Complete response to pembrolizumab and radiation in a patient with <scp>HIV</scp> ‐negative, <scp>EBV</scp> ‐positive plasmablastic lymphoma
Authors: Jorge J. Castillo, John Lamacchia, Joel Silver, Catherine A. Flynn, Shayna Sarosiek
Journal: American Journal of Hematology (2021)

To the Editor: The patient is a 79-year-old Caucasian man, who was in his usual state of health until August 2017, when he reported sore teeth during the fitting of a continued positive airway pressure machine. He developed a yellow nasal discharge and was treated with antibiotics. In November 2017, the patient reported left-sided facial numbness and bulging of the left cheek. Computed tomography (CT) scan of the face showed a 4.5 × 4 cm left maxillary mass with maxillary bone destruction (Figure 1(A)). A biopsy of the mass revealed large malignant cells with oval to round nuclear contours, open chromatin, variably conspicuous eosinophilic nucleoli, and moderately abundant cytoplasm. There is frequent individual cell necrosis, increased mitotic figures, and large areas of zonal tumor necrosis. Tumor cells were positive for CD138, MUM1, and CD4 and negative for PAX5, CD20, CD30, CD3, CD34, ALK, EBV LMP1, and HHV8 LANA1. There was a weak, variable expression of EMA and CD45. Epstein–Barr virus-encoded RNA (EBER) in situ hybridization was strongly positive. There was a clonal immunoglobulin heavy chain gene rearrangement. Serology studies for HIV, hepatitis B, and hepatitis C were nonreactive. Serum lactate dehydrogenase level was within normal limits. Positron emission tomography (PET)/computed tomography (CT) showed 18-F fluorodeoxyglucose (FDG) avidity in the left maxillary sinus extending into the left orbital region and did not show additional areas of disease. A bone marrow biopsy did not show evidence of lymphoma. These findings were consistent with an HIV-negative, stage I plasmablastic lymphoma (PBL).1 His International Prognostic Index (IPI) score was low-risk. The patient was started on bortezomib plus cyclophosphamide, doxorubicin, vincristine, and prednisone (V-CHOP).2 In March 2018, a PET/CT scan after four cycles of V-CHOP showed no residual 18-F FDG avidity, consistent with a complete metabolic response. Radiotherapy was planned as consolidation. However, there was a recurrence of nasal congestion and left maxillary fullness before radiotherapy initiation. Given rapid progression after an anti-lymphoma regimen, the patient was started on daratumumab, lenalidomide, and dexamethasone, an anti-myeloma regimen, and received two cycles in April 2018 without evidence of clinical improvement. A PET/CT scan showed persistent 18F-FDG avidity in the left maxillary sinus (Figure 1(B)). A repeat biopsy showed diffuse infiltrate of large plasmacytoid cells with eccentric nuclei, irregular nuclear borders, and abundant cytoplasm occurring in sheets, consistent with PBL relapse. Immunohistochemical studies (Figure 1, bottom) show that the tumor cells were positive for CD138 (subset), MUM1, and EBER. The Ki-67 proliferation index was 80%. PDL1 was strongly positive on a subset of tumor cells (5%-10%) and tumor-infiltrating macrophages, mainly in a perivascular pattern. Based on PDL1 expression by the tumor cells, the patient was started on intravenous (IV) pembrolizumab 200 mg every 3 weeks in June 2018. Within four cycles of therapy, there was a subjective improvement in nasal congestion and left maxillary fullness. The patient received adjuvant radiotherapy at 30 Gy in August 2018, and pembrolizumab continued. After six cycles of pembrolizumab, the patient attained a partial response based on PET/CT scan (Figure 1(C)). Pembrolizumab therapy was complicated by recurrent urinary tract infections, pneumonia, and ophthalmic herpes zoster infection. In August 2019, the patient developed shortness of breath and pleural effusions due to heart failure with a left ventricular ejection fraction (LVEF) of 10%. The patient was managed medically and received methylprednisolone 1 g IV once daily for 3 days followed by a prednisone taper. Pembrolizumab was stopped after 18 cycles of therapy. A PET/CT scan in June 2020 showed no evidence of 18F-FDG avidity, consistent with a complete response (Figure 1(D)). In December 2020, the patient's LVEF had improved to 45%. In June 2021, a PET/CT scan showed no evidence of 18-F FDG-avid disease, consistent with a sustained complete response, 43 months from the initial diagnosis of PBL and 22 months from the last dose of pembrolizumab. Plasmablastic lymphoma is a rare and aggressive CD20-negative lymphoma variant associated with a poor prognosis, which has been reported in HIV-infected, immunosuppressed (other than HIV infection) as well as immunocompetent individuals.3 The management of PBL is not standardized, and current guidelines recommend chemotherapy combination treatments. These recommendations, however, are made based on consensus and small retrospective experience. At our institution, we introduced the use of the proteasome inhibitor bortezomib in combination with chemotherapy in patients with PBL, based on previously published data suggesting a 5-year overall survival rate of 60%.4 Patients with an early stage at diagnosis and low-risk IPI scores have had better outcomes. The management of relapsed PBL is challenging, however, as most patients end up succumbing because of disease progression. In the present case, we illustrate the clinical course of an elderly HIV-negative patient with early-stage disease who attained a short-lived response to the combination of bortezomib and chemotherapy. The patient was also refractory to daratumumab, lenalidomide, and dexamethasone. It is possible that radiotherapy enhanced the efficacy of pembrolizumab in this case, as there are mounting data supporting a synergistic effect of ionizing radiation in combination with PD1/PDL1 blockade.5 High-dose steroids might also have played a role. The standard management of a relapsed aggressive lymphoma would have been additional chemotherapy, followed, if responsive, by higher doses of chemotherapy and an autologous stem cell transplant. Our patient would not have been an optimal candidate for this approach given his age and chemoresistant disease. One prior case has been reported on the use of nivolumab in a 34-year-old woman with HIV-negative PBL after progressing after dose-adjusted EPOCH; carfilzomib, lenalidomide plus dexamethasone; and ifosfamide, carboplatin plus etoposide.6 Nivolumab induced a partial response and the patient underwent a myeloablative conditioning regimen followed by a matched related allogenetic stem cell transplant. A recent study reported not only an increased expression of PD1/PDL1 in malignant cells and tumor-associated macrophages in PBL, but also a worse survival associated with PD1/PDL1 expression.7 Herein, we report the first case of PBL treated with the anti-PD1 monoclonal antibody pembrolizumab at standard doses approved for use in patients with relapsed or refractory Hodgkin lymphoma. The expression of PDL1 in the malignant cells and the tumor-associated macrophages served as the biological basis for our intervention. No treatment intervention is without potential toxicity, however. Our patient experienced a number of adverse events probably related to PD1 blockade. Cardiomyopathy with LVEF at 10% developed after 18 cycles of pembrolizumab therapy prompting permanent discontinuation. Cardiomyopathy with left ventricular systolic dysfunction appears to be a late adverse event associated with PD1 blocking agents.8 Fortunately, the cardiomyopathy improved after drug discontinuation. Our experience suggest that anti-PD1 monoclonal antibody therapy could be effective in the management of patients with PBL with PDL1 expression, especially in patients who might not be optimal candidates for combination chemotherapy or autologous stem cell transplantation. The authors have no conflicts of interest to disclose. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.