Hodgkin’s Lymphoma (HL)

Introduction

Hodgkin’s lymphoma (HL) is one of the most common NADCs among people living with HIV with an incidence of 0.63 [0.52-0.75]/1000 person-years1. Patients with Hodgkin’s lymphoma tend to be younger at diagnosis than those with other NADC types1. The RR of developing HL is estimated to be 15-fold higher in HIV positive patients as compared to uninfected people and most HL cases are of the unfavorable mixed cellularity subtype, whereas in the general population the predominant subtype is the nodular sclerosis one2. Of note, HL risk has significantly increased during the HAART era. Powles et al reported that both the use of HAART (hazard ratio [HR] 1.64 (95% CI 1.13-2.39)) and a nadir CD4 count of less than 200/µL (HR 1.67 (95% CI 1.10-2.54)) were associated with an increased risk for HL3.

When evaluating the different classes of antiretroviral agents, the authors found that only non-nucleoside reverse transcriptase inhibitors (NNRTI) were associated with a significant increase in the incidence of HL (HR 2.20). The relationship between HAART and HL, as well as immunosuppression and HL, is complex and still largely unclear2. In HL the malignant cell is the Hodgkin Reed-Sternberg cell (HRS), a transformed B lymphocyte, reported to be almost always EBV positive in immunocompromised subjects4-6.

HIV-infected individuals diagnosed with Hodgkin’s lymphoma have cumulative mortality estimates of 18.4% and 24.5% at 1 and 3 years, respectively. HBV positivity, lower hemoglobin level at NADC diagnosis and lower CD4 cell count are associated with mortality after Hodgkin’s lymphoma1. The prognosis of HIV-HL in the pre-HAART era was considerably worse than in HIV-negative patients, with complete remission (CR) rates ranging from 44% to 65%, and median overall survival (OS) of about 18 months. However, the outcome of HIV patients with HL has dramatically improved after the introduction of HAART; the CR rate, OS and disease-free survival (DFS) approach those seen in the general population7-9.

 

Signs and Symptoms

The majority of HL patients have “B” symptoms (i.e. fever, night sweats and/or weight loss of more than 10% of the normal body weight). At the time of diagnosis, HIV-infected people present more frequently with extranodal disease (bone marrow, liver and spleen being the most frequent sites) than HIV uninfected individuals2.


Diagnostic Tools

The diagnosis of HL, as that of any other lymphoid malignancy, should be based on a tissue sample biopsy, rather than on a cytological sample. Samples should be stained for CD20, CD3, CD15, CD30, BCL-2 and LMP-1 proteins7. Considering that bone marrow involvement may be found in more than 50% of patients, bone marrow biopsy is mandatory for adequate staging2.

Essential tests: CBC, differential, platelets, blood group, ESR, LDH, β2-microglobulin, LFT, albumin, BUN, creatinine, calcium, phosphate, pregnancy test; HBsAg, HBsAB, HepB core, anti HCV IgG, CMV IgG; chest X-ray, diagnostic chest/abdominal/pelvic CT (a separate diagnostic CT does not need to be done if it was part of the integrated PET/CT scan); adequate bone marrow biopsy in stage IB, IIB and stage III-IV; evaluation of ejection fraction for doxorubicin-containing regimens10.

Useful in selected cases: fertility preservation; neck CT if neck RT contemplated; pulmonary function tests (PFT including DLCO) if ABVD or BEACOPP are being used; Pneumococcal, H-flu and meningococcal vaccines, if spleen RT contemplated10.

Ann Arbor classification/Costwolds modification for staging HIV-associated Hodgkin Lymphoma7, 11:

  • Stage I: Involvement of a single lymph node group or lymphoid structure.
  • Stage II: Involvement of two or more lymph node groups on the same side of the diaphragm.
  • Stage III: Involvement of lymph node groups on both sides of the diaphragm.
  • Stage IV: Involvement of extra-nodal site(s) beyond those designated ‘E’.
  • X: Bulky disease: >10 cm or >1/3 widening of the mediastinum at T5–6.
  • E: Extra-nodal extension contiguous or proximal to known nodal site of disease or single isolated site of extra-nodal disease
  • A/B: Absence/presence of B symptoms (weight loss >10%, fever, drenching night sweats)

The International Prognostic Score (IPS) predicts for overall survival (OS), freedom from progression (FFP) and complete remission (CR) in HIV patients too7, 12:

  • Male sex
  • Age > 45 years
  • Stage IV
  • Albumin level <4 g/dL
  • Hg <10.5 g/dL
  • Lymphocyte count <8% or <0.6 x 109/L
  • Leukocyte count ≥15 x 109/L

 

Treatment Overview

Combined administration of HAART and chemotherapy regimens has significantly increased survival among HIV-infected subjects suffering from HL. In fact, HAART has been shown to reduce the risk of opportunistic infections and relapses2. Xicoy et al13 observed that the combination of HAART with standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy in  advanced-stage HL was associated with a CR rate of 87%, with a 5-year event-free survival (EFS) and 5-year OS of 71% and 76%, respectively, and with a relapse rate of 11% after 6 to 8 cycles, in contrast with a CR rate of 43% observed in the pre-HAART era, when administering ABVD alone14.

ABVD remains, in most parts of the world, the standard chemotherapy regimen for patients with HL. The number of cycles and the addition of radiotherapy (RT) depends on the stage and risk factors of the disease. Thus, in patients with early favourable stage HL (stage IA–IIA without bulky mediastinal disease), a short course of chemotherapy followed by involved-field (IF) RT is considered standard (ABVD x2–4 + IFRT 20-30 Gy)7, 15.

