Blood cancers

Ibrutinib-associated invasive fungal disease seen in patients with CLL

The risk of invasive fungal disease in CLL patients treated with ibrutinib may be higher than previously thought, a new study suggests.

Unusual presentations of IFD were seen in 35 patients with CLL and non-Hodgkin lymphoma, Israeli clinicians report in the journal Mycoses.

The cases were characterised by early-onset aspergillus infections in non-neutropenic patients who develop invasive disease with CNS and multiorgan involvement.

In response to increasing reports of aspergillosis being diagnosed shortly after beginning ibrutinib for CLL, they conducted a retrospective survey of international groups of haematologists.

They received reports of 26  cases of IFD in CLL patients and 9 in NHL patients after ibrutinib treatment. The IFD usually ensued shortly after initiating treatment with ibrutinib, in some as early as one day and in 59% of cases within two months, with a median duration of ibrutinib treatment before the onset of IFD of 45 days. Aspergillus species were identified in 63% of the patients, and Cryptococcus species in 26%.

While IFD is usually seen in the lungs and sinus, the ibrutinib-associated cases had an unusually high rate of CNS (49%), and multiorgan involvement (60%).The mortality rate was also high, at 69%.

The researchers estimated that the overall prevalence of IFD in their ibrutinib treated patients with CLL and NHL was 2.4%.

They said the cases were unusual in that most patients were not neutropenic in the month prior to initiation of treatment with ibrutinib, and there was rapid deterioration with neurological symptoms.

They postulated that Bruton’s tyrosine kinase (Btk) inhibition with ibrutinib may increase susceptibility to invasive aspergillosis since Btk is an important mediator of NFkB activation in macrophages and Btk inhibitors cause functional defects in fungal immune surveillance, by inhibition of myeloid cells.

But they said other predisposing factors were also likely important in the development of IFD with ibrutinib, including steroid use and comorbidities that contribute to poor immune responses.

“Physicians should be aware of the frequency, risk factors and unusual clinical manifestations of IFD in patients with NHL or CLL receiving ibrutinib,” they advised

“Staging CT scans constitute an opportunity to diagnose subclinical fungal infections in some patients who may be candidates for treatment with ibrutinib. Particular attention should be given when reviewing pre-treatment scans for evidence of silent fungal infections.”

And if IFD is suspected, physicians should consider stopping ibrutinib until the diagnosis is ruled out or the infection has been brought under control, they added.

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