Fusion Transcript Reduction in Core Binding Factor Acute Myeloid Leukemia: Maintenance Strategy with Hypomethylating Agents

Introduction:  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).  Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest.  Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML.  We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacytidine (AZA), can be used for MRD elimination to ultimately prolong relapse free survival.

Methods:  We performed a retrospective analysis of 23 patients with CBF-AML who received HMA after fludarabine, cytarabine and G-CSF (FLAG) with low dose gemtuzumab or idarubicin induction/consolidation.  RTPCR from peripheral blood or bone marrow was obtained approximately every 3 months.  Mutations in KIT, FLT3ITD, FLT3D835 and RAS genes were tested at baseline. 

Results:  A total of 23 patients [t(8;21)=15 and inv(16)=8] received maintenance HMA.  The reason for transition to HMA was persistent PCR positivity in 13 patients (57%), prolonged myelosuppression precluding chemotherapy based consolidation in 9 patients (39%), and molecular relapse after allogeneic stem cell transplant (SCT) in 1 patient (4%).  Three of these patients received salvage clofarabine, cytarabine and idarubicin (CIA) for relapsed CBF-AML after FLAG based therapy and then went on HMA for molecular MRD.  Of 23 patients, 21 received DAC and 2 received AZA.  Median age at diagnosis was 53 (range, 23-70).  Patients received a median of 6 cycles of FLAG based induction/consolidation (range, 1-7) prior to transitioning to HMA.  The median number of HMA cycles received was 6 (range, 1-17).  Seventeen patients had detectable MRD (RTPCR ≥ 0.01) at initiation of HMA maintenance with a median RTPCR of 0.06 (range, 0.03-0.91).  All 17 patients were in morphologic and cytogenetic complete remission (CR) when HMA was initiated.  Of these 17 patients, 5 patients (29%) had progressive disease post HMA initiation, including 1/7 with t(8:21) and 4/10 with inv(16).  The RTPCR values preceding HMA in these 5 patients were 0.34, 0.06, 0.08, 0.01, and 0.01, respectively (median=0.06).  All 5 patients had an increase in the RTPCR value soon after the initiation of HMA.  RTPCR for these 5 patients following the first or second cycle of HMA was 3.84, >100, 77.48, 1.33, and 0.17, respectively.  Four [inv(16)=3 and t(8;21)=1] of these 5 patients had a RAS mutation, while the patient with t(8;21) had a concomitant KIT mutation, and another patient with inv(16) had a FLT3D835 mutation.  All five patients failing HMA proceeded to SCT, and 3 are alive and disease free post SCT.  For the 12 patients without HMA failure, the median RTPCR at HMA initiation was 0.06 (range, 0.01-0.91).  Unlike the HMA failure subset described above, 11 of these patients had a reduction in RTPCR by first or second subsequent measurement following initiation of HMA.  One patient is in early follow up.  All 6 patients who started HMA with undetectable MRD remain MRD negative (RTPCR < 0.01) and in remission.  Eight patients continue on maintenance therapy.  Median follow up is 11.3 months (range, 2.9-67.7). 

Conclusions:  Despite a favorable prognosis in CBF-AML, relapse remains the primary cause of treatment failure.  Identifying patients who are more likely to relapse will be beneficial in extending relapse free survival.  Hypomethylating agents can potentially be used in patients with detectable RTPCR to prolong remission.  Determining which patients would benefit most from this therapy is an important task.  This data suggests that patients with low levels of RTPCR (between 0.01 and 0.05) following induction/consolidation chemotherapy might benefit most from maintenance HMA, particularly those that have a reduction in RTPCR on first or second subsequent measurement following initiation of hypomethylating agent therapy.