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High-risk acute myelogenous leukemia: maintenance therapy with Azacitadine and Valproic acid after allogeneic stem cell transplant

Relapse is the major cause of failure after allogeneic stem cell transplantation ( Allo-SCT ) for acute myelogenous leukemia ( AML ).
Allo-SCT for high risk acute myelogenous leukemia, defined by induction failure, relapse after remission and, adverse molecular and cytogenetic properties yield a dismal 1 year survival of approximately 40%.
These patients are ideal candidates for pharmacological maintenance following Allo-SCT but this has been challenging due to drug interactions and myelosuppression.

Researchers have reported data on phase II trial examining the use of Valproic acid ( VPA ) and Azacitadine ( AZA ) as maintenance following Allo-SCT for high risk acute myelogenous leukemia based on the previously reported synergism of a demethylating agent and an histone deacetylase inhibitor in this disease.

Researchers have enrolled patients with high risk acute myelogenous leukemia, no grade 3-4 acute GVHD ( Graft versus Host Disease ), and adequate organ function after Allo-SCT starting day + 40 on this IRB approved study.

Exclusion criteria included active or uncontrolled infections, low risk acute myelogenous leukemia in CR1, neutrophil counts less than 1500, and platelets less than 50,000.

Azacitadine was administered at 40 mg/m2 daily for 5 days ( days 1-5 ) via subcutaneous injection along with PO ( per os ) Valproic acid administered daily starting at 15 mg/kg and dose adjusted to achieve a trough level of bound Valproic acid of 100 mcg/ml as tolerated for up to 4 cycles in total, each lasting 4 weeks.

GVHD prophylaxis was Tacrolimus and mini-Methotrexate.

Primary outcome was expected one year overall survival greater than or equal to 60% ( vs 40% expected without therapy ) with secondary outcomes of relapse free survival, and ability to administer full doses of the regimen on time.

Median age for the 25 patients was 42 with a male predominance ( 72% ). Median Sorror Co-Morbidity Index was 2.5.

Graft type included 12 matched related, 5 cord blood, and 8 matched unrelated donors. Stem cell source was peripheral blood in 15 and bone marrow in 4.
All were high risk with at least 1 adverse factor: 8 ( 32% ) were not in complete response ( CR ) at transplant, 17 ( 68% ) had high risk cytogenetics, and 7 ( 28% ) had high risk molecular studies.

Myeloablative conditioning was used in 72%.

21 of the 25 patients completed all 4 cycles with 2 patients still on therapy and 2 discontinuing early due to relapse.

1 year overall survival is 80% ( 95% CI 68-95% ). 1 year relapse free survival is 79% ( 95% CI 66-95% ).

No acute GVHD was seen but 11 patients ( 44% ) developed chronic GVHD of which 8 ( 32% ) were extensive.

Toxicities were mostly grade I/II leukopenia, thrombocytopenia and fatigue.

The co-administration of Azacitadine and Valproic acid can be administered safely after Allo-SCT for 4 months to patients with acute myelogenous leukemia.

A promising 1 year overall survival of 80% without significant toxicity and a relapse rate of only 21% was reported.
Both compare favorably to published data in this patient population.
Given that patients enter at day +40 without GVHD, a phase III trial with molecular monitoring of MRD ( minimal residual disease ) will be needed to verify benefit. ( Xagena )

Hagen PA et al, BMT Scientific Meeting, 2017