E31 Lymphoma in HIV infection

Introduction

HIV-associated lymphomas are predominantly aggressive B-cell lymphomas. According to the World Health Organization (WHO) classification, HIV-associated systemic non-Hodgkin’s lymphomas (HIV-NHLs) include diffuse large B-cell lymphoma (DLBCL), HIV-associated primary central nervous system lymphoma (HIV-PCNSL), Burkitt lymphoma (BL), primary effusion lymphoma (PEL) and plasmablastic lymphoma of the oral cavity. Hodgkin disease, though not an AIDS-defining condition, is also increased in HIV-infected individuals. The epidemiology of HIV-associated lymphoma has changed since highly active antiretroviral therapy (HAART) becomes available in clinical practice.

In Hong Kong, 20 HIV-NHL patients have been managed at Queen Elizabeth Hospital (QEH) from 1995 to 2006, providing information for updating a previous series.[1] In this series, 17 patients had systemic NHLs and 3 PCNSLs. All PCNSLs were of B-cell origin. Among the systemic NHLs, 15 patients had aggressive B-cell lymphoma (DLBCL: 12, BL: 2, mantle cell lymphoma: 1) and 2 patients had plasmablastic lymphoma. The median CD4 count of patients with HIV-NHL was 60/μL. Among patients with systemic NHL, longer survival was associated with the use of HAART, having ≤2 adverse factors on presentation according to International Prognostic Index (IPI) for aggressive NHL [stage III or IV disease, age >60 years, elevated lactate dehydrogenase, ECOG (Eastern Cooperative Oncology group) performance status ≥2, ≥2 extranodal sites].

The characteristics of each form of HIV-related lymphoma are reviewed in this chapter. The impact of HAART, where appropriate, is discussed. The clinical course of PCNSL, PEL and plasmablastic lymphoma of the oral cavity is distinct and each is discussed separately.

HIV-associated systemic non-Hodgkin’s lymphoma

NHLs occur 160 times more frequently in HIV-infected patients as compared with the general population. Patients with HIV-NHL usually present with advanced stage disease and more frequently have B symptoms (fever, night sweats and weight loss) and involvement of uncommon sites, including oral cavity, gastrointestinal tract and central nervous system (CNS). They are associated with Epstein-Barr virus (EBV) or human herpesvirus type 8 (HHV-8) infections. A decade into the HAART era, multiple studies have demonstrated the decrease in incidence and mortality of HIV-NHL.

Diagnosis and work-up of HIV NHL

Diagnosis of HIV-NHL is normally established by histological confirmation through excisional or incisional biopsy of enlarged lymph nodes, bone marrow biopsy, or, less preferably, fine-needle aspiration. Staging of the extent of disease is based on clinical examination, computed tomographic (CT) examination of the chest, abdomen and pelvis for lymphadenopathy or visceral involvement, and bilateral iliac crest trephine biopsy. Blood tests for blood picture and CD4 lymphocyte counts, renal and liver function, lactate dehydrogenase, calcium and uric acid level provide information of prognostic and management significance. All patients, regardless of histology, should have a lumbar puncture saving for cell count, total protein, and cytology to rule out lymphoma involvement. The role of fluoro-deoxyglucose positron emission tomography (FDG-PET) in HIV-associated lymphomas is not well studied. FDG-PET results should be interpreted with caution as they can be confounded by co-existing inflammation from HIV-associated nodal reactive hyperplasia, lipodystrophy and infections. Before the availability of HAART, prognosis of HIV-infected individuals with NHL was poor with a median survival of 5 to 8 months.

Treatment

Before the widespread use of HAART, the AIDS Clinical Trials Group reported comparable response rate and overall survival in patients with HIV-NHL receiving low-dose versus standard-dose m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone].[2] The median survival in both groups was short (35 weeks in low-dose group versus 31 weeks in standard-dose group, p=0.25). Growth factor support was used routinely in the standard-dose group and administered as required in the low-dose group. There was lower incidence of grade 4 neutropaenia in the low-dose group (50% versus 69%, p=0.007). The result of this trial formed the basis for using low-dose chemotherapy in HIV-NHL during the pre-HAART era.

