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Patients with HIV disease are already at risk of opportunistic infections as a result of HIV-related immune suppression; chemotherapy would be expected to increase this risk. Furthermore, the bone marrow in AIDS patients is frequently impaired and likely to be seriously compromised as a result of marrow-toxic chemotherapeutic agents. The immunosuppressive effects of chemotherapy may precipitate acceleration of the HIV disease itself. Management therefore poses considerable problems with this group of patients.

However, the advent of HAART, improved prophylaxis against opportunistic infections and intrathecal prophylaxis support a more aggressive approach to treatment for systemic ARL, with better outcomes being reported. Many units now use standard-dose chemotherapy and are reporting response rates and overall survival that approach those in the immunocom-petent. The prognosis for primary cerebral lymphoma remains very poor such that palliative treatment is usually the only option.

Table 23.3 Features of AIDS-related non-Hodgkin's lymphoma.

Histopathology (%)

Diffuse large cell (DLC) Small cell non-cleaved (Burkitt's) Primary effusion lymphoma

65 (including primary cerebral lymphoma) 33 2

EBV implicated (%)

Burkitt's Systemic DLC Primary cerebral lymphoma Primary effusion lymphoma

< 50 80 100 100

Prognosis features for AIDS-related NHL* Major adverse prognostic factors

Prior AIDS diagnosis CD4 count < 100/||L ECOG performance status > 2 Primary cerebral origin

Minor adverse prognostic factors

Bone marrow involvement Extranodal disease Raised serum LDH Age > 35 years

*Good prognosis defined by less than two major adverse prognostic factors; poor prognosis is defined by more than one major adverse prognostic factor.

*Good prognosis defined by less than two major adverse prognostic factors; poor prognosis is defined by more than one major adverse prognostic factor.

In centres without access to HAART, a prognosis-stratified approach to the management of ARL may be taken. Patients falling into the poor prognosis group (Table 23.3) may be treated with palliative intent using a combination of prednisolone, vincristine and bleomycin, with radiotherapy for localized symptomatic lesions. The life expectancy for these patients is 3-6 months. Patients with a better prognosis may be treated with combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or mBACOD (metho-trexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), perhaps with the support of granulocyte colony-stimulating factor. Complete remission rates are approximately 60%. The role of rituximab (a monoclonal antibody directed against CD20) in ARL is under investigation.

Following chemotherapy, 40% of the patients with good prognostic features will remain in remission until another AIDS-related illness such as opportunist infection occurs. Recent studies show higher median survivals with little change in response rate for ARL, suggesting that the improved duration of survival is related to reduced deaths from opportunistic infections in the HAART era among patients who have durable remissions of their ARL.

The concomitant use of antiretroviral agents with chemotherapy is generally accepted practice with the possible exceptions of zidovudine, which significantly adds to the myelosuppression of combination chemotherapy, and didanosine, which may worsen the peripheral neuropathy caused by vincristine. Little is known about the pharmokinetic interaction of protease inhib itors and non-nucleoside reverse transcriptase inhibitors with chemotherapy.

It is routine practice to instigate prophylaxis against pneumo-cystis, M. avium intracellulare and toxoplasmosis in individuals receiving chemotherapy for ARL.

As there is a high rate of meningeal involvement in systemic ARL, intrathecal chemotherapy should be given to patients with meningeal disease or at high risk of cranial disease by virtue of Burkitt's histology or extensive paranasal sinus and base of skull disease. Most centres also recommend prophylactic chemotherapy for patients with bone marrow involvement.

A recent development in ARL chemotherapy has been the introduction of infusional therapy with CDE (cyclophosphamide, daunorubicin and etoposide) or EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide and daunorubicin). In a recent study by Little and co-workers, a dose-adjusted EPOCH regimen with suspension of HAART achieved a complete remission in 74% of patients and at 53 months median follow-up, disease-free and overall survival were 92% and 60% respectively. A multicentre trial is under way to confirm these results.

The dose-adjusted strategy was developed to reduce haemato-logical toxicity while maintaining maximum drug doses. In vitro studies have shown that tumour cells are relatively less resistant to prolonged low-concentration exposure compared with brief high concentration exposure. In addition, infusional therapy is more effective against highly proliferative tumours such as ARL.

The question is raised as to whether treatment with HAART alters the biology of the tumour, making it less resistant to chemotherapy. Low BCL-2 and high CD10 expression are observed, both implying a germinal centre origin, a feature associated with good-prognosis disease. The high expression of p53 indicates a highly proliferative tumour, but in HAART-treated patients this is not associated with a poor outcome.

In Little's study, discontinuing HAART during chemotherapy led to increases in viral load, which fell below baseline within 3 months of resuming treatment, and decreases in CD4 cells, which recovered within 4 months of reintroducing HAART. This suggests that withholding antiretroviral treatment does not significantly worsen the AIDS prognosis while avoiding the potentially adverse effects on lymphoma treatment.

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