The German HD11 study for patients with early unfavourable HL demonstrated that ABVD x4 + 30Gy resulted in a similar outcome, with less toxicity, than BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) x4 + 30Gy16.

The UK NCRN trial randomized patients with advanced-stage HL to ABVD x6-8 versus Stanford V (mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, bleomycin, etoposide) and demonstrated no significant differences in terms of PFS and OS17. HL RT is given to residual masses or sites of bulky disease at diagnosis7.

Supportive care (e.g. granulocyte colony-stimulating factor (G-CSF)) and anti-infectious prophylaxis (i.e. prophylaxis for Pneumocystis jirovecii, herpes simplex virus, MAI and fungal infections) should be associated with chemotherapy and HAART, in order to reduce hematological toxicity and the risk for opportunistic infections. Limited options are available for patients with refractory or relapsed HL. The association of high-dose chemotherapy and Autologous Stem-Cell Transplantation (ASCT) has represented a successful salvage therapy for HIV-positive patients with relapsing or progressing HL2, 7.

Patients who have received RT should have thyroid function tests checked regularly and female patients treated with Mantle RT should have surveillance mammography7.



Screening and Prevention

Although Hodgkin Lymphoma is one of the most common NADCs, it is currently unknown whether it can be screened (NCCN, EACS, BHIVA, IDSA Guidelines).

The exact cause of Hodgkin’s lymphoma is not yet known. There are no known lifestyle changes to lower the risk of developing the cancer18.

 

Drug-Drug Interactions19

Ritonavir and dacarbazine: ritonavir may increase the efficacy and toxicity of dacarbazine. Monitor side effects.

Atazanavir or Lopinavir, and doxorubicin: possible cardiac toxicities (EGC abnormalities and sometimes arrhythmias).

Rilpivirine and doxorubicin: possible cardiac toxicities (EGC abnormalities and sometimes arrhythmias).

Atazanavir and vincristine: atazanavir and atazanavir/ritonavir could potentially increase vincristine exposure. The same in vitro effect is observed with darunavir/ritonavir, fosamprenavir/ritonavir and lopinavir.

Efavirenz or Etravirine or Nevirapine, and vincristine: EFV or ETV or NVP, inducers of CYP3A4, could potentially decrease vincristine exposure. Monitor response to chemotherapy.

Elvitegravir/cobicistat and vincristine: EVG/COBI could potentially increase vincristine exposure.

Tenofovir and dacarbazine: concentrations of both substances could be possibly increased due to competition for active tubular secretion. Renal function and haematological parameters should be monitored.

Zidovudine and dacarbazine: possible haematological toxicities.

 

When to Refer20

In patients with a blood count or blood film reported as acute leukaemia, an immediate referral should be made. In patients with persistent unexplained splenomegaly, an urgent referral should be made. Any of the following additional features of lymphadenopathy should trigger further investigation and/or referral:

  • persistence for 6 weeks or more
  • lymph nodes increasing in size
  • lymph nodes greater than 2 cm in size
  • widespread nature
  • associated splenomegaly, night sweats or weight loss

 

References

  1. SW Worm, M Bower, P Reiss, et al., Non-AIDS defining cancers in the D:A:D Study - time trends and predictors of survival: a cohort study. BMC Infectious Diseases 2013, 13:471.
  2. Pinzone MR, Fiorica F, Di Rosa M, et al. Non-AIDS-defining cancers among HIV-infected people. Eur Rev Med Pharmacol Sci. 2012 Oct;16(10):1377-1388.
  3. Powels T, Robinson D, Stebbing J, et al.,. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol 2009; 27: 884-890.
  4. Herndier BG, Sanchez HC, Chang KL, et al., High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of HIV-associated Hodgkin’s disease. Am J Pathol 1993; 142: 1073-1079.
  5. Tirelli U, Errante D, Dolcetti R, et al., Hodgkin's disease and HIV infection: Clinicopathologic and virologic features of 114 patients from the Italian cooperative group on AIDS and tumors. J Clin Oncol 1995; 13: 1758-1767.
  6. Glaser SL, Clarke CA, Gulley ML et al. Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998. Cancer 2003; 98: 300-309.
  7. British HIV Association guidelines for HIV-associated malignancies 2013. Version 1. 25 July 2013.
  8. 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.
  9. Jacobson CA, Abramson JS. HIV-Associated Hodgkin's Lymphoma: Prognosis and Therapy in the Era of cART. Adv Hematol 2012; 2012: 507257.
  10. NCCN Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma. Version 2.2013.
  11. Lister TA, Crowther D, Sutcliffe SB et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7: 1630-1636.
  12. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 1998; 339: 1506-1514.
  13. Xicoy B, Ribera JM, Miralles P, et al.,. Results of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine and highly active antiretroviral therapy in advanced stage, human immunodeficiency virus-related Hodgkin’s lymphoma. Haematologica 2007; 92: 191-198.
  14. Levine AM, Li P, Cheung T, et al.,. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin’s disease: a prospective, multiinstitutional AIDS clinical trials group study (ACTG 149). J Acquir Immune Defic Syndr 2000; 24: 444-450.
  15. Eichenauer DA, Engert A, Dreyling M. Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6: vi55-58.
  16. Eich HT, Diehl V, Gorgen H et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 2010; 28: 4199-4206.
  17. Hoskin PJ, Lowry L, Horwich A et al. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 2009; 27: 5390-5396.
  18. © 2013 The University of Texas MD Anderson Cancer Centre.
  19. Drug Interactions. University of Liverpool. Updated October 2013. 
  20. NHS National Institute for Health and Clinical Excellence. Referral Guidelines for Suspected Cancer. Clinical Guideline 27. June 2005. www.nice.org.uk/CG027