Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs. high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62;

Side-effects Profile and Outcomes of Ponatinib in the Treatment of Chronic Myeloid Leukemia

Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits

Molecular characteristics and outcomes in Hispanic and non‐Hispanic patients with acute myeloid leukemia

Abstract Hispanic patients have been reported to have an increased incidence of AML and possibly inferior outcomes compared to non‐Hispanics. We conducted a retrospective study of 225 AML patients (58 Hispanic and 167 non‐Hispanic) at two academic medical centers in Florida. Disease characteristics, cytogenetics, mutation profiles, and clinical outcomes were assessed. Hispanic patients were younger at presentation than non‐Hispanics (p = 0.0013). We found associations between single gene mutations and ethnicity, with IDH1 mutations being more common in non‐Hispanics (95.2% vs. 4.8%, p = 0.0182) and WT1 mutations more common in Hispanics (62.5% vs. 37.5%, p = 0.0455). We also found an emerging trend towards adverse risk cytogenetics in Hispanic patients (p = 0.1796), as well as high risk fusions such as MLL‐r (70% vs. 30%, p = 0.004). There was no difference in overall survival (OS) between Hispanic and non‐Hispanics patients. When examining only newly diagnosed patients (n = 105), there was improved OS in Hispanics (median 44.7 months vs. 14 months, p = 0.026) by univariate analysis and equivalent OS by multivariate analysis (hazard ratio = 1.52 [95% CI = 0.74–3.15]). Hispanics with a driver mutation not class‐defining had improved survival compared to non‐Hispanics. Our study demonstrates significant genetic differences between Floridian Hispanics and non‐Hispanics, but no difference in OS in patients treated at an academic medical center

Increased Frequency of IDH1/2 Mutations in Extramedullary Acute Myeloid Leukemia

Abstract Introduction The identification of somatic genomic alterations in cancer has brought forth a paradigm change in the personalized management of patients with acute myeloid leukemia (AML). This is exemplified by the recent FDA approvals with the targeted small molecule inhibitors of mutant IDH1 (ivosidenib) and IDH2 (enasidenib) for patients with relapsed/refractory AML. IDH1/2 mutations have been reported to occur in approximately 16-20% of patients with AML based on the largest published cohorts to date (Dinardo et al., Am J Hematol, 2015; Papaemmanuil et al., NEJM, 2016). However, there remains a paucity of data on the frequency of IDH1/2 and other targetable mutations in extramedullary manifestations of AML (i.e. myeloid sarcoma and leukemia cutis; EM-AML). We sought to characterize the mutational landscape of EM-AML, with a focus on determining the frequency of IDH1/2 mutations. Methods This is a multi-institutional retrospective analysis of patients diagnosed with EM-AML, who were treated at Moffitt Cancer Center or Memorial Healthcare System and underwent next-generation sequencing (NGS). All patients were evaluated for IDH1/2 mutations and up to 435 additional genes. Clinical variables and outcomes of EM-AML patients were characterized at the time of sample procurement. Additionally, we acquired additional de-identified NGS data on EM-AML patients who underwent sequencing of the EM site at Genoptix. We describe the mutational landscape of patients and compared the frequency of IDH1/2 mutations to historical controls in AML from the published literature using Fisher's exact test. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of mutation identification. Results Thirty-five patients with EM-AML were identified (22 in the clinical cohort and 13 in the Genoptix cohort) and are included in this analysis. The distribution of EM-AML diagnoses were myeloid sarcoma in 71% of cases (n=25) and leukemia cutis in 29% (n=10). The sequenced samples were from an extramedullary site for 63% (n=22) of the cases. The median age of the cohort was 64 (IQR 52 - 72) with a male predominance (55%). Of the clinical cohort, 68% (n=15) were non-Hispanic White, 23% (n=5) were Hispanic, and 9% (n=2) were Black. The molecular landscape of the cohort is shown in Figure 1. The frequency of IDH1/2 mutations was 31% (11/35), with IDH1 and IDH2 mutations reported in 17% (n=6) and 14% (n=5) of cases, respectively. All IDH1 mutations were at position R132 (4 R132H and 2 R132C) and all IDH2 mutations were at R140 (4 R140Q and 1 R140G). The other most frequent genomic alterations were DNMT3A (29%), NPM1 (26%), FLT3 (23%; ITD in 18% and TKD in 5%; 11% in IDH wildtype), NRAS (21%), TET2 (17%), and ASXL1 (17%). Mutations in DNA methylation occurred in 54% of patients (n=19). Co-occurring NRAS/KRAS mutations were more frequent in IDH mutant patients (45%; 5/11) compared to 12% (3/24) of IDH wild type patients (P=0.01). DNMT3A mutations were reported in 45% (5/11) of IDH mutant cases compared to 21% (5/24) of IDH wildtype cases, although this was not statistically significant (P=0.23). In comparison to a historical frequency of IDH1/2 mutations in AML patients of 17.4% (n=2366), EM-AML patients had an increased frequency of 31% (P=0.04). The median OS of the cohort was 13.6 months. Within the clinical cohort 50% (4/8) of the IDH1/2 mutant patients were treated with an IDH inhibitor with CR in 1 patient, CRi in 1 patient, and stable disease in 2 patients. The patient who achieved CR developed widespread leukemia cutis during cycle 1 of enasidenib which resolved over 6 months and is in durable CR for 15 months. Conclusion Overall, EM-AML patients had targetable mutations (i.e. IDH1/IDH2/FLT3) in 40% of cases with an increased frequency of IDH1/2 mutations (31%) in comparison to the general AML population. IDH mutant EM-AML patients achieved clinical benefit to specific inhibitors. These data support mutational analysis of EM-AML patients in order to personalize therapeutic options for our patients. Figure 1. Figure 1. Disclosures Bhagat: Genoptix: Employment. Watts:Takeda: Research Funding; Jazz Pharma: Consultancy, Speakers Bureau. Sweet:Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; Agios: Consultancy; Phizer: Consultancy; Phizer: Consultancy; BMS: Honoraria. Komrokji:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau