Survival Outcomes in Patients with Waldenström Macroglobulinemia/ Lymphoplasmacytic Lymphoma According to MYD88 Mutation Status
Authors: Mian Agrima , Aboseif Albert , Wei Wei , Chakraborty Rajshekhar , Khouri Jack , Rudoni Joslyn , Winter Allison M. , Patel Sonam , Jagadeesh Deepa , Dean Robert M. , Pohlman Brad , Berg Stephanie , Cook James R. , Hill Brian T. , Mejia Garcia Alex V. 
Published: November 2019

Background:
Waldenström Macroglobulinemia (WM) or Lymphoplasmacytic Lymphoma (LPL) is an indolent B-cell neoplasm accounting for only 1-2% of all hematological malignancies. More than 90% of patients with WM carry a point mutation L265P in the MYD88 gene which promotes tumor survival and is shown to be significant for diagnostic and risk stratification. Criteria for diagnosis requires presence of serum monoclonal IgM protein and > 10% bone marrow lymphocytes with plasmacytoid differentiation. We aimed to present the patients characteristics and survival outcomes of WM/LPL patients treated at our center, according to their MYD88 gene status.
Methods:
We reviewed medical records of all patients diagnosed with WM/LPL between May 2002 and May 2018 for whom MYD88 status was known. Baseline demographic characteristics, ECOG PS, pertinent laboratory values including IgM level at diagnosis, initial therapy, mutation status and cytogenetics was obtained. Kaplan-Meier survival estimation curves were used to illustrate the probability of survival over time stratified by MYD88 status and compared by the log rank test.
Results:
A total of 99 patients diagnosed with WM/LPL were included, 91 Caucasians (92%), 54 (55%) male, median age 67 years (range, 43-89) and with 63 (64%) patients having ECOG PS 0 or 1. IgM level at diagnosis was available for 88 patients, with a median of 2055 mg/dL (range, 10-11,700) and serum free light chain ratio was estimated at a median of 2.13 (range, 0.01- 37331). Other pertinent laboratory data were: median hemoglobin 11.4 g/dL (range, 6.2- 16.4), median serum viscosity 2.4 CP (range, 1.5- 6.7), median serum M protein 1.4 g/L (range, 0- 5.84), median 24 hour urine protein 11mg (range, 4- 1344) and median serum LDH 173 U/L (range, 71-476). The median international prognostic score (ISSWM) for our cohort was 3. A mutant MYD88 was positive in 85 (86%) patients, while 14 (14%) patients had wild- type MYD88. Complex karyotype was present in 24 (25%) patients.
Rituximab monotherapy was the initial treatment in 48 (49%) patients. Twenty-two [22%] patients each received bortezomib-based and bendamustine-rituximab regimen as initial therapy and 7 (7%) patients received frontline rituximab- chemotherapy. Median follow-up of the cohort was 2.8 years (0.08-15.5). At last follow-up, 25 (25%) patients had died. Median OS from diagnosis for the entire cohort was 7.9 years (95% CI, 6.6 to N.R.). OS rate at 5 years was 0.73 (95% CI, 0.61 to 0.87). Patients with mutant MYD88 had significantly longer median OS as compared to those with wild-type MYD88 - 16.3 years (95% CI, 6.7 to N.R.) vs 6.6 years (95% CI, 1.9 to N.R.) [P=0.01] (Figure 1).
Conclusion:
Within the limitations of a retrospective study with a heterogeneously treated cohort, these data add to the body of literature supporting that outcomes of patients wild-type for MYD88 are worse than those with the L265P mutation when treated with rituximab alone, a proteasome inhibitor or conventional rituximab- chemotherapy. Also, despite an expansion on the therapeutic landscape, the treatment of choice in Waldenström Macroglobulinemia is still lead by rituximab monotherapy in newly diagnosed patients. Further studies should investigate the prognostic impact of MYD88 mutation in the context of BTK inhibitors.

Disclosures
Hill: Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria.