MYD88 Mutations in Chronic Lymphocytic Leukemia Exhibit Distinct Biological Behaviors and Prognostic Implications
Authors: Yan Yuting , Zhou Yulan , Chen Weihao , Wang Jun , Wang Tingyu , Yu Ying , Jia Yujiao , Yu Zhen , Qiu Lugui , Li Fei , Yi Shuhua 
Published: December 2024

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 (MYD88MUT) 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. MYD88MUT CLL showed a notable male predominance (P &lt; 0.001) and a higher prevalence of IGHV mutations (95.0% vs. 60.6%, P &lt; 0.001) compared to MYD88 wild-type (MYD88WT) 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 &lt; 0.001) and Del(11q) (1.6% vs. 12%, P &lt; 0.001), with a reduced incidence of complex karyotypes (11.0% vs. 26.6%, P &lt; 0.001).

Similar proportions of atypical CLL with a Matutes score of 3 were observed between MYD88MUT and MYD88WT patients (10.1% vs. 8.0%, P=0.398). MYD88MUT 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.

MYD88MUT 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 &lt; 0.001; m-PFS 132 vs. 49 months, P &lt; 0.001; m-OS not reached vs. 135 months, P = 0.001). Even within the IGHV-mutated subpopulation, MYD88MUT CLL showed significantly improved outcomes compared to MYD88WT CLL (m-TTFT 47 vs. 32 months, P = 0.040; m-PFS 132 vs. 72 months, P &lt; 0.001, m-OS not reached vs. 155 months, P = 0.019). MYD88MUT patients with IGHV-unmutated status demonstrated poorer outcomes, mirroring the outcomes of MYD88WT 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 MYD88MUT patients experienced significantly enhanced PFS across all treatment modalities compared to non-mutated counterparts. In the MYD88WT cohort, patients undergoing target therapy had superior PFS and OS compared to immunotherapy and chemotherapy groups. However, in the MYD88MUT 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 MYD88MUT CLL.

Among MYD88MUT 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.