RISK FACTORS AND PROFILE OF INFECTIONS ON IBRUTINIB THERAPY OUTSIDE CLINICAL TRIALS: A SINGLE CENTER EXPERIENCE OF 68 PATIENTS.
Author(s): ,
Caroline Protin
Affiliations:
Hematology,IUC Toulouse-Oncopole,Toulouse,France
,
Kim Paricaud
Affiliations:
Infectious diseases,CHU Purpan,Toulouse,France
,
Fabien Despas
Affiliations:
Pharmacology,Faculté de Médecine de Toulouse,Toulouse,France
,
Guillaume Martin-Blondel
Affiliations:
Infectious diseases,CHU Purpan,Toulouse,France
Loic Ysebaert
Affiliations:
Hematology,IUC Toulouse-Oncopole,Toulouse,France
(Abstract release date: 05/19/16) EHA Library. Protin C. 06/09/16; 132624; E1075
Dr. Caroline Protin
Dr. Caroline Protin
Contributions
Abstract
Abstract: E1075

Type: Eposter Presentation

Background
Ibrutinib is a first in class oral inhibitor of Bruton’s Tyrosin Kinase, a protein critical for the B-cell receptor signaling cascade, but with significant activity also against NK, T cell, and macrophage signaling pathway downstream other receptors. High response rates in relapse/refractory chronic lymphoid leukemia (CLL), mantle cell lymphoma (MCL) and Waldenström's disease have granted ibrutinib a global market approval in these lymphomas. In the context of various clinical trials, investigators reported 24% of grade ≥3 infections, more frequently bacterial. 

Aims
In this study, we aimed to assess in “real life” the profile of infections related to this targeted therapy, and identify risk factors.

Methods
Between March 01, 2014 and January 15, 2016, we included all patients starting ibrutinib (and exposed for >1 month), referred to the Toulouse University Hospital Cancer Center (IUC-Toulouse Oncopole).

Results
We enrolled 68 patients with a median age of 69.7 years, 76.5% of the patients with CLL and 23.5% with MCL. Forty-three infectious adverse events (IAE) occurred in 30/68 patients (44.1%), including 18/43 (41,9%) grade 1-2, 21/43 (48,8%) grade 3-4 and 4/43 (9,3%) grade 5. Median time to IAE onset was 2,9 ± 1,7 months, 33/43 (76,7%) being observed the first 6 months of therapy, suggesting recovery of the normal immune system with CLL improvement.Among 43 IEA, 23 were of unknown origin (treated with wide spectrum antibiotics, most therefore of bacterial origin), and 20 IAE were documented: 13 bacterial (including 2 Campylobacter jejunii and 3 Pseudomonas aeruginosa), 5 fungal (2 invasive aspergillosis, 1 mucormycosis, 1 pneumocystosis and 1 disseminated cryptococcosis) and 2 viral (hepatitis E virus reactivations). In accordance with published results from clinical trials (Maddocks et al., JAMA Oncol 2015), PFS was significantly shorter in those patients with onset of any grade IAE during the first 3 months of therapy (median PFS 8mo vs NR, p=0.02), or with onset of severe IAE grade ≥3 (median PFS 10mo vs NR, p=0.02). The baseline characteristics of the patients were well balanced between the two study groups (infected and non infected) regarding comorbidities, history of previous infections, number of previous lines of therapy (median of 3), or primary prophylaxis (cotrimoxazole+/-valaciclovir: 40% of patients with IAE vs 50% of patients without). There was no clinical or biological parameter before commencing ibrutinib correlated to IAE risk (median neutrophil and lymphocyte count, CD4/8 T lymphocyte count and gammaglobulin levels). However, peak lymphocytosis induced by ibrutinib at month 1 and 2 was correlated to IAE risk (median 126843/ml vs 69409/ml after 1 month, 100238/ml vs 63485/ml after 2 months, Mann-Whitney test p<0,05 for both).

