DNMT3A Mutations Do Not Affect Treatment Response or Outcomes for Patients with Polycythemia Vera Treated with Interferon Alpha
Authors: Abu-Zeinah Ghaith , Erdos Katie , Lee Neville , Silver Richard T. , Scandura Joseph M. 
Published: December 2024

Two recent papers indicate that DNMT3A mutations should be considered when recommending interferon-alpha (IFN) for patients (pts) with polycythemia vera (PV). Usart et al. (Blood 2024) showed that deletion of DNMT3A promotes JAK2V617F (JAK2) hematopoietic stem cell (HSC) self-renewal and resistance to IFN in mice. Similarly, Knudsen et al. (Blood Adv 2022) identified treatment-emergent DNMT3A mutations (DNMT3A+) in patients with PV treated with IFN (IFN-PV) who did not attain a complete hematologic response (CR). The mutation-enhanced international prognostic system did not associate DNMT3A+ with adverse risk in PV, suggesting an IFN-specific effect (Tefferi et al. Br J Haematol 2020).

Given these concerning findings and IFN's role as a first-line treatment (Rx) in PV associated with myelofibrosis-free, event-free, and overall survival (MFS/EFS/OS), it is critical to determine if DNMT3A+ affects IFN-PV outcomes. To address this potentially practice-changing issue, we conducted a retrospective study of long-term outcomes in 246 pts with PV who had next generation sequencing (NGS) data available in the largest single-center database of IFN-PV. Data were collected from 437 NGS reports and electronic health records. Fisher's test was used to compare frequencies, t-test for means, Kaplan-Meier and log-rank test for MFS/EFS/OS.

Median follow-up was 12 years (yr), with 912 pts-yr of IFN Rx (143 IFN-PV pts with 4 years median Rx time). DNMT3A+ was not more common in IFN-PV than in non-IFN pts (18/143 (13%) vs 14/103 (14%), p=0.8). All DNMT3A+ mutations were known/likely pathogenic, and the median initial VAF was 14% (range 1.1-50%). Between DNMT3A+ (n=32) and DNMT3A- (n=214) pts, there were no significant differences in age at Dx (median 55 yr vs 56 yr, p&gt;0.9), sex (females 59% vs 46%, p=0.2), race (90% vs 89% identified as White, p&gt;0.9), thrombosis history (19% vs 16%, p=0.7), JAK2 variant allele frequency (VAF) (median 32% vs 36%, p=0.9), time on interferon (median 3.4 vs 3.8 yr, p=0.9), or median interferon dose. The same was true for the subset of IFN-DNMT3A+ (n=18) compared to IFN-DNMT3A- (n=125).

The percentage of patients achieving CR-defined as 3 or more months of phlebotomy-free hematocrit&lt;45%, platelets &lt;450 x 103/mL, and white blood count &lt;11.5 x 103/mL -was similar for IFN-DNMT3A+ and IFN-DNMT3A- pts (94% and 93%, p&gt;0.9) with median time to CR of 0.8 yr and 0.6 yr, respectively. Molecular response (MR), defined by a relative decrease in JAK2 &gt;20% from baseline, was attained in 5 of 13 (38%) IFN-DNMT3A+ pts and 34 of 79 (43%) of IFN-DNMT3A- pts with serial VAFs (Fisher's p&gt;0.9). Serial NGS testing for DNMT3A &gt;1 year apart was available for 9 IFN-DNMT3A+ pts and none had an increasing DNMT3A VAF during Rx (6 stable and 3 with DNMT3A MR &gt; 20% from baseline).

In a Cox proportional hazards multivariable analysis considering age and IFN, DNMT3A status showed no significant association with MFS/EFS/OS (HR = 0.45/0.69/0.89, p=0.1/0.2/0.8 respectively). The 20-yr EFS (composite of thrombosis, myelofibrosis, leukemia and death) was favorable in IFN-DNMT3A+ at 73%, and not significantly different from IFN-DNMT3A- (44%, p=0.093).

In conclusion, despite preclinical evidence that DNMT3A loss can promote JAK2-HSC self-renewal and IFN resistance, we found no influence of DNMT3A+ on clinical response or MFS/EFS/OS outcomes in IFN-treated pts with PV. Therefore, DNMT3A+ should not influence the decision to use IFN in pts with PV.