Loss Of Complete Hematologic Response Research Articles

Olverembatinib (HQP1351) Demonstrates Efficacy Vs. Best Available Therapy (BAT) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic Myeloid Leukemia Chronic-Phase (CML-CP) in a Registrational Randomized Phase 2 Study

*Drs. Yifan Zhai and Xiaojun Huang are co-corresponding authors. Introduction This was a multicenter, randomized, registrational phase 2 study to assess the efficacy and safety of olverembatinib compared with BAT in pts with CML-CP who were resistant and/or intolerant to 3 TKIs (imatinib [I], dasatinib [D], nilotinib [N]) in China. Methods Eligible adult CML-CP pts were resistant and/or intolerant to 3 TKIs, were in ECOG PS 0-2, and had adequate organ function. Pts were randomized 2:1 to investigational olverembatinib (40 mg QOD) or the BAT arm, which could be one of the following per investigator choice: TKIs (I, D, or N), interferon (IFN), hydroxyurea (HU), and homoharringtonine (HHT). The primary endpoint was event-free survival (EFS), including time from randomization to AP or BP progression); all-cause mortality; relapse; treatment failure (no complete remission [CR] within 3 cycles); loss of complete hematologic response (CHR); and treatment intolerance as per investigator and study sponsor. Efficacy was analyzed in the intention-to-treat (ITT) efficacy population and safety in pts receiving ≥1 dose of olverembatinib. Results As of April 30, 2023, a total of 144 pts (96, olverembatinib; 48, BAT) were enrolled, including 69.4% male and 30.6% female, with a median (range) age of 49.0 (18-77) years. A total of 129 pts (89.6%) were previously treated with ≥ 3 TKIs (I, D, N). 15 pts (10.5%) with T315I mutation received ≥1 TKIs, of whom 9 (6.3%) received 2. Median (range) follow-up was 12.67 (0.0-40.9) and 2.94 (0.0-40.4) months in the olverembatinib and BAT arms, respectively. A total of 66 (45.8%) pts had ≥1 BCR::ABL1 mutation and 39 (27.1%) BCR::ABL1 T315I. A total of 97 pts discontinued therapies (56 [58.3%] olverembatinib, 41 [85.4%] BAT) due to disease progression/treatment failure, AE, consent withdrawal, poor compliance, or death. In the safety population, 82/96 (85.4%) pts receiving olverembatinib and 31/46 (67.4%) BAT experienced a grade ≥ 3 AE. Any-grade AEs (> 20% incidence) included thrombocytopenia; leukopenia; anemia; neutropenia; elevated CPK, ALT, and AST; and hypertriglyceridemia. Serious AEs (SAEs) (>5%) included thrombocytopenia. A total of 7 SAEs were possibly related to olverembatinib: 1 acute myocardial infarction, 3 coronary heart disease cases, 2 cerebral infarctions, and 1 congestive heart failure. Common AEs (≥10%) leading to discontinuation, dose reduction, or treatment withdrawal were thrombocytopenia, neutropenia, and leukopenia. Median (range) EFS was 21.22 (95% CI, 10.15-NR) months in the olverembatinib arm and 2.86 (95% CI 2.53-4.73) months in the BAT arm ( P < .001; HR, 0.352; 95% CI, 0.228-0.545). Compared with the BAT control arm, olverembatinib reduced the event risk 65%. In the olverembatinib arm, estimated EFS at 6, 12, and 24 months was 73% (95% CI, 62.5-81.0), 58.7% (95% CI, 47.5-68.2), and 46.9% (95% CI, 35.9-57.2), respectively. In the BAT group, it was 32.6% (95% CI, 19.7-46.2), 26.1% (95% CI, 14.5-39.3), and 16.9% (95% CI, 7.7-29.2), respectively. Median OS was NR in either group ( P = .41). Up to data cutoff, 34 (71%) pts in the BAT control arm were crossed-over to be treated with olverembatinib after EFS endpoint was reached. In the ITT efficacy group, among those treated with olverembatinib, 51/60 (85%) pts achieved a CHR; 42/88 (47.7%) MCyR; 32/88 (36.4%) CCyR; and 24/88 (27.3%) MMR. In the BAT group, 8/23 (34.8%) pts achieved a CR, 11/37 (29.7%) MCyR, 6/37 (16.2%) CCyR, and 3/37 (8.1%) MMR. Conclusions This study represents the largest population of pts with CML-CP resistant or intolerant to both 1G and 2G TKIs. Olverembatinib was observed to be better tolerated and more effective than BAT in treating these pts. Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681).

Molecular Response of ≤10% BCR::ABL1IS Is Predictive of Positive Outcomes in Treatment-Resistant Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib from the Phase 2 Optic Trial

