The Impact of Early Molecular Response in Event Free Survival in Patients with Chronic Myeloid Leukemia Treated with Imatinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5536-5536
Author(s):  
Laura Fogliatto ◽  
Marcelo Eduardo Zanella Capra ◽  
Mariza Shaan ◽  
Tito Vanelli Costa ◽  
Mayde Seadi Torriani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Molecular Response ◽  
Event Free Survival ◽  
Durable Response ◽  
Free Survival ◽  
The Impact

Abstract Background Monitoring response to TKI therapy is one of the key management strategies of chronic myeloid leukemia (CML). Early molecular response to first-line TKI therapy is emerging as an effective prognostic factor indicator of long-term durable response and survival. Objectives We conducted a study to evaluate the importance of the early molecular response (EMR) at 3, 6 and 12 months (mo), and 3-year event free survival (EFS). Methods This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 517 pts with CML-CP diagnosed since 1990. After a median observation time of 46 months, 5-year overall survival (OS) was 86% and 5-year event-free-survival was 53%. At 3 mo, EFS was 72,5% for 46 pts with BCR-ABLIS ≤10% compared to 58% for 14 pts with BCR-ABLIS >10% (p<0,07). Similarly, when EMR was analysed at 6 mo, the EFS was 81% for 75 pts with BCR-ABLIS ≤1%, while 31% of EFS was achieved for 38 pts with BCR-ABLIS >1% (p<0,001). At 12 mo, the 3-year EFS was 86% for 65 pts with with BCR-ABLIS ≤0,1% compared to 54% for pts with BCR-ABLIS>0,1% (p<0,001). Conclusions A significant proportion of pts achieve ERM after 3,6 and 12 mo of imatinib therapy with better 3-year EFS. ERM may could identify those pts more likely to have a favorable outcome. Disclosures No relevant conflicts of interest to declare.

Event-Free Survival According to Age in Patients with Chronic Myeloid Leukemia Receiving Imatinib Frontline: The Younger, the Later, the Worse?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4038-4038 ◽  
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Federico Vozella ◽  
Federico De Angelis ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Real Life ◽  
Age At Diagnosis ◽  
Molecular Response ◽  
Event Free Survival ◽  
Secondary Resistance ◽  
Free Survival

Abstract Differences in baseline features and follow-up among patients with chronic myeloid leukemia (CML) according to age at diagnosis have been recently reported in cohorts from clinical controlled trials (Castagnetti F et al, 2015). To evaluate this issue in a real-life setting, we revised 207 consecutive CML patients treated at our Institution with imatinib frontline from 6/2002 to 6/2013, dividing them in young adults (>20 <45 years) (YA), middle-aged adults (≥45 <65 years) (MA) and elderly (≥65 years) (EL). The main features at baseline of the whole cohort and of the 3 age groups are reported in the Table. Table.ALLYAMAELpN° of patients207617274M/F108/8930/3140/3238/360.752Median WBC (x 109/l)IQR66.1 (32.7 - 119.0)109.8 (65.9 - 148.0)59.5 (31.3 - 126.6)40.1 (26.5 - 81.4)<0.001Median Hb (g/dl)(IQR)12.5 (11.0 - 13.5)11.7 (9.8 - 12.7)12.7 (11.0 - 14.2)12.8 (11.3 - 13.7)0.002Median PLT (x 109/l)IQR414 (275 - 616)445 (291 - 597)378 (262 - 546)457 (271 - 732)0.287Spleen enlargement (>5cm) N° (%)17 (8.3)11 (18.3)4 (5.6)2 (2.7)0.003Sokal score (N°)Low/Int/High89/93/2047/9/338/27/54/57/12<0.001Comorbidities ≥ 2, N° (%)77 (37.2)5 (8.1)26 (36.1)46 (62.1)<0.001 The rates of complete cytogenetic response (CCyR) were similar (86.4% in YA, 95.5% in MA and 91.0% in EL, p=0.227) while the rate of major molecular response was higher in the MA group (89.7% vs 63.8% in YA and 75.8% in EL, p=0.001). The number of events (permanent discontinuation due to toxicity, primary or secondary resistance, any death for CML related or unrelated causes) was lower in the MA group [8 (11.1%) vs 21 (34.4%) in YA and 28 (37.8%) in EL, p=0.001]: no difference was observed in the rate of evolution to blastic phase [3 (4.9%) in YA, 1 (1.4%) in MA and 2 (2.7%) in EL, p=0.478]. The number of deaths was higher in the EL group [12 (16.2%) vs 2 (3.2%) in YA and 0 in MA, p<0.001]: it is worth of note, however, that 11/12 deaths in the EL group were not related to CML progression. The 4-year event-free survival (EFS) for the whole cohort was 73.5% (95%CI 67.0 - 80.0): the 4-year EFS in the MA group [92.0% (95%CI 85.1 - 98.9)] was significantly higher than in YA group [67.3% (95%CI 55.1 - 79.5)] and in EL group [61.1% (95%CI 49.5 - 73.7)] (p=0.001). The 4-year overall survival (OS) for the whole cohort was 94.4% (95%CI 90.9 - 97.9): the 4-year OS in the EL group [72.4.% (95%CI 56.9 - 87.9)] was significantly lower than in YA group [96.3% (95%CI 91.2 - 100)] and in MA group (100%) (p<0.001). In conclusion, age at diagnosis influences significantly the course of CML patients treated with imatinib: the MA group has the best follow-up with an excellent OS and EFS, while the relatively lower OS and EFS in the EL group are clearly related to the incidence of unrelated deaths like in the general aged population. A possible explanation of the counterintuitive worse course of YA group is the delayed diagnosis in these patients (higher WBC counts, lower Hb levels, higher rate of spleen enlargement > 5 cm) compared to aged patients, who have often concomitant diseases and make routinely blood analyses: however, a more aggressive biology of CML in YA could not be excluded and warrants further investigations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

