Characteristics of Patients with Chronic Myelogenous Leukemia in Chronic Phase Switched to Nilotinib or Dasatinib As Second-Line Therapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4447-4447
Author(s):  
Alexander R. Macalalad ◽  
Lei Chen ◽  
Annie Guerin ◽  
Jiayuan Luo ◽  
Eric Qiong Wu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Myelogenous Leukemia ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Chronic Phase ◽  
Patient Characteristics ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Analysis Group ◽  
Line Therapy

Abstract Abstract 4447 Background: Since 2007, nilotinib and dasatinib have been available for 2nd-line therapy for patients with chronic myelogenous leukemia in chronic phase (CML-CP) who are resistant or intolerant to imatinib. In clinical trials, both drugs have been shown to be effective and safe, but with different side-effect profiles. Currently, little is known about the characteristics of patients who are switched to nilotinib or dasatinib in a real-world setting. Methods: Through an online chart abstraction form, participating community physicians retrospectively submitted de-identified information on CML-CP patients ≥ 18 years old who switched after 10/28/2007 from imatinib to either 2nd-line nilotinib or dasatinib and who had at least 30 days of follow-up. When multiple patients met the selection criteria, up to 8 patients from each group were selected randomly by physicians. Patients enrolled in clinical trials or with concurrent malignancies were excluded. Information on patient characteristics at the time of switching TKI therapy was collected, including age, sex, race, comorbidities, prior imatinib dosing, reasons for switching, and the dose regimen of nilotinib or dasatinib at initiation. Characteristics were compared between nilotinib and dasatinib patients using Wilcoxon and chi-square tests. Results: 122 hematologists and oncologists provided information on 597 patients (301 on 2nd-line nilotinib and 296 on 2nd-line dasatinib). The table below summarizes the comparisons of the two groups. Both groups had similar age, sex, race, and comorbidity profile. Nilotinib patients were more likely than dasatinib patients to have had secondary imatinib resistance (p=0.047), more likely to have received a maximum imatinib dosing of 600 or 800 mg/day (p=0.006), and less likely to have switched due to imatinib intolerance (p=0.024). Conclusions: Patients switched to nilotinib vs. dasatinib had similar demographic and clinical characteristics at the time of switch, but nilotinib patients were more likely to have had an imatinib dose increase before the switch, and were more likely to have had secondary imatinib resistance. Patients switched to nilotinib vs. dasatinib were also less likely to have had imatinib intolerance. These findings suggest that resistance or intolerance to imatinib therapy have had more impact than patient demographics or clinical characteristics in deciding which drug to use for 2nd-line therapy. Disclosures: Macalalad: Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Luo:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Griffin:Novartis: Consultancy, Research Funding.

Comparison of Disease Outcomes for Patients with Chronic Myelogenous Leukemia in Chronic Phase Switched to Nilotinib or Dasatinib As Second-Line Therapy.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2796-2796
Author(s):  
James D. Griffin ◽  
Annie Guerin ◽  
Lei Chen ◽  
Alexander R. Macalalad ◽  
Jiayuan Luo ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Characteristics ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Free Survival ◽  
Analysis Group ◽  
Line Therapy

Abstract Abstract 2796 Background: Nilotinib and dasatinib are two tyrosine kinase inhibitors (TKIs) commonly used for the treatment of patients with chronic myelogenous leukemia in chronic phase (CML-CP) who are resistant or intolerant to imatinib. Both TKIs have been shown to be more potent than imatinib. However, no head-to-head clinical trials have been conducted comparing the efficacy of nilotinib to dasatinib as 2nd-line therapy for CML-CP patients resistant or intolerant to imatinib. This study compared disease outcomes of patients treated in the community who were switched from imatinib to 2nd-line nilotinib or dasatinib. Methods: Through an online chart abstraction form, participating community physicians submitted de-identified information on CML-CP patients ≥ 18 years old who switched after 10/28/2007 from imatinib to 2nd-line nilotinib or dasatinib with at least 30 days of follow-up. When multiple patients met the selection criteria, up to 8 patients in each group were selected randomly by physicians. Patients enrolled in clinical trials or with concurrent malignancies were excluded. Information was collected on demographics, clinical characteristics, cytogenetic response, progression to accelerated phase or blast crisis, and death from any cause. Documented complete cytogenetic response (CCyR) at a particular time point was defined as 0% Philadelphia chromosome positive cells on cytogenetic testing; patients with missing tests at that time point were counted as non-responders. Disease progression to accelerated phase or blast crisis, progression-free survival, and overall survival were compared using multivariate Cox proportional hazards models, adjusting for potential confounding factors, including patient demographics and clinical characteristics at the time the patient switched to a 2nd-line TKI. Results: 122 hematologists and oncologists provided information on 597 patients, including 301 patients on nilotinib and 296 patients on dasatinib. The median follow-up was 11 months for nilotinib patients and 10 months for dasatinib patients. Age, sex, race, comorbidities, and other clinical characteristics were similar for both groups, except that nilotinib patients were more likely than dasatinib patients to have switched due to secondary imatinib resistance (p=0.047) and were less likely to have switched due to imatinib intolerance (p=0.024). Nilotinib patients had similar rates of documented CCyR compared to dasatinib patients at 12 months (37% vs. 35%, p=0.54), 24 months (42% vs. 40%, p=0.62), and 36 months (44% vs. 44%, p=0.95) following the switch. However, nilotinib patients had lower risk of progression (p=0.004), higher progression free survival (p=0.023) and a trend towards prolonged overall survival (p=0.067), adjusting for potential confounders. The table below summarizes these results. Conclusions: Among patients with CML-CP switched to nilotinib or dasatinib for 2nd-line therapy, nilotinib patients had significantly lower rates of progression and longer progression-free survival compared to dasatinib patients. Disclosures: Griffin: Novartis: Consultancy, Research Funding. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Luo:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.

Comparison of Treatment Changes for Patients with Chronic Myelogenous Leukemia in Chronic Phase Switched From Imatinib to Nilotinib or Dasatinib As Second-Line Therapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4443-4443
Author(s):  
Alexander R. Macalalad ◽  
Lei Chen ◽  
Annie Guerin ◽  
Jiayuan Luo ◽  
Eric Qiong Wu ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Treatment Change ◽  
Satisfactory Response ◽  
Analysis Group ◽  
Line Therapy ◽  
Treatment Changes

Abstract Abstract 4443 Background: Nilotinib and dasatinib are two therapies approved by the US Food and Drug Administration for pts with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to 1st-line imatinib. Although these therapies were shown to be generally effective and tolerable, sometimes they are not, requiring treatment changes (e.g., discontinuation, dose modification, and drug holidays). To date, no head-to-head study has been conducted to compare treatment changes between 2nd-line nilotinib and dasatinibin clinical practice. Methods: Through an online chart abstraction form, participating community physicians retrospectively submitted de-identified information on Ph+ CML-CP pts ≥ 18 years old who switched after 10/28/2007 from imatinib to 2nd-line nilotinib or dasatinibwith at least 30 days of follow-up. When multiple pts met the selection criteria, pts were selected randomly by physicians. Pts enrolled in clinical trials or with concurrent malignancies were excluded. Information was collected on clinical characteristics and therapy changes in 2nd-line treatment, including dose modification (increase or decrease), drug holiday, and discontinuation of current therapy with or without switch to a 3rd-line therapy. Reasons for therapy changes were also collected, and treatment changes were classified as due to (1) lack of effectiveness if reasons included progression to accelerated phase or blast crisis, failure to achieve satisfactory response, or loss of satisfactory response; (2) intolerance if reasons included adverse events; (3) other reasons, including non-adherence, vacation, pregnancy, or economic reasons. Rates of treatment changes were compared between treatment groups using chi-square tests. Results: 122 hematologists and oncologists provided information on 597 pts (301 nilotinib pts and 296 dasatinib pts). The median follow-up was 11 months (range 1–54 months) for pts on nilotinib and 10 months (range 1–56 months) for those on dasatinib. The two groups had similar age, sex, race, and comorbidities. Overall, treatment change was infrequent for both nilotinib and dasatinib patients (10% vs. 13%, p=0.40), but nilotinib pts had significantly fewer dose increases vs. dasatinib pts (0.0% vs. 1.4%, p=0.04), and they tended to have fewer drug holidays (1.7% vs. 4.4%, p=0.05). When treatment changes were classified by reason for change, nilotinib pts were less likely to change treatment due to lack of effectiveness vs. dasatinib pts (2.0% vs. 5.1%, p=0.04). Further, among pts who discontinued, fewer nilotinib pts discontinued due to lack of effectiveness (29% vs. 61%, p=0.03). Nilotinib and dasatinib pts had similar rates of treatment changes due to intolerance or other reasons, except for drug holiday, where nilotinib pts had fewer events than dasatinibpts (0% vs. 1.7%, p=0.02). The table below summarizes the changes in treatment by reason for treatment change. Conclusions: For Ph+ CML-CP pts on 2nd-line nilotinib or dasatinib, pts on nilotinib were less likely than those on dasatinibto change treatment due to lack of effectiveness. Disclosures: Macalalad: Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Luo:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Griffin:Novartis: Consultancy, Research Funding.

Cost-Effectiveness Analysis in Canada of Dasatinib Versus Imatinib for the Treatment of Chronic Myelogenous Leukemia in Patients with Imatinib Resistance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3328-3328
Author(s):  
Jennifer C. Sambrook ◽  
Denise Zou ◽  
Matthew J. Taylor ◽  
Catherine C. Davis ◽  
Alexandre Joyeux ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Lifetime Cost ◽  
Chronic Phase ◽  
Cost Utility ◽  
Myelogenous Leukemia ◽  
Sensitivity Analyses ◽  
High Dose ◽  
Imatinib Resistance

Abstract Objective: To estimate the cost-utility of dasatinib versus high-dose imatinib (HDI, imatinib 800mg/day) for chronic myelogenous leukemia (CML) in patients with resistance to imatinib at standard doses. Methods: We adapted to the Canadian setting a Markov model with a monthly cycle length that followed hypothetical patients until death. Cost effectiveness was evaluated during three phases of CML: chronic (86% of Ontario patients in 2006), accelerated (9%) and blast crisis (5%). Efficacy of dasatinib and HDI (cytogenetic and hematologic response) and adverse events (AEs) were taken from randomized trials. Canadian costs of medications, laboratory tests, professional fees, hospitalizations, and AEs were obtained from published sources. Societal utility scores were estimated from a Canadian time trade-off study. Analyses were performed from the perspective of the Ontario Ministry of Health. Costs (2006 CDN$) and outcomes (QALYs) were discounted at 5% annually after the first year. Univariate and probabilistic sensitivity analyses were carried out to quantify uncertainty for the incremental cost-effectiveness ratios (ICERs). Results: Dasatinib dominated HDI in chronic phase patients with additional QALYs (3.92 vs. 3.47) and a lower lifetime cost ($379,678 vs. $444,934). The ICERs of dasatinib vs. HDI in accelerated and blast phase were $88,098/QALY and $173,922/QALY respectively. The higher cost/QALY of dasatinib in the advanced phases is explained primarily by the increased predicted survival of dasatinib patients and therefore the longer duration of drug therapy for these patients. Parameters with the greatest influence on results were the time horizon, drug costs and utility values. The interpretation of results remained robust in univariate and probabilistic sensitivity analyses. Conclusion: From an economic perspective dasatinib is an attractive treatment choice for the majority of imatinib resistant CML patients and provides better value for money than HDI.

Effect of Time to Dasatinib Initiation On Outcome of Imatinib-Intolerant Patients with Chronic-Phase Chronic Myelogenous Leukemia (CP-CML): Results From a European Observational Study (FORTE; CA180–211)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1689-1689
Author(s):  
David Marin ◽  
Enrica Morra ◽  
Mauricette Michallet ◽  
Andrzej Hellmann ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
Observational Study ◽  
Board Of Directors ◽  
Chronic Myelogenous Leukemia ◽  
Research Funding ◽  
Real Life ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Advisory Committees ◽  
Best Response ◽  
Observation Period

