Incorporating Bortezomib in the Management of Plasmablastic Lymphoma

Discussion

Patients with advanced plasmablastic lymphoma have a poor prognosis. A review of 76 cases of HIV-negative plasmablastic lymphoma found a median survival of 9 months and a 2-year survival rate of 10% (1). Morscio et al. performed a meta-analysis of 300 cases of plasmablastic lymphoma and reported a median survival of 11 months in HIV-negative immunocompetent cases (2). In an attempt to improve outcomes, current guidelines recommend more aggressive regimens than traditional CHOP (3). Amongst these infusional dose-adjusted regimens, EPOCH is the most commonly used. Similar attempts have been made to decrease the rate of relapse by performing autologous stem cell transplantation in patients who seem to be responding to chemotherapy. However, in the absence of any direct head-to-head comparison to CHOP, it is unclear if these more intense regimens improve survival.

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Figure 1.

Radiology images. CT (A) and MRI (B) showing soft tissue masses in left and right maxillary area, right orbit and calvarium with infiltration of underlying Dura Mater. (C) PET scan at the end of 6 cycles of EPOCH showing residual activity in left mandible, right shoulder, right proximal femur, both iliac bones and in the spine.

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Figure 2.

Pathology images. The tumor cells display plasmablastic appearance with eccentric nuclei, moderate amount of amphiphilic cytoplasm and some cells with prominent large nucleoli. The tumor cells are positive for CD138, CD56 and show Kappa light chains restriction pattern.

Given the significant overlap in pathological and clinical features of multiple myeloma and plasmablastic lymphoma, there has been interest in incorporating novel agents with activity in multiple myeloma, in the treatment of plasmablastic lymphoma. Of these, bortezomib has been thought to be the most promising. The combination of bortezomib with EPOCH regimen was first described in 2015 by Castillo et al. In this original case series, all three treated patients achieved a durable remission (4). A 2017 PubMed-based literature review of cases found that when combined with chemotherapy, the complete response rate to bortezomib based chemotherapy regimen is 89% with a 2-year survival of 55%. In the relapsed setting, bortezomib based combination chemotherapy induced a complete response in 16% with 2-year survival of 27% (5). More recently, Castillo et al. retrospectively reviewed outcomes of 16 patients with plasmablastic lymphoma treated with bortezomib plus EPOCH regimen and reported a complete response rate of 94% and 5-year survival rate of 65% (6).

Despite these encouraging results, it is unclear as to how best to incorporate bortezomib in the treatment of plasmablastic lymphomas. Concurrent use of bortezomib with chemotherapy is toxic with high rates of neuropathy, infections and febrile neutropenia (5). In the original case series of three patients described by Castillo et al., two developed grade 4 thrombocytopenia, one had reactivation of herpes zoster and one developed small bowel obstruction, prompting discontinuation of vincristine (4). Dose adjustment of doxorubicin, etoposide and cyclophosphamide, based on nadir neutrophil and platelet counts in the preceding chemotherapy cycle, is a key component of the da-EPOCH regimen. Dose of vincristine requires adjustment based on the degree of neuropathy (7). Neuropathy is common with bortezomib and both bortezomib and lenalidomide cause cytopenia. Therefore, using them with EPOCH can potentially compromise the possibility of dose escalation.

In this case report we describe an alternative way of incorporating bortezomib, in the upfront management of a patient with plasmablastic lymphoma. Delaying the introduction of bortezomib and lenalidomide in the treatment regimen till all planned cycles of EPOCH were completed allowed for successful dose escalation of chemotherapy required for pharmacodynamics, the clarification of the dose-effect relationship.

A “maintenance strategy” of using less intensive therapy to prevent relapses after completing intensive therapy is commonly used in many hematologic malignancies. For example, a regimen containing daily mercaptopurine with weekly pulses of methotrexate and monthly pulses of prednisone and vincristine is recommended to patients with acute lymphoblastic leukemia after completing intensive therapy (8). Maintenance therapy with bortezomib and lenalidomide have been shown to delay relapse and is commonly offered to patients with multiple myeloma (9, 10). Maintenance therapy with lenalidomide has also been shown to improve survival in elderly patients with diffuse large B cell lymphoma (11).

We used a bortezomib, lenalidomide-based maintenance regimen in our patient because her high IPI score and positive PET scan at the end of therapy predicted a high risk for relapse and she declined an autologous stem cell transplant (12). Prolonged exposure to lenalidomide in patients with multiple myeloma has been associated with risk of secondary malignancies. Bortezomib can cause cumulative neuropathy. Given the high proliferative rate of plasmablastic lymphoma, most of the relapses are expected to occur during or shortly after completing therapy. Therefore, we elected to continue maintenance therapy for 6 months and not longer.

In conclusion, a time-limited regimen of daily lenalidomide and biweekly bortezomib following completion of dose adjusted EPOCH allowed for the incorporation of these two agents safely in the successful management of a patient with plasmablastic lymphoma. Larger clinical trials are needed to fully evaluate the efficacy of this approach. In the meantime, clinicians who are concerned about overlapping toxicities when using chemotherapy concurrently with bortezomib can consider this approach as an option for their patients with plasmablastic lymphoma.