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.

scholarly journals Long-Term Results and Characteristics of Pleural Effusion in Late Chronic Phase Chronic Myeloid Leukemia Patients at Dasatinib Therapy after Imatinib Failure

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5141-5141
Author(s):  
Galina Gusarova ◽  
Anastasia Bykova ◽  
Alexandra Vorontsova ◽  
Sergey Kuznetsov ◽  
Oleg Shukhov ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Free Survival ◽  
Dasatinib Treatment

Abstract Background. The aim of chronic myeloid leukemia (CML) treatment with tyrosine kinase inhibitors (TKI) is not only effectiveness, but also safety. Long treatment duration makes the analysis of most significant complications very important. Pleural effusion (PE) is an important adverse event of dasatinib therapy with largely unclear cause. The optimal management of recurrent PE is unknown and the analysis of its treatment results is actual. Aim. To describe the characteristics of patients with recurrent PE at prolonged dasatinib treatment and to suggest the strategy of their management. Methods. Follow-up data of 23 CML late chronic phase patients at dasatinib therapy after imatinib failure in 2 clinical studies: phase II study comparing dasatinib 140 mg and imatinib 800 mg daily (N = 12) and phase III dasatinib dose-optimizing study in patients with imatinib-resistant or intolerant patients (N = 11). M:F ratio was 7:16. Median age at the beginning of dasatinib - 48 years (26-68), median CML duration - 11 years (4,1-19,2). The reason for TKI change was imatinib resistance: cytogenetic (N = 17) and hematological (N = 6). Results. Median duration of dasatinib treatment - 40 months (10-107); 13 patients (56,3%) are alive, 10 patients (43,5%) have died because of progression of CML. In 19 patients (82,6%) dasatinib treatment was stopped because of: blastic transformation - 6 (26,1%), hematological resistance - 3 (13,1%), cytogenetic resistance - 5 (21,7%), PE - 5 (21,7%). Four patients are still on dasatinib treatment with median duration 8,8 years (8,7-8,9), 3 of them retain complete/major molecular response. The best responses were: complete hematological response in 21 (91,3%), complete cytogenetic response - in 8 (34,8%), major molecular response - in 6 (26,1%) patients. Overall 8-year survival was 55,1%, progression-free survival - 55,4%, event-free survival - 26,1%. PE was observed in 11 (47,8%) patients, in 8 of them (72,7%) - recurrent. In one patient the prolonged PE was associated with fibrosis of adjacent lung and pleura. Median time to PE was 34 (6-83) months. In cases of PE dasatinib was interrupted (mean duration 21 d) and diuretics were started. Six patients (54,5%) also received corticosteroids. Five patients (45,6%) were treated with thoracocentesis. In recurrent PE the dasatinib dosage was decreased. The dasatinib discontinuation in 4 patients with recurrent PE has led to loss of major molecular response in 2 of them; in other 2 it is retained for 6,5 and 1,5 years. Event-free 8-year survival was 36,4% in patients with PE, 16,7% - without it. Discussion. The response rate in patients with PE was not worse, than in those without it. Most often PE begins at 3rd year of treatment; later events were only relapses. Among risk factors of PE 2 patients had arterial hypertension and hypercholesterinemia, 3 patients were > 65 yrs. The significantly high PE on rate (48%) was linked to high initial dasatinib dosage (> 100 mg/d) and bid prescription. We have not observed cases of absolute lymphocytosis due to large granular lymphocytes proliferation. The continuation of treatment generally leads to recurrences of effusion. According to our experience, once arising PE tends to recur. The compensation can be maintained with continuous treatment with diuretics. The prolonged PE may lead to fibrosis of adjacent lung and pleura. Prolonged treatment interruptions and decreased doses can cause treatment failure. The role of corticosteroids is unclear. Conclusion. Our experience in recurrent PE management at dasatinib treatment allow to recommend the usage of alternative TKI in patients with poor treatment response, and discontinuation of treatment in patients with deep molecular response with close monitoring of residual disease by PCR. Disclosures Turkina: Novartis International AG: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy.

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.

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.

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.