Conclusion
In this real-life practice series, 44% of patients have developed IAE of which 50% were severe (grade ≥3) including 13% fungal infection. As compared to clinical trials, we confirmed the significant correlation of early-onset IAE with PFS, and that IEA risk decreases with time (even after 3 months), without disappearing over time (10% IAE occuring >6 months). Interestingly, and consistent with an improvement of normal immune responses linked to the desinfiltration of lymph nodes/spleen/bone marrow, ibrutinib-induced lymphocytosis was associated with a lower incidence of infection. 

Session topic: E-poster

Keyword(s): Chronic lymphocytic leukemia, Infection, Targeted therapy
Abstract: E1075

Type: Eposter Presentation

Background
Ibrutinib is a first in class oral inhibitor of Bruton’s Tyrosin Kinase, a protein critical for the B-cell receptor signaling cascade, but with significant activity also against NK, T cell, and macrophage signaling pathway downstream other receptors. High response rates in relapse/refractory chronic lymphoid leukemia (CLL), mantle cell lymphoma (MCL) and Waldenström's disease have granted ibrutinib a global market approval in these lymphomas. In the context of various clinical trials, investigators reported 24% of grade ≥3 infections, more frequently bacterial. 

Aims
In this study, we aimed to assess in “real life” the profile of infections related to this targeted therapy, and identify risk factors.

Methods
Between March 01, 2014 and January 15, 2016, we included all patients starting ibrutinib (and exposed for >1 month), referred to the Toulouse University Hospital Cancer Center (IUC-Toulouse Oncopole).

Results
We enrolled 68 patients with a median age of 69.7 years, 76.5% of the patients with CLL and 23.5% with MCL. Forty-three infectious adverse events (IAE) occurred in 30/68 patients (44.1%), including 18/43 (41,9%) grade 1-2, 21/43 (48,8%) grade 3-4 and 4/43 (9,3%) grade 5. Median time to IAE onset was 2,9 ± 1,7 months, 33/43 (76,7%) being observed the first 6 months of therapy, suggesting recovery of the normal immune system with CLL improvement.Among 43 IEA, 23 were of unknown origin (treated with wide spectrum antibiotics, most therefore of bacterial origin), and 20 IAE were documented: 13 bacterial (including 2 Campylobacter jejunii and 3 Pseudomonas aeruginosa), 5 fungal (2 invasive aspergillosis, 1 mucormycosis, 1 pneumocystosis and 1 disseminated cryptococcosis) and 2 viral (hepatitis E virus reactivations). In accordance with published results from clinical trials (Maddocks et al., JAMA Oncol 2015), PFS was significantly shorter in those patients with onset of any grade IAE during the first 3 months of therapy (median PFS 8mo vs NR, p=0.02), or with onset of severe IAE grade ≥3 (median PFS 10mo vs NR, p=0.02). The baseline characteristics of the patients were well balanced between the two study groups (infected and non infected) regarding comorbidities, history of previous infections, number of previous lines of therapy (median of 3), or primary prophylaxis (cotrimoxazole+/-valaciclovir: 40% of patients with IAE vs 50% of patients without). There was no clinical or biological parameter before commencing ibrutinib correlated to IAE risk (median neutrophil and lymphocyte count, CD4/8 T lymphocyte count and gammaglobulin levels). However, peak lymphocytosis induced by ibrutinib at month 1 and 2 was correlated to IAE risk (median 126843/ml vs 69409/ml after 1 month, 100238/ml vs 63485/ml after 2 months, Mann-Whitney test p<0,05 for both).

Conclusion
In this real-life practice series, 44% of patients have developed IAE of which 50% were severe (grade ≥3) including 13% fungal infection. As compared to clinical trials, we confirmed the significant correlation of early-onset IAE with PFS, and that IEA risk decreases with time (even after 3 months), without disappearing over time (10% IAE occuring >6 months). Interestingly, and consistent with an improvement of normal immune responses linked to the desinfiltration of lymph nodes/spleen/bone marrow, ibrutinib-induced lymphocytosis was associated with a lower incidence of infection. 

Session topic: E-poster

Keyword(s): Chronic lymphocytic leukemia, Infection, Targeted therapy

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