2012 ◽  
Vol 30 (35) ◽  
pp. 4323-4329 ◽  
Author(s):  
Susan Branford ◽  
Dong-Wook Kim ◽  
Simona Soverini ◽  
Ariful Haque ◽  
Yaping Shou ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Close Monitoring ◽  
Event Free Survival ◽  
Free Survival ◽  
Transcript Levels ◽  
Imatinib Resistant

Purpose The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Conclusion Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.

Restrospective Multicenter Study Evaluating Efficacy and Safety of Dasatinib and Nilotinib in Patients with Imatinib-Resistant or –intolerant Chronic Myeloid Leukemia in Chronic Phase: Korean CML Working Party

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1691-1691
Author(s):  
Jeong-Ok Lee ◽  
Inho Kim ◽  
Joo-Seop Chung ◽  
Yeo-Kyeoung Kim ◽  
Ho-Young Yhim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Event Free Survival ◽  
Free Survival ◽  
Imatinib Resistant

Abstract Abstract 1691 Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p<0.05). The estimated PFS at 24 months was 85% and 56% in dasatinib and nilotinib group, respectively. (p<0.05) Overall survival rates were comparable in both treatment groups (24-months OS; dasatinib 91%, nilotinib 94%; p=0.65). Both were generally well tolerated. Hematologic toxicities were more frequent among patients receiving dasatinib. 10 patients (13%) had pleural effusion in dasatinib; 9 events were grade 1 or 2. Elevated liver enzyme were more frequent among patients receiving dasatinib. In conclusion, In this study population, nilotinib and dasatinib showed similar cytogenetic and molecular response rates and survival. Toxicity profiles of two drugs were different and both drugs showed tolerable toxicities. In terms of event-free survival and progression-free survival, dasatinib was superior to nilotinib, but caution is warranted in interpretation because baseline characteristics including hematologic and cytogenetic response at the time of start with dasatinib and nilotinib and sokal scores at the time of diagnosis were different. Disclosures: No relevant conflicts of interest to declare.

Impact of Comorbidity In Event-Free Survival, Toxicity and Adherence to Treatment In Chronic Myeloid Leukemia Patients Treated with Imatinib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2296-2296 ◽  
Author(s):  
Laura Fogliatto ◽  
Marcelo Capra ◽  
Mariza Schaan ◽  
Katia Fassina ◽  
Mario Sérgio Fernandes ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Subgroup Analysis ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Missing Information ◽  
Event Free Survival ◽  
Free Survival ◽  
Temporary Suspension ◽  
The Impact ◽  
Score Point

