Here , Michael R . Savona , MD , and David T . Bowen , MD , discuss the recent approval of oral azacitidine and where the agent fits in the context of maintenance therapies for patients with acute myeloid leukemia . Dr . Savona is Professor of Medicine and Cancer Biology at Vanderbilt University Medical Center in Nashville , Tennessee ; Dr . Bowen is Professor of Haematology and consultant hematologist at Leeds Teaching Hospital in the U . K .
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Michael R . Savona , MD
In Oral Maintenance Therapy in AML , Do All Roads Lead to the Epigenome ?
David T . Bowen , MD
● MAINTENANCE THERAPY to reduce relapse of acute myeloid leukemia ( AML ) and prolong overall survival ( OS ) has been explored since the 1960s . 1 Chemotherapeutic and immunologic approaches have all failed to improve OS . Only one intervention has been approved for this indication ( in 2008 , and in Europe only ): the rarely used combination of histamine dichloride and interleukin-2 .
The DNA methyltransferase inhibitors ( DNMTi ) azacitidine and decitabine – also called hypomethylating agents ( HMA ) – have demonstrated clinically meaningful activity as frontline therapy for myelodysplastic syndromes ( MDS ), chronic myelomonocytic leukemia ( CMML ), and AML . Subcutaneous azacitidine was first approved by the FDA for this indication in 2004 , and intravenous decitabine was approved for MDS and CMML in 2006 . However , the parenteral route of administration of these drugs in oncology clinics – administration on 5 to 7 days of every month , with therapy continued until toxicity or disease progression – is inconvenient , to say the least .
In 2020 , two oral DNMTi analogues became available in the U . S .: a fixed-dose combination of oral decitabine and cedazuridine ( ASTX727 ) and oral azacitidine ( CC-486 ). One of the challenges of developing oral DNMTi was first-pass metabolism by cytidine deaminase in the gut and liver , which rendered far less active drug in circulation compared with the equivalent parenteral dosing and with major differences in drug levels between patients .
ASTX727 is a fixed-dose combination of the DNMTi decitabine 35 mg and of cedazuridine 100 mg , a specific inhibitor of cytidine deaminase . In a series of bioequivalence studies , the fixed-dose combination led to blood levels of decitabine equivalent to those achieved with intravenous decitabine . 2 , 3 These data supported the FDA ’ s decision to approve Inqovi on July 7 for the first-line treatment of MDS and CMML . A combination of cedazuridine with azacitidine , ASTX030 , is currently in clinical trials .
FIGURE . Kaplan-Meier Plots of Overall Survival in the QUAZAR Trial
On September 1 , the FDA approved CC- 486 , not as first-line therapy but for “ continued treatment of patients with AML who achieved first complete remission ( CR ) or complete remission with incomplete blood count recovery ( CRi ) following intensive induction chemotherapy and are not able to complete intensive curative therapy ,” also known as maintenance therapy . Early dose-finding efforts attempted to dose escalate CC-486 to 600 mg to overwhelm cytidine deaminase and approximate the area under the curve of parenteral azacitidine , but pharmacokinetic analysis did not show bioequivalence . 4 Administering CC-486 over 14 or 21 days at various dose levels revealed meaningful drug activity ; as expected , though , the pharmacokinetic profile and pharmacodynamic impact were considerably different from parenteral azacitidine , leading to the reasonable conclusion that functionally , CC-486 is not purely an oral formulation of parenteral azacitidine , and oral azacitidine should not be used as a simple substitute for injectable azacitidine for first-line therapy in any setting . 5 , 6
CC-486 ’ s efficacy was evaluated in the phase III , randomized , double-blind , placebo-controlled QUAZAR trial , which compared CC-486 maintenance therapy ( 300 mg / day for 14 days of 28-day treatment cycles ) versus placebo in patients older than 55 whose AML was in CR or CRi after intensive induction . Of note , participants were required to be within 90 days of initial CR / CRi . Later in the trial , this was amended to 120 days due to poor enrollment . Eligible patients also may have received 0 ( 20 %), 1 ( 31 %), 2 ( 45 %) or an unknown number of consolidation courses ( 4 %).
With a median follow-up of 41 months , median overall survival ( OS ) was 24.7 months for patients treated with CC-486 and 14.8 months for those in the placebo arm , for a 31 % reduction in death in favor of
12 ASH Clinical News November 2020