Eradication of MRD with epigenetic therapy in CBF-AML

Despite a favorable prognosis following the conclusion of induction/consolidation chemotherapy, approximately 20–25% of Core Binding Factor Acute Myeloid Leukemia (CBF-AML) patients experience relapse which is usually preceded by an increase in Reverse Transcriptase Polymerase Chain Reaction (RTPCR) transcripts.

Brittany Knick Ragon from The University of Texas MD Anderson Cancer Center, Houston, Texas, and colleagues discussed results from their study which monitored Minimal Residual Disease (MRD) status by serial RTPCR in response to Hypomethylating (HMA) maintenance therapy in CBF-AML patients. The results of the study published in the American Journal of Hematology on 11^th May 2017.

Twenty-three CBF-AML patients (median age = 53 years) who received HMA (median cycle = 6, range [1–17]) maintenance therapy after fludarabine, cytarabine and G-CSF (FLAG) with low dose gemtuzumab or idarubicin induction/consolidation (NCT00801489) between August 2008 and August 2015 were included in this study.

The key results of the study were:

• 17/23 patients in morphological Complete Remission (CR) had detectable MRD at initiation of HMA maintenance; median RTPCR = 0.06 (range, 0.01–3.84)
• 29% (5/17) of patients had progressive disease and increasing RTPCR values after 1 or 2 cycles of HMA therapy; (range = 0.01–3.84)
• 71% (12/17) of patients did not fail HMA therapy and had a median RTPCR post HMA initiation of 0.06; range = 0.01–0.91
• Eleven patients who did not fail HMA therapy had a decrease in the RTPCR values after 1 or 2 cycles of HMA therapy

In summary, CBF-AML patients with “low levels of RTPCR (between 0.01 and 0.05) residual disease following induction/consolidation chemotherapy might benefit most from maintenance HMA, particularly those that have a reduction in the RTPCR within one or two cycles” of HMA therapy.

Abstract

Recurrent translocations, t(8;21) or inv(16), in core binding factor acute myeloid leukemia (CBF-AML) are amenable to monitoring for minimal residual disease (MRD) with reverse transcriptase polymerase chain reaction (RTPCR). Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML. Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest. We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacitidine (AZA) after induction/consolidation, can be used for MRD elimination to ultimately prolong relapse free survival. Real-time quantitative (RTPCR) trends were reviewed in 23 patients (median age 53 years) with CBF-AML that received HMA therapy following induction/consolidation with fludarabine, cytarabine and G-CSF (FLAG) with low dose gemtuzumab or idarubicin (NCT00801489). Of the 23 patients evaluated, 17 had a detectable RTPCR at HMA initiation. Five patients had progressive disease and a notable increase in RTPCR values over 1 to 2 cycles of HMA therapy. Twelve patients did not fail HMA and had a median RTPCR at HMA initiation of 0.06 (range, 0.01-0.91). Unlike the HMA failure subset, 11 of these patients had a reduction in RTPCR after the first or second cycle of HMA. Our data suggests that CBF-AML patients with low levels of RTPCR (between 0.01 and 0.05) at the conclusion of induction/consolidation chemotherapy benefit most from maintenance HMA, particularly those that have a reduction in the RTPCR within the first 2 cycles of HMA therapy.