Background TP53 gene mutations predict for poor prognosis in acute myeloid leukemia (AML). Methods Peripheral blood or bone marrow samples from 293 newly diagnosed AML patients were analysed with targeted amplicon-based next-generation sequencing based mutation analysis. Results We found TP53 mutations in 53 (18%; 45 were missense mutations; the most common pattern of amino acid substitution, in 13 of the 53 patients, was a substitution of arginine to histidine on different codons). The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML -TP53-mutated (n=53) vs. TP53-wildtype (n=240) were compared. TP53-mutations were significantly more likely in patients with complex karyotype, abnormalities of chromosome 5, 7, and 17, and therapy-related AML. TP53-mutated AMLs have significantly lower incidence of mutations in FLT3, RAS, and NPM1 and higher incidence of coexisting MPL mutations compared to wild type. Distribution of TP53-mutations was equal in both age groups(<60 years vs ≥ 60 years). TP53 mutated AML was associated with a lower response rate(CR 41% vs. 57%; p=0.04), significantly inferior complete remission duration (CRD) (at 2 yrs 30% vs. 55%; p=0.001) and overall survival (OS) (at 2 yrs 9% vs. 24%; p= <0.0001) irrespective of the age or the type of treatment used - high vs low intensity chemotherapies. Conclusions The type of treatment did not improve the outcome in younger or older patients with TP53 mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with TP53 mutations.
2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and the corresponding methyl (CDDO-Me) and imidazole (CDDOIm) esters induce peroxisome proliferator-activated receptor ␥ (PPAR␥)-dependent transactivation in SW-480 colon cancer cells, and these responses were inhibited by small inhibitory RNA for PPAR␥. Moreover, in a mammalian two-hybrid assay using the PPAR␥ 2 -VP16 fusion plasmid and GAL4-coactivator/ corepressor chimeras and a construct (pGAL4) containing five tandem GAL4 response elements, CDDO, CDDO-Me, and CDDO-IM induce transactivation and PPAR␥ interaction with multiple coactivators. A major difference among the three PPAR␥ agonists was the higher activity of CDDO-Im to induce PPAR␥ interactions with the corepressor SMRT. CDDO, CDDO-Me, and CDDO-Im inhibited SW-480, HCT-116, and HT-29 colon cancer cell proliferation at low concentrations and induced cell death at higher concentrations. Growth inhibition at lower concentrations correlated with induction of the tumor suppressor gene caveolin-1 which is known to inhibit colon cancer cell growth. Induction of caveolin-1 by CDDO, CDDOMe, and CDDO-Im was inhibited by the PPAR␥ antagonist N-(4Ј-aminopyridyl-2-chloro-5-nitrobenzamide (T007), whereas higher doses induced apoptosis [poly(ADP-ribose) polymerase cleavage], which was not inhibited by T007. These results illustrate that CDDO-, CDDO-Me, and CDDO-Im induce both PPAR␥-dependent and -independent responses in colon cancer cells, and activation of these pathways are separable and concentration-dependent for all three compounds.2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a synthetic triterpenoid-derived compound structurally related to the pentacyclic triterpenoids oleanolic and ursolic acids which exhibit anti-inflammatory and anticarcinogenic activities (Nishino et al., 1988;Huang et al., 1994;Suh et al., 1998). CDDO and related compounds inhibit the growth of multiple cancer cell lines, induced differentiation, and inhibited inducible nitric-oxide synthase and cyclooxygenase 2 activities (Nishino et al
Introduction FLT3-ITD (Internal tandem duplication) and FLT3-TKD (tyrosine kinase domain, D835) mutations are frequently seen in AML; FLT3-ITDs are associated with inferior survival. Development of FLT3-TKD mutation during FLT3 inhibitor-therapy is seen in up to 22% of patients and associated with FLT3 tyrosine kinase inhibitor (TKI) treatment failure (Cancer 2014). Crenolanib besylate is an orally bioavailable TKI with activity against both FLT3-ITD and FLT3-TKD mutations. We evaluated the clinical efficacy of crenolanib in relapsed/refractory AML pts with activating FLT3 mutations. Methods This was a single center phase II open label study of crenolanib administered at 200 mg/m2/day three times a day continuously in 28 day cycles. FLT3 mutated pts (either FT3-ITD or FLT3-TKD) with primary AML, therapy-related AML and AML following an antecedent hematological disorder were included. Pts were ≥18 years of age with ECOG PS of 0-2. Pts with CNS disease were excluded. Pts relapsing post-allogeneic stem cell transplant could be included if they were >30 days post-transplant. 