Background:BCR::ABL1 mutations are key contributing factors to tyrosine kinase inhibitor (TKI) resistance in patients with chronic myeloid leukemia (CP-CML). Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR::ABL1 with or without any single resistance mutation, including T315I. The Phase 2 OPTIC trial evaluated benefit/risk outcomes of ponatinib using a novel response-based dosing strategy in patients with heavily pretreated resistant CP-CML. In the OPTIC trial, all 3 dosing regimens demonstrated benefit in resistant patients, with optimal benefit/risk outcomes observed in patients who received the response-based dosing of 45 → 15 mg/day. Here we present a post hoc analysis of long-term outcomes (progression-free survival [PFS] and overall survival [OS]) of patients in the OPTIC trial who reached landmark clinical responses (≤1%, >1%-≤10%, and >10% BCR::ABL1IS by Months 3, 6, and 12). Methods: The OPTIC trial design has been previously described (Cortes J, et al. Blood. 2021;138:2042-50). Overall, 99% of patients had treatment-resistant disease; 61% of patients had a best response to their last prior therapy of complete hematologic response or worse; and 84% had a best response of >10% BCR::ABL1IS to prior therapy. This landmark analysis describes PFS and OS in patients with ≤1%, >1%-≤10%, and >10% BCR::ABLIS by Months 3, 6, and 12. Disease progression was defined as the loss of complete hematologic response or major cytogenetic response, development of acute- or blast-phase CML, death, or 2 instances of white blood cell count increases (>20,000 cells/μL, ≥4 weeks apart) after the first 4 weeks of treatment. Patients with ≤1% BCR::ABL1IS at baseline were excluded from this analysis. The probabilities of PFS and OS at 24 months were calculated using the Kaplan-Meier method. The proportion of patients attaining ≤1% BCR::ABLIS by 36 months was also assessed. Results: A total of 276 patients with resistant CP-CML were included in the intention-to-treat (ITT) population: 45-mg (n=93), 30-mg (n=93), and 15-mg (n=90) starting dose cohorts. At the cutoff date of May 9, 2022, 56 (20%), 78 (28%), and 95 patients (34%) had reached ≤1% BCR::ABL1IS by Months 3, 6, and 12, respectively. Among patients remaining within each dosing cohort at 36 months, most had attained ≤1% BCR::ABLIS (57%-65%). Among all ITT patients within each dosing cohort (45 mg, n=93; 30 mg, n=93; 15 mg, n=90), the highest response rate by 36 months was observed in the 45-mg cohort (35%). Four patients with ≤1% BCR::ABL1IS at baseline were excluded from the landmark analysis. Based on this landmark analysis, regardless of starting dose, patients who attained landmark response levels of ≤1% and >1-≤10% BCR::ABL1IS in 3-12 months had substantially improved PFS outcomes at 24 months compared with patients with >10% BCR::ABL1IS (Table). In the landmark analysis population, patients who did not reach ≤10% BCR::ABL1IS within 12 months had unfavorable PFS outcomes (Table). Long-term OS outcomes in the landmark analysis population were similar across all BCR::ABL1IS levels, regardless of whether response was reached by 3, 6, or 12 months (Table). Conclusion: Ponatinib provided robust responses in the OPTIC trial population comprising patients with heavily pretreated, TKI-resistant CP-CML. In this landmark analysis, attainment of ≤10% BCR::ABL1IS with ponatinib within 12 months was associated with improved long-term PFS outcomes compared with PFS outcomes associated with remaining at >10% BCR::ABL1IS. These findings underpin the clinical benefit of achieving molecular responses with ponatinib, especially achieving ≤10% BCR::ABL IS within 12 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML-401 Case Report of NGS Results in the Chronic Myeloid Leukemia Patient With Multiple Resistance to Tyrosine Kinase Inhibitors

The significance of BCR::ABL in pathogenesis of chronic myeloid leukemia (CML) is studied quite well and tyrosine kinase inhibitors (TKI) are really efficient in CML treatment. Nevertheless, there are still patients with TKI-resistance. This fact could be explained by BCR::ABL-independent pathways of disease maintenance and progression. A female (1959 year of birth) was diagnosed with CML in chronic phase (EUTOS-low risk, Sokal-high risk) according to CBC (leukocytosis, thrombocytosis, shift to blasts); presence of the Ph-chromosome; detecting of BCR::ABL(p210,b3a2,b2a2)-43.395% in 12/2018. The patient had tried multiple TKIs. Imatinib 600 mg/day since 12/2018 to 03/2019. Complete hematologic response (CHR) was achieved, but the treatment required dose reduction (150-300 mg/day) due to hematological toxicity (neutropenia grade 3). Therapy was discontinued after 3 months due to loss of CHR. No mutations of BCR::ABL gene were detected. Dasatinib 100 mg/day since 04/2019 to 07/2019. The reason for interruption was hematological toxicity (neutropenia, anemia grade 2-3 required G-CSF and epoetin). At 3 months there was a lack of cytogenetic response (100% Ph-positive metaphases), BCR::ABL-43.3% by IS. Nilotinib 800 mg/day started on 07/2019 but it was ceased on 08/2019 because of the non-hematologic intolerance (vomiting, nausea, amylase elevation). Bosutinib 500 mg/day since 09/2019. Treatment was stopped on 12/2019 due to severe neutropenia which persisted for 28 days. Ponatinib (7.5 mg/day - maximum tolerated dose) since 12/2019 up to date. BCR::ABL on 25-Dec-2019 - 31%. Given the multiple resistance to TKIs, next-generation sequencing (NGS) was performed. 32 mutations in 24 genes were detected: 16 were favorable, 9-possible favorable, 7-with unclear significance. Mutations with highest allelic burden were in genes EZH2, CIITA, CDKN2A, IKZF1, ATM, SETBP1, TET2. NGS results could be considered as one of the possible reasons of multiple resistance. Ponatinib treatment is still ongoing. Major molecular response (MMR) is not achieved (BCR::ABL(01/2022)- 17%). Neutropenia grade 3-4 persists throughout treatment but therapy is continued due to lack of alternatives. The discovery of mutated genes by NGS in this patient on multiple lines of TKI-therapy gives the evidence of non-BCR::ABL resistance mechanisms. The use of NGS could find the additional targets for treatment of CML resistant patients besides TKI.

A MULTICENTER NON-INFERIORITY STUDY OF EFFICACY AND SAFETY OF GENERIC IMATINIB IN CHRONIC MYELOID LEUKEMIA – FINAL ANALYSIS

This study aimed to evaluate efficacy and safety of generic imatinib (IM) compared to branded imatinib (Glivec) in chronic myeloid leukemia. The primary end-point was the achievement of a major molecular response (MMR) at 12 months and safety. Secondary end-points included response evaluation, overall (OS), event-free survival (EFS) progression-free survival (PFS) and toxicity. Ambispective, multicenter, observational, non-inferiority study, in newly diagnosed Brazilian patients with chronic phase CML patients treated with IM in first line. The historic cohort consisted of CML patients treated with branded IM (Glivec) from January 2010 to December 2011 and the prospective cohort was treated with generics between January 2015 and December 2018. A total of 493 cases (214 Glivec and 279 Generic) from 10 centers were enrolled, and 393 (80%) patients were eligible for analysis (Glivec = 163; Generics = 230). EFS was measured from the start of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated or blast crisis, no response or insufficient response to study therapy, after a predefined period of time or death from any cause at any time during initial therapy or permanent discontinuation of IM by adverse events. The median age was 45 and 49 years in Glivec and Generics groups, respectively (p = 0.056). Sokal score stratification in Glivec and generic groups, was respectively: low risk 50/50%; intermediate risk 49/38% and high risk 12/22% (p = 0.05). E14a2 (b3a2) frequency was 63% vs. 52% in Glivec and Generic group, respectively, and e13a2 (b2a2) 36% in both groups, e14a2+e13a2 were 1% vs. 12% (p = 0.005). There was no significant difference in gender, Eutos score and ECOG. The median time between diagnosis and treatment starting was 40 (0-169) and 28 (0-168) days (Glivec vs. Generics, respectively), p = 0.17. MMR rate at 12 months was 77/142 (54%) and 88/145 (61%) in Glivec and generics groups, respectively (p = 0.26). There were more failures in the generics group at 6 months (21% vs. 14%) (p = 0.03, respectively). There was no difference in grade 3-4 hematological and non-hematological toxicity in in the first 12 months. EFS at 24 months were higher in Glivec cohort and 76% vs. 53%, p < 0.0001, respectively), PFS and OS was not significantly different (respectively: 96% vs. 93%, p = 0.09 and 97% vs 96%, p = 0.41). The independent risk factors associated with inferior EFS were: generics use (HR = 1.78; 95%CI 1.06-2.99; p = 0.02) and High Sokal index (HR 2.25; 95%CI 1.38-3.67; p = 0.001). In the intention to treat analysis there was no significant difference in the primary end-point (MMR and safety at 12 months). The generics cohort presented more failures at 6 months compared to branded imatinib and inferior 24 month-EFS. There was no difference in the 24-month OS and PFS. The interpretation of the results should take into consideration the differences in CML management over the years.

