Brentuximab Vedotin in Patients With Relapsed HIV-Related Lymphoma

Authors:
Mitul GandhiFrom Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology & Oncology, Chicago, Illinois.

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Adam PetrichFrom Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology & Oncology, Chicago, Illinois.

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Lymphoma is a well-recognized complication in patients infected with HIV. Although its incidence has declined since the advent of antiretroviral therapy, it remains higher than seen in the general population. Several recent studies have noted improvement in clinical outcomes with the use of modern chemoimmunotherapy regimens. In patients who experience relapse, however, fewer data are available on the role of immunotherapy and its impact on outcomes. This case report presents 2 patients with relapsed HIV-associated lymphoma who experienced a second complete remission after treatment with the immunotherapy agent brentuximab vedotin.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is accredited for 1.0 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

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.

References

  • 1.

    Besson C, Goubar A, Gabarre J et al.. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 2001;98:23392344.

    • Search Google Scholar
    • Export Citation
  • 2.

    Franceschi S, Lise M, Clifford GM et al.. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer 2010;103:416422.

    • Search Google Scholar
    • Export Citation
  • 3.

    Engels EA, Pfeiffer RM, Goedert JJ et al.. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS 2006;20:16451654.

  • 4.

    Castillo JJ, Beltran BE, Bibas M et al.. Prognostic factors in patients with HIV-associated peripheral T-cell lymphoma: a multicenter study. Am J Hematol 2011;86:256261.

    • Search Google Scholar
    • Export Citation
  • 5.

    Biggar RJ, Engels EA, Frisch M, Goedert JJ. Risk of T-cell lymphomas in persons with AIDS. J Acquir Immune Defic Syndr 2001;26:371376.

  • 6.

    Weiss R, Mitrou P, Arasteh K et al.. Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival—results of the German Multicenter Trial. Cancer 2006;106:15601568.

    • Search Google Scholar
    • Export Citation
  • 7.

    Sparano JA, Lee JY, Kaplan LD et al.. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 2010;115:30083016.

    • Search Google Scholar
    • Export Citation
  • 8.

    Lim ST, Karim R, Tulpule A et al.. Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy. J Clin Oncol 2005;23:84778482.

    • Search Google Scholar
    • Export Citation
  • 9.

    Dunleavy K, Little RF, Pittaluga S et al.. The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood 2010;115:30173024.

    • Search Google Scholar
    • Export Citation
  • 10.

    Little RF, Pittaluga S, Grant N et al.. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003;101:46534659.

    • Search Google Scholar
    • Export Citation
  • 11.

    Hentrich M, Berger M, Wyen C et al.. Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study. J Clin Oncol 2012;30:41174123.

    • Search Google Scholar
    • Export Citation
  • 12.

    Montoto S, Shaw K, Okosun J et al.. HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era. J Clin Oncol 2012;30:41114116.

    • Search Google Scholar
    • Export Citation
  • 13.

    Bi J, Espina BM, Tulpule A et al.. High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin’s lymphoma. J Acquir Immune Defic Syndr 2001;28:416421.

    • Search Google Scholar
    • Export Citation
  • 14.

    Balsalobre P, Diez-Martin JL, Re A et al.. Autologous stem-cell transplantation in patients with HIV-related lymphoma. J Clin Oncol 2009;27:21922198.

    • Search Google Scholar
    • Export Citation
  • 15.

    Re A, Cattaneo C, Michieli M et al.. High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy. J Clin Oncol 2003;21:44234427.

    • Search Google Scholar
    • Export Citation
  • 16.

    Re A, Michieli M, Casari S et al.. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood 2009;114:13061313.

    • Search Google Scholar
    • Export Citation
  • 17.

    Bayraktar UD, Ramos JC, Petrich A et al.. Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999-2008 and treated with curative intent in the AIDS Malignancy Consortium. Leuk Lymphoma 2012;53:23832389.

    • Search Google Scholar
    • Export Citation
  • 18.

    Schneider C, Hubinger G. Pleiotropic signal transduction mediated by human CD30: a member of the tumor necrosis factor receptor (TNFR) family. Leuk Lymphoma 2002;43:13551366.

    • Search Google Scholar
    • Export Citation
  • 19.

    Pro B, Advani R, Brice P et al.. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012;30:21902196.

    • Search Google Scholar
    • Export Citation
  • 20.

    Younes A, Gopal AK, Smith SE et al.. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 2012;30:21832189.

    • Search Google Scholar
    • Export Citation
  • 21.

    Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 2010;61:3547.

  • 22.

    Kim JH, Psevdos G Jr, Gonzalez E et al.. All-cause mortality in hospitalized HIV-infected patients at an acute tertiary care hospital with a comprehensive outpatient HIV care program in New York City in the era of highly active antiretroviral therapy (HAART). Infection 2013;41:545551.

    • Search Google Scholar
    • Export Citation
  • 23.

    Tuccori M, Focosi D, Blandizzi C et al.. Inclusion of rituximab in treatment protocols for non-Hodgkin’s lymphomas and risk for progressive multifocal leukoencephalopathy. Oncologist 2010;15:12141219.

    • Search Google Scholar
    • Export Citation
  • 24.

    von Geldern G, Pardo CA, Calabresi PA, Newsome SD. PML-IRIS in a patient treated with brentuximab. Neurology 2012;79:20752077.

  • 25.

    Wagner-Johnston ND, Bartlett NL, Cashen A, Berger JR. Progressive multifocal leukoencephalopathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma 2012;53:22832286.

    • Search Google Scholar
    • Export Citation
  • 26.

    Carson KR, Evens AM, Richey EA et al.. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009;113:48344840.

    • Search Google Scholar
    • Export Citation
  • 27.

    Hoffmann C, Gerard L, Wyen C, Oksenhendler E. No evidence for an early excess incidence of progressive multifocal leukencephalopathy in HIV-infected patients treated with rituximab. J Acquir Immune Defic Syndr 2012;60:e121122.

    • Search Google Scholar
    • Export Citation

Correspondence: Mitul Gandhi, MD, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology & Oncology, 675 North St Clare Street, Suite 21-100, Chicago, IL 60611. E-mail: mitul-gandhi@fsm.northwestern.edu

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