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.

The Average Baseline BCR-ABL Levels Are Significantly Higher in Patients with Resistance to Dasatinib As First-Line Treatment for Early Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4436-4436
Author(s):  
Cristian Tomasetti ◽  
Hagop M. Kantarjian ◽  
Ritesh Ramchandani ◽  
Elias Jabbour ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Cancer Center ◽  
First Line ◽  
Number Of Patients ◽  
Significant Difference

Abstract Abstract 4436 Background: The development of drug resistance remains a problem for some chronic myeloid leukemia (CML) patients treated with tyrosine kinase. Point mutations are the main mechanism behind drug resistance, and they can occur prior to therapy. Thus, there may be a positive correlation between the baseline BCR-ABL levels and the occurrence of drug resistance. Methods: We define a “relapse/no-response” as a BCR-ABL/ABL transcript ratio of >10% (international scale) at 6 months or later during continuous dasatinib treatment. Statistical analysis is performed an all early chronic phase CML treated with dasatinib as first-line therapy (n=102) in a prospective clinical trial at the M.D. Anderson Cancer Center. The probability of having drug resistant leukemic cells already present at diagnosis is also estimated. Results: Seven of the 90 (7.8%) evaluable patients had a “relapse/no-response”. The mean (median) BCR-ABL/ABL transcript ratio at baseline for the “relapse/no-response” group was 23.3% (20.7%), while for the rest of the patients was 14.1% (9.9%), a statistically significant difference. The incidence rates of “relapse/no-response” for patients with a BCR-ABL/ABL transcript ratio at baseline equal to or larger than 20% was 13.8%, versus 7.8% overall for the entire dataset. Our estimates suggest that if the therapy were to be started on average one month earlier, the probability of a “relapse/no-response” would decrease from 7.8% to 6.9%. Conclusions: The BCR-ABL transcript levels at baseline are significantly higher for those patients later incurring in a “relapse/no-response”. Moreover, our estimates suggest that starting the treatment as soon as possible after diagnosis may be critical for reducing the number of patients developing drug resistance. Disclosures: Kantarjian: Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; Bristol-Myers Squibb: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

scholarly journals Prognostic Value of Multi-Drug Resistance 1 Gene (MDR1) Expression in Newly Diagnosed Patients with Chronic Myeloid Leukemia on Nilotinib Treatment—a Subanalysis of the ENEST1st Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3144-3144 ◽  
Author(s):  
Christian Dietz ◽  
Michael Lauseker ◽  
Benjamin Hanfstein ◽  
Philippe Rousselot ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Multi Drug Resistance ◽  
Newly Diagnosed ◽  
First Line ◽  
Molecular Responses ◽  
Expression Levels ◽  
Mdr1 Expression

Abstract Introduction MDR1 gene expression has recently been reported to be associated with clinical outcome in imatinib-resistant patients with chronic myeloid leukemia (CML) on second-line nilotinib treatment (Agrawal et al., Leukemia 2014). High MDR1 expression was predictive for achieving deeper cytogenetic and molecular responses as well as duration of chronic phase. We thus prospectively evaluated the value of MDR1 expression analysis in the first-line situation within a large European, multicenter trial of CML patients under treatment with nilotinib. Methods 305 patients enrolled on the ENEST1st study (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment, NCT01061177) consented to participate in this substudy. Of these, 225 patients were evaluable due to sample availability and presence of typical e14a2 and/or e13a2 BCR-ABL1 transcripts. The median age was 52 (range 18-83), 39% were female. Prior to therapy, the expression of MDR1, BCR-ABL1, and GUSB were determined using a serial dilution of a plasmid constructs harboring MDR1 and GUSB and BCR-ABL1 and GUSB sequences. Ratios MDR1/GUSB and BCR-ABL1/GUSB were calculated. ROC curves were established using initial MDR1 and BCR-ABL1 expression levels aiming to achieve the primary endpoint of MR4 (defined as BCR-ABL1 ≤ 0.01% on the International Scale [BCR-ABL1IS] or undetectable BCR-ABL1 in cDNA with ≥ 10,000 ABL1 transcripts) at 18 months or to achieve a MMR (≤ 0.1% BCR-ABL1IS) at 9 months. Mann-Whitney tests have been applied using a significance level of 0.05. Results At 9 months, 161 patients (72%) achieved MMR and at 18 months 111 patients (49%) a MR4. The median ratio MDR1/GUSB among all evaluable patients was 11.4% (range, 0.6-318.1), the median ratio BCR-ABL1/GUSB was 22.2% (range 0.09-198.7). Initial BCR-ABL1/GUSB levels did not predict MMR or MR4 at 9 or 18 months. However, initial ratios MDR1/GUSB were predictive for the achievement of MMR at 9 months (best cut-off 3.8%, sensitivity 88.8%, specificity 26.6%, AUC 0.598, p=0.022) and for reaching MR4 at 18 months (best cut-off 7.90%, sensitivity 72.1%, specificity 51.8%, AUC 0.624, p=0.001). Conclusions High MDR1 expression levels in newly diagnosed CML patients appear to be associated with deeper molecular responses within the first 18 months of nilotinib treatment. These data merit further exploration and if validated would justify the investigation of frontline CML therapy guided by baseline MDR1 expression levels. Disclosures Dietz: Novartis: Research Funding. Hanfstein:Bristol-Myers Squibb: Honoraria; Novartis: Research Funding. Rousselot:Novartis: Research Funding. Lange:Novartis: Consultancy, Honoraria, Research Funding. Maier:Novartis: Research Funding. Foroni:Novartis: Research Funding. Gerrard:Novartis: Research Funding. Talmaci:Novartis: Research Funding. Janssen:Novartis: Research Funding. Frank:Novartis: Employment. Saussele:Pfizer: Honoraria, Travel, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other. Giles:Novartis: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Müller:Novartis: Honoraria, Research Funding.

