Histone Deacetylase Inhibition with Panobinostat Combined with Intensive Induction Chemotherapy in Older Patients with Acute Myeloid Leukemia: Phase I Study Results

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

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A Phase I Study Of Nilotinib As a c-Kit Inhibitor Combined With Re-Induction Chemotherapy For Relapsed and Refractory c-Kit Positive Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.3961.3961 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3961-3961

Author(s):

Joseph M. Brandwein ◽

David Hedley ◽

Sue Chow ◽

Karen Yee ◽

Andre C Schuh ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Ex Vivo ◽

Significant Inhibition ◽

Dose Titration ◽

Titration Curves ◽

Acute Myeloid

Abstract Background A previous study in relapsed/refractory AML, combining re-induction chemotherapy with imatinib as a c-kit inhibitor, demonstrated that effective inhibition of downstream pAkt was associated with a higher CR rate (Brandwein et al, 2011). Nilotinib is also a c-kit inhibitor which diffuses into cells and is therefore not affected by potential defects in active cellular influx mechanisms. Methods Patients age 18-65 with acute myeloid leukemia (AML) who had persistent leukemia after 3+7 induction with cytarabine and daunorubicin, or relapsed within 24 months of achieving CR, and whose blasts were c-kit (CD117) positive, were enrolled in a phase I clinical trial with nilotinib on Days 1-12 combined with mitoxantrone 10 mg/m2/day IV Days 6-10, etoposide 100 mg/m2/day IV Days 6-10 and cytarabine 1.5 g/m2 IV q12h x 4 doses on Days 11-12. None of the cases harbored c-kit mutations. Nilotinib was escalated through 2 dose levels (400 mg daily and 400 mg BID) in successive 6 patient cohorts; up to 2/6 dose-limiting toxicities (DLTs) were permitted. Results At the 400 mg once daily nilotinib dose there were 2 DLTs, both hematologic and consisting of prolonged platelet and neutrophil recovery. At the 400 mg BID dose there was one DLT, consisting of grade 3 transient liver enzyme elevation; 5/6 patients experienced transient grade I-II bilirubin elevations at this dose. The median time to ANC > 0.5 x109/L was 38 days (range 28-54) and to platelets > 20 x109/L was 30 days (range 28-54). Complete responses were seen in 10 patients, 5/6 at each dose level. AML blasts from peripheral blood were assayed for pAKT, pERK and pS6 by flow cytometry, after stimulation with stem cell factor (SCF), on Days 1 and 6, pre- and 1.5 and 3 hours post-nilotinib dosing on each day. A decrease in the level of SCF-stimulated pAkt of at least 50% on Day 6 post-nilotinib, as compared to baseline, was seen in 1/6 patients at the 400 mg BID dose; the remaining 11 cases did not demonstrate an appreciable decrease in pAkt and other intermediates as compared to pre-nilotinib levels. Ex vivo dose titration curves showed that nilotinib inhibited c-kit mediated ERK and Akt activation in the blast cells of all cases, but concentrations >10 micromolar were needed to produce 50% inhibition in most cases. Conclusions The results indicate that nilotinib can be safely combined with this re-induction chemotherapy regimen, at doses up to 400 mg BID. Although the CR rate was high, in most cases nilotinib did not demonstrate significant inhibition of the c-kit pathway in leukemia cells in vivo. Dose titration curves showed that concentrations needed to produce 50% inhibition were generally above those achievable in vivo. Disclosures: Brandwein: Novartis: Honoraria, Research Funding. Off Label Use: nilotinib for acute myeloid leukemia.

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