Long-term outcome of tyrosine kinase inhibitor treatment in children and adolescents with newly diagnosed chronic myeloid leukemia in chronic phase.

Long-term outcome of tyrosine kinase inhibitor treatment in children and adolescents with newly diagnosed chronic myeloid leukemia in chronic phase.

Tyrosine kinase inhibitor resistance in pediatric chronic myeloid leukemia: a case report

Pediatric chronic myeloid leukemia (CML) is a hematopoietic malignancy, treated by tyrosine kinase inhibitor (TKI). Previously, imatinib resistance in CML was treated with nilotinib as a second line. However, in Indonesia, where the options of TKIs are limited, no case has been reported. We describe TKI-resistance of a pediatric CML case in Dharmais Cancer Hospital, Jakarta. A 17-year-old boy presented with loss of complete hematologic response after 4 years of imatinib treatment. Diagnosis of relapsed CML with blast crisis was confirmed, and nilotinib was given accordingly. He achieved hematological and optimal response after 2 weeks and 3 months of treatment, respectively. However, in the 12-month evaluation, he failed to achieve major molecular response and acquired the second resistance to TKI. Since imatinib resistance marks the poor prognosis, initial optimal response of nilotinib treatment remains inconclusive to predict the final outcome.

Imatinib in Children with Chronic Myeloid Leukemia in Chronic Phase: Long-Term Results of the French National Phase IV Trial

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p&lt;0,0001), abdominal pain 44% vs 16% (p=0,03), nausea 48% vs 16% (p=0,02), diarrhea 24% vs 0% (p=0,01) and neutropenia 84% vs 28% (p&lt;0,0001), respectively. Conversely, the incidence of lymphopenia appeared with duration of imatinib treatment (p=0,04). Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

ABL Kinase Domain Mutation in Chronic Myeloid Leukemia - Compliance to Imatinib Matters

Background: Imatinib resistance mutation analysis (IRMA) or abl kinase domain mutation analysis is performed in patients with Chronic myeloid leukemia (CML) whenever the response to treatment is inadequate. We have analyzed the reports of IRMA at our centre. Methods: The clinical details of 71 patients with CML on Imatinib, who underwent IRMA testing during the period of January 2017 to March 2019 were collected from the patient records and analyzed. IRMA was performed for failure or warning or progression, anytime during the course of treatment. IRMA was done by either Sanger sequencing (n=45) or next generation sequencing (n=26, Illumina, NGS). The associations between variables were tested using Chi - Square test. Results: Median age at diagnosis of 71 patients was 44 years (Range 18 - 71 years). Males constituted 70% (n=50). At diagnosis, 92% (n=65) of patients were in chronic phase and the remainder were in accelerated phase (n=4) or blast crisis (n=2). Mutations in the abl kinase domain were detected in 26 patients (37%). Next Generation Sequencing (NGS) could identify more mutations (13/26 - 50%) compared to conventional Sanger Sequencing (13/45 - 29%), but the difference was not significant (p=0.07). NGS could identify three or more mutations in 5 patients in contrast to Sanger. All the mutations detected were those previously described except for an insertion of 35bp near the C-Terminal which was identified in 3 patients. E459K translocation was identified in 6 patients. E355G translocation was identified in 4 patients. F359V, M351T, Y253H, G250E, H396R, T315I translocations were identified in 3 patients each. Patients who were not compliant to therapy had increased frequency of mutations (14/26 - 54%) compared to those who were compliant (12/45 - 27%), which was significantly different (p=0.02). Patients who had loss of complete hematological response (CHR) had significantly higher frequency of mutations (14/21- 67%) compared to other reasons for performing the test (p=0.001). Patients who had failure to achieve targets at various time points had a significantly lower frequency of mutations (4/23 - 17%, p=0.02) compared to other reasons for performing the test. Conclusion: Patients who were not compliant for treatment were more likely to have mutations. Loss of CHR showed an increased frequency compared to other reasons. NGS could identify mutations in more number of patients. NGS identified numerically higher mutations in patients. Larger prospective data are needed to confirm these observations. Table Disclosures No relevant conflicts of interest to declare.

Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Practical Recommendations)

Background. The tyrosine kinase inhibitors (TKI) era is marked by a long-term favorable prognosis of chronic myeloid leukemia (CML). In this context CML patients of reproductive age are faced with major issues of family planning with due regard to the risk of TKI treatment interruption during pregnancy. Additionally, TKI impact is another potential risk to the fetus. Aim. To develop differentiated approach to CML treatment during pregnancy. Materials &amp; Methods. Analysis includes literature data and clinical experience based on 166 pregnancies of 120 CML patients from CML Pregnancy Registry. Results. Pregnancy planning is recommended after achieving stable and deep molecular response (with BCR-ABL &gt; 0.01 %, IS) within the period of at least 2 years. At conception TKI therapy does not have to be interrupted. However, early pregnancy detection and TKI treatment interruption after pregnancy confirmation are of vital importance due to teratogenic risks. Furthermore, no TKI may be administered during organogenetic period, i.e. up to the 15&lt;sup&gt;th&lt;/sup&gt; week of gestation. In the absence or loss of complete hematologic response and growth of BCR-ABL &gt; 1 % after the 15&lt;sup&gt;th&lt;/sup&gt; week of gestation imatinib or nilotinib administration is justified in the interest of pregnant patients taking into account limited transfer of these drugs through placenta. In the absence of complete hematologic response before the 15&lt;sup&gt;th&lt;/sup&gt; week of gestation interferon-а can be administered. With BCR-ABL &lt; 1 % patients can be either followed-up without therapy or they can receive interferon-а throughout pregnancy. Dasatinib, bosutinib, and other TKI are contraindicated at any stage of pregnancy. There are no special recommendations for childbirth, delivery is to be adapted to obstetric conditions. Breast feeding is not recommended because of the lack of practical evidence for its safety. Conclusion. A regular molecular monitoring of BCR-ABL and hematologic status is indispensable, health condition of fetus should be continuously monitored as well. CML patient management should be conducted by cooperating hematologists and gynecologists.

