MYD88 (L265P) Mutation Confers Very Poor Response and Outcome after Second-Line Therapy in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Salar Antonio , Garcia-Pallarols Francesc , Fernández-Rodríguez Concepcion , Sánchez-González Blanca , Vela Mari Carmen , Gimeno Eva , Pairet Silvia , Senin Alicia , Camacho Laura , Serrano Sergi , Besses Carlos , Bellosillo Beatriz 
Published: October 2019

Abstract
BACKGROUND
Somatic mutations in the myeloid differentiation primary response gene 88 (MYD88) have been described in B-cell lymphomas, including DLBCL. Our group has confirmed the remarkable site-specific occurrence of MYD88 mutations at some immune-privileged locations and, in addition, has described that DLBCL patients are at high risk of progression and death after first-line treatment, with independence of other well-known clinical prognostic factors (Leukemia 2014).
AIMS
To further analyze the clinical responsiveness and outcome after second-line treatment in DLBCL patients carrying MYD88 L265P.
METHODS
A series of 175 patients with DLBCL diagnosed at our institution between 2000 and 2013 were included. Inclusion criteria were: full clinical data available, treatment with remission intention, enough material for DNA extraction and absence of HIV infection. The presence of MYD88 L265P mutation was assessed by allele-specific oligonucleotides (ASO)-PCR in DNA samples extracted from FFPE tissue.
RESULTS
In 129 patients (74%) treatment consisted on rituximab plus CHOP or CHOP-like schedules, while the remaining cases received other treatments depending on their clinical requirements. With a median follow-up time of 57 months, progression free survival (PFS) at 5 years after first-line treatment was 57%. Twelve of these patients (9.3%) had MYD88 L265P mutation, and these patients had a significantly worse PFS that patients who did not (18% vs 59%, p=0.018). Overall survival (OS) at 5 years after first line treatment was 65% (17% vs 72%, with vs without MYD88 mutation, respectively; p=0.001).
We further analyzed the outcome after second-line treatment in 32 cases: 6 patients had refractory disease (0 with MYD88 mutation) and 26 patients were in first relapse. Three out of 5 patients carrying MYD88 mutation and 25 out of 27 patients without MYD88 mutation were treated with chemotherapy. Only one out of 5 cases (20%) with MYD88 mutation responded to second-line therapy whereas response was observed in 16 out of 27 cases (59%) without MYD88 mutation(p=0.106). PFS at 4 years from starting second-line therapy was 0 % in cases with MYD88 DLBCL and 34% in those without MYD88 mutation (p=0.092). Moreover, OS at 4 years from starting second-line therapy was 0 % in cases with MYD88 DLBCL and 37% in those without MYD88 mutation (p=0.019)(Figure 1).
CONCLUSION
Our study shows that MYD88 L265P in DLBCL patients is not only associated to worse respond after first -line therapy, but also to a very poor response to second-line therapy, and consequently to a dismal outcome. New treatments are urgently needed for these patients.
Acknowledgments: This study was supported in part by 2014SGR567
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.