Abstract Abstract 1689 Background: Approximately half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) fail imatinib treatment, both in interventional (Deininger et al., Blood 2009 114: abstract 1126) and observational trials (Michallet et al., Curr Med Res Opin 2010;26(2): 307–17), primarily due to the development of resistance and/or toxicity (Kantarjian and Cortes. J Clin Oncol 2011; 29(12): 1512–16). Clinical evidence suggests that optimal outcomes are achieved when dasatinib is administered early after imatinib failure (Quintas-Cardama et al., Cancer 2009;115(13): 2912–21); however, limited data are available regarding outcome of patients intolerant to imatinib in the real-life setting. Aims: FORTE (Factors impacting On Response To dasatinib in Europe) is a European observational study that aims to estimate the relationship between time elapsed from first detection of imatinib resistance/intolerance until initiation of dasatinib and best response to dasatinib, adjusted for other potentially explanatory factors. Methods: Data were collected retrospectively and prospectively from medical records. Best response to dasatinib, as recorded in patient's charts, was reported by an ordered categorical variable, combining all types of response achieved by a patient and selecting the “highest” level. A predefined list of covariates (sex; age at dasatinib initiation; time from diagnosis to dasatinib initiation; best response to prior imatinib and last imatinib dose) were entered/removed in a Proportional Odds model to identify factors potentially influencing dasatinib best response over a 12-month observation period. Results presented here focus on the imatinib-intolerant subpopulation. Results: FORTE enrolled 549 adult patients with imatinib-resistant/intolerant CP-CML at 124 sites across 12 European countries. Of 457 eligible patients, 176 (39%) were imatinib intolerant, including 71 (16%) who were both resistant and intolerant to imatinib. Approximately half (47%) of intolerant patients were male. Median age at dasatinib initiation was 59 years and median times from CML diagnosis to imatinib and dasatinib initiation were 1.5 and 39.8 months, respectively. Sokal and Hasford scores were intermediate/high in 74% and 72% of assessed patients, respectively. Overall, 54% of 171 imatinib-intolerant patients had achieved a complete cytogenetic response (CCyR) or major molecular response (MMR) on imatinib. During the 12 month observation period, 72% of imatinib-intolerant patients achieved a CCyR or MMR with dasatinib. Adjusting for the effect of best imatinib response, an analysis of 161 evaluable patients showed strong statistical evidence (p<0.0001) that shortening the time elapsed between imatinib intolerance and dasatinib initiation was more likely to result in a better response to dasatinib (including CCyR/MMR), with an estimated odds ratio of 0.96 [95% CI: 0.943–0.977]. Conclusions: Results from the imatinib-intolerant population of the FORTE study suggest that an early switch to dasatinib provides a clinical advantage to CP-CML patients intolerant to imatinib. Findings from this real-life observation are consistent with data from interventional trials. Disclosures: Marin: Bristol-Myers Squibb: Research Funding. Morra:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen Cilag: Speakers Bureau. Niederwieser:Bristol-Myers Squibb: Speakers Bureau. Schloegl:AOP Orphan: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ho:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Ossenkoppele:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Guerra:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Mori:Bristol-Myers Squibb: Employment. Pans:Bristol-Myers Squibb: Employment. van Baardewijk:Bristol-Myers Squibb: Employment. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau.