Abstract Abstract 2296 Background: Comorbidity in cancer has been shown to be a major determinant in treatment selection and survival. The most used instrument for measuring comorbidity in Hematology is the Charlson comorbidities index (CCI). It is a list of 19 conditions with weight assigned from 1 to 6, derived from relative risk estimates of a proportional hazard regression model using clinical data. The ACE-27 is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition. Little is known about the impact of comorbidity in chronic myeloid leukemia (CML). Aims: Our objectives were to evaluate the impact of comorbidity in the outcomes of a cohort of chronic phase chronic myeloid leukemia (CP-CML) patients (pts) treated with imatinib and compare the results from the 2 indexes (CCI and ACE-27). Methods: We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet recommendations. Comorbidity conditions were registered at any point during evaluation and CCI and ACE-27 scores were applied to each patient. The outcomes were event-free survival rate (EFS) and imatinib temporary suspension rate. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Imatinib suspensions were considered if superior to 20 days. We conducted 3 types of analysis concerning treatment suspension: suspension for any reason (toxicity and nonadherence), suspension only due to toxicity and only due to nonadherence to treatment. Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (range 4 – 85). The median time from diagnosis to imatinib was 7 months (range 0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with interferon was used in 70% pts. CCI distribution among pts: score point 0 was assigned to 136 pts, score point 1 to 24 pts, score point 2 to 11 pts, score point 3 – 6 to 13 pts and 1 pt with missing information. ACE-27 distribution among pts: score point 0 was assigned to 92 pts, score point 1 to 51 pts, score point 2 to 21 pts, score point 3 to 19 pts and 2 pts with missing information. The indexes showed a strong correlation (Spearman's coefficient 0,7, P<0,0001). The projected EFS rate at 4 years was 68% after a median follow-up time of 4 years. We found a significant association between both indexes and EFS rate at 4 years. The EFS in each group of ICC was: 73% in score 0 group, 65% in score 1 group, 41% in score 2 group and 36% in score 3 to 6 group (P=0,04, Fig 1). The EFS in each group of ACE-27 was: 80% in score 0 group, 69% in score 1 group, 56% in score 2 group and 33% in score 3 group (P<0,001, Fig 2). A significant association between both indexes and drug temporary suspension rate was also found. For the CCI, 32% of score 0 pts had at least one suspension due to any reason, compared to 41% of pts with score 1, 46% of pts with score 2 and 73% of pts with score 3–6 (P=0,04). Subgroup analysis revealed a significant association between CCI and interruption due to toxicity (P=0,03) and due to nonadherence (P=0,03). For the ACE-27, 32% of score 0 pts had at least one suspension due to any reason, compared to 36% of pts with score 1, 27% of pts with score 2 and 69% of pts with score 3 (P=0,03). Subgroup analysis revealed a significant association between ACE-27 and interruption due to toxicity (P=0,02) but not due to nonadherence (P=0,69). Conclusions: In our population of pts with CP-CML, event-free survival, imatinib toxicity and nonadherence seem to be associated with the presence of comorbidities. Both CCI and ACE-27 can be used in the stratification of patients at risk to have major toxicities, lack of adherence or an event during treatment with imatinib. ACE-27 was a better tool in predicting EFS, in the other way, CCI was superior in predicting nonadherence. Disclosures: No relevant conflicts of interest to declare.

Chronic Myeloid Leukemia (CML) Patients with “Suboptimal” Response to Imatinib (IM) According to European LeukemiaNet Criteria Have a Poorer Outcome with Respect to “Optimal” Responders: A GIMEMA CML WORKING PARTY Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2196-2196 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Marilina Amabile ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Working Party ◽  
Lower Probability ◽  
Molecular Response ◽  
Grey Zone ◽  
Long Term Outcome ◽  
Free Survival

