scholarly journals Adherence to Chronic Myeloid Leukemia Monitoring and Treatment Guidelines in Canadian Registries

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3079-3079
Author(s):  
Christopher M Hillis ◽  
Lambert Busque ◽  
Julie Stakiw ◽  
Donna L. Forrest
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Data Collection ◽  
Real World ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Guidelines ◽  
Imatinib Therapy ◽  
Molecular Monitoring ◽  
First Line ◽  
Time Period

Abstract Background: Registry data in chronic myeloid leukemia (CML) complement clinical trial data, and can help determine how closely real world clinical practice adheres to guidelines. Several reports addressing this issue have suggested adherence to monitoring guidelines varies. However, no Canadian data on this topic has been published to date. To provide insight into this issue, we present data from the British Columbia (BC), Saskatchewan (SK), Ontario (ON) and Quebec (QC) CML registries. Methods: Data on cytogenetic and molecular monitoring were analyzed for CML patients treated with first-line imatinib from 2001-2015 in the BC registry, 2009-2014 in the SK registry and 2001-2014 in the ON registry. From 2006, clinicians in BC and SK were advised to follow the European LeukemiaNet (ELN) monitoring recommendations. Molecular monitoring of BCR-ABL for these provinces was conducted at the BC Cancer Agency Molecular Genetics Laboratory according to standard practices. In ON, clinicians were not advised to follow any particular guidelines and molecular and cytogenetic tests were conducted by the Hamilton Regional Laboratory Medicine Program using contemporary standards. In QC, province-specific guidelines were in place beginning in 2012 (see www.gqr-lmc-nmp.ca for specific guidance). Treatment patterns for patients treated with first-line imatinib from BC, SK and QC were analyzed for the 2001-2015, 2001-2014 and 2002-2012 time periods, respectively. Results: Monitoring data were collected for 234, 58 and 104 patients from BC, SK and ON, respectively. As shown in table 1, adherence to monitoring recommendations in Canada was 70% to 80% at 12 months. Treatment data were available for 234 BC patients, 73 SK patients, and 223 QC patients. Data on adherence to treatment recommendations were available for 58 SK patients diagnosed with CML and treated with first-line imatinib between 2009 and 2014. Of these 58 patients, over a quarter (n=15) experienced treatment failure or failed to meet ELN milestones without a change in therapy. Smaller proportions of patients receiving first-line imatinib therapy in BC and QC remained on imatinib therapy (see table 2). Discussion and Conclusions: These data suggest there is room for improvement with regards to adherence to CML monitoring and treatment recommendations in Canada. However, assessment of adherence to recommendations and inter-provincial comparisons are limited by the fact that monitoring and treatment guidelines have evolved over the data collection time period, as well as by differences in data collection strategies. For instance, in the ON registry, monitoring at the 3-month time point may be lower as testing was not typically conducted at 3 months in ON during the early 2000s. The opposite pattern observed in BC (with higher testing rates at 3 months dropping off by 18 months) may be attributable to the strict time period definition, with more patients receiving testing outside of the 4-week window after 1 year or more on treatment. In spite of these limitations, data collection through these registries continues to improve our understanding of real world CML populations and its management in Canada, as well as to spur initiatives aimed at improving CML care. This study was sponsored by Bristol-Myers Squibb. Professional medical writing and editorial assistance was provided by MedPlan Communications Inc. and was funded by Bristol-Myers Squibb. Disclosures Hillis: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria; Celgene: Consultancy. Busque:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Stakiw:Roche: Research Funding; BMS: Honoraria; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jansen: Honoraria, Speakers Bureau. Forrest:BMS: Consultancy, Research Funding; Ariad: Honoraria, Speakers Bureau.