Clinical Significance of Myelosuppression Associated with the Use of Dasatinib and Nilotinib As Initial Therapy in Chronic Phase (CP) of Chronic Myeloid Leukemia (CML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2761-2761
Author(s):  
Theresa Liu-Dumlao ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Clinical Significance ◽  
Research Funding ◽  
Chronic Phase ◽  
Patient Characteristics ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2761 Background: Frontline treatment with tyrosine kinase inhibitors (TKIs) has improved prognosis for patients with chronic myelogenous leukemia (CML). Myelosuppression is the most common adverse event (AE) seen during therapy with frontline second generation TKIs, dasatinib and nilotinib. The impact that grade 3/4 myelosuppression has on future outcome has not been described. Aim: To define the patient characteristics and clinical significance of myelosuppression associated with the use of dasatinib or nilotinib as initial therapy for CML. Methods: From August 2005, 204 patients (pts) diagnosed with CML-CP were treated with dasatinib (n=99) or nilotinib (n=105) in parallel trials. Prior imatinib exposure of less than 4 weeks was allowed. Complete blood counts (CBC) and differentials were done weekly in the first month, every 1–2 months up to the first year, every 3–4 months in the second year, and every 4–6 months thereafter. Results: A total of 44 (42%) pts developed grade 3/4 myelosuppression (MS) defined under CTCAE v4.0 criteria as hemoglobin (Hb)<8g/dL (n=5), absolute neutrophil count (ANC)<1×109/L (n=32), and platelet count (Plt)<50×109/L (n=21); 12 (30%) developed more than one cytopenia. MS occurred in 30 pts on dasatinib (anemia 13%, neutropenia 73%, thrombocytopenia 40%), and 14 pts on nilotinib (7%,71%,64%, respectively). Comparing patient characteristics between those who experienced myelosuppression vs. no myelosuppression, there was no significant difference in age, prior imatinib therapy, percent Ph positivity, or baseline hematologic parameters. There was a trend for more pts in the intermediate Sokal risk category among pts with MS. Of the 44 patients with MS, 39 (89%) experienced the event for the first time within 3 months from initiation of therapy. Five (11%) experienced the event after the first 3 months of treatment: 2 eventually came off study (one for resistance and the other for disease progression, both on nilotinib), and 3 (all on dasatinib) continued on therapy, able to achieve CMR. Complications associated with MS included hospitalization in 2 pts (one for pneumonia, and another for flu and prolonged QTc); 6 (14%) required antibiotics; 2 (5%) required blood transfusions; and 2 (5%) required growth factors (erythropoietin). MS led to TKI dose reduction in 9% of all pts treated (41% of those with MS), including 13% of those on dasatinib, and 5% of those on nilotinib. Dose reduction resolved MS in most instances. Recurrence of MS was seen in 10 pts, 2 of whom had progression of disease to blast phase/AML. The outcome of pts with MS is described in table 1 compared to those without MS. Patients with MS had a significantly lower rate of CCyR, MMR, CMR and EFS compared to those without MS. Conclusion: MS is a common AE among pts receiving therapy with dasatinib or nilotinib as initial therapy for CML that frequently leads to dose reductions, and is associated with an inferior outcome. Whether the worse outcome reflects decreased dose intensity, or whether the outcome and decreased tolerance to therapy reflect an intrinsic difference in disease biology remains to be determined. Disclosures: Kantarjian: BMS: Research Funding; Novartis: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Jabbour:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Analysis of Molecular Data and the Emergence of Mutations for Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) Patients Treated with Dasatinib After Imatinib Failure.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3282-3282
Author(s):  
Susan Branford ◽  
Andreas Hochhaus ◽  
Martin Mueller ◽  
Erkut Bahceci ◽  
Lynn Ploughman ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Second Line ◽  
Imatinib Resistance ◽  
Mutation Status ◽  
New Mutations

