MYD88 Mutations in Chronic Lymphocytic Leukemia Exhibit Distinct Biological Behaviors and Prognostic Implications

Background: MYD88 has been identified as a pivotal driver gene in hematologic B-cell malignancies. While MYD88 mutations are rare in western CLL populations (0.5%-3%), they are significantly more common in Asian cohorts, including China, Korea, India and Singapore, with an incidence of 10-20%. These mutations potentially correspond to a distinct CLL subtype with distinctive biological behaviors and survival outcomes. This study aims to delineate the clinical profiles and prognostic implications of MYD88-mutated (MYD88^MUT) CLL patients under various treatment backgrounds.

Methods: We analyzed clinical data from 1,081 CLL patients diagnosed between 2000 and 2024, who underwent MYD88 detection via next-generation sequencing or Sanger sequencing. We gathered information on laboratory indicators, IGHV status, genetic traits, treatment regimens, and survival rates.

Results: In our cohort, we identified MYD88 mutations in 139 patients (12.86%). Specifically, 58 (39.7%) harboring the L265P variant, 49 cases (35.3%) with V217F, 15 (10.8%) with S219C, and 11 (7.2%) with M232T. MYD88^MUT CLL showed a notable male predominance (P < 0.001) and a higher prevalence of IGHV mutations (95.0% vs. 60.6%, P < 0.001) compared to MYD88 wild-type (MYD88^WT) patients. These patients also exhibited a higher presence of monoclonal gammopathy and marked absence of adverse cytogenetic aberrations, such as Del(17p) (1.6% vs. 11.9%, P < 0.001) and Del(11q) (1.6% vs. 12%, P < 0.001), with a reduced incidence of complex karyotypes (11.0% vs. 26.6%, P < 0.001).

Similar proportions of atypical CLL with a Matutes score of 3 were observed between MYD88^MUT and MYD88^WT patients (10.1% vs. 8.0%, P=0.398). MYD88^MUT CLL showed a reduced FMC7 negativity rate and a significantly diminished CD38 positivity. IGH VH3-7 and VH3-74 were prevalent in V217F and S219C mutations, whereas VH3-23 and VH4-34 were dominant in the MYD88 L265P variant.

MYD88^MUT CLL demonstrated superior clinical outcomes, including extended time to first treatment (TTFT), progression-free survival (PFS), and overall survival (OS) (m-TTFT 43 vs. 19 months, P < 0.001; m-PFS 132 vs. 49 months, P < 0.001; m-OS not reached vs. 135 months, P = 0.001). Even within the IGHV-mutated subpopulation, MYD88^MUT CLL showed significantly improved outcomes compared to MYD88^WT CLL (m-TTFT 47 vs. 32 months, P = 0.040; m-PFS 132 vs. 72 months, P < 0.001, m-OS not reached vs. 155 months, P = 0.019). MYD88^MUT patients with IGHV-unmutated status demonstrated poorer outcomes, mirroring the outcomes of MYD88^WT patients with unmutated IGHV.

Patients were categorized into three treatment groups based on their first-line therapy: target therapy, immunotherapy, and chemotherapy. Subgroup analysis based on initial treatment showed that MYD88^MUT patients experienced significantly enhanced PFS across all treatment modalities compared to non-mutated counterparts. In the MYD88^WT cohort, patients undergoing target therapy had superior PFS and OS compared to immunotherapy and chemotherapy groups. However, in the MYD88^MUT CLL group, all three treatment groups resulted in comparable PFS and OS, with impressive long-term outcomes across all groups (5-year PFS exceeding 90%, 5-year OS surpassing 80%, and 10-year OS above 70% in all three groups). The survival benefit of targeted therapy was not evident in MYD88^MUT CLL.

Among MYD88^MUT patients, those harboring the L265P mutation (39.7%) experienced a notably shorter TTFT compared to non-L265P mutated patients. Nevertheless, there were no significant differences in PFS and OS based on the mutation sites.

Conclusion: CLL patients with MYD88 mutations exhibited distinct biological characteristics, and had excellent survival outcomes, irrespective of the treatment modality.