Long Term Adherence to Imatinib Therapy Is the Critical Factor for Achieving Molecular Responses in Chronic Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3290-3290 ◽  
Author(s):  
Alex Bazeos ◽  
Jamshid Khorashad ◽  
François-Xavier Mahon ◽  
Lina L Eliasson ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Adherence Rate ◽  
Molecular Response ◽  
Molecular Responses ◽  
Adherence To Therapy

Abstract Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C>T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or >90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p<0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve. Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

Specific Drug Transporter Genotypes Are Significantly Associated with Increased Rates of Major and Complete Molecular Responses In Newly Diagnosed Chronic Myeloid Leukemia Patients Treated with Imatinib – A TOPS Correlative Substudy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 670-670
Author(s):  
Simona Soverini ◽  
Sabrina Angelini ◽  
Eleonora Turrini ◽  
Matt Burnett ◽  
Gloria Ravegnini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Favorable Alleles ◽  
Summary Measures

Abstract Abstract 670 The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield:Novartis: Employment. Martinelli:Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

Baseline Characteristics Of Patients With Chronic Myeloid Leukemia In a Prospective Observational Study (SIMPLICITY)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4026-4026 ◽  
Author(s):  
Jorge E. Cortes ◽  
Rüdiger Hehlmann ◽  
Carlo Gambacorti-Passerini ◽  
Stuart Goldberg ◽  
H. Jean Khoury ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Chronic Myeloid Leukemia ◽  
Clinical Research ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
First Line ◽  
Historical Cohort ◽  
Prospective Cohorts

Abstract Background Oral BCR-ABL tyrosine kinase inhibitors (TKIs), including imatinib (IM), dasatinib (DAS) and nilotinib (NIL), have improved survival in chronic-phase chronic myeloid leukemia (CP-CML). Few data are available that compare TKIs in daily clinical practice across multiple regions. Methods SIMPLICITY is an ongoing observational cohort study of adult patients with newly diagnosed CP-CML receiving first-line treatment with IM, DAS or NIL in the USA and Europe (Eu) outside of clinical trials (NCT01244750). The primary objective is to assess effectiveness of these TKIs in clinical practice. The study includes three ‘prospective’ cohorts of patients treated with IM, DAS or NIL since 2010 (the study opened after first-line approval of all three TKIs) and a ‘historical’ cohort treated with IM since 2008. Preliminary baseline demographics are presented for prospective cohorts. Results 860 prospective patients (Eu: 32%, USA: 68%) were enrolled through June 20, 2013, receiving IM (n=399), DAS (n=229) or NIL (n=232). Median age at initiation of first-line TKI was 56 years, with significant differences in pairwise comparisons between DAS and IM and NIL and IM (Table). Demographics were consistent across cohorts. Only 30% of patients had Hasford or Sokal scores recorded. ECOG performance status (PS) was available in 54% of patients. The number of baseline comorbidities per patient (mean: 3.2 + 2.7) was balanced across cohorts; 51% of patients presented with ≥3 comorbidities. Patients in the IM cohort had a higher prevalence of gastrointestinal comorbidities (P=.006 and .007 for DAS vs IM and NIL vs IM, respectively), and the NIL cohort had a higher prevalence of musculoskeletal comorbidities than the DAS cohort (P=.015). The proportions of patients with cardiovascular comorbidities were 38%, 36% and 42% in the DAS, NIL and IM cohorts, respectively, consisting primarily of hypertension (31%) and hyperlipidemia (17%) (P>.05 across cohorts). Coronary artery disease was present in 9%, cardiac arrhythmias in 6%, myocardial infarction in 3% and peripheral arterial disease in 2% of patients. The proportion of patients with diabetes was 10%. Clinicians reported effectiveness as the most common reason for TKI selection; familiarity and cost were also cited as reasons for IM selection (P<.001 vs DAS and NIL). Comorbidities were not drivers of TKI selection in this analysis. Conclusions This is the first report from the prospective cohorts of SIMPLICITY. Demographics were consistent across cohorts. Overall, the SIMPLICITY population is older with potentially more comorbidities than patients enrolled in first-line clinical trials with restrictive inclusion criteria (NEJM 2003 348 994; NEJM 2010 362 2260; NEJM 2010 362 2251). Initial TKI selection does not appear to be driven by baseline comorbidity, rather by perceived effectiveness, cost and familiarity. Hasford/Sokal scores were not recorded in the majority of patients prior to starting first-line TKI therapy. Outcomes data are being collected across cohorts that will inform about a multi-region population treated outside clinical trials. Disclosures: Cortes: Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Hehlmann:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Oncology: Honoraria, Research Funding, Speakers Bureau; Ariad: Honoraria, Research Funding, Speakers Bureau. Khoury:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Teva: Honoraria. Mauro:Novartis Oncology: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Paquette:Ariad: Consultancy; Incyte: Consultancy, Honoraria; Novartis: Consultancy. Foreman:ICON Clinical Research: Employment, My employer ICON Clinical Research receives research funding from pharmaceutical companies including manufacturers of CML drugs Other. Mohamed:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Hirji:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment.

