Primary Refractory Double Hit Diffuse Large B Cell Lymphoma: Complete Response to Ibrutinib and Rituximab

Editorial

Double hit lymphoma (DHL) associated with translocations in MYC and BCL-2 or BCL-6 gene accounts for approximately 5-10 % of all diffuse large B cell lymphoma (DLBCL) [1]. These patients are distinct from double-expressers who stain positive on immunohistochemistry for MYC and BCL2 or BCL6 accounting for approximately 25-35% of all DLBCL. Double expresser DLBCL have relatively poor outcomes but DHL is associated with extremely aggressive course and poor prognosis. With R-CHOP, R-EPOCH or similar induction therapy a complete response rates of 30-70% have been reported for DHL with 5 years survival of only 27-36% [2]. Patients with primary refractory DHL have dismal prognosis with limited therapeutic options. Additionally, in absence of chemo sensitivity, these patients are not candidate for high-dose chemotherapy and autologous stem cell transplantation (ASCT). We herein report a patient who failed multiple chemotherapies but surprisingly had complete pathologic response to Ibrutinib and rituximab (IR).

Standard lymphoma staging, international prognostic index defined initial diagnosis and RECIST criteria were utilized for lymphoma response [3]. A 62 years old Caucasian male was diagnosed with stage IVB DLBCL (IPI score-4) in February 2013. Cervical node biopsy was positive for C-MYC and BCL-2 translocation with proliferative index of 70%. Bone marrow was involved, CSF was negative, LDH was elevated and he had 40 pounds weight loss with night sweats. Treatment with 4 cycles of rituximab, cyclophosphamide, Adriamycin, vincristine and prednisone (R-CHOP) produced partial response with persistence of PET avid (SUV down to 9 from 17) disease in retro peritoneum that was bulky (17 x21 cm). He subsequently received 2 cycles of rituximab, ifosfamide, carboplatin and etoposide (RICE) and 2 cycles of hyper fractionated cyclophosphamide, vincristine, Adriamycin and dexamethasone (Hyper-Cvad) with stable response and progressive disease respectively (Table 1).

In February of 2019 he developed pancytopenia that did not improve with cessation of Ibrutinib. Bone marrow biopsy revealed therapy related MDS with 30% diploid blasts with NMP-1 as sole molecular abnormality.

Response to Ibrutinib and rituximab combination in previously heavily treated primary refractory DLBCL is encouraging. An overall response rates of 29-37 % has been documented for Ibrutinib in relapse refractory DLBCL with mostly non GCB DLBCL patients responding (response rate of 30-40% vs. 5% for GCB DLBCL) [7]. In these studies, approximately 10% patients with DLBCL achieved CR with Ibrutinib; it is not clear if any of these were DHL. In conclusion, we document marked and durable activity of immunotherapy alone in primary refractory DHL after failing multiple cytotoxic chemotherapy regimens. Ibrutinib likely did not contribute to MDS, an association not yet described.