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

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

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

scholarly journals Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 630-630 ◽  
Author(s):  
Danthala Madhav
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Comparable Efficacy ◽  
Molecular Response ◽  
Free Survival

Abstract Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point. Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib. Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available. Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively. Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits. Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively. There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%). Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Retrospective Application of European LeukemiaNet Provisional Criteria for Second-Generation TKI Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2270-2270
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Fabio Stagno ◽  
Antonella Gozzini ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Primary Resistance ◽  
Free Survival ◽  
Optimal Response ◽  
Monitoring Response

Abstract Abstract 2270 An update of the European LeukemiaNet criteria for monitoring response of chronic myeloid leukemia patients was recently published and provisional criteria to evaluate patients during second generation TKI therapy after resistance to imatinib were proposed. In our study we retrospectively tested these criteria in a large series of CML patients resistant to imatinib further treated with second generation TKIs with the aim to analyze the outcome of suboptimal response and failure patients compared to those with optimal response and to validate the provisional criteria for monitoring response. One hundred twenty-seven CML patients resistant to imatinib were collected from 6 different Italian hematologic centers. There were 66 males and 61 females, median age 54 years (range 25–80). Twenty-seven patients were in late chronic phase after IFN resistance. Ninety-seven patients received second-generation TKI after acquired resistance, whereas 30 patients had primary resistance. We found that at different time points (3, 6 and 12 months), patients classified as failure showed significantly worse 2-year overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) than sub-optimal and optimal response patients. At 3 months, “failure” patients, had an OS of 83% compared to 86% of sub-optimal and 97% of optimal response patients (p=0.001); PFS was 77% for failure patients compared to 92% and 99% for sub-optimal and optimal response patients, respectively (p=0.001), whereas EFS was 41% for failure vs 59% for sub-optimal (p=0.001) and 85% and optimal response patients, respectively (sub-optimal vs optimal p<0.001). At 6 months, OS was 82%, 88% and 99% for failure, sub-optimal and optimal response patients (p=0.05), respectively; PFS was 82% for failure compared to 94% and 99% for sub-optimal and optimal response patients, respectively (p=0.001); EFS was 47% vs 69% for failure and sub-optimal response (p=0.001) and 86% for optimal response patients (sub-optimal vs optimal, p<0.001). At 12 months again OS was 84% for failure patients compared to 95% and 99% for sub-optimal and optimal response patients (p=0.04); PFS was 86%, 95% and 99% for failure, sub-optimal and optimal response patients, respectively (p=0.001) and EFS was 48% for failure, 67% for sub-optimal response patients (p=0.002) and 89% for optimal response patients (sub-optimal vs optimal, p<0.001). We found that ELN provisional criteria identified at any times worse EFS for sub-optimal response patients, similar to that of failure patients, and failure criteria at 3 months identified patients who had worse PFS and EFS. ELN provisional criteria for second-generation TKIs treated patients appear to clearly predict outcome and can be useful to identify patients at high risk of progression. Disclosures: No relevant conflicts of interest to declare.

Mutations of TET2, IDH1, IDH2 and ASXL1 In Chronic Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3377-3377
Author(s):  
Catherine Roche-Lestienne ◽  
Marceau Alice ◽  
Elise Labis ◽  
Olivier Nibourel ◽  
Valérie Coiteux ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Candidate Genes ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Haematopoietic Stem Cell ◽  
Molecular Response ◽  
Genetic Event ◽  
Myeloid Malignancies