38 pts enrolled in 2 parallel cohorts of which 34 were evaluable, 13 in cohort A (FLT3 TKI-naïve) and 21 in cohort B (progressed on prior FLT3 TKI). Results Median age was 61 (30 – 87). Patients had undergone a median of 3.5 prior therapies (range 1 – 8); 38% of pts had diploid and 23% complex cytogenetics. Among patients with available information, NPM1 mutation was identified in 62% (10/16) and DNMT3A in 57% (8/14). Median baseline marrow blast % was 58% (7 – 97%). Of cohort B patients, prior therapy was sorafenib in 57%, quizartinib in 14%, PLX3397 in 5% and midostaurin in 10%. 9% and 5% had received 2 and 3 FLT3 TKIs, respectively. 10 enrolled patients had progressed post-transplant (SCT) (3 allogeneic in cohort A; 6 allogeneic, 1 autologous in cohort B). Median duration of study therapy was 9 wks (range 5 – 24), 2 pts remain on study. Reasons for study cessation were disease progression in 66%, no response in 16%, toxicity in 6%, clinical deterioration due to other co-morbidities in 6%, 3% lost to follow up and 3% to receive SCT. At a median follow up of 14 weeks (wks), ORR was 47%: 12% achieved complete response with incomplete count recovery (CRi), 32% hematological improvement (Hi) (85% of them with >50% decrease in blast count) and 3% morphologic leukemia-free state (MLFS). 21% had progressive disease and 32% no response. The median event-free survival (EFS) was 8 wks and overall survival (OS) was 19 wks for the whole cohort. The response by cohort was: Table FLT3 TKI naïve Prior FLT3 Therapy Response % CRi 23 5 MLFS 8 0 Hi 31 33 NR 31 33 PD 8 29 Median OS 55 wks 13 wks (p=0.027) Median EFS 13 wks 7 wks (p<0.001) Pts achieving marrow response (CRi and MLFS) had superior EFS (median 22 wks vs 8 wks for non-responders, p=0.003), with a trend toward superior OS for the marrow responders (median 55 weeks versus 15 wks, p=0.166). 2 of the 4 pts with FLT3-TKD in cohort A responded (CRi, Hi). Among pts with both mutations, 1/1 pt in cohort A achieved CRi and 5/6 pts in cohort B achieved Hi. EFS and OS were not influenced by complex cytogenetics, number of prior therapies or the presence of NPM1 or DNMT3A mutations. OS and EFS were, for patients with ITD (19 wks; 7 wks), D835 (6 wks; 8 wks) or both FLT3 mutations (12 wks; 9 wks), p=0.908; 0.391 respectively. The main grade 3 toxicities were GI side effects (abdominal pain and nausea). There was no death attributed to treatment related toxicity. Conclusions Crenolanib is a well-tolerated FLT3 TKI with clinical efficacy in heavily pre-treated, relapsed/refractory FLT3 mutated AML patients. The superior results in FLT3 inhibitor-naïve patients suggests that on-target FLT3 inhibition is likely primarily responsible for drug efficacy. Combination therapy (e.g., with chemotherapy or hypomethylating agents) could potentially provide additive efficacy in both treatment-naïve and relapsed/refractory pts. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
The identification of aberrant cellular pathways and dysfunctional molecules important in neoplastic transformation has begun to provide us with a number of targets for drug development. It is likely that many of these agents will be incorporated into our existing treatment strategies that include cytotoxic agents. Sorafenib, a multi-kinase inhibitor has been approved in the United States for the treatment of renal cell carcinoma as well as hepatocellular cancer. Its potential role in hematological malignancies, particularly acute myeloid leukemia (AML) is under evaluation. Here we describe the biological pathways in AML that are the potential targets of sorafenib action and discuss the early clinical data with the agent in solid tumors and AML.
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