MYD88 wild‐type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival

Abstract

MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM-secreting B-cell malignancies. Diagnostic discrimination can be difficult among suspected wild-type MYD88 (MYD88 ) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88 WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88 WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10-year survival was 73% (95% confidence interval [CI] 52-86%) for MYD88 versus 90% (95% CI 82-95%) for mutated (MYD88 ) WM patients (Log-rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B-cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88 and MYD88 patients, respectively (Odds ratio 23·3; 95% CI 4·2-233·8; P < 0·001). Overall survival was shorter among MYD88 patients with an associated DLBCL event (Log-rank P = 0·08). The findings show that among suspected MYD88 WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88 disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88 disease.

Impact of MYD88L265P mutation status on histological transformation of Waldenström Macroglobulinemia

“…Although a signal for increased risk of histological transformation in a smaller cohort of our patients was evident previously, a finding subsequently validated externally. 10,29 The current study implicates MYD88 L265P mutation status as an inde- Hence, the disparate sensitivities are unlikely to hinder the interpretation of the study results as elaborated in a previous publication. 32 Regardless, our findings were further strengthened by the establish- In summary, although an infrequent event, the development of histological transformation adversely alters the survival of patients with WM.…”

Comparing apples to oranges: A commentary on the Mayo study of MYD88 significance in Waldenstrom's macroglobulinemia.

“…It is interesting that the rate of transformation to an aggressive lymphoma also differed greatly between MYD88 WT and MYD88 L265P patients, with rates of 16% and 4%, respectively, highlighting differences in disease biology. The higher incidence of disease transformation was also observed by us in MYD88 WT patients, 10 Reply to Castillo et al…”

“…9 Using such a careful approach to determining MYD88 status, we confirmed in a larger population of WM patients that MYD88 mutation status continues to be a highly significant determinant of overall survival by multivariate analysis. 10 Other potential flaws to this study are worth noting. A survival analysis from time of diagnosis to death of any cause was oddly not used.…”

“…Furthermore, studies have recently shown that non-BTK inhibitor-based regimens are effective in WM, irrespective of the presence of MYD88 mutation. [10][11][12] The retrospective data presented by Castillo and coworkers reported a poorer prognosis in patients with wild-type disease compared to patients with mutations in the MYD88 gene appear incomplete, without the crucial information regarding the therapies administered. 9 Our rationale for assessing OS in patients with WM from the time of treatment initiation i.e.…”

How Recent Advances in Biology of Waldenström’s Macroglobulinemia May Affect Therapy Strategy

“…A highest BM disease burden and a better prognosis were initially reported in MyD88-mutated (mut) versus MyD88 wild-type (WT) patients but these data are still controversial [11][12][13]. Indeed, Treon showed, in 326 patients, an estimated 10-year survival of 73% versus 90%, in MyD88 WT versus MyD88 mut patients respectively [13]. But, more recently, no difference in tumor burden or overall survival were found by Mayo Clinic group in 219 patients [11].…”