Abstract Abstract 2196 Poster Board II-173 BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for Chronic Myeloid Leukemia (CML) in early chronic phase (ECP). The European LeukemiaNet (ELN) recommendations were designed to help identify ECP CML patients responding poorly to front-line IM, suggesting, at given time points, when the treatment strategy should be changed (”failure”), or when “the long-term outcome of the treatment would not likely be as favourable” (“suboptimal response”). Suboptimal response is a “grey zone”: the patient may still have substantial benefit from continuing IM, but other therapies should be considered. AIM: To assess the outcome of “failure” and “suboptimal responders” Philadelphia-positive (Ph+) CML patients in a large multicentric, nationwide experience. METHODS: Between January 2004 and April 2007, 559 patients were enrolled in an observational study and in 2 independent intervention studies of the GIMEMA CML WP (Clin Trials Gov. NCT00514488 and NCT00510926). Response monitoring was based on conventional cytogenetic examination of bone marrow cell metaphases every 6 months and RT Q-PCR evaluations of blood cells after 3, 6, 12 months, and every 6 months thereafter. Definitions: major molecular response (MMR): BCR-ABL/ABL ratio < 0,1%IS; failure (according to ELN criteria): no hematologic response (HR) at 3 months, no complete HR (CHR) at 6 months, no cytogenetic response (CgR) at 6 months, no partial CgR (PCgR) at 1 year, no complete CgR (CCgR) at 18 months, loss CHR or CCgR, progression or death; suboptimal response (according to ELN criteria): no CHR at 3 months, no PCgR at 6 months, no CCgR at 12 months, no MMR at 18 months ; optimal response: non-suboptimal and non-failure at each time-point; event: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. RESULTS: The patients who fitted the ELN criteria for failure had a significantly lower probability of subsequently achieving a CCgR and a MMR, and had a significantly lower overall survival (OS), failure-free survival (FFS) and event-free survival (EFS). The patients who fitted the ELN definitions of suboptimal response at 6 months (data not shown) and at 12 months (figure 1) had a significantly lower probability than “optimal” responders of subsequently achieving a CCgR and a MMR, and a significantly poorer FFS and EFS (figure 1), while the OS was not different in the two groups (90% and 95%, p= 0.35). CONCLUSIONS Our data confirms that suboptimal responders at 6 and at 12 months have a poorer outcome with respect to “optimal” responders, comparable to the outcome of failure patients. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

Early Assessment of Molecular Response in Chronic Myeloid Leukemia Patients On Dasatinib After Imatinib Failure Identify Patients with Poor Cytogenetic and Molecular Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3787-3787
Author(s):  
Katia B. Pagnano ◽  
Beatriz F Ribeiro ◽  
Eliana C M Miranda ◽  
Marcia T Delamain ◽  
Carmino Antonio De Souza ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Internal Control ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Early Assessment ◽  
Molecular Responses ◽  
Free Survival ◽  
Dasatinib Treatment

Abstract Abstract 3787 Dasatinib is effective at inducing complete cytogenetic response (CCyR) in approximately half of chronic myeloid leukemia (CML) patients treated in the chronic phase (CP) after failing imatinib. The aim of this work was to evaluate the role of molecular monitoring in predicting the outcome of patients treated with dasatinib after imatinib therapy. Between 2008 and 2012, it was analyzed 55 consecutive patients with CML with imatinib intolerance or resistance treated in a single center. Patients received dasatinib (50–140 mg) as second or third line therapy. Cytogenetic analysis was performed at 3, 6, 12 and 18 months after dasatinib introduction. BCR-ABL1 transcripts were measured in the blood at 3 months intervals using real-time quantitative PCR (RQ-PCR). Results were expressed as percent ratios relative to an ABL1 internal control. Major molecular response (MMR) was defined as a transcript level ≤ 0.1% on the international scale. Kinase domain (KD) mutations were performed before starting therapy and/or after dasatinib resistance. The probabilities of overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were calculated using the Kaplan-Meier method. An event was defined as the loss of a CCyR or complete hematologic response, progression to AP and BP, death, or discontinuation of dasatinib. The probabilities of cytogenetic and molecular responses were calculated using cumulative incidence (CI) and x2method. Results: 33 patients were male (60%) and 22 female (40%), with median age of 48 years (15–81). At diagnosis Sokal scores were low for 11/34 (32.4%), intermediate for 6 (17.6%) and high for 17 (50%) (21 NA). Thirteen patients had a previous CCyR with imatinib. The median time between diagnosis and dasatinib treatment was 25 (2–223) months. The median follow-up was 12 months. Disease phase at beginning of dasatinib treatment: 32 (58%) CP, 13 (24%) accelerated phase (AP) e 10 (18%) blast phase (BP). Eight-seven percent achieved RHC, 55% CCyR and 38% MMR. At 3 months 67% (25/37) had BCR-ABL1/ABL1 transcript ratio '10%, at 6 months 48% (14/29) ≤ 1% and at 12 months 27% (6/22) RQ-PCR ≤ 0.1%. After introduction of dasatinib, patients with the 3-month BCR-ABL1/ABL1 transcript ratio of >10% had a lower chance of achieving CCyR (12.5% vs 81.5%, p= 0.001) and MMR (8.3% vs. 58.3%, p= 0.005). Patients with the 6-month BCR-ABL1/ABL1 transcript ratio of >1% had a lower chance of achieving CCyR (8% vs. 75%, p= 0.01) and MMR (26.6% vs. 64.2%, p=0.06) compared with patients with ratio ≤ 1%. The probability of OS, PFS and EFS in 48 months while on treatment was 83%, 70% and 29%, respectively. PFS was 88%, 76% e 11% in CP, AP and BP respectively (p< 0.0001). EFS was 36%, 32% e 10% in CP, AP and BP (P< 0.0001). Dasatinib was discontinued in 26/55 because of resistance (12), intolerance (5) or transplant (1). BCR-ABL KD mutations were detected in 13/38 cases, two before (L387M e M351T) and 11 during dasatinib treatment (T315I-6, M244V-2, E255V-1, E499E-1, M351T-1). Patients with mutations had an inferior EFS (p=0,05). In conclusion, this study indicates that evaluation of molecular response at 3 and 6 months can identify patients with less chance of response to dasatinib in patients with imatinib failure. The early identification of patients with poor outcome is important for planning future treatments. Disclosures: No relevant conflicts of interest to declare.

