Serious infections after 5-year ibrutinib therapy

In March 2018, Tilly Varughese from the Memorial Sloan Kettering Cancer Center, NY, and colleagues, published online ahead of print in the Clinical Infectious Diseases journal, a retrospective analysis of the safety outcomes of 5-year ibrutinib treatment in patients with lymphoid malignancies.

Ibrutinib–a clinically approved drug–has been widely used for the treatment of various lymphomas, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia (WM) and mantle cell lymphoma (MCL). Recently, in a US real-world analysis, a summary of the most common ibrutinib-mediated toxicities in CLL patients was reported, justifying the reasons for its restriction from clinical use. In this study, the authors determined the spectrum and occurrence of serious infections, following a 5-year ibrutinib regimen, in patients with CLL or non-Hodgkin lymphoma (NHL).

Patient characteristics & study design

• N = 378, aged ≥ 18 years, receiving 5-year ibrutinib therapy (monotherapy or in combination with other drugs)
• Mean age (range): 66 (19–95) years (66% males)
• Patient diagnosis:
  • CLL: n = 165 (44%)
  • NHL: n = 213 (56%)
  • MCL: n = 61 (16%)
  • Diffuse large B-cell lymphoma (DLBCL): n = 52 (13%)
  • WM: n = 34 (9%)
  • Follicular lymphoma (FL): n = 23 (6%)
  • Marginal zone lymphoma (MZL): n = 15 (4%)
  • Primary central nervous system lymphoma (PCNSL): n = 14 (4%)
  • Other: n = 14 (4%)
• Infections were identified by evaluating laboratory data, imaging studies and when available, histopathologic or cytology results in combination with clinical chart review
• Serious infections were defined by the need for hospitalization and/or parenteral antimicrobial therapy, occurring at any time from ibrutinib initiation until 30 days after its discontinuation

Key findings

• Most frequently administered daily ibrutinib doses: 420 mg (66%) and 560 mg (23%)
• Mean ibrutinib treatment duration: 413 (3–1631) days
• Patients receiving ibrutinib monotherapy: 84%
• Rituximab was the most common combination drug for ibrutinib treatment:
  • R-ICE (rituximab, ifosfamide, carboplatin and etoposide): n = 18
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone): n = 5 patients
• Median number of prior lines (range): 2 (0–10)
• Ibrutinib as first-line treatment: n = 71 (19%)
• Ibrutinib as second or later line treatment: n = 307 (81%)
• NHL patients received on average higher daily doses of ibrutinib and more commonly in combination with other drugs, as compared to CLL patients

Infections

• Serious infections developed in n = 43 patients (11.4%)
  • Developed infection while on ibrutinib: n = 31
  • Developed infection within 30 days of ibrutinib cessation: n = 12
• Median time from ibrutinib initiation to infection (range): 136 (8–1082) days
• Infections occurring during the first year of ibrutinib treatment: 84%
• Deaths due to infection progression: n = 6 (1.6%)
• Infection types (in the 43 patients):
• Bacterial infections: n = 23 patients (53.5%) (staphylococcus aureus being the most common)
• Fungal infections: n = 16 (37.2%) (invasive aspergillosis, pneumocystis jiroveci pneumonia, pulmonary cryptococcus, candida albicans)
• Viral infections: n = 4 (9.3%) (respiratory pneumonia viruses, hepatitis B reactivation)
• Risk factors associated with the development of serious infections:
  • Univariate and multivariate analyses:
  • Receipt of at least 3 prior anti-tumor therapies
  • Presence of neutropenia at any time during ibrutinib treatment
• Ibrutinib daily or cumulative dose was not associated with infection risk (164953 mg vs 191775 mg for infected and uninfected patients respectively; P = 0.2375)
• Invasive fungal infections (IFIs) were associated with corticosteroid use at any time during ibrutinib treatment (univariate analysis)
  • IFIs developed in 4.2% of ibrutinib-treated patients
  • None of the patients with IFIs had received hematopoietic stem cell transplantation (HSCT)

The authors concluded that patients receiving long-term ibrutinib treatment might be at risk of developing serious infections, including IFIs. They stated that due to the study design, it was not possible to prove the direct contribution of ibrutinib to infection risk. Nevertheless, none of the evaluated patients presented with traditional risk factors associated with IFIs (i.e. HSCT, corticosteroids etc.). This, together with other studies and the fact that IFI frequency was the same in patients receiving ibrutinib as first or later line therapy, is suggestive of the possible ibrutinib-mediated risk for infection, in patients with CLL or NHL. Another limitation of this study was the fact that the patient sample was derived from only one center, the Memorial Sloan Kettering Cancer Center. It is evident that further studies evaluating the specific patient population that will benefit the most from ibrutinib treatment, along with the consideration for targeted prophylaxis therapies, are essential.