Alemtuzumab

Alemtuzumab is a monoclonal antibody targeting CD52, which is expressed on B and T lymphocytes, monocytes, macrophages, eosinophils, NK cells, thymocytes, and dendritic cells.31,32 Cells bearing CD52 on their surface are eliminated from the blood within a few hours of alemtuzumab administration; T cells may take as long as 2 years to recover to pre-treatment levels.32 Approved in 2001 by the FDA for the treatment of CLL, alemtuzumab is also used in the treatment of lymphoma, autoimmune disorders, and as part of transplant conditioning and/or post-transplant immunosuppressive regimens.33

An early retrospective analysis of 27 patients with lymphoproliferative disorders receiving alemtuzumab at a single center between 2001 and 2003 showed that 82% of patients developed non-opportunistic infections and 44% developed cytomegalovirus (CMV) viremia, although the viral loads were not specified.33 These patients had received PCP and herpes simplex virus preventive therapy. The same investigators reviewed the pre-existing literature on infections associated with alemtuzumab in patients with lymphoproliferative disorders. Herpes simplex and CMV reactivation were found to be the most common opportunistic infections, followed by PCP and invasive pulmonary aspergillosis.33 Isolated cases of toxoplasmosis, histoplasmosis, cryptococcosis, zygomycosis, PML, and tuberculosis were reported in their single center analysis and/or the literature review.33 A survey of studies of patients with CLL receiving alemtuzumab alone reported a CMV reactivation rate of 4% to 29%.34 In patients from 6 Asian countries receiving alemtuzumab either alone or in combination with other immunosuppressive therapy for hematologic disorders, hepatitis B and tuberculosis were also important infections.31 A review of PML cases reported to the FDA Adverse Event Reporting System (FAERS) from 2009 to 2015 demonstrated that 15 were associated with alemtuzumab therapy.35

In an observational study of 547 patients receiving alemtuzumab for solid organ transplant rejection prevention or rejection treatment in a single center, CMV disease (26%) and esophageal candidiasis (19%) were the most common opportunistic infections encountered; of note, opportunistic infections occurred in only 4.5% of patients receiving alemtuzumab for rejection prevention vs 21% of patients receiving it for rejection treatment.36 Because solid organ transplant recipients receiving alemtuzumab usually receive additional immunosuppressive agents such as corticosteroids, lymphocyte-depleting antibody, and/or calcineurin inhibitors, the contribution by alemtuzumab to the development of opportunistic infections is not clear.

The profound immunosuppression associated with alemtuzumab therapy warrants post-alemtuzumab preventive therapy against herpes simplex virus and PCP, continued until the patient’s CD4 count is > 0.2×109 cells/l.37 Also, preventive therapy for hepatitis B in HepBsAg+ or HepBcAb+ patients, strict blood DNA by PCR monitoring for CMV and other viruses such as Epstein-Barr virus, human herpesvirus 6, BK virus, and adenovirus, and monitoring for the development of invasive fungal infection with fungal biomarkers, aspergillus PCR, and computed tomography (CT) scans are warranted, as well as pre-alemtuzumab screening for tuberculosis exposure and stool for Strongyloides stercoralis (in at-risk patients).37 These precautions are similar to the infection prevention/surveillance recommended in patients with allogeneic bone marrow transplant. In patients with neurologic changes post-alemtuzumab treatment, PML should be considered and cerebrospinal fluid for John Cunningham (JC) virus should be obtained.

Brentuximab

Brentuximab vedotin is comprised of an anti-CD30 monoclonal antibody conjugated to the toxin monomethyl auristatin E, which affects microtubule physiology to cause death of the targeted cell.38,39 CD30 is expressed on activated lymphocytes and certain hematologic tumor cells and is approved for use in refractory Hodgkin’s lymphoma and refractory anaplastic large cell lymphoma.39 In 2012 the FDA issued a boxed warning for the association between PML and brentuximab therapy on the basis of 3 reported cases.40 Subsequently, several more cases of PML associated with brentuximab therapy were published.41,42 In the review of PML cases reported to FAERS from 2009 to 2015, 15 were associated with brentuximab therapy.35 In a study of 25 patients receiving brentuximab for relapsed Hodgkin’s disease after allogeneic stem cell transplant, 5 developed CMV viremia, considered clinically significant in 1 case,43 but the importance of brentuximab is clouded by the previous transplants in these cases. In a study of 32 patients treated with brentuximab between 2011 and 2016, 3 cases of CMV retinitis occurred.44 While these numbers are small, it may be prudent to monitor for CMV viremia in patients who receive brentuximab therapy.

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