Abstract Abstract 3377 It is generally accepted that the BCR-ABL oncoprotein transformes haematopoietic stem cell and initiates chronic myeloid leukemia (CML). However, leukemogenesis is a complex process, and genomic heterogeneity of the chronic phase (CP) of the disease has been reported. At the molecular level, this intrinsic heterogeneity could support a causative link with the varying response to treatment and disease progression. Genetic analysis of candidate genes in myeloid malignancies reported mutations of the ten-eleven translocation 2 (TET2), the isocitrate deshydrogenase (IDH) 1 and IDH2, and the additional sex combs like 1 (ASXL1) genes in myeloproliferative, acute myeloid and myelodysplasic neoplasms. Similarly, we can stipulate that these candidate genes may contribute to phenotypic heterogeneity of CML. To investigate whether TET2, IDH1, IDH2 and ASXL1 defect could represent a significant event in CML, we selected 91 CML patients (pts) treated with imatinib (IM) at first line and presenting five profiles of IM response at time of the analysis: 1) 25 pts in major molecular response (MMR) at 12 months of IM; 2) 11 pts in CCR but presenting additional Philadelphia (Ph) negative clonal evolution; 3) 20 pts in partial cytogenetic response at 18 months of IM, referred as primary resistant (R1); 4) 20 pts in acute transformation 4 to 72 months after onset IM; and 5) 15 pts relapsing in CP of the disease, referred as secondary resistant (R2). The search for mutation was performed by sequencing the entire TET2 coding region (11 exons), the IDH1 and IDH2 exon 4 and the ASXL1 exon 12. Analysis of paired samples from CML diagnosis, time of IM response and, when available, CCR revealed: 1) 2 pts (2.2%) in acute transformation presenting 3 TET2 stop mutations not located within conserved region (del at A2079, substitution T4893A - both also been detected at diagnosis -, and del at C4851 which has not been detected at diagnosis, even by mutation-specific ASO-PCR); 2) no IDH1 and IDH2 mutation; and 3) 8 pts (8.7%) presenting ASXl1 stop mutations at diagnosis. Among them, 3 pts (two ins at G646 and one ins at V751) have reached MMR without detected mutations at this time; one R1 pt presenting ins at G646 had major cytogenetic response with 5% Ph+ cells but the mutation was not found at this time and the pt have progressed to MMR 9 months later; one pt with 23 bp del at R634 has evolved in acute transformation with detected mutation at this time; and 3 R2 pts presenting either 4 bp del at S895, del at R860 or 2 pb ins at A752 have lost CCR associated with lost of hematologic response in one case. In this later group of 3 pts, except for del at R860, all ASXL1 mutations were found in samples at time of relapse. We therefore conclude that, contrary to what has been reported in other myeloid malignancies, TET2, IDH1 and IDH2 are not commonly acquired in CML and may not represent a major genetic event in CML transformation. However, ASXL1 alteration seems to be an early event in CML leukemogenesis but does not seem to participate in the disease transformation. Disclosures: No relevant conflicts of interest to declare.

hOCT1 Gene Expression Might Predict Molecular Response In Patients with Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4838-4838
Author(s):  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Concha Boqué ◽  
Silvia Marce ◽  
Jordi Ribera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Organic Cation Transporter ◽  
Initial Response ◽  
Molecular Response ◽  
Hematopoietic Malignancy

Abstract Abstract 4838 Introduction: Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by the presence of BCR/ABL fusion gene. The resulting protein has a high tyrosine kinase (TK) activity. The first-line treatment for CML is Imatinib, which allow the achievement of cytogenetic and molecular response in most of patients with CML in chronic phase. However, some patients do not respond to this treatment or lose their initial response. Imatinib has been reported to be incorporated into the cell through hOCT1 transporter (human organic cation transporter). The aim of this study was to determine whether the expression of hOCT1 at diagnosis of CML influenced the achievement of molecular response. Patients and Methods: We analyzed hOCT1 gene expression by quantitative PCR in 42 patients at diagnosis and 18 months after treatment with Imatinib. We compared the expression with the presence of compleat molecular response (CMR) at 18 months. We consider CMR when the Ratio (BCR-ABL/ABL)×100 was <0.1% (after International Scale correction). For statistical analysis methods we have used Kolmogorov-Smirnov and Mann-Whitney nonparametric methods. Results: Of the 42 patients, 2 were in hematological response, 22 were in cytogenetic response and 18 in CMR at 18 months. We found a higher hOCT1 gene expression at 18 month than at diagnosis (53.3 versus 29.6, p<0.001) in all patients (Figure 1). We have found some tendency of higher hOCT1 expression at diagnosis in patients with CMR at 18 months than in those who did not had (25.5 versus 18.8, p = 0.07) (Figure 2). Conclusions: Partially funded by FICJ-P-EF-09, RD06/0020/1056 de RTICC and Novartis. We want to thank Dr. David Marin for providing us plasmid for quantitative analysis. Disclosures: No relevant conflicts of interest to declare.

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