Two-Year Consolidation By Nilotinib Is Associated with Successful Treatment Free Remission in Chronic Myeloid Leukemia with MR4.5: Subgroup Analysis from STAT2 Trial in Japan

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1889-1889 ◽  
Author(s):  
Naoto Takahashi ◽  
Chiaki Nakaseko ◽  
Kaichi Nishiwaki ◽  
Hisashi Wakita
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Subgroup Analysis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Second Line ◽  
First Line ◽  
Prior Therapy ◽  
Line Therapy ◽  
Treatment Free Remission

Abstract Background Nilotinib (NIL) is a second-generation tyrosine kinase inhibitor (TKI) that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). Superior rates of deeper molecular responses (DMR) were achieved with NIL vs. imatinib (IM) in patients newly diagnosed with CML in chronic phase (CML-CP) in the ENESTnd trial. In addition, the ENESTcmr study demonstrated that switching to NIL after a minimum of 2 years on IM led to increased rates of DMR vs. remaining on IM. Switching to NIL treatment for 2 years safely led to MR4,5 (BCR-ABLIS…0.0032%) in 47.5% of patients with major molecular response (MMR) on long-term IM therapy in our STAT1 trial. Recently, treatment free remission (TFR) was proposed as one of the goals in CML treatment. Indeed, prospective trials suggest that IM therapy may be safely and successfully discontinued in 40% of CML patients with MR4.5. STAT2 is the first study to evaluate the efficacy of two-year consolidation by NIL for successful TFR in patients with CML-CP who had achieved MR4.5. Before enrolling in STAT2, some patients were treated by not only IM but also NIL because of MMR but no MR4.5 after IM therapy, and some patients changed over from STAT1 to STAT2. Here, we present the results of the subgroup analysis from STAT2 based on the prior treatments at the time of entry into the study. Methods In the STAT2 trial, patients who achieved MR4.5 on IM front line therapy (subgroup 1; SG1) or NIL second line therapy after IM therapy (subgroup 2; SG2) were eligible and NIL was given twice daily at the dose of 600 mg/day for 2 years in consolidation phase. The primary endpoint of STAT2 was the proportion of patients with successful TFR, defined as no confirmed loss of MR4.5 (2 consecutive IS RQ-PCR tests), within the first 12 months of TFR phase. Thirty-five institutions in STAT study group participated. The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was signed by all patients according to institutional guidelines. The study was approved by all institutional review boards and registered with UMIN-CTR (000005904). Results Between July 2011 and December 2012, 96 patients were enrolled in STAT2. Among 96 patients, 50 patients were treated by IM first line only as prior therapy (SG1). On the other hand, 40 patients were treated by IM first line and NIL second line including 21 patients who changed over from STAT1 to STAT2 because they achieved MR4.5 (SG2). Six patients were excluded in this analysis because second generation TKIs were taken as a first line therapy. Among patients treated by NIL for 2 years in this study, 40/50 (80%; 95% CI, 68.4%-88.7%) in SG1 and 33/40 (82.5%; 95% CI, 69.6%-91.5%) in SG2 entered the TFR phase, respectively. The median age was 54.5 years in SG1 and 56.0 years in SG2. The ratio of men to women was 26:14 in SG1 and 18:15 in SG2. The total duration of TKI treatment was 110 months for the SG1 with a median of 86 months of IM, and 24 months of NIL, and 93 months in SG2 with a median of 62 months of IM, and 31 months of NIL,, respectively. All patients achieved MR4.5 at the time of entry into the study and the median time to MR4.5 was 47 months in SG1 and 60 months in SG2.The proportion of patients who maintained TFR at 12 months after stopping NIL was similar across the 2 subgroups: 25/40 (62.5%; 95% CI, 48.3%-77.3%) in SG1, and 23/33 (69.7%; 95% CI, 54.0%-82.5%) in SG2. The Kaplan-Meier (KM) analysis of TFR survival showed that in the 2 subgroups, the majority of events occurred within the first 6 months after stopping NIL (Figure 1). There were no significant differences between these 2 subgroups. Conclusion After two-year consolidation by NIL of CML-CP patients who achieved MR4.5, the TFR rate was 67.9% (90%CI: 58.2% to 76.6%) at 12 months in the STAT2 trial. In the present analysis looking at the prior TKI exposure, the TFR rate was similar in patients treated with IM first line only or who switched from IM to NIL before entering the study, despite the fact that the treatment duration of switched patients was slightly shorter. These findings suggest that two-year consolidation by NIL is associated with successful TFR in CML with MR4.5 that was achieved with IM alone or after switching to NIL. Figure Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Figure. Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Disclosures Takahashi: PFIZER: Honoraria, Research Funding; BMS: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Nishiwaki:Novartis PHARMA: Research Funding.

