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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/37131; and 4) view/print certificate.
Release date: January 23, 2014; Expiration date: January 23, 2015
Learning Objectives
Upon completion of this activity, participants will be able to:
Describe the challenges associated with the management of patients with HIV-related lymphoma
Summarize the treatment options for patients with HIV-related lymphoma
Discuss the safety and efficacy of brentuximab vedotin in the treatment of patients with HIV-related lymphoma
Patients infected with HIV continue to face an increased risk of both non-Hodgkin’s lymphoma (NHL) and classical Hodgkin’s lymphoma (cHL), even after the broad availability of highly active antiretroviral therapy (HAART), which has been associated with a significant decrease in the risk of lymphoma.1,2 Although the most common histologic variant of NHL in this population remains diffuse large B-cell lymphoma (DLBCL), cHL has become more prevalent in the HAART era.3 T-cell NHLs are significantly less frequent, whereas peripheral T-cell lymphoma (PTCL) not otherwise specified, along with cutaneous and systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL), seem to be the most common variants.4 Based on the cumulative data, similar to B-cell NHL, HIV positivity seems to confer a definite risk of developing a PTCL compared with the overall population.5
Clinical outcomes have improved with modern chemoimmunotherapy and HAART in HIV-related DLBCL, with rates of complete remission (CR) and overall survival approaching those achieved in patients who are HIV-negative.6-10 Recent studies suggest a similar trend in HIV-cHL.11,12 However, a paucity of prospective data exists for the treatment of relapsed disease, although modest success has been reported with the ESHAP regimen13 (etoposide, methylprednisolone, arabinose cytosine, cisplatin). Notably, outcomes with salvage high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) appear to be comparable with those observed in non-HIV cohorts,14-16 although the precise role of transplantation remains debatable.17
The cell-surface marker CD30, which is part of the tumor necrosis factor receptor superfamily,18 is universally expressed in cHL and ALCL but variably expressed on other types of NHL. Brentuximab vedotin (BV), a humanized anti-CD30 IgG1 antibody conjugated to the cytotoxin monomethyl auristatin E, gained regulatory approval in 2011 for the treatment of relapsed/refractory cHL and ALCL.19,20 However, patients who were HIV-positive were excluded from the trials leading to its approval, and the authors are unaware of reports of its use in persons infected with HIV. This report describes 2 patients with HIV-associated lymphoma who were treated with BV with excellent safety and efficacy.
Case Reports
Patient 1
Patient 1 is a 42-year-old man originally diagnosed with HIV in February 2010. He was started on HAART therapy with emtricitabine-tenofovir, darunavir, and ritonavir, and continues on this regimen currently. Although this resulted in a reduction of his viral load to undetectable levels, his CD4 counts persistently remained below 100 cells/μL, with a nadir of 22 cells/μL. In December 2010, the patient developed Kaposi sarcoma. This was treated with interferon-alpha and liposomal doxorubicin, ultimately to a CR. Approximately 6 months after completion of therapy he developed new nodular, moderately tender skin and subcutaneous lesions, diffusely on his extremities. Concurrently, the patient noted a 10-lb unintentional weight loss and frequent night sweats. Biopsy of a skin nodule showed a lymphomatous infiltrate consistent with ALK-negative ALCL. The malignant cells were positive for CD3, CD4, CD5, and CD30. Functional imaging with PET showed hypermetabolic activity in the inguinal, femoral, and presacral nodes indicative of disease. Subsequently, he was diagnosed with advanced ALK-negative cutaneous ALCL with systemic involvement. He was treated with ifosfamide, carboplatin, and etoposide (ICE), experienced a CR, and underwent a consolidative ASCT in December 2011.
The patient did well for approximately 8 months posttransplant. In August 2012, however, he developed significant lethargy and lower extremity weakness requiring hospital admission. Imaging demonstrated diffuse adenopathy and excisional lymph node biopsy confirmed the presence of relapsed ALCL, with malignant cells again expressing CD2, CD7, CD5, and CD30. He was then treated with BV at 1.8 mg/kg every 21 days. Restaging after 3 cycles showed a complete response. Treatment was complicated by reversible grade 2 neuropathy and grade 2 neutropenia, neither of which required dose delay or reduction. As of most recent follow-up, he had completed 8 cycles of therapy with durable CR. He is being considered for an allogeneic stem cell transplant.