scholarly journals First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY

2017 ◽  
Vol 92 (11) ◽  
pp. 1214-1223 ◽  
Author(s):  
Stuart L. Goldberg ◽  
Jorge E. Cortes ◽  
Carlo Gambacorti-Passerini ◽  
Rüdiger Hehlmann ◽  
H. Jean Khoury ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Routine Clinical Practice ◽  
Treatment Selection ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

BCR-ABL Fusion Transcript Do Not Significantly Influence the Outcome of Chronic Myeloid Leukemia Patients In Early Chronic Phase Treated with Imatinib Mesylate: a GIMEMA CML WP Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1230-1230
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Fusion Transcript ◽  
Advisory Committees ◽  
Free Survival

Abstract Abstract 1230 Background: Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL fusion gene. Different types of BCR-ABL transcripts can be found, due to different genomic breakpoints and alternative splicing. The most frequent transcripts are the e13a2 (b2a2) and the e14a2 (b3a2), that codify for a p210 protein. Occasionally, both transcripts may be present. In the imatinib (IM) era, few data about the prognostic significance of the transcript type are available, particularly in the setting of early chronic phase (ECP): one study suggested that patients with the b2a2 transcript may be more sensitive to IM (de Lemos et al. Genet Mol Res 2005), while two larger studies suggested that patients with b3a2 transcript may have better responses to IM (Vega-Ruiz et al. ASH 2007; Lucas et al. Haematologica 2009). No systematic evaluations in the context of large prospective clinical trials have been performed. AIM: To investigate the influence of the type of BCR-ABL fusion transcript on the responses and the outcome of CML patients treated with IM in ECP. Methods: We performed an analysis of 3 concurrent clinical trials of the GIMEMA CML Working Party (Clin Trials Gov. NCT00514488, NCT00510926 and the observational trial CML/023). Response monitoring was based on conventional cytogenetic examination (bone marrow) and quantitative molecular (Q-PCR) evaluation (peripheral blood). Definitions: Complete Cytogenetic Response (CCgR): 0% Ph+; Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1% (International Scale); failures: according to the revised European LeukemiaNet criteria (Baccarani et al. J Clin Oncol 2009). Results: 559 consecutive CML patients in early CP have been enrolled from January, 2004 to January, 2007. Patients expressing rare transcript types (e1a2 and e19a2) and patients with the presence of both b2a2 and b3a2 transcripts were excluded: 493 out of 559 patients were evaluable, 203 (41%) with a b2a2 transcript and 290 with a b3a2 transcript (59%). The 2 groups were comparable (no significant difference in sex, age, Sokal and Hasford scores, clonal chromosomal abnormalities in Ph+ cells before IM and imatinib dose). The median observation time is currently 60 (extremes 2–80) months. In patients with b2a2 and b3a2 transcript, the observed 12-months CCgR rates were 77% and 80%, respectively; the cumulative incidence of CCgR was 89% and 88%, respectively (no significant differences). The time to MMR was significantly shorter for patients with b3a2 transcript (fig.1), but the cumulative incidence of MMR was not significantly different (81% and 86% in patients with b2a2 and b3a2 transcript, respectively). The probabilities of Failure-Free Survival, Progression-Free Survival and Overall Survival were 69% and 75%, 83% and 89%, 87% and 92% in patients with b2a2 and b3a2 transcript, respectively (fig. 1); no difference was statistically significant. Conclusions: In our experience, based on 493 early CP CML patients treated frontline with IM, the type of BCR-ABL fusion transcript had no relevant prognostic impact and no outcome differences have been observed so far. Acknowledgments: Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: Castagnetti: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Saglio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

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