Abstract Abstract 3282 Poster Board III-1 The kinase inhibitor dasatinib has demonstrated efficacy in patients with CML-CP who fail imatinib due to resistance or intolerance. Imatinib failure is often associated with the acquisition of resistant mutations within BCR-ABL. Failure of dasatinib is associated with a limited spectrum of mutations, which are T315I/A, V299L, and F317L/I/V, suggesting these mutations are dasatinib resistant (DR). Only a fraction of patients with T315I respond to dasatinib, most patients with F317L have hematologic responses but few have cytogenetic responses, and V299L is uncommon in imatinib-resistant patients but is mostly seen after dasatinib failure. In vitro data suggests Q252H and E255K/V also confer a degree of dasatinib resistance. However, their clinical association with dasatinib resistance or inferior response is unclear. This retrospective analysis seeks to determine if the mutation status at the start of dasatinib impacts the initial molecular response, and to examine the type of mutations lost and gained during therapy. To assess the significance of intermediate sensitivity (DI) mutations (Q252H and E255K/V), BCR-ABL levels were measured against the International Scale (IS), and mutation status was assayed at initiation of dasatinib (baseline), at progression, or study termination or completion (progression/completion). Data were taken from 479 patients with CML-CP treated with dasatinib 70 mg twice daily, after imatinib failure for the phase II START-C or -R studies. Patients were grouped according to their baseline mutation status: DR, DI, dasatinib sensitive (DS, all other mutations not DR or DI), and no mutations. Patients with more than one mutation at baseline that qualified for more than one grouping were rare, and classified according to the most resistant mutation. By 6 months of dasatinib therapy, patients with DR mutations at baseline had the highest levels of BCR-ABL transcripts (Table 1). By comparison, those with DI, DS, or no mutations had a reduced proportion with high transcript levels. In addition, no patients with DR at baseline achieved a reduction of BCR-ABL by 6 months to IS ratio < 1, whereas significant reductions were identified in patients with DI, DS, or no mutations. A subset of 267 patients had mutation analysis performed at progression/completion. Of these, 115 had mutations at baseline and 152 had no mutations. The patients with baseline imatinib resistance were more likely than those with imatinib intolerance to acquire new mutations. Of the resistant patients with no mutations at baseline, 7% (9/124) developed new mutations and the majority (7/9) was DR. Among resistant patients with baseline mutations, 23% (26/112) had new mutations and the majority was DR (20/26). Although 36 patients gained new mutations (including 16 T315I/A, 8 F317L, and 6 V299L), many baseline mutations were no longer detectable at progression/completion. DS mutations were lost in 68/102 patients. In total, 76 patients had detectable mutations at progression/completion, with 51% (39/76) having DR mutations but only 5% (4/76) with DI mutations. Patients with baseline DR mutations were more likely to retain their DR mutations (11/13). Of 8 patients with DI mutations at baseline, only 3 retained their DI mutations and 3 gained DR mutations. Of 94 patients with only DS mutations at baseline, 36 (38%) retained their DS mutations, and 17 (18%) developed DR mutations. Patients with high levels of BCR-ABL at 3 months had the highest incidence of new DR mutations at progression/completion (18/145 evaluable patients; 12%) compared to patients with lower levels (5/79; 6%). In conclusion, the development of new mutations during second-line dasatinib is rare (36/267). Patients who harbored DI mutations at baseline were also rare, and an expanded prospective analysis of dasatinib efficacy in this cohort may be necessary to clarify their significance. However, from the current analysis there is no compelling clinical evidence to suggest that these patients have an inferior molecular response. Relative to DR mutations, the DI mutations (Q252H and E255K/V) were rarely present at progression/completion. Patients with baseline mutations and 6-month BCR-ABL transcript level after second-line dasatinib IS ratio ≤ 1.0 1 < IS ratio ’ 10 IS ratio > 10 DR 0% (0/13) 23% (3/13) 77% (10/13) DI 56% (5/9) 0% (0/9) 44% (4/9) DS 36% (46/128) 20% (25/128) 45% (57/128) No mutations 42% (92/221) 18% (40/221) 40% (89/221) Disclosures: Branford: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Ploughman:Bristol-Myers Squibb: Employment. Mukhopadhyay:Bristol-Myers Squibb: Employment. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Frequency of Molecular Monitoring Correlates with Long Term Outcomes in Chronic Phase Chronic Myelogenous Leukemia Treated with First-Line Imatinib: Results of a Community Survey

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1685-1685
Author(s):  
Stuart L. Goldberg ◽  
Lei Chen ◽  
Solveig G. Ericson ◽  
Alexander R. Macalalad ◽  
Annie Guerin ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Myelogenous Leukemia ◽  
Molecular Monitoring ◽  
First Line ◽  
Free Survival ◽  
Analysis Group ◽  
Cytogenetic Testing ◽  
Sokal Score