Patient 2
Patient 2 is a 42-year-old man with a history of HIV, who began HAART therapy on diagnosis in early 2005. His initial regimen of raltegravir, abacavir, and fosamprenavir remains unchanged. In 2006, he was diagnosed with Burkitt lymphoma and treated to CR with infusional etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (EPOCH). In 2008, the patient developed advanced-stage cHL and was treated with the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). He again experienced CR, but subsequently developed Stage D nonischemic cardiomyopathy, almost certainly the result of anthracycline exposure. After placement of a biventricular-assist device, he was evaluated for cardiac transplantation. At this point, most of the patient’s symptomatology was related to his advanced heart failure; specifically, he had low energy levels and exertional dyspnea, but no clear pattern of weight loss, night sweats, or persistent fevers. A PET scan performed as part of his pretransplant evaluation was remarkable for a hypermetabolic left supraclavicular node, and a bone marrow biopsy confirmed recurrence of cHL. The neoplastic cells were positive for CD15, CD30, and Epstein-Barr virus-encoded RNA; weakly positive for PAX5; and negative for CD45 and CD20.
Given his cardiomyopathy, it was thought that treatment options involving salvage chemotherapy and a potential HDT-ASCT would place him at very high risk for an adverse treatment-related outcome. Subsequently, he began treatment at standard dose BV in November 2012. PET imaging obtained after 3 cycles showed complete resolution of FDG avidity, and a bone marrow biopsy was negative for residual lymphoma.
He continues on treatment with BV and is now undergoing a second consideration for cardiac transplant.
Discussion
This report describes the on-label use of BV to treat 2 patients’ relapsed HIV-associated lymphoma. Both patients experienced rapid and complete remissions with minimal toxicity, and remained in durable remission as of December 2013.
The treatment of HIV-related lymphoma is complicated by the combination of the immunosuppressive effects of HIV; myelosuppression resulting from chemotherapy and sometimes from antiretroviral agents; and rituximab-related lymphocyte depletion. This risk seems to be greatest in patients with CD4 counts less than 50 cells/μL.7 Immunosuppressed patients, including those with HIV and those treated for lymphoma, are at risk for clinically significant infection with the JC virus, and the resulting syndrome progressive multifocal leukoencephalopathy (PML).21,22 It has been reported in patients exposed to rituximab23 and those exposed to brentuximab,24,25 and has led to so-called black box warnings for both agents. Although the median time to a clinical diagnosis of PML after rituximab therapy is reported to be 5 months,26 it may be on the order of weeks after treatment with BV. Subsequently, concern exists that immunotherapy may heighten the already elevated risk of PML in patients with HIV, although a recent analysis suggests incidence is rare.27 Notably, neither of the present patients has developed signs or symptoms suggestive of PML several months after exposure to BV.
The AIDS Malignancy Consortium recently began enrolling patients in a multicenter prospective trial investigating the combination of brentuximab with conventional chemotherapy for front-line treatment of HIV-cHL (ClinicalTrials.gov identifier: NCT01771107). Given the reports of PML in patients treated with BV, eligibility criteria will include absolute CD4 count greater than 50 cell/μL, active antiretroviral therapy, and a pretreatment brain MRI. Until prospective clinical trial data are available for the safety and efficacy of BV in HIV-related lymphomas, clinicians must continue to rely on clinical judgment as to when and how this agent can be used in this population, and case reports and case series will remain an important source of data.
Dr. Gandhi has disclosed that he has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Petrich has disclosed that he receives research funding from and is on the advisory board for Seattle Genetics, Inc.
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network
Ms. Green has disclosed that she has no relevant financial relationships.
CE AUTHORS
Deborah J. Moonan, RN, BSN, Manager, CE Supporter Outreach
Ms. Moonan has disclosed the following relationship with commercial interests: AstraZeneca: Stockholder/Former Employee.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations
Ms. Gregory has disclosed that she has no relevant financial relationships.
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