RESPONSE TO IBRUTINIB OF AN AGGRESSIVE IG-A LYMPHOPLASMACYTIC LYMPHOMA CARRYING THE MYD88 L265P GENE MUTATION

Lymphoplasmacytic lymphoma (LPL) is characterized by the prolif- eration of B lymphocytes with varying degrees of plasmacytic differ- entiation involving bone marrow (BM), lymph nodes or spleen. Waldenstrom macroglobulinemia (WM) is a subset of LPL in which the malignant clone produces an IgM paraprotein. LPL patients with IgA/IgG paraprotein account for less than 5% of LPLs. MYD88 muta- tion triggers survival through BTK activation in WM, a disease respond- ing to ibrutinib, whereas non-IgM LPL has not been extensively investigated at the molecular level. In 2014 a 66 year-old woman pre- sented with symptomatic anemia (Hb 9 g/dl), with IgAk monoclonal spike (1.6 g/dl) (Figure 1) and an otherwise unremarkable serum chem- istry profile. A BM biopsy showed an 80% infiltrate by lymphocytes and lym- phoplasmacytoid cells. A CT scan documented neither adenopathy nor splenomegaly. Diagnosis of IgA-secreting LPL was made. The patient was treated with RCD with minor response (Figure 1). Eighteen months later she presented with progressive disease (Hb 8 g/dl, IgAk mono- clonal spike 1.9 g/dl). After 5 cycles of bendamustine, the BM aspirate showed 90% lymphoid cells. Adenopathies, splenomegaly and ascitis were noted on a CT scan. After CHOP (3 cycles) our patient developed thrombocytopenia (30x109/L), transfusion-dependent anemia (Hb 7.7 g/dl) and clinical deterioration (Figure 1). We performed genetic studies with a targeted NGS approach detecting mutations in 20 genes fre- quently mutated in CLL (ATM, BIRC3, BRAF, CDKN2A, PTEN, CDH2, DDX3X, FBXW7, KIT, KLHL6, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, POT1, SF3B1, TP53, XPO1, ZMYM3). The MYD88 L265P mu- tation was identified. Given the identification of MYD88 L265P in the peripheral blood, ibrutinib appeared a reasonable option. In February 2018 our patient started ibrutinib 420 mg/die (Figure 1). Hb and PLT improved from day +35 (Hb 10-12 g/dl, PLT > 100x109/L). In July 2018 no ascitis and 50% reduction of adenopathies and spleen were shown on a CT scan. In April 2019 the patient is still on full dose ibrutinib with transfusion independence and good performance status. To the best of our knowledge this is the first case of response to ibrutinib in an ag- gressive IgA LPL with MYD88 mutation.