scholarly journals Prevalence of Comorbidities Relevant to the Choice of Second-Generation (2-G) Tyrosine Kinase Inhibitor (TKI) for the Treatment of Chronic Myeloid Leukemia (CML) in the United States Using Real-World Claims Databases

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4265-4265 ◽  
Author(s):  
Elias J. Jabbour ◽  
Min You ◽  
Trong Kim Le ◽  
John Brokars ◽  
Alexander Brun ◽  
...  
Keyword(s):  
Heart Disease ◽  
Pleural Effusion ◽  
Lung Disease ◽  
Real World ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Comorbid Conditions ◽  
First Line ◽  
Nccn Guidelines ◽  
Medicare Database

Abstract Introduction: NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Chronic Myeloid Leukemia recommend taking certain comorbidities into consideration when selecting a 2-G TKI. Based on toxicity profiles, dasatinib or bosutinib is preferred for patients (pts) with heart disease, arrhythmias, pancreatitis, and/or hyperglycemia; nilotinib or bosutinib is preferred for pts with a history of lung disease and/or who are at risk for pleural effusion. The prevalence of these relevant comorbidities in pts with CML was reported to be high in the US managed care setting, particularly in pts aged ≥ 65 years (Jabbour et al. CLML 2015), supporting the NCCN Guidelines® recommendations. To better understand the patterns of 2-G TKI selection in the first-line setting, this study was designed to assess the prevalence of relevant comorbid conditions in pts newly diagnosed with CML and treated with dasatinib or nilotinib using US real-world databases. Methods: Data for pts diagnosed with CML between 4/1/2013 and 3/31/2016 were extracted from the Truven Health Analytics Commercial and Medicare MarketScan Research databases, and data for pts diagnosed with CML between 4/1/2013 and 12/31/2016 were extracted from the Clinformatics Commercial and Medicare Claims databases. Eligible pts were adults treated with a TKI (imatinib, dasatinib, nilotinib) within 6 months after initial CML diagnosis who had continuous enrollment data for 6 months prior to CML diagnosis and 12 months after TKI initiation. The first TKI prescription was defined as the index date. Comorbidities of interest as stated in the NCCN Guidelines® (heart disease, arrhythmia, diabetes, pancreatitis, lung disease, and pleural effusion) were assessed within 6 months before initiation of a TKI. Results: A total of 649 pts and 471 pts were identified from the MarketScan and Clinformatics databases, respectively. Within these totals, 118 pts were identified from the MarketScan Medicare database, and 223 pts were identified from the Clinformatics Medicare database. The median age of pts from MarketScan was 55 years (dasatinib and nilotinib: 54 years), with 83% aged < 65 years (dasatinib: 86%; nilotinib: 85%). The median age of pts from Clinformatics was 63 years (dasatinib: 64 years; nilotinib: 62 years), with 54% aged < 65 years (dasatinib: 53%; nilotinib: 62%). Men comprised 57% (dasatinib: 58%; nilotinib: 55%) and 55% (dasatinib: 51%; nilotinib: 59%) of the population from MarketScan and Clinformatics, respectively. Forty-four percent of pts from MarketScan and 57% of pts from Clinformatics had at least 1 comorbidity of interest, as classified by the National Comprehensive Cancer Network® (NCCN®) (Table). For pts identified from the Medicare databases (typically aged > 65 years), 69% from MarketScan and 74% from Clinformatics had at least 1 comorbidity of interest. In the overall MarketScan and Clinformatics databases, respectively, 18% and 24% of pts with at least 1 instance of lung disease and/or pleural effusion were prescribed dasatinib, and 36% and 52% of pts with at least 1 instance of heart disease, arrhythmia, diabetes, and/or pancreatitis were prescribed nilotinib. In the MarketScan and Clinformatics Medicare databases, respectively, 18% and 33% of pts with at least 1 instance of lung disease and/or pleural effusion were prescribed dasatinib, and 61% and 70% of pts with at least 1 instance of heart disease, arrhythmia, diabetes, and/or pancreatitis were prescribed nilotinib. A relatively high proportion of pts treated with nilotinib had relevant comorbidities present at the time of treatment choice. Conclusions: In this large retrospective analysis using 2 US claims databases, up to 57% of pts had comorbidities relevant to the treatment of CML with TKIs. Despite this high incidence of comorbidities and the recommendations in the NCCN Guidelines®, a significant proportion of pts were prescribed a 2-G TKI with a side-effect profile that could exacerbate preexisting comorbid conditions. These data suggest that physicians may not be consistently considering comorbidities when choosing a first-line 2-G TKI for the treatment of pts with CML in the real-world setting. This study did not review the impact of dose adjustments due to relevant comorbidities per the NCCN Guidelines®. To ensure optimal care of pts with CML, increased awareness of the importance of comorbidities when selecting a TKI is needed. Disclosures Jabbour: Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Research Funding. You:Bristol-Myers Squibb: Employment. Le:Bristol-Myers Squibb: Employment. Brokars:Bristol-Myers Squibb: Employment. Brun:Bristol-Myers Squibb: Employment. Makenbaeva:Bristol-Myers Squibb: Employment.