The Clinical Impact of Time to Response in De Novo Accelerated Phase Chronic Myeloid Leukemia (CML-AP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 72-72 ◽  
Author(s):  
Maro Ohanian ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Elias J. Jabbour ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Chronic Phase ◽  
Molecular Response ◽  
Long Term Outcome ◽  
Free Survival ◽  
Excellent Outcome ◽  
The Impact

Abstract Abstract 72 Background: Early (3-month) response is important in chronic phase chronic myeloid leukemia (CML-CP). Whether this applies also to CML in accelerated phase (CML-AP) has not been analyzed. Aim: To describe the impact of time to response on the outcome of patients (pts) with CML-AP. Methods: Frontline tyrosine kinase inhibitor (TKI) therapy was administered on consecutive or parallel clinical trials to 58 CML pts presenting with features of AP at the time of diagnosis, defined as blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=22), or more than 1 feature (n=3). 36 pts received imatinib. 22 pts received a 2nd generation TKI (2GTKI) (dasatinib, n = 5 or nilotinib, n= 17).We analyzed the impact of various degrees of molecular and cytogenetic responses at 3, 6, and 12-months on rates of major molecular response (MMR), MR4.5, overall survival (OS), event free survival (EFS), and transformation (to blast phase) free survival (TFS). Results: After a median follow-up of 73 months (range 3 to 142) the overall rate of CCyR was 81% (imatinib 75%, 2GTKI 91%), and MMR 69% (imatinib 64%, 2GTKI 77%). At 3 yrs, TFS was 92%, EFS 90% and OS 87%. At 3 months 43 (81%) out of 53 evaluable pts had achieved a major cytogenetic response (MCyR) (71% of pts treated with imatinib, 95% of pts treated with 2GTKI); BCR-ABL/ABL <10% was achieved in 27 (96%) out of 28 evaluable pts (100% with imatinib, 95% with 2GTKI). At 6 months, 44 (86%) out of 51 evaluable pts had achieved a MCyR (83% of pts treated with imatinib, 90% of pts treated with 2GTKI); BCR-ABL/ABL <10% was achieved in 26 (93%) out of 28 evaluable pts (100% with imatinib, 90% with 2GTKI). The probability of achieving various outcomes: MMR, MR4.5, OS, EFS, and TFS by response at 3 and 6 months are shown in Table 1 and 2. The number of pts evaluable for both cytogenetic and molecular responses at 3 and 6 months were 44 and 45 respectively. Conclusion: Pts with de novo CML-AP have an excellent outcome with TKIs, particularly 2GTKIs. As for chronic phase, pts with deep responses at 3 months (MCyR or BCR-ABL <10%) have the best probability of a favorable long-term outcome, although a few have not achieved MCyR at 3 months. TKIs should be standard for all pts with AP features at the time of diagnosis. Disclosures: Kantarjian: Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy. Ravandi:BMS: Honoraria, Research Funding; Novartis: Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

