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