Survey of the Frontline Treatment and Management of Chronic Myeloid Leukemia (CML) in a Real-Word Setting: The 3rd Annual Update of the Worldwide Observational Registry Collecting Longitudinal Data on Management of Chronic Myeloid Leukemia Patients (The WORLD CML Registry)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1695-1695
Author(s):  
Ricardo Pasquini ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
David Joske ◽  
Luis A Meillon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Disease Status ◽  
Asia Pacific ◽  
Primary Therapy ◽  
Molecular Monitoring ◽  
Advisory Committees

Abstract Abstract 1695 Background: A global, prospective registry was established to document the frequency of diagnostic testing, management (mgmt) strategies, and outcomes of patients (pts) with CML. Here, we summarize the reported deviations from published disease mgmt recommendations and the overall efficacy achieved by pts. Methods: 1853 pts (≥ 16 years of age) within 6 months (mo) + 2 weeks of CML diagnosis were enrolled from Latin America (LA; n = 497), United States (US; n = 379), Asia Pacific (AP; n = 465), Middle East and Africa (MEA; n = 209), and Russia and Turkey (RT; n = 303). Baseline demographics and medical history were collected at enrollment; current disease status and mgmt information were collected at approximately 6-mo intervals or with a change in disease status or mgmt. Results: From February 2008 to June 2011, data were available for 1831 (99%) pts. Across all regions, nearly all (93.8%) screened pts were in chronic phase CML. Regardless of the time of evaluation (eval), disease burden was mostly assessed through the use of hematologic counts (Table 1). Cytogenetic testing and molecular monitoring were used in a minority of pts at any timepoint. Hydroxyurea (HU) and imatinib were the first agents used in 61.9% and 29.5% of pts, respectively (Table 2). Overall, 81.1% of pts received imatinib therapy at some time and it was the most common second agent (48.1%) pts received. Among the 49% of pts who had response assessments, subsequent treatment changes occurred most frequently (23.9% of pts) at the 3-mo timepoint (Table 1). The median time from disease eval to dose/regimen modification was 3 days. Of those who received imatinib, 32% had dose modifications primarily for: lack of efficacy (20%), physician request (20%), and adverse events (19%). Of the pts with a corresponding eval at 12 mo after diagnosis, 88% had a CHR, 65.4% had a CCyR, and 42.5% had a MMR (BCR-ABLIS ≤.1%). These data are preliminary; response assessments by treatment, as well as further efficacy analyses, are ongoing. Conclusions: Overall, the majority of pts did not have cytogenetic or BCR-ABL transcript level testing performed per the European LeukemiaNet recommendations. Furthermore, despite availability of more effective therapies for the treatment of CML, HU is still used as a primary therapy in a substantial proportion of pts. Based on this analysis, pts outside the US primarily receive HU as initial therapy rather than tyrosine kinase inhibitors (TKIs). Overall, second-generation TKIs, such as nilotinib and dasatinib, are infrequently used. These results illustrate the need for continuing education on the mgmt of CML in order to improve outcomes for all pts. Disclosures: Pasquini: Bristol Myers Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cortes:Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuitcals: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Zernovak:Novartis: Employment, Equity Ownership. Sivarathinasami:Novartis: Employment. Collins:Novartis: Employment. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy Of Dasatinib Therapy In Patients With Imatinib-Resistant Or -Intolerant Chronic Myeloid Leukemia From Physician’s and Patient’s Perspective: “Real World” Data

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5185-5185
Author(s):  
Tatyana I Ionova ◽  
Tatyana P Nikitina ◽  
Taras A Gritsenko ◽  
Valentina L Ivanova ◽  
Galina B Kuchma ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Real World ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Base Line ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Patient Reported ◽  
Dasatinib Treatment

Abstract There is limited published data about the efficacy and safety of the second-line therapy with dasatinib in patients in chronic phase chronic myeloid leukemia (CML-CP) in a “real world” patients setting outside clinical trials. In addition, comprehensive evaluation of benefits and risks of the treatment is worthwhile to better define treatment outcomes in this patients’ population. We aimed to study clinical and patient-reported outcomes as well as safety of dasatinib treatment in a “real world” setting within the context of its approved indication through the analysis of prospectively collected data in patients with imatinib resistance or intolerance receiving dasatinib as the second-line therapy. 75 CML-CP patients resistant or -intolerant to imatinib were enrolled in the prospective, multicenter, non-interventional study (mean age 51.3 years old, SD 15.4; range 22–83 years; male/female – 37/38). The median of disease duration was 5.0 years (0.75–17 years). 63 patients had resistance to imatinib; 12 patients were intolerant to imatinib; the median duration of imatinib treatment 40 months (3–121 months). All the patients received dasatinib as the second-line therapy (100 mg daily). Median follow-up was 12 months. For quality of life (QoL) and symptom assessment patients filled out the SF-36 and Comprehensive Symptom Profile in Chronic Myeloid Leukemia Patients (CSP Leuk-CML), respectively, at base-line, in 1, 3, 6 months after treatment start and every 6 months thereafter. Comparison of QoL and symptom scores was conducted using t-test. QoL scores were analyzed using t-test, adjusting for sociodemographic and disease status. Mean symptom severity and percentage of patients with moderate-to-severe (ratings ³ 5) symptoms was evaluated. After 12 months of treatment 83% patients achieved or maintained complete hematologic response and 35 % – complete cytogenetic response. The twenty four-month progression free survival rate was 93% (95% CI; 84–97%). Four cases of pleural effusion events were registered: they were easily managed in 3 cases; one patient died at 1 month after treatment start due to accompanied infection complication. No severe hematological adverse effects were observed except two cases of grade III-IV neutropenia. Two patients were resistant to dasatinib. Two patients died of disease progression at 6 months of follow-up. At 12 months of dasatinib treatment QoL parameters were stable for 5 out of 8 scales; vitality, social functioning and mental health significantly improved as compared with base-line (p< 0.01). At 24 months of dasatinib treatment improvement of physical functioning, vitality, social functioning and mental health as compared with base-line was registered (p< 0.01); no worsening was observed for other QoL scales. Before treatment 75% of patients experienced at least one moderate-to-severe symptom; more than 40% had more than 7 moderate-to-severe symptoms. The majority of patients (96%) experienced fatigue; half of them suffered from moderate-to-severe fatigue. While treatment the number of patients with moderate-to-severe symptoms decreased. After 12 months of therapy only 25% of patients experienced moderate-to-severe fatigue. Before treatment 36% of patients exhibited critical or severe QoL impairment. Remarkably, in the subgroup of patients (44%) with critical or severe QoL impairment at base-line dramatic QoL improvement was observed: QoL index increased 3.4 fold (p<0.01). Thus, our study on “real world” patient data confirms that dasatinib as second-line therapy in CML-CP patients is effective both in terms of clinical outcomes and patient-reported outcomes, as well as exhibits good tolerability. Comprehensive evaluation of the outcomes of the second-line treatment of CML-CP allows to assess the benefits and risks of therapy both from physician’s and patient’s perspective. Disclosures: Ionova: BMS: Research Funding. Nikitina:BMS: Research Funding. Gritsenko:BMS: Research Funding. Ivanova:BMS: Research Funding. Kuchma:BMS: Research Funding. Shnaider:BMS: Research Funding. Sannikova:BMS: Research Funding. Fedorenko:BMS: Research Funding. Kurbatova:BMS: Research Funding.

