and nilotinib. 13 Dasatinib and nilotinib are each indicated for firstline treatment of CML and in patients with resistance or intolerance to prior therapy, including imatinib. 8,14 The effectiveness of dasatinib is based on hematologic and cytogenetic response rates. Early detection of imatinib failure allows for therapeutic switch to dasatinib, which has shown favorable results for major molecular response in imatinib resistance. 14 Bosutinib and ponatinib are newer TKIs reserved for use when a patient fails therapy with a first-line CML TKI. Conventional laboratory work, along with special cytogenetic and molecular testing, plays a critical role in the diagnosis, treatment, and follow-up of CML patients. The National Comprehensive Cancer Network (NCCN) constructed CML monitoring guidelines. 15 Initial diagnosis should include a CBC, platelet count, bone marrow cytogenetics (including fluorescence in situ hybridization [FISH]), and baseline Q-PCR. Definitions of complete hematologic response, cytogenetic responses, and partial hematologic response as defined by the NCCN are listed in Table 1. When peripheral blood counts are normalized, a patient is in hematologic remission. Cytogenetic remission can be determined via bone marrow aspiration and cytogenetic evaluation. In a patient with CML, evaluation of therapy response should be carried out every 3 months for the remainder of the patient s life. 15 Testing every 3 months promotes early detection of resistance; this allows treatment maximization for each patient. BCR-ABL analysis should be performed every 3 months, while cytogenetic testing should be performed at treatment months 6, 12, and If a patient experiences imatinib failure, a mutational analysis is warranted. Our aim was to utilize data from CML patients within Horizon Blue Cross Blue Shield (Horizon BCBS) and establish whether the patterns of care adhered to the 2008 NCCN CML clinical practice guidelines for the following outcomes: time from initial diagnosis to initiation of drug therapy, choice of initial treatment regimen, and patterns of follow-up monitoring of drug therapy (completion rates of the specific recommended specialty tests). METHODS This retrospective longitudinal cohort study used a hybrid database that included data from Horizon BCBS and their primary laboratory. The study period ranged from July 1, 2006, through June 30, Eligibility criteria included presence of the diagnostic code for CML (International Classification of Diseases, Ninth Revision, Clinical Modification code 205.1), being 18 years or older, insurance enrollment for 6 months or more, 90 days or more e148 The American Journal of Pharmacy Benefits November/December 2015

3 CML Patterns of Care of designated specialty laboratory data, and 2 or more CML drug claims. Patients were required to have a new diagnosis of CML after July 1, 2006, for inclusion in the study. Patients without 2 or more designated specialty laboratory tests from the primary laboratory were not included. The primary measures were the times from initial diagnosis of CML to initiation of cancer therapy, to initial drug treatment, and to completion of specialty cytogenetic and molecular tests. Cytogenetic and molecular tests included normal bone marrow karyotyping, chromosomal analysis by FISH, BCR-ABL RT-PCR, BCR-ABL Q-PCR, and BCR- ABL KD mutational analysis. Per NCCN 2008 CML guidelines, bone marrow cytogenetics or FISH were indicated along with polymerase chain reaction monitoring of BCR- ABL transcript number. For patients responding, BCR-ABL transcript numbers should have been monitored every 3 months. Bone marrow cytogenetics should have been performed at months 6 and 12 post therapy initiation, and at 18 months if CCR was not achieved at 12 months. With disease progression, drug resistance, or changing BCR-ABL transcripts, patients should have been followed monthly with the possibility of additional testing using KD mutational analysis prior to drug change. Statistical analyses were performed using JMP version 7.0 (SAS Institute, Cary, North Carolina). Descriptive statistics (percents, mean SDs) were used to characterize the CML population based on patient age, gender, and comorbidities. Comorbidities included coronary artery disease, diabetes, heart failure, hypertension, and chronic obstructive pulmonary disease Time-to-treat was defined as time (in days) from initial diagnosis to first CML drug treatment; this outcome was reported as mean SD. Length of treatment was also reported as mean SD and defined as time (in months) from start of CML drug until cessation. The length of treatment was reported for each drug a patient received. Follow-up for each patient included any therapy changes and all CML special tests throughout the study period. We calculated the number of special tests performed for patients with a change in drug or dosage during the study period. Patients in this subgroup included those with intolerance (such as toxicity) or those who experienced overt progression (resistance to particular drug therapy). We also identified the percentage of patients that did not have recommended special tests completed prior to drug therapy change. This study was conducted in accordance with the ethical principles that have their origin in the current Declaration of Helsinki and were consistent with the International Conference on Harmonization Good Clinical Practice, Good Epidemiology Practices, and all applicable regulatory requirements. Table 1. NCCN Guideline Criteria for Response 15 Cytogenetic response (minimum of 20 metaphases) Complete No (Ph+) metaphases Major 0% to 