Efficacy and Safety of Generic Imatinib Compared to Glivec in Chronic Phase - Chronic Myeloid Leukemia - a Multicenter, Observational Study

Glivec was the first tyrosine kinase inhibitor (TKI) approved for chronic myeloid leukemia (CML) treatment and its efficacy has been demonstrated in a large number of trials. Generic formulations have been used recently as a more cost effective treatment, but there are few studies that have prospectively evaluated the efficacy and safety of these drugs.Aims: The present study aimed to evaluate the efficacy and safety of generic imatinib in CP-CML in first line therapy. Methods: This is a multicenter, observational, cohort-type study. The prospective cohort consisted of patients who initiated treatment with generic imatinib between January 2015 and September 2017; whereas the retrospective cohort was treated with Glivec between January 2010 and December 2011. All patients started imatinib in CP, less than six months from diagnosis. Patients were managed according to European Leukemia Net (ELN) 2009 and 2013 recommendations. The definition of the responses followed the ELN 2013 criteria. Adverse events were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.3, 2010. Event-free survival (EFS) was measured from starting date of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated (AP) or blast crisis (BC) or death from any cause at any time during initial therapy or discontinuation of imatinib by any cause. Patients that switched from Glivec to generic where censored. Overall survival (OS) was measured from starting date of imatinib until to the date of death from any cause while on therapy or last seen. Progression-free survival (PFS) was measured from starting date of imatinib to transformation to AP or BC or deaths while on therapy. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Cox regression was used with Backward Wald Method. SPSS version 21.0 was used applying the chi-square and t-test, when adequate. All analysis considered p-value <0.05 as significant.Results:A total of 445 patients were analyzed (Glivec=285; Generic=160). The median age was 54 years (18-87) in Glivec and 50 (18-89) in the Generic group (P=0.027). Sokal score stratification in Glivec and generic groups, was respectively: low risk 14.4%/25.7%; intermediate risk 42.3%/38.2% and high risk 43.3%/36.1% (P=0.02). B3a2 frequency was 51.5% vs. 37.7% in Glivec and Generic group, respectively, and b2a2 41.4% vs. 53.8% (P=0.017). There was no significant difference in gender, Hasford, EUTOS scores and ECOG. The median follow-up was 25 months (0-71) and 11 months (0-31) for Glivec and Generic groups, respectively (P<0.0001). The median time between diagnosis and imatinib starting was 18 days (0-119) in Glivec and 27 days (0-168) in the Generic group (P= 0.015). The rate of treatment failure at 3 months according to the ELN 2013 criteria was 6.6% and 14.7% in Glivec vs. Generic (P=0.04); whereas at 6 months there were no significant differences (12.3% vs. 18.9%; P=0.09). There was no significant difference in grade 3 and 4 hematological and non-hematological toxicity during the follow-up. There were 5 and 3 cases of progression in the Glivec and Generic group, respectively. In the Cox regression multivariate analysis, the independent factors for EFS were age at diagnosis (HR=1.03; CI95% 1.00-1.07; P=0.039) and toxicity grade 3-4 (HR 3.37; CI95% 1.08-10.4; P=0.036). The initial therapy was discontinued for the following reasons, in Glivec and generic group respectively: resistance (19.7% vs. 47.5%), intolerance (15.3% vs. 23.7%), non-adherence (4.4% vs. 3.4%), death (2.0% vs. 6.8%), clinical trial (0.5% vs. 10.2%), progression (2.0% vs. 5.0%), pregnancy (0 vs. 3.4%), switch from Glivec to generic (56.1%). OS, PFS and EFS at 24 months were higher in Glivec group in comparison to Generic (99% vs. 96%, P=0.016), (98% vs. 95%, P= 0.026) and (73% vs. 58%; P<0.0001 respectively.Conclusion: The group treated with generic imatinib presented higher rate of failure at 3 months and lower OS, PFS and EFS at 24 months. Differences between the groups included a longer time to initiate treatment in the Generic group, a higher proportion of patients with b2a2 transcripts, which were related to an inferior rate of molecular responses and survival in other studies. There was no difference in the safety profile. The long-term impact in prognosis will be evaluated after a longer follow-up. DisclosuresPagnano:Shire: Other: Lecture; Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Novartis: Consultancy. Magalhaes:Novartis: Consultancy, Other: Lecture. Clementino:EMS: Other: Financial support for congress. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Centrone:EMS: Other: Financial support for congress, Speakers Bureau; Bristol Meiers-Squibb: Other: Financial support for congress, Speakers Bureau; Novartis: Other: Financial support for congress, Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Other: Financial support for congress, Speakers Bureau. Fogliatto:Novartis: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding. Giai:Pfizer: Consultancy; Novartis: Consultancy. Bortolheiro:Abbvie: Consultancy, Speakers Bureau; Sanoffi: Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Analysis of Adverse Events of Dasatinib and Nilotinib in Chronic Phase Chronic Myeloid Leukemia Patients Treated Outside Clinical Trials

▪Background Patients with chronic myeloid leukemia (CML) encounter lifelong treatment. Incidence and severity of adverse events (AEs) of tyrosine kinase inhibitors (TKIs) are therefore one of the most important factors when making treatment decisions; yet studies focusing on AEs in "real life" setting and their impact on drug discontinuation and treatment outcomes are lacking.Methods We retrospectively analyzed the rates and severity of AEs in 201 patients with chronic phase CML treated with nilotinib or dasatinib used as both first- and second-line therapy in two Korean tertiary care centers. AEs were graded according to Common Terminology Criteria for Adverse Events version 4.03. Event-free survival (EFS) was defined as the time from the start of the treatment to the earliest date of any of following event: treatment discontinuation due to AEs, loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), loss of major molecular response (MMR), 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. Progression-free survival (PFS) was defined as the time from the start of the treatment to the earliest date of any of following event: loss of CHR, MCyR, MMR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy.Results There were 135 men (67%) and 66 women (33%). One-hundred and twenty (60%) received nilotinib (first line, n = 68; second line, n = 52) and 81 (40%) patients received dasatinib (first line, n = 37; second line, n = 44). For the majority of patients who received second line treatment with nilotinib and dasatinib, reason for imatinib discontinuation was resistance (81% in nilotinib group and 80% in dasatinib group). The median starting dose of nilotinib was 600mg/day (range 600 - 800mg/day) and dasatinib 100mg/day (range 100-140mg/day). During the median follow-up of 36.9 months (8.0 - 114.1) for nilotinib group and 37.2 months (2.2 - 95.0) for dasatinib group, 88.3% (106/120) of patients in nilotinib group and 86.4% (70/81) in dasatinib group experienced AEs. Dasatinib group had significantly higher grade 3-4 AEs compared to nilotinib group (21.7% vs. 54.3%, p < 0.001); however, rate of grade 3-4 non-hematological AEs were similar in both groups (13% vs. 14%, p = 0.960). Dasatinib group had more frequent dose reduction, interruption, and drug discontinuation (p < 0.001, p = 0.004, and p = 0.006, respectively).At the time of analysis, 58 out of 201 (29%) discontinued treatment because of AEs (n = 47, 23%), resistance (n = 9, 5%), or other reasons (n = 2, 1%). Eighty one percent (47 out of 58) of drug discontinuation was due to AEs, and half of AE leading to drug discontinuation was grade 2. Treatment discontinuation occurred more rapidly in the first line setting than in the second line setting (duration of treatment, 2.9 months vs. 15.6 months, p = 0.015). Pleural effusion occurred in 35% (n = 28) in dasatinib group, and led to dasatinib discontinuation in 14 patients (Grade 2, n = 11; Grade 3, n = 3). One patient stopped dasatinib due to pulmonary artery hypertension. In nilotinib group, stroke, acute coronary syndrome and peripheral artery occlusive disease (PAOD) occurred in 5% (n = 6); only PAOD led to nilotinib discontinuation.Dasatinib group had significantly shorter duration of EFS than nilotinib group (median EFS not reached [NR] vs. 48.7 months, p = 0.040 for first line treatment; NR vs. 50.5 months, p = 0.036 for second line treatment). However, PFS did not show statistically significant differences (p = 0.505 for first line and p = 0.179 for second line).Conclusion AE was the main cause of nilotinib and dasatinib discontinuation in CML patients. Persistent grade 2 AEs, especially pleural effusion, were hard to manage and this translated into early discontinuation of drug especially in the first line setting and significantly shorter EFS in dasatinib treated patients compared to nilotinib treated patients. Large, prospective population based studies with long term follow-up are warranted to confirm our finding. DisclosuresNo relevant conflicts of interest to declare.

Influence of BCR-ABL Transcript Type on Outcome in Patients with Chronic-Phase Chronic Myeloid Leukemia Treated with Imatinib 400 Mg

The prognostic significance of BCR-ABL1 transcripts in chronic myeloid leukemia (CML) is controversial. A recent report demonstrated that patients with e13a2 transcripts have inferior outcomes with imatinib 400 mg and those patients with e14a2 or that express both transcripts have more chance of an optimal response and longer event-free and transformation-free survival, while others do not confirm this data.The aim of this study was to evaluate the impact of BCR-ABL transcript type in CML patients outcome.Patients and methods: all consecutive CML patients in chronic phase treated with imatinib 400 mg/day from February 2004 to January 2016 were enrolled. Patients’ responses were monitored with cytogenetic analysis at 3, 6 and 12 months, then every six months until a complete cytogenetic response (CCR). Real-time polymerase chain reaction was assessed at baseline, then every 3 months for the first year until reaching a stable major molecular response, then every 3-6 months. Demographic and baseline disease characteristics were collected at diagnosis. The type of BCR-ABL1 transcript was evaluated by multiplex RT-PCR from cDNA synthesized from total leukocytes RNA at diagnosis. We included patients with BCR-ABL transcripts e13a2, e14a2, and with coexpression of e13a2 and e14a2. Statistical analysis: Event-free survival (EFS) was measured from the start of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated (AP) or blast phase (BC) or death from any cause at any time while on initial therapy. Overall survival (OS) was measured from the start of imatinib until to the date of death from any cause at any time or last follow-up. Transformation-free survival (TFS) was measured from the start of imatinib to transformation to AP or BC or deaths while on therapy. The differences between variables were analyzed by the χ2 and the Kruskal-Wallis tests for categorical and continuous variables. Survival probabilities were calculated using the Kaplan-Meier method and compared by the log-rank test. The Cox regression estimated the hazard ratio values. All analysis considering p-value < 0.05 and using SPSS 21.0 software. Results: A total of 190 patients were treated with imatinib 400 mg/day. Median age was 48 years (18-87) and Sokal risk was high in 47/151 patients (31%), intermediate in 55/151 (36%) and low in 49/151 (33%). Twenty patients were excluded from the analysis: 14 patients due to Interferon treatment before Imatinib; two patients that started imatinib after six months from diagnosis; two patients with e1a2 transcripts and two patients with no RT-PCR test available at diagnosis. The remaining 170 patients presented typical BCR-ABL1 transcripts: e13a2 (n=56; 33%), e14a2 (n=94; 55%) and both transcripts (n=20; 12%). A total of 44 (26%) patients discontinued imatinib and 24 (14%) switched to second-line tyrosine kinase inhibitor. No differences were observed in sex, age, leukocytes, hemoglobin and platelets count at diagnosis, Sokal or EUTOS score according to transcript type. The proportion of patients with e13a2, e14a2 and both achieving complete cytogenetic response at 6 months was 19/44 (43%); 42/60 (70%) and 9/14 (64%) (P=0.02); and at 12 months was 28/45 (62%); 47/60 (78%) and 11/14 (78%) (P=0.16). However, the proportion of patients with major or lower molecular responses at 18 months was 13/24 (54%), 25/36 (69%) and 6/9 (66%), which was not significantly different. There were no statistical difference in EFS, PFS, and OS among the e13a2, e14a2 and e14a2+e13a2 groups. However, there was a superior 10-year overall survival in patients with transcripts e13a2 compared to e14a2 (alone or coexpressed with e13a2) (93% vs. 73%, P=0.03), although the 5-year overall survival was 96% vs. 88%, respectively (P=NS). In the multivariate analysis, high/intermediate Sokal score and e14a3/e14a3+e14a2 were independent factors for poor OS (P=0.023 and 0.041, respectively).Conclusion: The type of BCR-ABL transcripts did not affect molecular responses. Although patients with e14a2 transcripts presented higher rates of CCR at 6 months, compared to e13a2 or both transcripts, at long term, there was a superior overall survival among patients with transcripts e13a2 compared to e14a2 (alone or coexpressed with e13a2). The biological mechanism responsible for that difference is not known and should be investigated in larger trials. DisclosuresPagnano:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria.