SNPs in the Promoter of the Gene Encoding Transmembrane Transporter SLC22A4 (hOCTN1) Are Significantly Associated with an Alteration of Gene Expression and with Resistance to the Imatinib Treatment in Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2463-2463
Author(s):  
Monika Jaruskova ◽  
Rajna Hercog ◽  
Nikola Curik ◽  
Vladimir Benes ◽  
Hana Klamova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Domain ◽  
Imatinib Treatment ◽  
First Line ◽  
Promoter Regions ◽  
Optimal Response

Abstract Introduction: Apart from the mutations in the kinase domain of BCR-ABL, other important mechanisms of resistance to the first line imatinib (IM) therapy in chronic myeloid leukemia (CML) are pharmacokinetics factors, especially an intracellular concentration of IM. ATP Binding Cassette (ABC, ensuring efflux) and Solute Carrier (SLC, ensuring uptake) super families are responsible for transportation several drugs including IM. Gene expression and activity of the SLC and ABC transporters may be affected by polymorphisms in their promoter regions and may notably contribute to the treatment failure. Objectives: The aim of this study was to identify polymorphisms in the promoter regions of the selected SLC and ABC transporter encoding genes and evaluate their association with the response to the first line IM therapy in CML patients in chronic phase. Material and Methods: The patient cohort consists of 40 CML patients with optimal response and 40 resistant patients (without mutations in the BCR-ABL kinase domain) to the IM in the first line with 24 months follow-up from the therapy initiation. All 80 CML patients were taking a standard dose of IM and in none of them were evidence of non-compliance. The promoter regions (~1000bp) of selected ABC (n=4) and SLC (n=15) genes with the annotated function of drug transportation were amplified. The next generation sequencing was applied for ultra-wide sequencing of altogether 1419 amplicons (454 GS Junior, Roche AppliedScience; MiSeq Series, Illumina). The obtained sequences were analyzed and evaluated with the focus on the presence of single nucleotide polymorphisms (SNPs) using NextGENe software (Softgenetics). The Fisher´s exact binomial test of goodness of fit was used to evaluate haplotype frequency distribution among patient cohort. The expression analysis of a selected gene was analyzed using RT-qPCR (TaqMan® Assays) in total leukocytes of peripheral blood with GUS as a housekeeping gene. Results: Among 1419 evaluated sequences we identified 96 SNPs (2-12 SNPs per one promoter) of which nine was not yet annotated. We identified 2 SNPs, rs460089 (C/G) and rs460271 (C/G), with uniform alleles co-segregations in the promoter of the gene SLC22A4 when GG haplotypes were significantly more frequent in resistant patients (P<.05). Of all resistant patients, 69% carried GG haplotypes, 17% CG and 14% CC. The frequency of haplotypes among responding patients was 31% of GG, 53% CG and 16% CC. As SLC22A4 is imatinib transporter (He L et al. Hum Genomics 2009), we measured the level of the gene expression associated with both co-segregated SNPs. Among all patients analyzed regardless of the response to IM, the GG haplotypes showed a significantly lower expression of SLC22A4 in comparison to CG and CC haplotypes (P<.05). Even greater significant differences in the expression were found when comparing GG haplotypes within patients resistant to IM in comparison to CG haplotypes within patients with optimal response (P<.01). Conclusion: In this work, we found a significantly decreased gene expression of SLC22A4 in total leukocytes of peripheral blood that was associated with GG haplotypes of 2 SNPs in the SLC22A4 promoter, where GG haplotypes were significantly more frequent in CML patients resistant to the first line imatinib treatment in comparison to the patients with an optimal response. We assume that GG haplotypes have altered activity of SLC22A4 promoter resulting in the reduced hOCTN1 expression and thus in lower intracellular IM concentration that may be insufficient for optimal response. The experiments on the SLC22A4 promoter activity alterations associated with GG haplotypes are ongoing. We believe that screening for rs460089 (C/G) and rs460271 (C/G) SNPs among patients with newly diagnosed CML could be an important prognostic genetic factor helping to select a tyrosine kinase inhibitor that is not dependent on the active transportation through the cell membrane. This work was supported by the Ministry of Health of Czech Republic, grant IGA MZ CR NT/13899 and Charles University in Prague, project GA UK/177815. Disclosures Klamova: Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Machova Polakova:Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