35% Ph+ metaphases (complete and partial) Partial 1% to 34% Ph+ metaphases Minor 35% to 90% Ph+ metaphases Complete hematologic response Complete normalization of peripheral blood counts (leukocyte count <10 x 10 9 /L and platelet count <450 x 10 9 /L) No Ph+ metaphases No immature cells in peripheral blood No signs or symptoms of disease including disappearance of palpable splenomegaly Major hematologic response Partial hematologic response Same as complete hematologic response except: Immature cells present in peripheral blood Platelet count <50% of pretreatment count but >450 x 10 9 /L Splenomegaly persists but is less than 50% of pre-treatment size Minor hematologic response Molecular response Break point cluster region Abelson murine leukemia Complete (BCR-ABL) mrna undetectable by reverse-transcriptase polymerase chain reaction Major 3-log reduction of BCR-ABL mrna Ph+ indicates Philadelphia chromosome. RESULTS Of 145 CML patients identified in the hybrid database, 60 met inclusion criteria. The Figure shows the breakdown of patient eligibility for study inclusion. See Table 2 for demographic results of the 60 patients included in the study. CML diagnosis was assumed with the first identified primary lab specialty laboratory test. Forty-eight patients had a primary lab specialty test prior to their first dose of CML treatment. For 43 of these 48 patients (90%) the primary lab specialty lab test was performed 30 days or less (median 8.5 days) prior to the first dose of treatment. For 48 patients (80% of patients in study) with a confirmed primary lab specialty test, time to first drug claim from first specialty test was a median of 3.7 months (mean = 5.7 months; SD = 6.1 months). Twelve patients had no primary lab specialty test identified prior to first dose. Four of these 12 patients had no labs within 30 days of drug treatment. The remaining 8 patients had a specialty lab within 30 days of drug therapy, but not prior to therapy initiation. If these 8 patients were included in the secondary analysis (by giving them a value of 0 for the time-to-first drug), Vol. 7, No. 6 The American Journal of Pharmacy Benefits e149

4 n Bell Richards Frei Koeller Table 2. Patient Demographics (N = 60) Age in years, median 55 (range = 20-78) Gender, male 34 (57%) Comorbidities 0 36 (60%) 1 18 (30%) 2 6 (10%) Types of comorbidities Coronary artery disease 10 (17%) Diabetes 9 (15%) Heart failure 5 (8%) Hypertension 4 (7%) median time would be 2.2 months and mean time would be 4.9 months. A majority of patients (87% [n = 52]) received imatinib as first-line therapy; dasatinib was the first-line therapy for 5 patients (8%). Cytarabine, hydroxyurea, and nilotinib were each used for 1 patient. This patient received interferon alfa-2b initially, but was switched to cytarabine in less than a month. Hydroxyurea was used for 2 other patients. There were a mean of 10.6 drug claims per patient (median = 8) for a total of 635; 91% of all drug claims were for imatinib. The median time between first and last drug claim was 17.4 months (15.8 mean) and ranged from 0.9 to 24.2 months based on a 28-day (4 week) month The median and mean number of days between drug claims were 34 days and 46.2, respectively. During the study period, 9 patients were switched to second-line therapy. All 9 patients had a specialty lab performed within 30 days of change. Q-PCR was the primary test used. Five of those 9 patients had been on imatinib and switched to another TKI (4 to dasatinib, 1 to nilotinib). Mean time to switch was 10.1 months. Three patients received hydroxyurea as first-line therapy, but were subsequently switched to imatinib. The mean time for these switches was 0.6 months. Specialty laboratory tests were analyzed for type and frequency and then compared with NCCN guidelines. Forty-eight patients (80%) consistently had specialty labs performed every 3 months or more frequently, meeting NCCN guidelines. However, 12 patients had at least 1 3-month period without a specialty lab test. Overall, 51 patients (85%) had Q-PCR performed, while 8 patients (13%) had RT-PCR. One patient had FISH performed. No bone marrow karyotyping or ABL KD mutational analysis was identified. The 1 patient in whom the use of FISH was identified, had 19 drug and 35 laboratory claims for FISH over a 22-month period. Before each drug claim for this patient, a mean of 1.8 FISH tests were identified. For the 8 patients in whom RT-PCR was performed, the median number of RT- PCR tests performed per patient was 26. Before each drug claim, RT-PCR testing ranged from 0.7 to 7.5 tests. For the 51 patients who had the Q-PCR test performed, a median of 38 tests were performed per patient. Before each drug claim, patients averaged between 0.4 and 5.0 Q-PCR tests. DISCUSSION Our study sample correlated with the average CML population in the United States. In 2009, the National Cancer Institute estimated that 5050 patients in the United States would receive a diagnosis of CML each year. 16 The age range of patients in our study corresponded with the age range of the US CML population. Nationally, the median age at diagnosis was 66 years; the median age in our study was 11 years lower. The sample in our study had more male patients than females, which correlates with CML population national trends. Demographically, our study sample follows the statistics of the US population of CML patients, which allows for extrapolation of study results to the larger national population. A majority of patients in this study had a diagnosis of CML established prior to any CML drug claims. Our study showed a high compliance rate