Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Clinical Characteristics of Patients
3.2. Incidence of Infections
3.3. Type of Infections
3.4. Outcomes of Patients Who Developed Infections
3.5. Impact of Baseline Characteristics of Patients on Infections
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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n (%) | |
---|---|
Number of patients | 494 (79.7) |
Median duration of exposure to ibrutinib, months (range) | 35 (4–85) |
Gender male Gender female | 338 (68.4) 156(31.6) |
Median age, years (range) | 69 (32–92) |
Median time from CLL diagnosis, years (range) | 6 (3–34) |
Median CIRS, (range) | 4 (0–16) |
Patients with CIRS > 6 | 185 (37.4) |
Patients with CrCl < 70 mL/min | 167 (33.8) |
Patients with COPD | 78 (15.8) |
Smokers | 123 (24.9) |
Patients with diabetes | 78 (15.8) |
Pneumonia or grade ≥3 infections within 1 year before starting ibrutinib | 118 (23.9) |
Median IgG levels, mg/dL (range) | 625 (82–5220) |
Patients with IgG levels ≤ 400 mg/dL on Ig support | 99/472 (21.0) |
Median Hb × 109/L (range) | 12.0 (3.8–17.4) |
Median neutrophil count × 109/L (range) | 3.2 (0.11–9.9) |
Patients with neutrophil count < 1 × 109/L | 39 (8) |
Median lymphocyte count × 109/L (range) | 36.7 (0.5–99.1) |
Rai stage III-IV | 260 (52.6) |
Del17p and/or TP53 mutation | 228/413 (55.2) |
Unmutated IGHV | 319/434 (73.5) |
Mutated IGHV | 115/434 (26.5) |
CD38 ≥ 30% | 130/335 (38.8) |
Untreated patients (1) | 89 (18.0) |
Previously treated patients | 405 (82) |
Median number of prior treatments (range) | 1 (0–9) |
Prior treatments = 1 | 169 (34.2) |
Prior treatments = 2 | 101 (20.4) |
Prior treatments > 2 | 135 (27.4) |
Patients on TMP-SMX prophylaxis | 365 (73.9) |
Patients on HBV prophylaxis | 41 (8.3) |
Patients on fungal prophylaxis | 1 (0.2) |
Patients on concomitant steroids | 83 (16.8) |
n = 494 (%) | |
---|---|
Ibrutinib exposure, person-years | 1264 |
Median exposure to ibrutinib per patient, years | 2.6 |
Patients with at least pneumonia or grade ≥3 infection events | 156 (32) |
Total pneumonia or grade ≥3 infection events | 193 |
IR per 100 person-years | 15.3 |
Median time to onset of the first infection, months (range) [IQR] | 6 (0–54) (2–13) |
Number of patients with pneumonia or grade ≥3 infections who discontinued ibrutinib | 43 (9) |
Number of patients with fatal pneumonia or grade ≥3 infections | 29 (6) |
Patients with pneumonia | |
Number of patients with at least one pneumonia event | 100 (20) |
Total pneumonia events | 126 |
IR of pneumonia events per 100 person-years | 10.0 |
Median time to pneumonia, months (range) [IQR] | 7 (0–51) [3,4,5,6,7,8,9,10,11,12] |
Number of patients with pneumonia who discontinued ibrutinib | 19 (4) |
Number of patients with a fatal pneumonia | 17(3.5) |
Patients with grade ≥3 non-opportunistic infections | |
Number of patients with at least a grade ≥3 non-opportunistic infection | 32 (6.5) |
Total grade ≥3 non-opportunistic infections | 42 |
IR of grade ≥3 non-opportunistic infections per 100 person-years | 3.3 |
Median time to grade ≥3 non-opportunistic infections, months, (range) [IQR] | 9 (1–48) [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] |
Number of patients with a grade ≥3 non-opportunistic infections who discontinued ibrutinib | 10 (2) |
