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2017 ASCO Annual Meeting!


Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant

Type: Poster Session

Time: Monday June 5, 8:00 AM to 11:30 AM

Location: Hall A

Correlation between mutation clearance and clinical response in elderly patients with acute myeloid leukemia (AML) treated with azacitidine and pracinostat.

Sub-category:
Acute Leukemia

Category:
Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant

Meeting:
2017 ASCO Annual Meeting

Abstract No:
7034

Poster Board Number:
Poster Session (Board #234)

Citation:
J Clin Oncol 35, 2017 (suppl; abstr 7034)

Author(s): Koichi Takahashi, Yasmin Abaza, Ehab L. Atallah, Bruno C. Medeiros, Sam Khal, Martha Lucia Arellano, Mrinal Patnaik, Richard Ghalie, Guillermo Garcia-Manero; The University of Texas MD Anderson Cancer Center, Houston, TX; Medical College of Wisconsin, Milwaukee, WI; Stanford School of Medicine, Stanford, CA; City of Hope, Duarte, CA; Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA; Mayo Clinic, Rochester, MN; MEI Pharma, Inc., San Diego, CA

Abstract Disclosures

Abstract:

Background: In a phase II study in 50 elderly patients (pts) with AML who were not eligible for intensive chemotherapy, treatment with pracinostat + azacitidine (AZA) was well tolerated, led to 42% complete remission (CR) rate and a median overall survival (OS) of 19.1 months (Blood 2016: 128;100). Here we investigate the impact of somatic mutations and their clearance on disease response and patient outcomes. Methods: 88 samples from 41 study pts were sequenced. All 41 pts were analyzed pre-treatment, and a median of 3 longitudinal samples were analyzed from 19 pts between Cycle 2 and 9. Mutations were assayed by SureSelect targeted capture exon sequencing (Agilent) of 295 genes that are recurrently mutated in hematologic malignancies. Longitudinal mutation clearance was analyzed by plotting variant allele frequency (VAF). Results: At baseline, 96 mutations in 28 genes were detected in 38 pts, with the most frequent being in SRSF2 (27%), DNMT3A (20%), IDH2 (17%), RUNX1 (17%), and TET2(17%). Mutations associated with CR rate and OS are indicated in the Table. A CR was achieved in 10/19 pts that had longitudinal sequencing analysis and at the time of CR, 9 (90%) had persistently detectable mutations in their bone marrow. In 7 of them, continued exposure to pracinostat + AZA lowered the VAF or cleared residual mutations. In 2 pts, relapsed samples showed re-expansion of the founder clone. Conclusions: Mutations in NPM1, and DNA methylation pathway were associated with a better response to pracinostat + AZA, while TP53 mutation was associated with a poor response. Persistent mutation at the time of CR suggests residual preleukemic clonal hematopoiesis in this elderly population. Benefit of prolonged exposure to pracinostat + AZA was also confirmed at molecular level where continued decline of mutation VAF was seen after achieving CR. Clinical trial information: NCT01912274

Gene; n (%)CR rate (%)
Wild-typep value
Mutated
NPM1; 6 (15)83300.025
DNA methylation pathway*; 15 (37)60220.027
CEBPA; 3 (7)100330.052
TET2; 5 (12)80320.066
RAD21; 3 (7)100330.052
TP53; 5 (12)0460.065
OS (months)
CEBPA; 3 (7)Not reached14.80.061
NF1; 3 (7)3.0190.005
RUNX1; 6 (15)7.918.10.078

* DNTM3A, IDH1, IDH2, or TET2

 
Other Abstracts in this Sub-Category:

 

1. Deep molecular response to gilteritinib to improve survival in FLT3 mutation-positive relapsed/refractory acute myeloid leukemia.

Meeting: 2017 ASCO Annual Meeting Abstract No: 7003 First Author: Jessica K. Altman
Category: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant - Acute Leukemia

 

2. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study.

Meeting: 2017 ASCO Annual Meeting Abstract No: 7004 First Author: Eytan M. Stein
Category: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant - Acute Leukemia

 

3. Distinct patterns of somatic mutation clearance and association with clinical outcome in patients with AML.

Meeting: 2017 ASCO Annual Meeting Abstract No: 7005 First Author: Koichi Takahashi
Category: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant - Acute Leukemia

 

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