Immune restoration in response to HAART results in decreased incidence of opportunistic infections and better tolerance of chemotherapy. This facilitates the use of standard- or even high-dose chemotherapy in treating patients with HIV-NHL. In addition, infusional regimen has been developed to enhance the efficacy of chemotherapeutic agents. Optimal treatment for HIV-associated systemic NHL has not yet been defined.[Box 31.1] CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or DA-EPOCH (dose adjusting – etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) is currently favoured in treating patients with HIV-NHL. Rituximab, when given with chemotherapy, is associated with improved control of HIV-NHL. However, caution should be exercised in patients with CD4 count of less than 50/μL because of the potential increased risk of life-threatening infectious complications. CNS prophylaxis with intrathecal chemotherapy should be given in patients with Burkitt lymphoma (BL), and in patients with diffuse large B-cell lymphoma (DLBCL) having risk factors for meningeal recurrence: more than 2 extranodal sites accompanied by elevated lactate dehydrogenase (LDH), or involvement of specific high risk sites such as bone marrow, paranasal sinus, testis, or epidural space. Prophylaxis for opportunistic infection should be given in accordance to the CD4 count.

Poor treatment response is associated with older age, advanced lymphoma staging or extranodal involvement, CD4 count below 100 or previous AIDS diagnosis and intravenous drug use. In addition, HIV-NHL has a higher incidence of multidrug resistance (MDR-1) expression which is associated with poorer response to conventional combination chemotherapy.

The appropriate timing of institution of HAART in relation to chemotherapy regimens has been evaluated in several clinical trials but no definite conclusion was reached. Concomitant administration of HAART with chemotherapy may be beneficial for patients with low CD4 count at time of HIV-NHL diagnosis or history of opportunistic infections and those likely to adhere to multiple oral medications aiming to achieve a non-detectable HIV viral load. However, in view of the potential increase in toxicities due to drug interaction between chemotherapy and HAART, particularly protease inhibitor-based (PI-based) regimens, close communication between haematologist/oncologist and HIV physicians is essential.

HIV-associated primary CNS lymphoma [Algorithm 31]

HIV-related primary CNS lymphoma (PCNSL) typically occurs in patients with CD4 count below 50/μL. Its incidence has decreased by three-folds since the introduction of HAART. The presenting signs and symptoms include headache, subtle personality changes, altered conscious level, memory loss, focal neurological deficit or seizures.

Diagnosis of HIV-PCNSL

It is often difficult to distinguish PCNSL from cerebral lesions due to infection such as toxoplasmosis since both conditions can present as single or multiple contrast-enhancing mass lesions on CT or MRI. However, toxoplasmosis typically has ring-enhancing lesions and the surrounding oedema is not as marked as lymphoma. Other features that suggest diagnosis of lymphoma include: location of deep white matter such as corpus collosum, periventricular, or periependymal areas, and size larger than 4 cm.[3]

Definitive histopathologic diagnosis of focal brain lesion in AIDS patients requires stereotactic biopsy. However, the location of some lesions may be technically inaccessible. In addition, it should be recognised that corticosteroid administered to reduce cerebral oedema can produce brisk tumour response, resulting in a false-negative biopsy. Hence, if brain biopsy is to be performed, it is advisable to withhold corticosteroid unless the patient is in immediate danger of herniation. Alternatively biopsy should be performed as soon as possible after the first dose of steroid.

Recent advances in the diagnosis of HIV-PCNSL include the use of Thallium-201 single-photon emission computerised tomography (SPECT) and detection of EBV-DNA in cerebrospinal fluid (CSF).

Nearly all HIV-PCNSL are associated with EBV infection, and EBV is otherwise rarely detected in the CSF of HIV patients without PCNSL. SPECT has been demonstrated to facilitate differentiation of malignant from infectious brain lesions. The presence of increased uptake on SPECT together with positive EBV DNA in the CSF had 100% sensitivity and 100% positive predictive value for PCNSL.[4] With positive result for both tests, radiotherapy for PCNSL can be started without the need for brain biopsy. Negative results for both tests had 100% negative predictive value and can confidently exclude the diagnosis of lymphoma. With discordant results, brain biopsy should be performed to establish the diagnosis. For patients in whom SPECT and PCR examination for EBV DNA is not available and brain biopsy is not feasible, empirical radiotherapy for PCNSL may be tried after failure to respond to a course of anti-toxoplasmosis therapy.

Treatment of HIV-related PCNSL

Before the HAART era, the median survival for untreated AIDS-related PCNSL was approximately 4 to 8 weeks. Use of radiotherapy had resulted in improvement in the performance status and slightly prolonged the median survival to 2 to 5 months. However, most patients ultimately died of opportunistic infections.

