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<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<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.

Effect of echocardiogram prior to induction therapy for acute myeloid leukemia on detection of cardiac dysfunction and treatment modifications.

e18514 Background: Standard induction therapy for acute myeloid leukemia (AML) includes “cytarabine and anthracycline”. Anthracyclines are known to cause acute, subacute and chronic cardiac complications ( Lefrak , EA et al, Cancer 1973:32(2):302-314; Singal, PK et al, NEJM 1998;339(13):900-905). It is recommended to do base line cardiac function assessment with echocardiogram prior to induction therapy containing anthracycline. This study was done to find the frequency of changes made in avoiding anthracycline usage following this evaluation. Methods: The Mayo clinic data base was interrogated to identify patients with newly diagnosed AML who underwent echocardiogram prior to anthracycline containing induction chemotherapy. Echocardiogram results, including left ventricular ejection fraction (LVEF), diastolic dysfunction, valvular disease, and any resultant treatment alterations were reviewed. Results: Three hundred twenty six patients were identified. The median (range) age was 61 (17-82) years and 62% were male. The median (range) LVEF was 65% (30-87), and 3 (0.9%) patients had LVEF < 50% (range 30-47%). Of these 3 patients, 1 had 4 vessel CABG a decade ago, his EF was 46% and treated with full dose idarubicin; 2 of them presented with blastic crisis, 1 had EF 46% and improved to 51% after 5 days and then given daunorubicin, the other one had an EF of 30% and treated with 50% dose reduced cytarabine alone. Sixty five (23%) patients had previous chemotherapy or radiation exposure, including 24 (7.4 %) with previous anthracycline, 14 (4.3%) had prior radiation to the chest wall. No patient with previous chemotherapy or radiation exposure had a reduced LVEF. Conclusions: Echocardiography prior to anthracycline therapy rarely detects abnormal LVEF. Screening echo may be helpful in those presented with leukemic blastic crisis or had previous exposure to chemo-radiation.

Whole Exome Sequencing Reveals That DNMT3A and ASXL1 Mutation Are Involved in the Development of Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia Patients without ABL1 Tyrosine Kinase Domain Mutation

BACKGROUND: Tyrosine kinase inhibitor (TKI) resistance is the most relevant event during the treatment of chronic myeloid leukemia (CML), which correlates with high risk of treatment failure, disease progression and death, explaining half of treatment failed CML patients. However, the remaining half with TKI resistance does not show any ABL1 tyrosine kinase domain (TKD) mutation indicating the presence of alternative pathogenic pathways behind TKI resistance. Thus we hypothesized that the novel mutation besides ABL1-TKD mutation occurs during the development of TKI resistance. Using whole exome sequencing, we screened 13 pairs of CML cases with TKI resistance, but without ABL1-TKD mutation. The present study attempts to: 1) explore novel mutation(s) developing TKI resistance to CML treatment and 2) validate the somatic variants in an independent cohort of CML patients (n=100). METHODS: Thirteen CML cases with TKI resistance but not having ABL1 TKD mutation were included prospectively. Reason for TKI resistance includes Loss of MCyR (n=7) with (n=2) or without additional cytogenetic abnormality (ACA; n=5), progression to blastic crisis (n=3), development of ACA (n=1), development of clonal evolution in Ph neg clone (n=1), primary cytogenetic resistance (n=1). TKI resistance were demonstrated to imatinib (n=12), dasatinib (n=5), nilotinib (n=4) or ponatinib (n=2). The latest treatment includes ponatinib (n=3), dasatinib (n=8) alone (n=4), with smoothen inhibitor (n=2), or with after systemic chemotherapy (n=2), omacetaxine (n=1), and nilotinib (n=1). Disease stage at the time of exome sequencing was chronic phase (n=10) or blastic crisis (n=3). Germline and tumor samples at the time of TKI resistance were compared using whole exome sequencing (Illumina TruSeq kit, HiSeq 2000). Targeted sequencing for selected variants was performed to validate the result. All patients were confirmed the absence of ABL1-TKD mutations using Sanger sequencing. RESULTS: 1) Exome sequencing (Illumina Truseq kit) was performed as per the manufacturer's protocol using an Illumina HiSeq 2000 sequencer. DNA from buccal mucosa was used as a control for variant calling. Exome sequencing reads processing includes mapping to human genome hg19, marking PCR duplicates, realignment of indels, fixing mate information, and discard the reads with more than 2 mismatches to increase the true positive rate. In the end, we have on-target-coverage of 57x. Lastly, 72% of target positions are mapped more than 30x. 2) One hundred nineteen somatic variants were identified in 13 patients in 108 genes. Among them 5 genes have variants in multiple patients including DNMT3A (n=3), ASXL1 (n=2), NPIPB5 (n=2), ATXN3 (n=2) and EFEMP1 (n=2) . We also found at least 1 mutation in well-known driver genes in 6 patients (6/13 = 46%). 3) Three out of 4 patients with ACA carry variants at least one of DNMT3A (n=2), ASXL1 (n=2), and SETBP1 (n=1). Also, 2 out of 3 cases progressed to blastic crisis demonstrate variants in DNMT3A (n=1) and IDH1 (n=1). 4) Interestingly, in one patient, exome sequencing reveals ABL1-TKD mutation (T315I), which was not detected at the initial screening by Sanger sequencing. 5) The result of targeted sequencing in an independent cohort of CML patients (n=100) will be presented in the annual meeting of American Society of Hematology in Dec 2015. CONCLUSION: Our study suggest that DNMT3A and ASXL1 mutations seem to be the driver mutations involved in the development of TKI resistance/progression, independent of ABL1-TKD mutation. Also, exome sequencing can detect ABL1-TKD mutations including T315I prior to be detected by initial Sanger sequencing. Disclosures Lipton: Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.