Lymphoma, Non-Hodgkin (NHL)

Annie Antar, M.D., PhD

PATHOGENS

CLINICAL

  • Classification of AIDS-related NHL:
    • Systemic NHL: >80%, which includes
      • Diffuse large B cell lymphoma (DLBCL): 60%
      • Burkitt lymphoma: 20%
      • Indolent B cell lymphoma: < 8%
      • T cell lymphoma: < 3%
      • Plasmablastic lymphoma < 1%.
    • Primary CNS lymphoma (PCNSL): 15%.
    • Primary effusion/body cavity lymphoma: < 5%.
  • Systemic NHL symptoms include lymphadenopathy, B Sx (fever, weight loss, night sweats), unexplained hematological/biochemical abnormalities and/or symptoms related to extralymphatic tissue infiltration by tumor. Most common extranodal sites of involvement: GI tract, bone marrow, liver, lung, and CNS.
  • Often advanced stage at presentation.
  • Late manifestation of HIV disease, most often associated with CD4 < 100, though can occur at any CD4 count. Low nadir CD4 and high HIV viral load or high cumulative VL ("area under the VL curve") are also risk factors.
  • No obvious environmental factors, but possible genetic predisposition: more common in men and in those with SDF-1 mutations.
  • Incidence of all AIDS-related lymphomas (ARL) has declined with ART, but decline less dramatic for lymphoma than for OIs, making it a common AIDS-defining illness.
  • Two subtypes almost uniquely associated with HIV are primary effusion lymphoma and plasmablastic lymphoma of the oropharynx.
  • EBV infection of the primary tumor (and EBV DNA in CSF) associated with CNS metastasis.

DIAGNOSIS

  • When possible, obtain Bx of node or affected organ. FNA is NOT desired mode of Dx, although it can often be used when Bx is not feasible.
  • Immunophenotyping of paraffin block or flow cytometric analysis of cell surface markers in combination with molecular studies (EBV or HHV-8, cytogenetics, FISH).
  • Staging workup should include chest/abdomen/pelvic CT vs PET, bone marrow Bx and aspirate, CBC, LDH and complete chemistries. LP should be performed with Burkitt lymphoma and in many cases of DLBCL. Brain MRI with gadolinium warranted depending on level of suspicion and subtype, and stool guaiac in any patient with abdominal involvement.

TREATMENT

Prognosis

  • Poor risk features: older age at Dx, lower CD4 count and higher VL at Dx, aggressive subtype (PCNSL, DLBCL, Burkitt), on ART at Dx.
  • Survival rates vary based on subtype; 5-year survival of Burkitt: 50%, of DLBCL: 44%, of PCNSL: 23%.

General Considerations

  • ART should be started or adjusted to achieve virologic suppression.
  • Choice of chemotherapy and/or radiation therapy based on subtype of NHL and stage.
  • ART toxicity notes: Etoposide, vincristine, cyclophosphamide, and prednisone serum levels may be increased with PI co-administration. AZT can prolong or exacerbate chemotherapy-induced neutropenia; ddI and/or d4T can increase risk of neuropathy
  • G-CSF routinely used during chemotherapy to shorten duration of neutropenia.
  • Gastric or intestinal DLBCL is well-described presentation of ARL associated with increased risk GI bleeding or perforation during chemotherapy (compared with GI DLBCL in non-AIDS population). Such pts often made NPO and placed on parenteral nutrition during first cycle of chemotherapy.
  • Rituximab (anti-CD20 monoclonal antibody) routinely used in ARL despite initial concerns of increased infectious complications.
  • In post-ART era, survival following treatment for ARL approximates that for lymphoma in non-AIDS population.
  • If R-EPOCH is given, PCP prophylaxisand antibiotic prophylaxis for enteric organisms should be given. Antiviral and anti-candidal prophylaxis is often considered.

Regimens

  • For DLBCL, effective regimens include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-EPOCH (rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin given by continuous infusion with prednisone). If CD4 < 50, rituximab may be deleted from regimens.
  • Burkitt lymphoma generally requires more intensive regimens that may require PCP prophylaxis and antibiotic prophylaxis for enteric organisms +/- antiviral anti-candidal prophylaxis.
  • Intrathecal chemotherapy with methotrexate or cytarabine recommended if CNS involvement, and often part of standard Burkitt lymphoma treatment.
  • High-dose therapy with autologous stem cell transplantation can be used for relapsed or refractory disease.

References

  1. Gopal S, Fedoriw Y, Kaimila B, et al. CHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi. PLoS One. 2016;11(3):e0150445.  [PMID:26934054]

    Comment: First prospective study of survival after CHOP for NHL in Subsaharan Africa (Malawi).

  2. Gopal S, Patel MR, Yanik EL, et al. Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst. 2013;105(16):1221-9.  [PMID:23892362]

    Comment: Multi-site review of survival, poor prognostic factors, and presentation of 23,050 HIV-infected patients who had or developed HIV-associated lymphoma.

  3. Goshen E, Davidson T, Avigdor A, et al. PET/CT in the evaluation of lymphoma in patients with HIV-1 with suppressed viral loads. Clin Nucl Med. 2008;33(9):610-4.  [PMID:18716509]

    Comment: Small study which revealed 25% false positive rate for PET in HIV-related lymphoma patients. Suggested higher incidence of false positive in patients with high viral loads.

  4. Miralles P, Berenguer J, Ribera JM, et al. Prognosis of AIDS-related systemic non-Hodgkin lymphoma treated with chemotherapy and highly active antiretroviral therapy depends exclusively on tumor-related factors. J Acquir Immune Defic Syndr. 2007;44(2):167-73.  [PMID:17117144]

    Comment: Describes prognostic factors associated with improved outcome.

  5. Boué F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol. 2006;24(25):4123-8.  [PMID:16896005]

    Comment: Phase II study demonstrating feasibility of R-CHOP regimen in HIV patients.

  6. Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas. Blood. 2005;105(2):874-8.  [PMID:15388574]

    Comment: Discusses role of transplant in ARL.

  7. Bower M, McCall-Peat N, Ryan N, et al. Protease inhibitors potentiate chemotherapy-induced neutropenia. Blood. 2004;104(9):2943-6.  [PMID:15238428]

    Comment: Discusses important interactions with PI based HAART regimens and chemotherapy.

  8. Herida M, Mary-Krause M, Kaphan R, et al. Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol. 2003;21(18):3447-53.  [PMID:12972519]

    Comment: Makes note of persistence of NHL as an AIDS-defining illness in post-HAART era.

  9. Ambinder RF. Epstein-Barr virus associated lymphoproliferations in the AIDS setting. Eur J Cancer. 2001;37(10):1209-16.  [PMID:11423253]

    Comment: Useful summary of EBV-associated lymphomas in HIV disease.

  10. Antinori A, Cingolani A, Alba L, et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS. 2001;15(12):1483-91.  [PMID:11504980]

    Comment: Suggests that clinical outcomes of AIDS-related NHL resembles those of non-AIDS-related NHL if viral loads are effectively controlled.

  11. Cingolani A, Gastaldi R, Fassone L, et al. Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin's lymphomas. J Clin Oncol. 2000;18(19):3325-30.  [PMID:11013271]

    Comment: Describes evidence for what has become an important prognostic and staging tool in AIDS-related NHL.

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Last updated: December 4, 2016