HAART has led to improvement in the survival of patients with AIDS-related PCNSL, particularly for those with good CD4 and virological response. However, with extended survival of the patients, late complications of radiotherapy such as leukoencephalopathy and radiation necrosis may become a concern. Immune recovery following HAART has increased the feasibility of using systemic chemotherapy in AIDS-related PCNSL. In a series of 15 patients with AIDS-related PCNSL, up to six cycles of high dose methotrexate (3g/m² IV Q14 days) with leucovorin rescue were administered.[5] Whole-brain radiation therapy was reserved for cases with disease progression or relapse. Seven of the 15 patients achieved complete radiological response. The overall median survival was 10 months while the median survival for complete responders was 19 months. Side effects, including gastrointestinal upset and mucositis, were tolerable and did not result in dose modification or treatment delay.

Current data support initiation or optimisation of HAART upon diagnosis of HIV-PCNSL. Whole-brain irradiation can be administered to improve performance status and survival. For patients with relatively good performance status or reasonably controlled HIV replication, systemic high-dose methotrexate may be a treatment option, while reserving radiotherapy for disease progression or relapse.

HIV-associated primary effusion lymphoma

Primary effusion lymphoma (PEL) accounts for approximately 1-5% of HIV-associated lymphoma and is seen most frequently in advanced AIDS. Clinically, the disease is characterised by lack of nodal or extranodal solid tumours with malignant serous effusions being the predominant feature. Kaposi sarcoma-associated herpesvirus (KSHV, or named HHV-8) can be demonstrated in nearly 100% of tumour specimens and has been implicated in the pathogenesis of this uncommon entity. EBV is also detectable in the majority of cases, raising the possibility of a second hit model of lymphomagenesis. Morphologically, PEL cells are distinct. They resemble large cells of a null phenotype on immunohistochemical stains, but immunoglobulin gene rearrangements are usually positive, indicating a clonal B-cell origin.

Treatment of HIV-PEL

Before the advent of HAART, patients with HIV-PEL had short overall survival, ranging from 3 to 6 months. However, unlike some other HIV-associated lymphomas, the impact of HAART on survival in patients with HIV-PEL is less significant.

Simonelli et al reported 8 PEL patients with 5 receiving HAART in addition to a CHOP-like regimen. One patient was treated with HAART alone and two other patients received neither chemotherapy nor HAART. Three of the 7 assessable patients – 1 on CHOP plus HAART, 1 on CEOP (cyclophosphamide, epirubicin, vincristine, prednisolone) plus HAART and 1 on HAART alone – achieved complete remission, giving a complete remission rate of 42% and median survival of 6 months.[6] In other series, performance status greater than 2 and absence of HAART before PEL diagnosis were found to be independent predictors for shorter survival.

There is no recommended standard treatment for this rare entity. As CD20 expression is usually negative on tumour cells, there is a lack of response to anti-CD20 monoclonal antibody, a major drug responsible for the improvement of clinical outcome in B-cell lymphomas. Moreover, the presence of body cavity fluid makes delivery of high-dose methotrexate difficult. However, it would be reasonable to treat patients having HIV-PEL with HAART in conjunction with combination chemotherapy that are used for systemic HIV-NHL.

HIV-associated plasmablastic lymphoma

Plasmablastic lymphoma occurs predominantly in patients with advanced HIV disease, although it has also been reported in HIV-negative individuals. It accounts for approximately 2.6% of all HIV-NHL. The tumour primarily occurs in the jaw and oral cavity but it can also involve a variety of other sites, such as gastrointestinal tract and lung. Morphologically, the malignant cells resemble plasmablasts, but carry a phenotype typical of mature plasma cells with high proliferative fraction and are EBV-associated. On flow cytometry, the cells are negative for B- and T-cell markers but positive for markers of plasma cell differentiation, including VS38c, CD79a and CD138, light chain epithelial membrane antigen (EMA) and immunoglobulin G. Ki-67 staining is typically quite high in 75-95%. The absence of a serum monoclonal gammopathy helps to distinguish this entity from multiple myeloma.

Treatment of plasmablastic lymphoma

Data from the pre-HAART era showed that plasmablastic lymphoma carried a poor prognosis with nearly all patients died within 12 months of diagnosis.

