Aggressive BCell Lymphoma Arising From Lymphoplasmacytic Lymphoma with

Aggressive B-Cell Lymphoma Arising From Lymphoplasmacytic Lymphoma with a Distinct Genomic Profile Deniz Gur, David C Park. Department of Hematopathology, Memorial Sloan- Kettering Cancer Center, New York, NY, USA

Clinical History • 64 -year-old man with severe atrial fibrillation • April 2009 (work up for radiofrequency ablation treatment): Hb: 9 g/d. L Ig. M: 3. 6 g/d. L Ig. A: 1. 0 g/d. L Ig. G: 1. 1 g/d. L • Bone marrow biopsy (April 2009): Lymphoplasmacytic lymphoma (LPL) with 40 -50% involvement

At the Time of Dx Lab. values BM Bx Treatmen t No response Hb: 9 g/dl Anemia Ig. M: 3. 6 g/dl Ig. M: 3. 2 g/dl LPL, 40 -50% involvement LPL, 95% involvement Everolimus (RAD 001) failed switched to CDR with rituximab maintenance (8 cycles) Good Response Hb: 11 g/dl Persistent disease with progression Severe anemia Plt: very low Ig. M: 0. 4 g/dl BDR (bortezomib, dexa. rituximab) BDR (bortezomib dexa. rituximab) 09/ 2015 07/ 2015 12/2013 03/ 2013 08/ 2010 04/ 2009 Clinical History Ibrutinib swithed to bendamustine rituximab Hb: 10 g/dl Plt: 76 k/mc. L Hb: 9. 6 g/dl Plt: 17 k/mc. L Ig. M: 3. 7 g/dl Ig. M: 2. 8 g/dl LPL, (95%) Suspicious for transformation Aggressive B cell lymphoma with large cell transformation (100%) Ca. RD (carfilzomib rituximab, dexa. ) Refused further treatment

Clinical History Cytogenetics: Bone marrow aspirate (4/21/2010): 46, XY [20]; Normal male karyotype Molecular Studies: Mutations identified by comprehensive genomic profiling are as follows: • ARID 1 A Q 2037* • CXCR 4 H 341 fs*1+ • MYD 88 L 265 P • TP 53 G 245 D, R 249 T, S 241 F – subclonal

Bone Marrow Biopsy (07/23/2015) Necrotic area Extensive involvement by LPL

Bone Marrow Biopsy (07/23/2015) CD 79 a

Bone Marrow Biopsy (07/23/2015) MUM 1 MYC LPL, more than 95% involvement with extensive tumor necrosis highly concerning for transformation to diffuse large B cell lymphoma

Bone Marrow Biopsy and Aspirate (09/04/2015)

Bone Marrow Biopsy (09/04/2015) PAX 5 CD 138

Bone Marrow Biopsy (09/04/2015) MUM 1 P 53 MYC

Bone Marrow Biopsy (09/04/2015) Ki 67 Aggressive B cell lymphoma consistent with large cell transformation of lymphoplasmacytic lymphoma

Interesting Features • Compared to CLL/SLL, the risk of LPL/WM to transform into an aggressive B cell lymphoma is much lower and has been reported as isolated case reports or small series • Risk factors for adverse prognosis in LPL/WM patients: – cytopenias – heavy tumor burden – complex karyotype – poor response to therapy • Our patient had most of the risk factors (cytopenias, high tumor burden and poor response to therapy), however he had a normal karyotype

Interesting Features • Comprehensive genomic profiling detected 6 genomic mutation in 4 genes – ARID 1 A Q 2037* – CXCR 4 H 341 fs*1+ – MYD 88 L 265 P – TP 53 G 245 D, R 249 T, S 241 F – subclonal • Concurrent mutations may explain the adverse outcome and aggressive transformation in our patient – Patients with both ARID 1 A and MYD 88 mutations have a greater involvement of bone marrow, lower hematocrit and platelet counts – ARID 1 A and p 53 mutations promote tumor development in a codependent fashion – CXCR 4 mutations are also shown to be associated with increased disease activity

Summary • Large cell transformation in LPL/WM cases is not well studied and the underlying molecular mechanisms are not known • This is a rare case of LPL/WM with distinct genomic profile, transformed into an aggressive large B cell lymphoma • Studying these cases may help identifying LPL/WM patients with a high risk of transformation and also help tailoring optimal chemotherapeutic intervention