Rare Case of Alternative Splicing Form Caused By L248V Mutation in CML Patient

Clinical data: Subject: Male, 45 years old, diagnosed in 2001 with Ph+ CMLCP (low Sokalrisk).From 2001 to 2005 he was treated with Hydrea and Interferon with low dose Cytarabine. In 2005 he was switched to imatinib 400 mg/day. Due to cytogenetic resistance Imatinib dose was escalated to 600mg/day in 2006 and 800mg/day in 2007. No cytogenetic response was obtained. In 2009 patient was switched to nilotinib. Nilotinib therapy was discontinued in 2012 due to loss of complete hematologic response. Patient refuses unrelated donor allo HSCT. INFa 3000 U/3 times a day was given with prolonged stable complete hematologic response. Myeloid blasts crisis was diagnosed in Jan 2013. (The time patient was hospitalized to Almazov medical research center). Dasatinib 140mg/day was started without rapid blast reduction.The response lost in a few weeks, followed by 2 couses of FLAG regimen. Patient died in Dec 2013.BCR-ABL KD mutations history: 2007- no mutations found; 2009- no mutations found, February 2013 -L248V mutation; July 2013 mutation analysis returns no result due to the poor sequence quality;T315I mutation revealed in samples obtained from October 2013.BCR-ABL mutation analysis: Bcr-Abl analysis performed as described before (Branford et al., 2002). KD sequence was amplified from cDNA using seminested PCR, PCR product extracted from gel and sequenced in the both directions on ABI 3130 genetic analyzer. For confirmation we used genomic DNA extracted from stored peripheral blood samples. Primers specifically amplifying exon 4 and 5 of ABL used for genomic DNA analysis. Analysis of the sequences was done using UGENE software.Results: We analyzed two sets of probes- one dated March 2011 and another dated October 2013. After performing semi-nested PCR on BCR-ABL KD sequence we found at least two bands in each of the samples. Sequencing of this bands revealed 81 bp deletion translated into absence of 27 aa position at 248-274. Genomic DNA analysis confirmed alternative splicing and appearance of the truncated form. We found SNP resulted in T315I mutation presented either in full or in short isoform of BCR-ABL in samples from October 2013. Also we confirmed L248V mutation presented in all analyzed samples.Conclusion: SNP that cause L248V mutation in BCR-ABL transcript known to activate cryptic promotor in ABL exon4 with subsequent appearance of alternative splicing form described before (Gruber et al., 2006). Truncated form known to be kinase dead and have no influence on disease course (Shebenou et al., 2008). On the other hand it disturbs the Sanger sequence quality, masking the appearance of the additional mutations. Extensive attention requires in obtain proper sequence quality: use genomic DNA for Sanger sequencing or alternative sequencing methods, e.g. single-molecule long-read sequencing for revealing mutations in multiple splice isoforms.

Does the Achievement of MR4.5 Improve the Outcome of Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Front Line Tyrosine Kinase Inhibitors (TKI)?

Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy.Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason.Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table).Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials.Table 1Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points.Time pointEFSFFSTFSOSHR95% CIp-valueHR95% CIp-valueHR95% CIp-valueHR95% CIp-value12 months0.820.42-1.610.570.940.58-1.530.810.990.46-2.120.981.060.47-2.390.8918 months0.960.51-1.820.90.750.45-1.250.271.340.69-2.810.361.410.68-2.940.3524 months0.850.44-1.650.630.80.49-1.330.390.90.41-2.010.80.990.43-2.250.9730 months0.750.35-1.620.470.640.36-1.150.140.820.34-1.960.650.980.40-2.390.9736 months0.980.46-2.090.960.550.30-1.020.061.110.47-2.650.811.240.52-2.950.6348 months0.860.35-2.100.730.70.35-1.400.310.840.29-2.430.750.860.30-2.480.78 DisclosuresPemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

Impact of Transition to Generic Imatinib in the Molecular Response Among Patients with Chronic Myeloid Leukemia

Background: The introduction of Imatinib Mesylate (Gleevec™), a tyrosine kinase inhibitor (TKI), has revolutionized the management of Chronic Myeloid Leukemia (CML). Recently, on April 2, 2013, Health Canada approved two generic versions of imatinib mesylate (Apotex and TEVA) for sale in Canada—both of which, have been shown to be bioequivalent to the brand name Gleevec™, with similar serum imatinib levels and area under the curve after oral ingestion. In one of the largest case series reported to date (N=126), it has been reported that complete hematologic response (CHR) was lost in 33% of CML patients who were switched from brand name to generic imatinib. In an effort to assess the generalizability of this claim, we conducted a retrospective review of all patients with CML treated with Gleevec™ at a single tertiary care centre to evaluate whether there was a change in CHR or major molecular responses (MMR) in all patients who were switched to generic imatinib.Method: We retrospectively evaluated adult CML patients who were treated from January 1, 2002 to December 2011 with brand name Imatinib (Gleevec™) and were switched to generic imatinib (Apotex or TEVA) during 2013. Patient-reported side effect profiles were also collected in a subset of patients before and after the change from Gleevec™ to generic. A follow-up period was defined as 12 months from the time of switch from brand name to generic. The primary outcome was a composite of rates of loss of CHR and/or MMR, based on the Canadian Consensus Group of the Management of Chronic Myelogneous Leukemia (CCGM-CML). Secondary outcome include side effect profiles, graded as per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), during the follow-up period.Results: During our study period, a total 71 adult CML patients were identified. Of these, only 30 patients were included in the analysis. Among the 41 patients who were excluded, data could not be retrieved in 23 (32.4%), 9 (12.7%) were on dasatinib, 3 (4.2%) were on nilotinib, 2 (2.8%) were transplanted and 4 (5.6%) had died at the time of the switch. Data was collected using electronic medical records from patient clinic visits. The median age of all included patients was 54 years and 16 (53.3%) were male. The primary endpoint was seen in 2 of 30 patients (6.7%; 95% CI 3.5-25.6). There was a loss of MMR in 1 (3.3%) where the BCR-ABL transcript declined from a 4.19 log reduction to a 2.78 log reduction after switching to TEVA-imatinib. There was a loss of CHR in 1 (3.3%) patient, where a 20 g/L drop in hemoglobin was seen after switching to APO-imatinib. In both patients in whom the primary endpoint was seen, their imatinib dose was 200 mg before and after switching. Further, in both patients, these losses of response were transient. The secondary outcomes will be presented at the meeting.Conclusion: The generic formulations of imatinib used in Canada do not seem to be associated with the same previously reported lack of clinical efficacy when compared to brand name Gleevec™ during a follow-up period of 12 months. Further, a loss of MMR and a loss of CHR were transient in the 2 of 30 patients identified. Despite these infrequent events, treating physicians should consider that a switch to a generic formulation may be a contributing factor for the patient’s loss of MMR or CHR. However, given the wide confidence intervals, larger studies and longer follow up are needed to address this issue. DisclosuresNo relevant conflicts of interest to declare.