The impact of HAART has not been well studied but reports suggested that its prognosis may have improved. In a report of 6 HIV-positive patients with plasmablastic lymphoma treated with various regimens,[7] all had received HAART (4 previously on HAART while 2 were newly diagnosed with HIV infection and initiated on HAART at the time of lymphoma diagnosis), 5 were alive with a median follow up duration of 17 months. Other series showed that for patients with concurrent diagnosis of plasmablastic lymphoma and HIV infection but good immunological and virological response to HAART, the lymphoma could be under control and in complete remission for 1-2 years after initial diagnosis.

Currently no standard treatment has been recommended for this rare entity. HAART and systemic chemotherapy with CHOP, CODOX/M-IVAC (cyclophosphamide, vincristine, doxorubicin / methotrexate – ifosfamide, mesna, etoposide, cytarabine) or EPOCH had been used in reported series. Newer agents e.g. bortezomib, brentuximab and lenalidomide have been used as single agent or in combination regimens in plasmablastic lymphoma with response reported.[8][9] Dosing schedule and optimal combination remains to be determined.

HIV-associated Hodgkin Lymphoma

HIV-associated Hodgkin Lymphoma (HIV-HL) is not included among the Centers for Disease Control and Prevention (CDC) AIDS-defining illnesses. However, several groups had demonstrated that there was increased risk of HL among patients with AIDS.

Compared to HIV-negative cases, patients with HIV-HL tend to present at a younger age. It’s commoner to have extranodal or bone marrow involvement, advanced stage disease, B symptoms (fever, night sweat, weight loss), while mediastinal adenopathy appeared less frequently. In the pre-HAART era when patients were more severely immunosuppressed, there was a predominance of two unfavourable subtypes, namely mixed cellular and lymphocyte depleted. EBV is positive in 78-100% of patients with HIV-HL as compared to 15-48% of patients with non-HIV-related HL. In the HAART era, there has been an increased incidence of nodular sclerosis which occurs more commonly at higher CD4 counts. In contrast to aggressive B-cell NHL, HAART has not reduced the incidence of HL in this population.

Treatment of HIV-HL

In the pre-HAART era, the median survival of patients with HIV-HL was only 8-20 months. With the advent of HAART, there has been significant improvement in the outcome. In a retrospective review of 108 patients treated over a 15-year follow-up period[10] there was significant difference in the estimated 2-year survival (45% in the pre-HAART period versus 62% in the HAART period, p=0.03), mainly due to a decrease in AIDS-associated deaths. The median survival was only 19 months in the pre-HAART period while that for patients treated in the HAART era had not been reached at time of analysis. Two other studies showed that incorporation of HAART into chemotherapy in treating HL is both safe and feasible, yielding complete remission rates of 90% and a two-year overall survival of 90%.[11][12] Most importantly, overall and progressive survival rate did not seem to be affected by the positive HIV status.

The optimal treatment regimen for HIV-HL has not been defined. Regimen that had been used in HIV-HL includes the following as listed. ABVD is less toxic than Stanford V and BEACOPP, and may be the preferred regimen in people living with HIV/AIDS (PLWHA).

• ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
• EBVP (epirubicin, bleomycin, vinblastine, prednisone)
• Stanford V (doxorubicin, vinblastine, mecloretamine, etoposide, vincristine, bleomycin, prednisone)
• BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

There are several points which are of particular relevance in the treatment of HL in PLWHA:

• While use of growth factor support is not encouraged during ABVD treatment in HIV negative patients due to its potential interactions with bleomycin, its use may be necessary in PLWHA especially when the CD4 count is low, and in the setting of prolonged neutropaenia and neutropaenic fever.
• While dose reduction for neutropaenia in HIV negative individuals is not recommended, such may be appropriate in prolonged and/or severe cytopaenias, and if CD4 count is <100/μL.
• PET-guided treatment in HL in PLWHA is feasible. Cautious interpretation of imaging results is necessary as non-malignant diseases may show up as PET-avid lesions.

• The impact of HAART suspension has not been well studied in HIV-HL. Given the relatively long treatment duration and bolus schedule of ABVD, continuation of HAART during chemotherapy is recommended. However, drug interactions are possible. Cases of severe neurotoxicity with ABVD while receiving ritonavir-boosted antiretroviral therapy were reported. Use of antiretroviral agents that do not cause profound inhibition of the 3A4 isoenzyme of cytochrome P450 system should be considered.

References