Abstract Abstract 1685 Background: Molecular monitoring is recognized as an important part of evaluating treatment response in Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP). The latest guidelines from the National Comprehensive Cancer Network (NCCN) recommend quantitative polymerase chain reaction (QPCR) testing in the first 3 months with a goal of <10% Bcr-Abl transcripts using the international scale (IS), and then testing every 3 months to achieve at some point and maintain a 3 log reduction in transcripts (Major Molecular Response). Regular molecular monitoring provides an opportunity to detect resistance or adherence problems early. However, it remains unknown how patterns of use of molecular monitoring impact long term outcomes in non-research community settings. Methods: Community physicians who treat CML patients were invited to retrospectively submit information on Ph+ CML-CP patients in their practice who were ≥18 years old when started on first-line imatinib between 2006–2011 and who had ≥6 months of follow-up. Patients enrolled in clinical trials were excluded. Clinical characteristics at treatment initiation were collected. For each 3 month period after treatment initiation while the patient was on tyrosine kinase inhibitor (TKI) therapy, information was collected on molecular monitoring performed to assess treatment response. Information on death and progression to accelerated phase or blast crisis was collected over the entire follow-up period. Patients were grouped by the average number of QPCR tests received on TKI therapy (scaled to rate per year): the 0 tests group if they never had a QPCR test; the 1–2 tests group if they had on average more than 0 but 2 or less QPCR tests/year; and the 3–4 tests group if they had on average more than 2 but 4 or less QPCR test/year. Progression, mortality, and combined progression/mortality rates were reported for each group. In addition, Cox proportional hazards models were used to test the association between progression and progression-free survival and the average number of QPCR tests per year, controlling for the average number of cytogenetic tests per year, and for potential confounders including age, race, initial imatinib dose, Sokal score, and enlarged spleen at diagnosis. Results were reported as hazard ratios (HR) with 95% confidence intervals (CI). Results: 38 hematologists and oncologists from community practices throughout the US submitted information on 402 patients initiated on first-line imatinib. Patients were followed retrospectively for a median duration of 36 months. Of these, 52 (13%) had no molecular monitoring, 164 (41%) had 1–2 tests/year, and the remaining 186 (46%) had 3–4 tests/year. The figure below shows progression, mortality, and progression/mortality by frequency of molecular testing. The progression/mortality rates tended to decrease with the number of tests received. Adjusting for cytogenetic testing frequency and potential confounders aside from the Sokal score, a higher average number of QPCR tests per year was significantly associated with a lower rate of progression and longer progression-free survival. Each additional QPCR test per year significantly decreased the risk of progression by 45% (HR=0.55; CI [0.35, 0.87], p=0.011), and progression/mortality by 48% (HR=0.52; CI [0.35, 0.79], p=0.002]. Since 48% of patients did not have a reported Sokal score at diagnosis, a separate analysis was done to also adjust for the Sokal score among those without missing data, with nearly identical results. Conclusions: Ph+ CML-CP patients who underwent QPCR testing every 3–4 months experienced decreased progression and longer progression-free survival compared to those patients monitored less frequently, with the impact of molecular monitoring being independent of the frequency of cytogenetic testing. It is possible that molecular monitoring identifies impending treatment failure earlier and enables adjustment of therapy before hematologic and cytogenetic failure occur. This analysis underscores the value of molecular monitoring every 3 months for Ph+ CML-CP patients on TKI therapy and also demonstrates that a significant number of Ph+ CML-CP patients are not undergoing QPCR at the frequencies recommended in published guidelines. Additional community based education on CML monitoring is needed to assure optimal outcomes. Disclosures: Goldberg: Novartis Oncology: Research Funding, Speakers Bureau. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Own stock in Novartis Other. Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Liu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Kaminsky:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.

Pegylated Interferon-α 2a in Combination to Nilotinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Provides High Rates of MR4.5. Preliminary Results of a Phase II Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 166-166 ◽  
Author(s):  
Franck E. Nicolini ◽  
Gabriel Etienne ◽  
Viviane Dubruille ◽  
Lydia Roy ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Chronic Phase ◽  
Pegylated Interferon ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Front Line ◽  
Molecular Responses ◽  
Line Therapy ◽  
Grade 3