Efficacy of Nilotinib Vs High-Dose Imatinib Vs Sustaining Standard-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Response to Frontline Imatinib

Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of nilotinib (NIL) versus high-dose IM versus sustaining standard-dose IM for CCyR patients with suboptimal molecular response to frontline IM therapy.Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were divided into 3 treatment groups; NIL 400mg BID (800 mg/day; group 1) vs IM 400 mg BID (800 mg/day; group 2) vs IM 400mg QD (400mg/day; group 3). Group 1 and 2 patients were selected in RE-NICE multicenter study and group 3 patients were selected with the same inclusion criteria of RE-NICE.The efficacy endpoints are MMR rate by 12 months and MMR rate and undetectable molecular residual disease (UMRD) rates by 36 months. Safety profiles of each group were compared.Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or intolerance to treatment were allowed to switch to other treatment.Results. With a data cut-off date of 17 Jul 2014, a total of 83 patients were evaluated; 29 patients in NIL group (group 1), 29 patients in high-dose IM group (group 2) and 25 patients in standard-dose IM group (group 3).With a median follow-up of 36 months (range, 1-63), all patients in group 1 remained in nilotinib treatment, 17 patients in group 2 switched to NIL 400mg BID due to intolerance (n=4) and lack of response (no MMR; n=13). In group 3, with a median follow-up of 71 months (range, 6-132), 15 patients switched to other treatment due to intolerance (n=5) and lack of response (no MMR; n=10).Up to now, all patients in three groups have maintained CCyR without progression or resistance.10 in 29 (35%), 8 in 29 (28%) and 5 in 25 (20%) patients achieved MMR by 12 months, and 20 in 29 (69%), 15 in 29 (51%) and 11 in 25 (44%) patients achieved MMR by 36 months in group 1, group 2 and group 3 respectively. Overall, 3 patients in group 1 (3/29, 10%) achieved confirmed UMRD.Overall 3 years probability of MMR was significantly higher in group 1 than the other two groups (67.8% vs 41.0% vs 40.4%, group 1, 2, 3 respectively, group 1 vs 2, P=0.089, group 1 vs 3, P=0.035, group 2 vs 3, P=0.614).Compare to other groups, the patients in group 2 showed higher toxicities, such as leukopenia, anemia, thrombocytopenia, edema, fatigue, dyspnea and hypophosphatemia.Conclusions. Nilotinib 400mg twice daily treatment showed better efficacy than high-dose or same standard-dose imatinib for the treatment of patients who have suboptimal molecular response to initial standard-dose imatinib. Additionally, a switch to nilotinib in suboptimal molecular responder to imatinib would also be preferable option in terms of tolerability. Updated data with longer follow-up duration will be presented in the meeting. DisclosuresNo relevant conflicts of interest to declare.

Chronic Myeloid Leukemia in Chronic Phase: Survival in the Era of Tyrosine Kinase Inhibitors Is Similar to That of the General Population in All Age Groups

Abstract Introduction Tyrosine kinase inhibitors (TKIs) are effective treatments for chronic myeloid leukemia in chronic phase (CML-CP) in terms of response rates and clinical outcomes including overall survival (OS). The purpose of this study was to compare OS in each age group with newly diagnosed CML-CP compared to that of general population in the same age group in the era of multiple TKIs. Methods Response and survival data for 483 patients (pts) with newly diagnosed CML-CP who enrolled in five consecutive or parallel prospective clinical trials of imatinib at a dose of 400 mg or 800 mg daily, imatinib at a dose of 800 mg with pegylated interferon, dasatinib, or nilotinib were analyzed. The pts were divided into groups by age at diagnosis, as follows: 15-45 years; 45-65 years; 65-85 years; over 65 years. All pts, regardless of age, were divided into the following response groups within 1 year of treatment: complete cytogenetic response (CCyR); major molecular response (MMR); MR4.5 defined as more than or equal to 4.5 log reduction of BCR-ABL on the international scale; or complete molecular response (CMR). Pts also were assessed for OS, event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). OS was dated from the start of therapy until death from any cause at any time. EFS was calculated from the start of therapy to loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated (AP) or blast phase (BP), or death from any cause during study therapy. TFS was calculated from the start of therapy to transformation to AP or BP, or death during study therapy. FFS was calculated from the start of imatinib, dasatinib or nilotinib to an event (as defined above), discontinuation for any reason, or death. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test was used for univariate comparisons. Pvalues of less than 0.05 were considered statistically significant. Five-year relative survival rates were calculated from the five-year absolute OS divided by the estimated five-year OS in the general population. Estimated OS rates in the U.S. general population were obtained from national vital statistics reports for the year 2009. Results Of the 483 pts analyzed in the study, 271 were treated with imatinib, 101 with nilotinib, and 111 with dasatinib. The age breakdown was as follows: 15-45 years, 197 pts; 45-65 years, 222 pts; 65-85 years, 64 pts; over 65 years, 64 pts. No pts older than 85 years were enrolled in this study. Sokal risk score at diagnosis, and type of TKI treatment were analyzed by age group, cumulative best response, and five-year OS, EFS, TFS, and FFS, and the results are summarized in Table 1. Five-year OS in the general population, relative five-year OS in all age groups, and relative five-year OS by response group are also described in Table 1. As expected, 5-year OS decreased with increasing age groups, but for all age groups OS was similar to 5-year OS in the corresponding age group in the general population. 5-year OS in pts of ages 15-85 who achieved CCyR or better was similar to that in the general population. Conclusion In the era of TKIs, the OS rates in pts with newly diagnosed CML-CP in all age groups are only slightly lower to that of general population. However, the OS rates in pts who achieved CCyR or better within 1 year of treatment is similar to that of general population. Table 1. Patient Characteristics and Outcomes by Age Group Age 15-45 [n= 197] No. (%) Age 45-65 [n= 222] No. (%) Age 65-85 [n= 64] No. (%) P Sokal Risk Score .419 Low 129 (65) 158 (71) 48 (75) Intermediate 56 (28) 48 (22) 12 (19) High 12 (6) 16 (7) 4 (6) Type of TKIs .364 Imatinib 113 (57) 116 (52) 42 (66) Nilotinib 42 (21) 50 (23) 9 (14) Dasatinib 42 (21) 56 (25) 13 (20) Cumulative Best Response CMR 91 (46) 124 (56) 33 (52) .142 MR4.5 127 (64) 158 (71) 47 (73) .230 MMR 162 (82) 197 (89) 54 (84) .162 CCyR 171 (87) 208 (94) 59 (92) .048 5-y Outcome (%) FFS 77.9 74.5 60.6 .043 TFS 93.8 93.4 87.4 .224 EFS 81.0 89.2 78.9 .094 OS 96.2 93.5 80.1 &lt; .001 5-y Absolute OS 5-y Relative OS 5-y OS in General Population Age Group (%) Ages 15-45 96.2 96.9 99.3 Ages 45-65 93.5 97.1 96.3 Ages 65-85 80.1 97.1 82.5 Ages 15-85 92.7 98.2 94.4 Ages 15-85 by Response (%) CCyR within 1 year 97.3 103.1 94.4 MMR within 1 year 97.9 103.7 94.4 MR4.5 within 1 year 97.1 102.9 94.4 CMR within 1 year 96.7 102.4 94.4 Disclosures Jabbour: Ariad, Novartis, BMS, Pfizer, and Teva : Consultancy. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