with the NCCN guidelines on testing in regards to initiation of chemotherapy, with a majority of patients having a specialty test prior to first drug claim. This compliance increased in the secondary analysis, when patients who received treatment prior to specialty test were included. In our study, 80% of patients consistently had a specialty lab performed every 3 months. The most frequent test was the Q-PCR, performed an average of 3.8 times per patient. We did not know the actual disease status of these patients; therefore, it was hard to determine if the frequency of these specialty labs was justified. However, it appeared some patients received more molecular tests than guidelines recommend. We also identified 12 patients with at least one 3-month period without a specialty lab test. Again, without knowing the clinical status of these patients, it was difficult to determine if circumstances existed that precluded the use of a specialty test. Although cytogenetic evaluation is part of the NCCN guidelines, we only identified 1 patient with FISH evaluation. We expected to identify additional patients with bone marrow and or FISH analysis. The reason for lack of cytogenetic determination was not clear. Certainly, educational efforts aimed at physicians to highlight current CML monitoring guidelines would be prudent. e150 The American Journal of Pharmacy Benefits November/December 2015

5 CML Patterns of Care Figure. Patient Sample Selection Based on Eligibility Criteria Hybrid database: all chronic myelogenous leukemia patients aged 18 years with insurance enrollment 6 months (n = 145) Primary laboratory specialty labs (n = 97) 90 days specialty lab data (n = 93) 2 drug claims (n = 60) 48 patients excluded 4 patients excluded 33 patients excluded Indications for ABL KD mutation analysis should be performed according to the CML stage of the patient. For patients in the chronic phase of CML, ABL KD mutation screening is indicated at several points: without complete hematologic response at 3 months, minimal cytogenetic response at 6 months, or major cytogenetic response at 12 months. This screening is also indicated in chronic phase if there is any sign indicating loss of response to treatment (hematological, Ph+, or transcript relapse). In the accelerated and blast crisis phases of CML, the testing for ABL KD mutations should be routinely performed at 3-month intervals in high-risk patients, regardless of their response level to the TKIs. Again, we did not identify any ABL KD mutational analysis performed. This may be explained by the fact that this test had been relatively recently accepted as an addition to the 2008 NCCN guidelines at the time of the study; physicians may not have been familiar with this test or may have been hesitant to utilize it routinely. Limitations The limitations of this analysis are primarily related to availability of specialty laboratory data. The hybrid database was generated using specialty laboratory results obtained from the primary contracted lab of the health insurer. Specialty lab values were not available for this analysis if these labs were performed in a different offcontract laboratory. Additionally, the contracted laboratory only recalled 2 years worth of the requested specialty lab data, which limited the study time frame. Sample size was limited to the patients included in the hybrid database. Medicare patients may not have been included, which may be why our median age was lower than the national average. While impact of this research may be greater with a larger study group, we did not have access to additional hybrid databases at the time of this study. CONCLUSIONS It appears that the use of CML-specific molecular tests met 2008 NCCN guidelines. PCR testing was carried our prior to chemotherapy change; however, the use of mutation analysis was not identified. Educational efforts to promote the use of karyotyping/fish analysis and to use molecular tests with appropriate frequency should be considered. Author Affiliations: Department of Pharmacy Practice, The University of Mississippi School of Pharmacy (AMB), Jackson, MS; Center for Pharmacoeconomic Studies, Health Outcomes and Pharmacy Practice Division (KMR), The University of Texas at Austin College of Pharmacy (CRF, JMK), Austin, TX; The University of Texas Health Science Center San Antonio (CRF, JMK), San Antonio, TX. Funding Source: Partial funding by Bristol-Myers Squibb. Author Disclosures: Mr Koeller received a CML grant from Bristol- Myers Squibb for this, and other studies. Dr Frei has a grant pending from Forest, and has received a research grant from Bristol-Myers Squibb for a different study. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Authorship Information: Concept and design (JMK); acquisition of data (JMK); analysis and interpretation of data (AMB, KMR, CRF, JMK); drafting of the manuscript (AMB, JMK); critical revision of the manuscript for important intellectual content (AMB, KMR, CRF, JMK); statistical analysis (KMR); obtaining funding (JMK); administrative, technical, or logistic support (CRF, JMK); and supervision (CRF, JMK). Address correspondence to: Jim M. Koeller, MS, Pharmacotherapy Education and Research Center (PERC), The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, MC-6220, San Antonio, TX koeller@uthscsa.edu. REFERENCES 1. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340(17): Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin. 2009;59(4): Faderl S, Talpaz M, Estrov Z, O Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341(3): Ren R. 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