Cytarabine not Effective in PML Associated with AIDS
ABSTRACT & COMMENTARY
Source: Hall CD, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 1998;338: 1345-1351.
In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy (PML) were randomly assigned to one of three treatments for a 24-week period: antiretrovirals; antiretrovirals with intravenous cytarabine; or antiretrovirals with intrathecal cytarabine administered through an Ommaya reservoir.
There were no significant differences in survival in the three groups (P = 0.85), with median survival times of 11, 8, and 15 weeks, respectively. At last analysis, 14 patients in each group had died and only seven patients completed the 24-week treatment period. Anemia and thrombocytopenia were more frequent in the intravenous cytarabine group.
The investigators concluded that cytarabine did not improve the prognosis for AIDS related PML, nor did high-dose antiretrovirals appear to improve survival over that previously reported in untreated patients.
COMMENTARY
PML results from dysmyelination caused by the DNA papovavirus JC virus, occurring in conditions with deficient cell-mediated immunity. There is no established effective therapy. PML can complicate a wide range of medical conditions, including leukemia and lymphoma, with or without chemotherapy, or chronic immunosuppression for rheumatologic disease or organ transplantation. The incidence of PML has increased greatly with the spread of HIV, and PML accounts for as many as 4% of deaths of patients with AIDS.
The proper diagnosis of PML in AIDS without brain biopsy can be clinically challenging, given the broad differential diagnoses, including CNS lymphoma, CMV or other viral encephalitis, toxoplasmosis, or other opportunistic infections. PCR amplification of JC virus DNA has been helpful in supporting a probable clinical diagnosis without a brain biopsy.
Mixed past reports had suggested a benefit of cytarabine for PML in AIDS, leading to its frequent use despite considerable risks, including worsening immunosuppression. This important study by the AIDS Clinical Trials Group has failed to support any benefit of cytarabine treatment by both intrathecal and intravenous administration using the absolute endpoint of mortality. While neurologic function was not specifically described, all groups at baseline had identical median Karnofsky performance scores measuring functional ability.
In this grim prognostic situation, not even antiretrovirals, which theoretically might boost immune function to limit the JC virus, had any significant benefit for median survival (1.75-3.5 months) compared to historic controls in the literature. The recent advent of more effective combination antiretroviral drugs in a few cases, however, may prolong survival in PML (abstracts referenced in Colin, et al).
These negative results have direct relevance to clinical practice: Cytarabine should not be used, and brain biopsies need not be performed for a clinically probable diagnosis, which can be non-invasively supported by PCR analysis of CSF. -ba
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