Al‐Kali, Aref

AbstractTherapy related myeloid neoplasms (t‐MN) including therapy related myelodysplastic syndromes (t‐MDS) and acute myeloid leukemia (t‐AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t‐CMML. T‐CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t‐CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t‐MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t‐CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t‐CMML in comparison to d‐CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t‐CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4‐3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5‐3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5‐3.7). In summary, we highlight the unique genetics and independent prognostic impact of t‐CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t‐MN.

Abstract Purpose: Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors. Experimental Design: Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene-specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice, and in nilotinib-treated leukemia patients were determined. Results: Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation, and the upregulation of the p15INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression. Conclusions: Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia. Clin Cancer Res; 23(20); 6254–66. ©2017 AACR.

Outcomes of acute myeloid leukemia (AML) in elderly patients unfit for intensive chemotherapy is challenging. Hypomethylating agents (HMAs) can be effective in these patients but responses are usually short‐lived. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs. The data on 56 AML patients at Mayo Clinic, Rochester were reviewed. Patients were considered for our study if they received HMA as frontline therapy for their AML. Out of 56 patients, 15 (27%) patients received azacitidine (AZA) and 41 (73%) received decitabine. Complete remission was found in 10 (18%), with overall response of 28% and median response duration of 10 months. Thirteen (81%) out of 16 responders relapsed. Therefore 53 patients were included in the primary or secondary failure analysis with a median overall survival (OS) of 2 months after the date of failure. Out of 53 patients, 12 (23%) received subsequent treatments. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs. 2 months, P = .0009). Outcome for patients who have primary or secondary failure is very poor. Our study provides important historical data for future novel therapies, which are sorely needed for these patients.

SummaryThe definition of the myelodysplastic syndrome (MDS) subtype ‘MDS with isolated del(5q)’ was expanded to include cases with one additional non‐chromosome 7 based cytogenetic abnormality in the 2016 revised World Health Organization classification. This study applied the revised definition to a large primary MDS cohort, and evaluated the prognostic impact of the additional cytogenetic abnormality. Seventy‐two of 1067 patients (7%) met the ‘MDS with isolated del(5q)’ criteria, 11 (1%) of whom had an additional cytogenetic abnormality. There was no survival difference between patients in whom del(5q) occurred alone, compared to those with one additional cytogenetic abnormality (P = 0·52).