ASH Clinical News Focus on Myeloid Malignancies | Page 15

The inhibition of both histone deacetylation ( HDAC ) and DNA hypermethylation induces re-expression of silenced genes in vitro in cell lines and in primary cells from patients with myeloid malignancies . The DNA hypomethylating agents ( HMAs ) azacitidine and decitabine are U . S . Food and Drug Administration-approved for myelodysplastic syndromes ( MDS ), though it is unclear just how these drugs exert their clinical effects in patients . A previous study demonstrated that pracinostat – an HDAC inhibitor – exhibited modest single-agent activity in patients with relapsed acute myeloid leukemia ( AML ). state ( per International Working Group criteria ). Median time to BM blasts < 5 percent was 57 days ( range = 25-243 days ) and exceeded 168 days ( 6 cycles ) in three patients ( 12 %). Median duration of cCR was 13.2 months ( 95 % CI 10.9-21.5 ), with 23 percent of patients ( n = 6 / 26 ) continuing therapy for a period ranging from 20.5 to 29.5 months .

After a median follow-up of 21 months , the median overall survival ( OS ) was 19.1 months ( 95 % CI 10.0-not reached ). One- and two-year OS rates were 62 percent and 45 percent , respectively . See

TABLE for survival outcomes based on baseline characteristics .

In an open-label , phase II study presented at the 2016 ASH Annual Meeting , pracinostat plus azacitidine led to a composite complete response rate ( cCRR ; primary endpoint , including complete response with or without hematopoietic recovery , as well as morphologic leukemia-free state ) of 52 percent . “ Pracinostat plus azacitidine led to a high rate of responses in elderly patients with AML … that were durable ,” the authors noted .

Guillermo Garcia-Manero , MD , of the University of Texas MD Anderson Cancer Center in Houston , and co-authors enrolled 50 older patients ( median age = 75 years ; range = 66-84 years ) with AML who were ineligible for induction chemotherapy from 15 U . S . centers between December 2013 and December 2014 . Patients were eligible if they had untreated de novo or secondary AML , ≥20 percent bone marrow ( BM ) blasts , were not a candidate for intensive therapy because of comorbidities or were unlikely to respond favorably to intensive therapy because of adverse AML features such as high-risk cytogenetics , and had not received prior treatment with HDAC inhibitors or HMAs .

A majority of patients ( n = 33 ) had de novo AML , while 17 had secondary AML , and the median BM blast was 40 percent ( range = 20-89 %). Twenty-seven patients had intermediate-risk cytogenetics , 21 had high-risk cytogenetics , and two were unknown . Most patients ( 84 %) had an Eastern Cooperative Oncology Group performance status of 0-1 .

Patients received pracinostat 60 mg orally three times per week for three weeks together with azacitidine 75 mg / m 2 administered via subcutaneous injection or intravenous infusion daily for the first seven days of each 28-day cycle . Patients received a median of 6.5 treatment cycles ( range = 1-24 + cycles ).

Twenty-one patients ( 42 %) achieved complete remission ( CR ), while two ( 4 %) achieved CR with incomplete hematologic recovery , and three ( 6 %) achieved a morphologic leukemia-free

Cytogenetics Intermediate-risk High-risk

Age ≥75 years ( n = 26 ) 66-74 years ( n = 24 )

Type of AML De novo ( n = 33 ) Secondary ( n = 17 )

ECOG Performance Status 0-1 ( n = 42 ) 2 ( n = 8 )

Grade ≥3 non-hematologic adverse events ( AEs ; reported in > 5 % of patients ) included fatigue ( 34 %), anorexia ( 10 %), cellulitis ( 8 %), pneumonia ( 8 %), asthenia ( 8 %), sepsis ( 8 %), urinary tract infection ( 6 %), nausea ( 6 %), back pain ( 6 %), hypoxia ( 6 %), hyponatremia ( 6 %), and syncope ( 6 %). Grade ≥3 hematologic AEs included thrombocytopenia ( 46 %), febrile neutropenia ( 44 %), neutropenia ( 36 %), anemia ( 30 %), and pancytopenia ( 6 %). Thirty- and 60-day mortality rates were 2 percent and 10 percent , respectively .

The authors noted that a phase III study of pracinostat plus azacitidine in untreated patients with AML who are ineligible for standard induction chemotherapy is underway . A randomized study of this combination in previously untreated patients with MDS was reported in 2015 and did not show benefit for the combination compared with azacitidine alone .

Reference

48 % 38 %

42 % 42 %

42 % 41 %

41 % 50 %

59 % 48 %

58 % 46 %

52 % 53 %

50 % 63 %

Not reached ( 95 % CI 10.7-not reached ) 13.5 ( 95 % CI 2.4-not reached )

13.5 ( 95 % CI 9.0-21.5 ) 26.5 ( 95 % CI 8.0-26.5 )

13.02 ( 95 % CI 5.7-26.5 ) Not reached ( 95 % CI 16.4-not reached )

19.08 ( 95 % CI 10.0-19.1 ) 13.0 ( 95 % CI 8.0-26.5 )

CR = complete remission ; cCR = composite complete response rate ( CR + CR with incomplete count recovery + morphologic leukemia-free state ); AML = acute myeloid leukemia ; ECOG = Eastern Cooperative Oncology Group

Garcia-Manero G , Atallah E , Khaled SK , et al . A phase 2 study of pracinostat and azacitidine in elderly patients with acute myeloid leukemia ( AML ) not eligible for induction chemotherapy : response and long-term survival benefit . Abstract # 100 . Presented at the 2016 ASH Annual Meeting , December 3 , 2016 ; San Diego , California .

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