scholarly journals Timely Molecular Monitoring and Achievement of Major Molecular Response in Chronic Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3072-3072
Author(s):  
Adi J. Klil-Drori ◽  
Laurent Azoulay ◽  
Hui Yin ◽  
Alexa Del Corpo ◽  
Michaël Harnois ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Treatment Guidelines ◽  
Patient Adherence ◽  
Point Estimate ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Molecular Monitoring

Abstract Background: Timely molecular monitoring is the cornerstone of chronic myeloid leukemia (CML) treatment guidelines. These guidelines are based on the design of clinical trials, but none have been validated prospectively. We hypothesized that timely molecular monitoring in routine patient care increases the likelihood of achieving major molecular response (MMR) in CML. Methods: We conducted a prospective cohort study using the Québec CML Registry, which comprises 713 patients from 16 hospitals. Patients with newly-diagnosed CML (2009-2014) and measurable disease by quantitative PCR were followed from tyrosine kinase inhibitor (TKI) initiation. Timely PCR (tPCR) was defined as a PCR performed at 2-4, 11-13, and 17-19 months. (Figure). Study outcome was the achievement of MMR at 25 months, defined as international scale ratio (IS) <0.1% or a 3-log reduction in BCR-ABL1 copy number. Achievement of MMR was determined using any PCR during follow-up. Generalized estimating equations (GEE) using an exchangeable correlation structure, to account for patient clustering by center, were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of achieving MMR comparing adherence and nonadherence to tPCR. The models were adjusted for age, sex, first-line TKI, year of study entry, and Charlson comorbidity index. Results: A total of 246 patients with 25 months of follow-up were included in the analysis (Table 1). Patients were excluded due to diagnoses before 2009 (350), insufficient follow-up (76), and other (41). The mean (standard deviation) age was 56.1 (15.5), 43.9% were female; 67.5% were started on imatinib, and 47.6% were treated in higher-volume (>50 CML patients) centers. Timely PCRs were performed in 76.3%, 69.5%, and 61.0% of patients at 2-4, 11-13, and 17-19 months, respectively. When compared with not performing tPCRs, performing one and two tPCRs were associated with achieving an MMR by 25 months (OR: 17.05, 95% CI: 5.18-56.09 and OR: 14.96, 95% CI 3.63-61.73, respectively, Table 2). The highest OR of achieving MMR was observed among those who underwent three tPCRs (OR: 24.02, 95% CI: 7.07-81.55). Conclusions: To our knowledge, this is the first study to assess clinical outcomes associated with timely molecular monitoring in early CML. While performing one and two tPCRs was associated with achieving MMR at 25 months, the point estimate for performing three tPCRs was the highest. These findings indicate that timely monitoring may allow for faster switching of TKI, which ultimately permits patients with early failure to "catch up." Alternatively, more regular testing may increase patient adherence to therapy. If replicated, these findings support routine and punctual monitoring of patients on TKI therapy. Disclosures Assouline: Pfizer: Speakers Bureau; BMS: Speakers Bureau.

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