Abstract Abstract 166 Background Imatinib mesylate combined to pegylated interferon alfa 2a (Peg-IFN) has been reported to significantly enhance the molecular responses for de novo chronic phase chronic myeloid leukemia (CP-CML) patients compared to Imatinib alone in a Phase 3 study (Preudhomme et al. NEJM 2010). Second generation tyrosine kinase inhibitors (TKI2) such as nilotinib induce significantly higher levels of cytogenetic and molecular responses than imatinib as front line therapy for CP-CML (Saglio et al., NEJM 2010). Aims Test the combination of nilotinib + Peg-IFN as front line therapy in CP-CML patients in order to check the safety and evaluate the molecular response rates (EudraCT 2010–019786–28). Methods In this 2-step French national study, patients were assigned first to Peg-IFN (± HU) for a month at 90 mg/wk prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 mg/wk for ≥ 1 year. The primary endpoint was the rate of confirmed (on 2 datapoints) molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in %. Results In the first cohort, 40+1 patients (1 screen failure) were enrolled and a second cohort of 20 patients was planned once the last patient of cohort 1 attained 1 year of treatment, if the primary endpoint would have not been reached. The current median follow-up is 13.6 (10.1–16.3) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. Euro score was high for one patient. The median age was 53 (23–85) years. Two patients had a masked Philadelphia chromosome, 3 a variant form, and 1 had additional chromosomal abnormalities, all patients had a “major” BCR transcript. Five percent of patients were in CHR at 1 month of Peg-IFN and 100% at month (M) 2 (after 1 month of combination therapy). The rates of Complete Cytogenetic Responses (CCyR) at 3, 6, and 12 months of combination (i. e. at 2, 5, 8 and 11 months of TKI2) were 47%, 71%, 100% respectively on evaluable samples. The incidence of molecular responses are mentioned in figure 1. Of note, 87% of the patients had a BCR-ABLIS ≤10% at M3. The rates of molecular responses broke down by major molecular response (MMR): 27%, 4 log reduction (MR4): 36%, and ≥4.5 log BCR-ABL reduction (MR4.5, MR5 and undetectable): 21% with a total number of 84% patients in ≥MMR and beyond (17.5% and 67.5% in intention-to-treat respectively) at 1 year. Confirmed molecular results at 1 year will be presented. Nilotinib trough levels centrally analysed at M3, 6 and 12 for the vast majority of patients were ≥ 1000 ng/ml and Peg-IFN did not seem to impact on its pharmacokinetics. One patient went on unmutated myeloid blast crisis at M6 and is alive after allogeneic stem cell transplantation. Four additional patients were withdrawn from study: At M2 for non observance, at M6 for seizures related to an extra-dural hematoma, at M6 for recurrent grade 3 hepatic toxicity, at M9 for recurrent grade 3 pruritus. The median dose of Peg-IFN delivered to the patients during the first month was 90 (0–180) mg/wk, 45 mg/wk at M2, 3, 9, 12, and 33.75 mg/wk at M6. The median doses of nilotinib delivered to the patients were 600 mg daily at M2, 3, 6, 9, 12 and 15 as initially planned. The rate of grade 3–4 hematologic toxicities overall were anemia 2.5%, thrombocytopenia 41%, neutropenia 41% and pancytopenia 5%. These were observed mainly during M2 (16% neutropenia, 24% thrombocytopenia, 3% anemia), M3 (16% neutropenia, 13% thrombocytopenia, 3% pancytopenia) and M6 (12.5% neutropenia, 5% thrombocytopenia) and disappeared thereafter. Grade 3–4 toxicities occurred mostly during the first 3 months with 15% cholestatic episodes, 5% of ALAT elevation, 2.5% of lipase elevation, 2.5% arthro-myalgias, 2.5% abdominal pain without lipase elevation, 2.5% of depression. No PAO was observed and, to date, no dyslipidemia. Conclusion The combination of nilotinib and Peg-IFN seems relatively well tolerated despite frequent initial and transient hematologic and hepatic toxicities, and provides very high rates of molecular responses at 1 year and beyond. According to the initial methodology of this trial, the second cohort of patients will not be enrolled as the MR4.5 rates at M12 are beyond the initial expectations. A randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is warranted. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy. Roy:Novartis, BMS: Speakers Bureau. Huguet:Novartis, BMS: Speakers Bureau. Legros:Novartis, BMS: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:Novartis, BMS: Speakers Bureau. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Rea:Novartis, BMS: Consultancy, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis, BMS: Speakers Bureau. Rousselot:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy, Speakers Bureau. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Speakers Bureau.

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