Acquisition Of Compound BCR-ABL1 Alleles As A Mechanism Of Resistance To Ponatinib In Chronic Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 853-853
Author(s):  
Don L Gibbons ◽  
Sabrina Pricl ◽  
Paola Posocco ◽  
Erik Laurini ◽  
Maurizio Fermeglia ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
The Impact ◽  
In Cells

Abstract BACKGROUND Ponatinib targets the inactive conformation of the ABL1 kinase and avoids interacting with the side chain of the mutated 315 residue. In vitro, ponatinib inhibits all single-point BCR-ABL1 mutations. Yet, a significant proportion of patients with chronic myeloid leukemia in chronic phase (CML–CP) do not respond to ponatinib and a subset loses their response during the course of treatment. The mechanisms of resistance to ponatinib are currently not well characterized. OBJECTIVE To determine the impact of compound BCR-ABL1 mutations (polymutants) on the activity of ponatinib. METHODS BCR-ABL1 mutational status was determined in 70 pts with CML-CP post imatinib failure and during dasatinib therapy by DNA expansion of specific clones followed by DNA sequencing of ≥10 clones. Free energy of binding (DGbind) for the unmutated and all mutant BCR-ABL1 kinase/inhibitor complexes were obtained using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methodology. Single and polymutant BCR-ABL1 alleles obtained by direct mutagenesis and their expression was forced into Ba/F3 cells by electroporation by the pMX/eGFP-BCR-ABL1 expression vector using the Amaxa System. RESULTS After imatinib failure, 125 ABL1 kinase domain mutations at 113 amino acid positions were detected in 61/70 (87%) pts, including 38 (54%) with mutations in ≥20% of sequenced clones. Mutations conferring resistance to >1µM imatinib were detected in 30 (43%) pts. Polymutant BCR-ABL1 alleles were detected in 29/70 (41%) pts. These patients received dasatinib for a median of 19 mos (range, 2-52), during which dasatinib-resistant mutations were detected in 10/32 (31%) assessable cases (5 with T315I). Polymutants were present in 16/32 (50%) pts (all of them dead in blast phase). The proportion of clones carrying unmutated BCR-ABL1 was markedly lower in patients who only achieved a minor or no cytogenetic response compared to those achieving a major cytogenetic response (p=0.0001), suggesting exhaustion of unmutated clones and expansion of mutant (and polymutant) clones linked to clinical dasatinib resistance. Then, we performed 3D structural analyses to determine the thermodynamic impact of 21 BCR-ABL1 mutants (11 single and 10 double mutants) in the ability of ponatinib to bind the kinase domain (Table). Most single mutants did not result in high ponatinib resistance (except for E255K, IC50=8.8nM; DGbind=-10.99±0.01). However, the association of any 2 of 3 point mutants (T315I, F317L, V299L) in a dual polymutant produced highly resistant BCR-ABL1 proteins that exhibited fold change values from 19 to 40, compared to the unmutated protein, with T315I/F359V displaying the highest resistance (IC50=61nM; DGbind=-10.23±0.03 kcal/mol), unveiling a mechanism of escape to ponatinib. In Ba/F3-based assays, ponatinib (but not imatinib or dasatinib) was active against Ba/F3-BCR-ABL1T315I cells. Polymutants exhibited very high ponatinib resistance (10-fold higher than that of cells carrying BCR-ABL1T315I). As predicted in silico, BCR-ABL1T315I/F359V was the most resistant polymutant tested. Cell growth inhibition was coupled with CrkL and STAT5 phosphorylation inhibition. Ponatinib, while suppressing STAT5 phosphorylation, could not suppress CrkL phosphorylation in cells expressing the BCR-ABL1T315I/F359V polymutant kinase, even at 100 nM (50-fold the IC50 required to inhibit BCR-ABL1T315I). CONCLUSIONS Polymutants are very frequent in pt samples after TKI failure (particularly after sequential TKI therapy) and tend to induce high ponatinib resistance. Our in silico platform predicted very accurately TKI sensitivity in cells carrying different BCR-ABL1 mutations, which makes it clinically applicable for matching specific mutations to the most effective TKI. Some polymutants require ponatinib concentrations not clinically reachable, thus representing a mechanism of escape to ponatinib therapy through selection and expansion of refractory clones. Disclosures: Talpaz: ariad: Research Funding. 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. Quintas-Cardama:ariad: Consultancy.

