Daratumumab with ifosfamide, carboplatin and etoposide for the treatment of relapsed plasmablastic lymphoma

Abstract

Plasmablastic lymphoma (PBL) is a rare and aggressive form of non-Hodgkin lymphoma (NHL) that arises from a post-germinal centre B-cell that has taken on many characteristics of a fully differentiated plasma cell. The classic PBL cell immunophenotype lacks B-cell markers, including CD19, CD20, and paired box 5 (PAX-5), but expresses plasma cell markers such as CD138 and multiple myeloma oncogene 1 (MUM-1). Additionally, PBL cells universally express CD38.1 Limited data exist on the front-line treatment of PBL and virtually no data exist for managing relapsed PBL. Extrapolating from common NHLs, the approach to relapsed disease involves salvage chemotherapy with the goal of achieving a complete response (CR) prior to autologous stem cell transplant. Although outcomes are worse for PBL, at least some data support taking a similar approach.2 A standard lymphoma salvage regimen consists of ifosfamide, carboplatin, and etoposide (ICE).3 In order to improve the CR rate, we combined this regimen with daratumumab (D-ICE). In this report, we describe four patients with relapsed PBL that received the novel regimen, D-ICE (Table 1). A 64-year-old human immunodeficiency virus (HIV)-negative female patient presented with lower extremity swelling, pain, and erythema. A cutaneous biopsy revealed PBL (CD138+, lambda restricted). She completed six cycles of bortezomib-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) followed by radiation, and achieved a CR. She progressed 3 months later and was given two cycles of gemcitabine-oxaliplatin without a response. Subsequently, she was started on the novel regimen, D-ICE. The regimen was administrated with standard ICE dosing at 3-week intervals, along with daratumumab 16 mg/kg IV given weekly. After one cycle, the patient’s pain and swelling improved and her LDH decreased from 2911 to 657 u/l. A positron emission tomography/computed tomography (PET/CT) after cycle 2 showed a Deauville 3 CR (Figure 1). The patient developed Grade 4 myelosuppression, which required a dose reduction of her etoposide. She had difficulty with stem cell mobilisation for autologous stem cell transplant but remained in remission for 2 months before again progressing in her lower extremity. She received several months of ixazomib-based therapy, but ultimately progressed and entered hospice. A 55-year-old HIV-positive (CD4+ cell count: 0.154 ×109/l) male patient presented with right lower quadrant pain and CT showed a large mass in the right kidney. A biopsy revealed PBL (CD138+, kappa restricted). Fluorescence in situ hybridisation (FISH) evaluation was negative for a MYC gene rearrangement. The patient received six cycles of bortezomib-EPOCH, attaining a CR. Three months later, he presented with right upper quadrant pain, and CT showed a recurrent mass in the right abdominal wall; a biopsy was consistent with PBL. He received four cycles of D-ICE with daratumumab given weekly via IV at a dose of 16 mg/kg and attained a CR after two cycles of therapy. The patient experienced Grade 4 febrile neutropenia and septic shock after his last cycle. He recovered and proceeded to autologous stem cell transplant. He is without evidence of disease 69 months after transplant. A 38-year-old male patient presented with a synchronous diagnosis of HIV (CD4+ cell count: 0.180 ×109/l) and perirectal mass. On PET/CT the patient had a large mass in the ischiorectal space and pelvic lymphadenopathy (LAD). A biopsy was consistent with PBL (CD56+, CD138+, Epstein-Barr encoding region [EBER]+, kappa restriction, CD20−). FISH evaluation was positive for a MYC/IGH translocation. He completed six cycles of bortezomib-EPOCH but had residual disease that was treated with radiation. He subsequently progressed and was initiated on D-ICE with daratumumab 1800 mg subcutaneous weekly. He completed three cycles of D-ICE complicated by Grade 4 neutropenia. He achieved a Deauville 1 CR on PET/CT and is awaiting autologous stem cell transplant. A 42-year-old HIV-positive (CD4+ cell count: 0.192 ×109/l) male patient presented with a testicular mass. PET/CT revealed a mass in the right testicle, thyroid, and LAD. An orchidectomy was performed, and a biopsy was consistent with PBL (CD38+, MUM-1+, EBER+, CD20−). FISH showed MYC gene rearrangement. The patient received six cycles of bortezomib-EPOCH with intrathecal methotrexate and radiation to the contralateral testicle. PET/CT imaging showed a partial response (PR) at the end of treatment with persistent uptake in the thyroid. A repeat biopsy showed PBL. The patient then received three cycles of D-ICE (daratumumab 16 mg/kg IV weekly) and attained a CR. Therapy was complicated by Grade 4 febrile neutropenia after cycle three. The patient underwent an autologous stem cell transplant and remains without evidence of disease 5 months after transplant. With an incidence of <0.1 cases per 100 000 people in the USA, PBL is exceedingly rare.4 Front-line treatment is based on extrapolation from similar types of lymphoma, as well as small case series. Because of the poor survival of PBL, specialists have turned to novel combinations. Promising agents include those that have shown efficacy in targeting plasma cell neoplasms. Bortezomib, a proteasome inhibitor initially used in multiple myeloma, has been combined with chemotherapy and shown to be effective in frontline PBL.5 In the relapsed setting, PBL treatment is even more difficult and new approaches are required. Daratumumab, a CD38-targeting human immunoglobulin G, subclass 1, κ light chain (IgG1κ) monoclonal antibody, is an important agent in the treatment of multiple myeloma, but limited data exist for its use in NHL. One case report evaluated daratumumab with bortezomib and lenalidomide in the relapsed setting.6 This patient achieved a PR followed by allogeneic stem cell transplant. A prospective trial evaluating this regimen is currently active (NCT04915248). Recently, a small series of four patients with PBL was described.7 Three patients received front-line daratumumab with EPOCH and one received daratumumab with lenalidomide, dexamethasone and doxorubicin in the relapsed setting. All four patients achieved a CR and three of the four patients remained in remission for at least 15 months. A small prospective study conducted by the AIDS Malignancy Consortium is examining daratumumab-EPOCH in the front-line setting (NCT04139304). Based on the data evaluating daratumumab in PBL, we combined this targeted agent with a standard NHL salvage regimen, ICE. In our limited evaluation of four patients, the novel regimen D-ICE, was safe and effective with all four patients achieving a CR after three to four cycles of therapy. The most concerning adverse effect was myelosuppression, and future research may lead to dosing or frequency changes to the regimen to mitigate this effect. These findings are promising and warrant further evaluation of D-ICE in a prospective trial. Drs Dittus, Miller, Wehbie, and Castillo all participated in the design and writing of the study. Dr Dittus has consulted for Seagen, BeiGene and Genmab. Dr Castillo has consulted for Abbvie, AstraZeneca, BeiGene, Janssen, Pharmacyclics, Polyneuron, Roche, TG Therapeutics. Drs Miller and Wehbie have no financial disclosures. Descriptive data can be provided upon request. Consent waived as photographs contain no personal identifiers. There are no copyrighted works included in this manuscript.

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