There has been a recent report of Progressive Multifocal Leukoencephalopathy (PML) in three patients with CLL treated with rituximab, and this has aroused some alarm in patients. The paper by D'Souza et al at the William Beaumont Hospital, Royal Oak Michigan has been published electronically in the journal Clinical Lymphoma, Myeloma & Leukemia Volume 10 pp E1 to E9.
PML is a disease of the nervous system caused by a virus named after John Cunningham (the JC virus) which most people contract in early life but which lays dormant controlled by the immune system for the rest of their lives. It is reactivated when the immune system fails and spreads to the brain where it infects oligodendrocytes and to a lesser extent astrocytes. There is a failure to make myelin, the insulating material around nerve cells, leading to confusion, disorientation, personality changes, loss of speech and balance, dementia and death. There is no effective treatment.
Although the three patients reported had all been treated with rituximab, they were all severely immunosuppressed from other treatments: the first with long term chlorambucil and then fludarabine, the second with fludarabine and cyclophosphamide and the third with chlorambucil, fludarabine, alemtuzumab, pentastatin and cyclophosphamide. They had had CLL for respectively 3 years, 8 years and 9 years.
Although PML is most commonly associated these days with AIDS, where it occurs in between 3-5% of patients, it was originally recognized in hematologic cancers including CLL. Immunity to the JC virus resides in the T cells rather than antibody, and the T-cell depletion seen in CLL patients treated with fludarabine or Campath is comparable with that seen in AIDS.
In Bournemouth, despite seeing close to 1000 patients with CLL we have not seen PML. This contrasts strongly with Royal Oak, Michigan where these three cases were among only 45 cases of CLL seen by them. I don't think we are missing the diagnosis.
Inpatients who have transplants it is much more common to reactivate other dormant viruses like Herpes Zoster, CMV and EBV, but PML does occur. In CLL it is often unrecognized how immunodeficient patients who have longstanding CLL plus multiple treatments can be. It is this group who are most likely to succumb to PML. Patients who receive rituximab alone or as part of FCR first line are most unlikely to reactivate JC.