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

BackgroundMonitoring 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.ObjectivesWe 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).MethodsThis 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.ResultsWe 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).ConclusionsA 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. DisclosuresNo relevant conflicts of interest to declare.

Phase II Clinical Trial Results of Dasatinib for Frontline Therapy in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)

▪Background: Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005, we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP.Objective: To determine the long-term outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was achievement of major molecular response (MMR) at 12 months (mos).Methods: Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for <1 month, or hydroxyurea.Results: From November 2005 to August 2014, a total of 155 pts have been enrolled. For this analysis, we included only those pts with a minimum of 12 mos follow-up: 107 pts (77 QD, 30 BID). Median age was 48 years (yrs) (range 16–83 yrs). Median baseline counts: WBC 26.4 K/uL, peripheral blood blasts 0%, bone marrow blasts 2%, and platelets 333 K/uL. Twenty-seven pts (25%) had brief prior exposure to IM. Sokal score by distribution: Low (76%), Intermediate (21%), High (4%). Median follow-up is 62.9 mos (11.7 - 104.1 mos). Of the 99 evaluable pts who were not in CHR at the start of therapy, 99 (100%) achieved CHR. Of 105 evaluable pts (ie, followed for at least 3 mos), 105 (100%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 94 pts (90%), including 59 pts (56%) with complete molecular response (CMR; minimum 100,000 ABL copies). BCR-ABL/ABL <10% at 3 mos occurred in 100/106 evaluable (94%) and at 6 mos in 98/104 evaluable (94%). At 6 mos, 93/102 evaluable (91%) pts had achieved a CCyR and 69/101 evaluable (68%) an MMR; corresponding figures at 12 mos are 92/97 pts evaluable (95%) and 73/95 pts evaluable (77%), respectively. Fifty-eight pts (54%) have required at least one dose reduction (most common reasons: 22 pts had dose reductions due to pleural effusions, 8 due to neurologic/headaches, 4 due to thrombocytopenia). The actual median daily dose for all pts was 80mg (20–140mg). Five pts lost CCyR: (2/5 of these pts who lost CCyR ultimately progressed to accelerated phase (CML-AP)). The 3-yr and 5-yr overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) are shown in the Table. There have been two deaths on study (1 pt: 74 yr-old woman with sepsis/infection; 1 pt: 53 yr-old man with morbid obesity and hypertension who died of unknown causes). Twenty-six (24%) pts have discontinued therapy: 11 due to toxicity (most commonly due to pleural effusion in 7 pts), 5 pt choice, 5 lost CCyR, 2 died on study, 2 pt non-adherence, 1 due to development of T315I mutation.Conclusion: Rapid CCyR occurs in nearly all pts, and MMR was achieved in 90% of pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. Deep responses occur early. Only two patients experienced transformation to CML-AP, and only one patient developed T315I mutation. These results confirm the sustained efficacy of dasatinib as initial therapy for CML-CP.Table:Outcomes at 3-year and 5-year timepoints in patients with CML treated with frontline dasatinibTotalEvents3-Year5-YearOS107598%95%EFS107895%92%TFS107499%95%FFS1072484%76%*Definitions:EFS: includes, at any time on study: International Randomized Study of Interferon and STI571 trial (IRIS)-defined events, which includes loss of major cytogenetic response, loss of complete hematologic response, transformation to accelerated or blast phase, death from any cause while on study. FFS: includes loss of complete cytogenetic response, failure to achieve response at set times as defined by European Leukemia Net, treatment intolerance, or treatment discontinuation for any reason while on study. TFS: measured from start of therapy to date of transformation to accelerated or blast phases while on therapy or to date of last follow-up. DisclosuresKantarjian:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Research Funding. O’Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Ravandi:BMS: Honoraria, Research Funding. Verstovsek:Incyte Corporation: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

TKI Treatment Discontinuation: How Many Patients Could Stop Tyrosine Kinase Treatment According to Discontinuation Trials Criteria? Incidence and Prognostic Impact of Deep Molecular Response in a Cohort of Chronic Myeloid Leukemia Patients of South Brazil’s Hematology Centers

Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment.OBJECTIVESThe main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial.PATIENTS AND METHODSThis is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated 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. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (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. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive.RESULTSData from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information.CONCLUSIONIn our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. DisclosuresNo relevant conflicts of interest to declare.