Ibrutinib‐associated <i>Pneumocystis jirovecii</i> pneumonia
Authors: Regina Lee, Afrouz Nayernama, S. Christopher Jones, Tanya Wroblewski, Peter E. Waldron
Journal: American Journal of Hematology (2017)

Pneumocystis jirovecii pneumonia (PCP) is a serious infection that occurs in immunocompromised individuals, most commonly among HIV-infected patients, hematopoietic stem cell and solid organ transplant recipients receiving immunosuppressants, and patients with hematologic malignancies. The common feature of patients at high risk for PCP is defective T-cell immunity, induced by underlying diseases or immunosuppressive therapy. Prolonged corticosteroid exposure is a frequently identified immunosuppressive associated with PCP risk.1 The clinical presentation of PCP may differ between non-HIV infected patients and HIV-infected patients, with more acute onset of symptoms and significantly higher mortality rates (30%-60%) in non-HIV infected patients compared to those with HIV (10%-20%).2 We report a series of cases of PCP associated with the use of ibrutinib that were submitted to the FDA Adverse Event Reporting System (FAERS). The Division of Pharmacovigilance at the U.S. Food and Drug Administration reviewed postmarketing cases of PCP from FAERS and the published literature among patients treated with ibrutinib for chronic lymphocytic leukemia (CLL), small lymphocytic leukemia, mantle cell lymphoma, and B cell lymphoma. We defined a case of PCP as confirmed if criteria 1, or both 2 and 3 were met: (1) documentation of P. jirovecii in induced sputum by microscopy with appropriate stains or bronchoalveolar lavage fluid by microscopy, or by polymerase chain reaction; (2) new onset of respiratory system findings supported by compatible radiographic findings as follows: chest radiograph or computed tomography demonstrating diffuse bilateral interstitial infiltrates, solitary or multiple nodules, pneumatoceles, blebs and cysts, asymmetric disease, upper lobe localization, or pneumothorax;2 (3) treatment of presumed PCP infection with PCP specific treatment.3 A case was considered unconfirmed if the reporter stated that the case involved PCP, but the report did not provide the results of diagnostic testing required of a confirmed case. We identified 13 FAERS cases of ibrutinib-associated PCP, and five of these cases included statements which fulfilled the confirmed criteria. Using the World Health Organization-Uppsala Monitoring Centre causality assessment scale, we determined the causal association of PCP with ibrutinib for all of the FAERS cases as possible. The time from ibrutinib initiation to PCP diagnosis exhibited a wide range, with a median of 89 days (range of 7–772 days). Overall, the onset of PCP occurred during the first six months of ibrutinib treatment in 7 of 13 (54%) cases, which is consistent with that reported in the literature.4 Seven of 13 cases reported the use of no other immunosuppressive therapy. Table 1 summarizes the characteristics of the FAERS cases. All FAERS cases resulted in clinically significant outcomes with five deaths and eight requiring hospitalization. PCP was reported as the sole cause of death in three cases. In these three cases, the times to death from PCP diagnosis were 8, 12, and 29 days. In the fourth fatal case, the cause of death was multifactorial including septic shock, PCP, and respiratory failure. No cause of death was reported in the fifth case. We assessed the cases for the presence of confounding factors. In addition to the underlying diseases, ten cases had refractory disease indicating prior exposure to other immunosuppressive therapy, and six cases reported the concomitant use of other immunosuppressive agents (refer to Table 1). One case reported no exposure to other immunosuppression prior to ibrutinib treatment, and two cases did not report prior therapy. We identified one published case series, which comprised five cases of PCP that developed among 96 patients with CLL who participated in two single-agent ibrutinib studies at the US National Cancer Institute.4 Four of the five patients received ibrutinib as first-line treatment, which removes the confounding factors of prolonged disease duration and concomitant immunosuppressive therapy.4 The clinical presentations of PCP in these patients were mild, ranging from asymptomatic pulmonary infiltrates to chronic cough. All of these patients resolved their infection with early recognition and trimethoprim/sulfamethoxazole treatment. The close, scheduled monitoring as part of a study protocol, and early detection of PCP in these study patients, may have contributed to improved outcomes compared to the FAERS cases. Biological plausibility for PCP risk with ibrutinib is supported by its irreversible inhibitory effect on interleukin-2–inducible kinase (ITK), the critical role of ITK in T Helper 2 (Th2) T-cells, and the essential role of Th2 cells in PCP immunity.5 Given the serious outcomes in this FAERS cases series, practitioners should be aware of a possible contribution of ibrutinib to the risk of PCP. Mitigating the risk of mortality with PCP infection in non-HIV patients requires an appropriate assessment of the risk for PCP infections based on underlying disease and concomitant or prior medications to include immunosuppressive therapy, institution of appropriate prophylaxis regimen, and early diagnosis and prompt use of effective antibiotics.6 We recommend a careful consideration of the benefits and risks of PCP prophylaxis when patients are exposed to ibrutinib, especially in the context of additional risk factors which can diminish T-cell immunity. The sponsor updated the Warnings and Precautions section of the ibrutinib prescribing information to include the occurrence of PCP in patients treated with ibrutinib and consideration for prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Regina Lee http://orcid.org/0000-0001-7726-2373