Ibrutinib Treatment May Predispose to Fungal Infections, Study Cautions

Although previous research has demonstrated that ibrutinib is associated with fewer infectious complications than standard chemotherapy in patients with chronic lymphocytic leukemia (CLL), a study published in Blood found that the drug may be associated with early-onset invasive fungal infections, particularly aspergillosis.

“Impaired humoral and cellular immunity related either to CLL itself or to its treatments, steroid use, and chronic neutropenia are risk factors [for infections],” the study authors, led by David Ghez, MD, PhD, of the Department of Hematology at Gustave Roussy in Villejuif, France, wrote of their findings. “Patients [receiving] ibrutinib should be closely monitored, in particular when other risk factors of fungal infections are present.”

The investigators reported results from a multicenter, retrospective survey of 33 patients (median age = 70 years; range = 31-82 years) with CLL who were treated at 16 centers of the French Innovative Leukemia Organization between 2013 and 2017 and experienced infections following ibrutinib treatment.

All but one patient received ibrutinib for relapsed/refractory disease. Participants received a median of two prior therapies (range = 0-4 therapies), and the median time between last line of therapy and ibrutinib was 10.5 months (range = 1-96 months). Thirty patients had CLL, including 15 with del17p mutation. Among the others, one patient had mantle cell lymphoma and two had Waldenström macroglobulinemia. No one had undergone hematopoietic cell transplantation.

Invasive aspergillosis was “overrepresented” among the study population, accounting for 27 cases of infections (82%), including a “strikingly high incidence of central nervous system involvement (n=11; 40.7%),” the authors reported. Other infections included four cases of disseminated cryptococcosis, one mucormycosis, and one pneumocystis pneumonia.

According to European Organisation for Research and Treatment of Cancer criteria, 17 cases of invasive aspergillosis were deemed “proven,” nine were “probable,” and one was “possible.”

The researchers observed that most invasive fungal infections had early onset: The median time from ibrutinib initiation to invasive fungal infection diagnosis was three months (range = 1-30 months). Most cases (n=28; 85%) were diagnosed within six months, and 20 were diagnosed within three months. Only two patients had very late-onset pulmonary aspergillosis, occurring after 15 and 30 months.

This early onset of infections suggests that “impairment of antifungal response occurs rapidly, before the immune reconstitution that has been observed with prolonged ibrutinib treatment,” the authors explained.

Invasive fungal infections led 21 patients to discontinue ibrutinib, while others continued treatment at a lower dose or resumed treatment after invasive fungal infection resolution. At last follow-up (date not provided), 17 patients died because of invasive fungal infections (n=9), underlying CLL (n=5), or unrelated causes (n=3).

The authors found that most patients had predisposing factors for invasive fungal infections, including:

  • chemotherapy within 6 months of ibrutinib (n=10)
  • neutropenia (n=5)
  • corticosteroids (n=4)
  • rituximab plus corticosteroids (n=3)
  • concomitant immunochemotherapy (n=3)
  • rituximab (n=2)
  • diabetes mellitus (n=2)
  • cirrhosis (n=1)
  • azathioprine (n=1)
  • HIV (n=1)

“Altogether, this suggests ibrutinib alone may not in most cases be sufficient for [invasive fungal infection] development, but its effect can be unmasked when an underlying immune deficiency is associated,” the authors wrote. “This might explain … why nearly all [patients had] relapsed/refractory disease, as these patients are potentially more immunosuppressed than firstline patients.”

Overall, invasive fungal infections appeared to be infrequent in the general CLL patient population, “considering the number of patients who received ibrutinib for the last four years in France,” the researchers noted, though they added that the study was not designed to determine incidence.

The study is also limited by its retrospective design and reliance on patient-reported outcomes. Research into how ibrutinib may decrease antifungal immunity is warranted, the authors noted.

“While it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of invasive fungal infection after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” the authors concluded.

Dr. Ghez reports financial support from Janssen.


Reference

Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018 January 20. [Epub ahead of print]

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