TP53 Mutation Status Predicts Response to Decitabine for Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have unfavorable-risk cytogenetic abnormalities and TP53 mutations responded to treatment with decitabine, according to research published in the New England Journal of Medicine. However, patients who responded to decitabine treatment never experienced complete mutation clearance.

John S. Welch, MD, PhD, of the Washington University School of Medicine in St. Louis, Missouri, and co-authors used exome and gene-panel sequencing in 116 patients with MDS or AML to determine whether the presence of specific mutations correlated with response or resistance to decitabine, which is commonly used as a single agent in this setting but is associated with poor response rates.

“Surprisingly, we found that clinical responses were highly correlated with the presence of TP53 mutations in the founding clone at presentation,” Dr. Welch and co-authors noted. Also, “the rate of overall survival (OS) with 10-day courses of decitabine was similar [between] patients with unfavorable- and intermediate-risk cytogenetic abnormalities.”

In this prospective, uncontrolled trial, patients with AML, relapsed AML, or transfusion-dependent MDS received decitabine 20 mg/m2 on days 1-10 of 28-day cycles at the Washington University in St. Louis between March 2013 and November 2015. The researchers also included an additional cohort of 32 patients: 24 received decitabine 20 mg/m2 on days 1-10 of 28-day cycles between April 2005 and March 2010 at the University of Chicago, and eight received decitabine 20 mg/m2 on days 1-5 of 28-day cycles between January 2009 and June 2014 at Washington University in St. Louis.

All patients were ≥60 years old and had an Eastern Cooperative Oncology Group performance status of ≤2 and preserved end-organ function. “Eligibility requirements were intentionally broad and designed to reflect typical patterns in decitabine use,” the authors noted.

The total cohort of 116 patients (median age = 74 years; range = 29-88 years) included 21 patients with TP53 mutation and 78 patients with wild-type TP53(17 patients were not evaluated for TP53). Most patients with TP53 mutations had unfavorable-risk cytogenetics (n=20; 95%; TABLE).

During cycles one and two, 128 grade 3-5 adverse events were recorded, including febrile neutropenia or other infectious events (n=93 events in 56 patients) and bleeding complications or transfusion reactions (n=9 events in 8 patients). Eight treatment-related deaths occurred as a result of infection (n=6), acute kidney injury (n=1), and cardiac arrest (n=1).

In the full cohort, 15 patients (13%) achieved complete remission (CR) and 38 patients had bone marrow blast clearance (<5% blasts), for an overall response rate (ORR) of 46 percent. Nine patients achieved a partial response (8%), 23 had stable disease (20%), and 19 had progressive disease (16%).

As seen in the TABLE, the rates of bone marrow blast clearance (defined as CR, CR with incomplete count recovery, or morphologic CR) were the same among patients with unfavorable- and intermediate-risk cytogenetic profiles (67% vs. 67%; p<0.001). However, patients with TP53 mutations had significantly higher rates of blast clearance (100% vs. 41%; p<0.001).

OS did not appear to be affected by cytogenetic risk or TP53 mutation status: Median OS was 11.6 months for those with unfavorable-risk profiles and 10 months for those with favorable- or intermediate-risk profiles (p=0.29), whereas median OS was 12.7 months for those with TP53 mutations and 15.4 months for those with wild-type TP53 (p=0.79).

However, “decitabine did not clear all leukemia-specific mutations in any patient tested,” the authors wrote. “Thus, the short durations of remission are due to incomplete clearance of leukemia cells bearing the pathogenetically relevant driver mutations.”

The study is limited by its small, heterogeneous patient population, as well as its lack of a comparison group. The study was also not able to elucidate the mechanisms underlying the sensitivity of patients with AML or MDS and TP53 mutations to decitabine, nor report on more clinically meaningful endpoints such as overall survival improvement in TP53 mutated patients treated with decitabine.

“Decitabine as a single agent is not a cure for anyone with these diseases,” the authors concluded. “However, the use of decitabine may be an important way to induce clinical remission in patients with AML who have TP53 mutations and who have disease that is notoriously resistant to induction therapy with standard cytotoxic chemotherapy.”


Reference

Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375:2023-36.

TABLE. Patient Characteristics and Response to Decitabine
  All Patients (n=116) TP53 Mutations (n=21) Wild-Type TP53 (n=78) TP53 Not Evaluated (n=17) p Value
Cytogenetic Risk Group, n (%)
Favorable 5 (4) 0 4 (5) 1 (6) 0.58
Intermediate 66 (57) 1 (5) 54 (69) 11 (65) <0.001
Unfavorable 43 (37) 20 (95) 19 (24) 4 (24) <0.001
Not performed 2 (2) 0 1 (1) 1 (6)
Response, n (%)
Bone marrow blast clearance <5% blasts 53 (46) 21 (100) 32 (41) 0 <0.001
CR with recovery of peripheral blood counts 15 (13) 4 (19) 11 (14) 0 0.73
CR with incomplete count recovery 24 (21) 9 (43) 15 (19) 0 0.04
Morphologic CR with hematologic improvement 6 (5) 5 (24) 1 (1) 0 0.002
Morphologic CR without hematologic improvement 8 (7) 3 (14) 5 (6) 0 0.36
No bone marrow blast clearance 63 (54) 0 46 (59) 5 (29) <0.001
Partial response 9 (8) 0 9 (12) 0 0.05
Stable disease 23 (20) 0 18 (23) 5 (29) 0.006
Progressive disease 19 (16) 0 19 (24) 0 0.003
Samples not available for evaluation 12 (10) 0 0 12 (71)
CR = complete remission

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