Outcome and Molecular Measurable Residual Disease Monitoring in Adult B-Cell Acute Lymphoblastic Leukemia Patients with MEF2D Fusions

Oncogenic gene fusions caused by chromosomal rearrangements are the major hallmarks of B-cell acute lymphoblastic leukemia (B-ALL). With the application of next-generation sequencing technologies, several non-scarce recurrent fusion genes have been identified in B-ALL, and MEF2D fusions is the one. More clinical data is needed to clarify the incidence and prognosis. Furthermore, the prognostic significance of measurable residual disease (MRD) monitored by the quantitative detection of MEF2D fusions remains absent to date.

A total of 357 adult Ph-negative B-ALL cases who were consecutively diagnosed and received treatment in our institute from 2009 to 2021, and have available bone marrow cDNA samples at diagnosis were retrospectively screened MEF2D fusions. All patients have been tested common fusion transcripts at the time of diagnosis. MEF2D fusions were tested by the multiplex TaqMan-based real time quantitative polymerase chain reaction technology. A total of 7 fusion partners were included. The split-out real time PCR was performed to identify the partner.

Totally 16 patients were identified MEF2D fusions with the incidence of 4.5% in Ph-negative BCP-ALL. The distributions were as follows: 7 MEF2D-BCL9, 7 MEF2D-HNRNPUL1, 1 MEF2D-DAZAP1 and 1 MEF2D-FOXJ2. Their median transcript levels were 65.0% (range, 20.9%-335.5%) at diagnosis. The median age of these 16 patients were 30 (range, 17-60) years and 10 of them were male (63%).

The median follow-up time of 16 patients with MEF2D fusions was 26 months (range, 8-156 months). 9 (61.1%) patients were alive at the last follow-up. 14 and 2 patients individually achieved complete remission (CR) after 1 and 2 courses of CODP ± L regimen for induction. Thereafter, 8 patients received hyper-CVAD-based chemotherapy alone and all of them relapsed after 1-6 cycles of consolidation, then 2 relapsed patients received allogeneic hematologic stem cell transplantation (allo-HSCT) as salvage treatment after achieving the 2nd CR (CR2); the remaining 8 patients received chemotherapy followed by allo-HSCT (matched sibling donor, n = 3; haploidentical related donor, n = 5) in CR1. The median follow-up time after HSCT was 19 (6-148) months, and 5 patients (4 CR1, 1 CR2) relapsed at a median of 9 (range 6-15) months post-HSCT. The 3-year relapse free survival [RFS] and overall survival (OS) rates of all 16 patients were 30.0% (95% confidence interval [CI]: 10.2%-53.0%) and 54.6% (95% CI: 23.9%-77.5%) (Fig 1).

Bone marrow samples serially collected after treatment were retrospectively tested MEF2D fusion transcript for MRD monitoring. 58.3% (7/12) and 50.0% (6/12) of patients were PCR-negative at the time of achieving CR1 and after one cycle of consolidation, respectively. PCR-negative at the above both time-points was not related to relapse (P=1.0 and 0.45).

For patients receiving allo-HSCT, the scheduled monitoring time-points were 0, 1, 2, 3, 4.5, 6, 9, 12, 18, 24 months post-HSCT then every 12 months thereafter. There was a tendency that PCR-negative at the time of receiving HSCT was related to a lower relapse rate (post-HSCT 2-year RFS rate, 75.0% [95% CI, 12.8%-96.1%] vs 20.0% [95% CI, 0.8%-58.2%], P=0.13). 5 patients who were in continuous CR were tested MEF2D fusion transcript at a median of 9 (range, 3-11) time-points after HSCT, 38 (97.4%) samples were PCR-negative. 5 patients who relapsed post-HSCT were tested MEF2D fusions at a median of 5 (range, 4-7) time-points before relapse, they all were in continuous PCR-negative from 1 to 2-6 months post-HSCT, then all became PCR-positive before the occurrence of relapse. Their intervals between the 1st PCR-positive and relapse were 1.5-6 months. As a result, occurrence of PCR-positive post-HSCT was significantly related to relapse (post-HSCT 2-year RFS rate, 100.0% (95% CI, 100%-100%) vs 33.0% (95% CI, 4.3%-67.2%), P=0.039, Fig 2).

In conclusion, MEF2D fusions confer adverse prognostic significance to adult B-ALL, and relapse is a treatment challenge. PCR-negative of MEF2D fusion transcript at the time of achieving CR and after the 1st consolidation could not predict long-term CR, whereas PCR-positive after HSCT predict relapse. The benefit of urgent allo-HSCT after achieving CR and MEF2D fusion transcript levels directed intervention post-HSCT remains to be investigated.

No relevant conflicts of interest to declare.