WM

MYD88 mutation shown not to impact overall survival in WM

A study by Jithma P. Abeykoon, from the Department of Internal Medicine at the Mayo Clinic, Rochester, MN, and colleagues, evaluated the impact of MYD88 mutation status in Waldenström macroglobulinemia (WM). The authors compared outcomes for patients with MYD88L265P mutation and MYD88WT (wild-type) in this retrospective analysis of patients diagnosed between 1995 and 2016 at the Mayo Clinic.

Patient mutation status was assessed using the amplification-refractory mutation system and patients who did not show the MYD88L265P mutation were placed in the MYD88WT cohort. Patients were further categorized as either intermediate/high-risk (age >65 or two or more high-risk defining variables based on international prognostic scoring system for WM criteria) or low-risk (patients with one qualifying variable, except age >65). The main outcomes evaluated were overall survival (OS) and time-to-next therapy (TTNT).

Key Findings
  • 219 patients had MYD88L265P mutation status
    • 174 (79%) patients with genotype MYD88L265P, 157 had active disease
    • 45 (21%) patients with genotype MYD88WT, 44 had active disease
  • Results for MYD88L265P:
    • Median follow-up = 6 years (95% CI, 5.8–7.5)
    • Median OS = 2 years (95% CI, 8.4–16.5)
    • Median TTNT = 9 years (95% CI, 2.4–4.7)
  • Results for MYD88WT:
    • Median follow-up = 7 years (95% CI, 5.2–8.8) P = 0.27
    • Median OS = 9 years (95% CI, 6.4–29.3) P = 0.86
    • Median TTNT = 1 years (95% CI, 0.6–4.5) P = 0.48
  • The number of patients with smoldering WM was similar in the two groups (MYD88L265P n = 56 (32%) and MYD88WT n = 10 (24%), P = 0.2) yet there was a shorter median time-to-progression to active disease in patients with MYD88WT but it was not statistically significant
    • MYD88L265P = 2.8 years (95% CI, 2.2–3.8)
    • MYD88WT = 1.9 years (95% CI, 0.7–3.1) P = 0.21
  • Transformation of disease or patients who developed therapy-related myelodysplastic syndrome (t-MDS) was higher in the MYD88WT cohort
    • MYD88L265P = 4% n = 6)
    • MYD88WT = 16% (n=7) P = 0.009

The authors found that the MYD88L26P mutation status did not impact OS or TTNT in patients with WM. They noted possible limitations of their study, including bias with retrospective studies and further data being required for identification of CXCR4 and non-L265P MYD88 gene mutations. The authors concluded that though MYD88L26P mutation status did not affect patient outcomes, it may be of interest to assess the mutation for prognostic significance.  

Abstract

Waldenström macroglobulinemia (WM) is an immunoglobulin M-associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88L265P. Due to low prevalence of the wild-type (WT) MYD88 genotype in WM, clinically-relevant data in this patient-population are sparse, with one study showing nearly a 10-fold increased risk of mortality in this subgroup compared to patients with MYD88L265P mutation. We studied a large cohort of patients with MYD88L265P and MYD88WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016 to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88L265P mutation status, as determined by allele-specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88L265P, 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88WT genotype; 44 had active disease. The estimated median follow-up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4-16.5) for MYD88L265P vs. 13.9 years (95% CI: 6.4-29.3) for the MYD88WT (p=0.86). The time-to-next therapy from frontline treatment and the presenting features were similar in the two patient-populations. For patients with smoldering WM at diagnosis, the median time-to-progression to active disease was 2.8 years (95% CI: 2.2-3.8) in the MYD88L265P cohort and 1.9 years (95% CI: 0.7-3.1) in the MYD88WT cohort, (p=0.21). MYD88L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease-defining feature in WM. Our findings warrant external validation, preferably through prospective studies.

References
  1. Abeykoon JP. et al. Impact of MYD88 Mutation Status in Waldenström macroglobulinemia. American Journal of Hematology. 2017 Oct 28. DOI: 10.1002/ajh.24955. [Epub ahead of print]