Quadruple Hit Lymphoma: A Rare Entity with Dismal Prognosis

Introduction

The WHO 2016 classification for hematologic malignancies has introduced a new entity: High-grade B cell lymphomas (HGBL), with MYC and BCL2 and/or BCL6 rearrangements. The oncology community, to reflect MYC and BCL2 or BCL6 rearrangement, is increasingly using the term double-hit lymphoma (DHL). When all three genes are rearranged, the term "triple-hit" has been used; A disease with very aggressive clinical features and dismal outcome. DHL tends to present with advanced stage, high International Prognostic Index (IPI), and increased LDH. There is high frequency of extra-nodal involvement, including the bone marrow and central nervous system. Though relatively rare, DHL has been the subject of intense investigation due to its aggressive clinical course and resistance to conventional chemotherapy. A "quadruple hit" lymphoma is a rare genetic variant that is seldom documented in the literature adding to the "triple hits", a Cyclin-D1 rearrangement. We sought to catalogue all the known published cases of quadruple hit lymphoma to better understand this rare aberration. We hereby describe the salient features of this rare entity and its prognosis.

Material and Methods

To better understand the clinical behavior of this rare entity, systematic review of PUBMED, Medline and EMBASE databases via OVID engine was conducted to search for primary articles and case reports under keywords "quadruple hit lymphoma" or "B‐cell lymphomas with MYC, BCL2, BCL6 or CCND1 rearrangements". The search was limited to the English literature. The PubMed search was conducted on May 28, 2018 and yielded 336 results. Two reviewers carefully reviewed the articles. Cases were considered "quadruple-hit" if MYC, BCL2, BCL6 and CCND1 were simultaneously rearranged in the same patient. Only three articles of quadruple hit lymphoma met the criteria and were included for further analysis. One case diagnosed recently and treated at our institution was included in the descriptive statistics.

Results

After our extensive review of the literature, only four cases met the inclusion criteria. With our case, we report five cases. The median age at diagnosis of quadruple hit lymphoma in this cohort was 72 years (range: 51-81). Three out of five cases were males. The Ki67 in the patients, when available, was at least 80%. When reported, LDH was universally elevated (range: 522-989). Out of the five patients, four received chemotherapy, though no two patients received the same regimen. Regimens used: RCHOP, dose adjusted REPOCH alternating with high dose methotrexate and cytarabine and Rituximab/ifosfamide and cytarabine. The response to treatment varied widely among the patients. Survival ranged from 6 days to at least 30 months in the youngest patient with the median overall survival being only four months. Complete response was achieved in two patients, one with RCHOP and the other with a combination of alternating REPOCH alternating with high dose methotrexate and cytarabine (this case was treated in our institution). The cytogenetics were uniformly complex in all cases. Our patient successfully underwent autologous bone marrow transplant as consolidation. The patient is still alive eight months after diagnosis but unfortunately, he relapsed three months after autologous bone marrow transplantation.

Conclusion

Quadruple hit lymphoma is an extremely rare entity occurring in patients diagnosed with high-grade B cell lymphoma with the rearrangements of four genes: MYC, BCL2, BCL6 and CCND1. Most patients present with bone marrow involvement, high IPI score and extra-nodal disease. There is no consensus on the optimal treatment and the prognosis is dismal despite aggressive initial therapy.

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