scholarly journals Outcomes and Side Effect Profile of Ponatinib in Treatment of Chronic Myeloid Leukemia (CML): A Retrospective Single-Center Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4259-4259 ◽  
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Leidy Isenalumhe ◽  
Michael Fradley ◽  
Samantha Shams ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Small Sample ◽  
Categorical Variables ◽  
Routine Practice ◽  
Molecular Response ◽  
The Impact ◽  
Dose Dependent

Abstract BACKGROUND: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) used to treat resistant chronic myeloid leukemia (CML). It has been associated with cardiovascular adverse events (CAEs); most specifically hypertension and arterial thrombotic events. Most CAEs are dose-dependent. The frequency of CAEs in the real-world setting has not been previously described. In this study, we describe the survival outcomes and associated toxicities in ponatinib-treated patients at Moffitt Cancer Center (MCC). METHODS: A retrospective review of CML patients treated with ponatinib at MCC between years 2011 and 2017 was performed to identify patients treated with ponatinib. Demographics, disease-specific variables and clinical outcomes were collected in accordance with the Institutional Board Review approved protocol. Frequency of adverse events on ponatinib were categorized. Pearson's chi-square test for independence was used to determine significance for categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). RESULTS: A total of 78 patients (38 females/40 males) treated with ponatinib with median age of 42.5 (range 14-70) years were included in the analysis. At the time of ponatinib initiation, 51 patients were in chronic phase (CP), 9 in accelerated phase (AP), and 18 in blast phase (BP). Ponatinib was 3rd or 4th line therapy in 65% of CP patients, with a mean starting dose of 39.65 mg per day. Dose reduction occurred in 64.7% of patients with CP and the mean duration of ponatinib was 14.6 months. The most common non-cardiovascular adverse events (NCAEs) were thrombocytopenia (39.7%), abdominal pain (33.3%), anemia (28.2%), elevated lipase (28.3%), and rash (26.9%) in a dose-dependent fashion. Most common new onset CAEs included arrhythmia (9%) and hypertension (7.7%). Three patients (3.8%) experienced a myocardial infarction, and two of these had significant cardiovascular risk factors at baseline. No other arterial thrombotic events were reported. A total of 18 patients (23.1%) experienced some form of CAE. Prior to 2014, more patients were placed on 45 mg ponatinib and more CAEs occurred during that time. After 2014, there is an increased awareness of potential cardiotoxicity associated with ponatinib and referral to cardio-oncology (CO) became a routine practice in our institution. Figure 1 summarizes the cardiac safety profile of ponatinib and frequency of CO referral. Ponatinib 45 mg and CAEs are not independent (X2 (1, N = 82) = 7.68, p < 0.05), but this correlation was lost when testing CAEs against patients who were on ponatinib 45 mg and either referred to CO or on cardiac protective medications (X2 (1, N = 82) = 3.55, p > 0.05) suggesting CAEs become independent of ponatinib dosing when cardioprotective measures are put in place. In patients with CP-CML, 69.6% achieved a complete cytogenetic response (CCyR) and 58.7% had a major molecular response (MMR). Patients with AP and BP achieved CCyR in 37.5% and 68.8%, respectively. Among the BP patients who achieved at least CCyR (n = 11), 81.1% of the patients had received TKI with chemotherapy at the time of BP. Five-year median OS of the entire cohort was 63%. With a median follow up of 32.5 months, the median OS from ponatinib initiation was not reached (NR) in CP with allogeneic stem cell transplantation (allo-SCT) (n = 17) or without allo-SCT (n = 34); was 32.9 months in AP with allo-SCT (n = 4), NR in AP without allo-SCT (n = 5); and NR in BP with allo-SCT (n = 6), and 5.45 months in BP without allo-SCT (n = 12) (p < 0.0001). CONCLUSIONS: In our series, the incidence of new arterial thrombotic events and hypertension appears lower than reported in the PACE trial. The incidence of CAEs declined after 2014 when early dose reductions became standard practice and early referrals to cardio-oncology increased. Non-CAEs and outcomes were similar to previous reports. Limitations of this analysis include its retrospective nature and small sample size. Future studies analyzing the impact of specific interventions on mitigating cardiovascular events are needed. Disclosures Sweet: BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; BMS: Honoraria; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau.

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