Number of patients with a fatal grade ≥3 non-opportunistic infections | 3 (0.6) |
Patients with grade ≥3 opportunistic infections | |
Number of patients with at least a grade ≥3 opportunistic infections | 24 (5) |
Total grade ≥3 opportunistic infections | 25 |
IR of grade ≥3 opportunistic infections per 100 person-years | 2.0 |
Median time to grade ≥3 opportunistic infections, months, (range) [IQR] | 3 (0–54) [1,2,3,4,5,6,7,8,9,10] |
Number of patients with a grade ≥3 opportunistic infection who discontinued ibrutinib | 14 (3) |
Number of patients with a fatal grade ≥3 opportunistic infection | 9 (2) |
Number of Patients n = 494 | Number of Infections n = 193 (IR per 100 Person-Years = 15.3) | p Value | |
---|---|---|---|
Gender M Gender F | 338 156 | 127 (14.6) 66 (16.7) | 0.38 |
Age ≥ 70 years | 228 | 83 (14.7) | 0.65 |
Age < 70 years | 266 | 110 (15.7) | |
CIRS ≥ 6 | 185 | 86 (17.8) | 0.07 |
CIRS < 6 | 309 | 107 (13.7) | |
CrCl ≥ 70 mL/min | 327 | 124 (14.4) | 0.23 |
CrCl < 70 mL/min | 167 | 69 (17.2) | |
Smokers | 123 | 42 (14.0) | 0.53 |
Non-smokers | 371 | 151 (15.7) | |
Patients with diabetes | 78 | 32 (17.2) | 0.46 |
Patients without diabetes | 416 | 161 (14.9) | |
Patients with COPD | 78 | 56 (27.7) | <0.0001 |
Patients without COPD | 416 | 137 (12.9) | |
Pneumonia or a grade ≥3 infection 1 year before starting ibrutinib presentabsent | 118 376 | 84 (32.3) 109 (10.9) | <0.0001 |
Patients on TMP-SMX prophylaxis | 365 | 134 (14.4) | 0.21 |
Patients not on TMP-SMX prophylaxis | 129 | 59 (17.6) | |
Patients with IgG levels ≤ 400 mg/dL | 99 | 56 (22.1) | 0.002 |
Patients with IgG levels > 400 mg/dL | 373 | 129 (13.2) | |
Neutrophil count >1000 ×109/L | 416 | 156 (14.0) | 0.001 |
Neutrophil count ≤1000 × 109/L | 49 | 28 (28.6) | |
Rai stage 0–II | 234 | 71 (10.7) | <0.0001 |
Rai stage III–IV | 260 | 122 (20.2) | |
Del17p and/or Tp53 mutation present | 228 | 94 (16.5) | 0.29 |
Del17p and Tp53 mutation absent | 250 | 92 (14.1) | |
IGHV unmutated | 319 | 126 (15.3) | 0.98 |
IGHV mutated | 115 | 46 (15.2) | |
Prior treatments 0 | 89 | 20 (8.8) | 0.003 |
Prior treatments ≥ 1 | 405 | 173 (16.7) | |
Prior treatments ≤ 1 | 258 | 69 (10.6) | <0.0001 |
Prior treatments ≥ 2 | 236 | 124 (20.2) | |
Front-line ibrutinib | 65 | 16 (10.5) | 0.23 |
Front-line ibrutinib+rituximab | 24 | 4 (5.3) | |
Patients with concomitant steroids | 83 | 45 (23.2) | 0.003 |
Patients without concomitant steroids | 411 | 148 (13.7) |
Univariate Analysis HR (95%CI) | Multivariate Analysis HR (95%CI) | Bootstrap Validated Coefficients HR (95% CI) | |
---|---|---|---|
Pneumonia or grade ≥3 infections 1 year before starting ibrutinib (yes vs. no) | 3.09 (2.24–4.27) | 2.72 (1.94–3.81) | 2.72 (1.93–3.91) |
Chronic obstructive pulmonary disease (yes vs. no) | 2.23 (1.55–3.21) | 1.49 (1.01–2.19) | 1.49 (1.01–2.22) |
Number of prior treatments (≤1 vs. ≥2) | 1.88 (1.36–2.59) | 1.67 (1.20–2.33) | 1.67 (1.21–2.37) |
Number of prior treatments (0 vs. ≥1) | 1.99 (1.20–3.29) | NS | |
Neutrophil count (≤1000 vs. >1000 × 109/L) | 1.83 (1.16–2.88) | NS | |
IgG levels (<400 vs. >400 mg/dL) | 1.71 (1.20–2.43) | NS | |
Steroids (yes vs. no) | 1.60 (1.09–2.34) | NS | |
RAI stage (III–IV vs. 0–I–II) | 1.48 (1.08–2.05) | NS |
Variables | Risk Points | ||
---|---|---|---|
Pneumonia or gr ≥3 infections 1 year before starting ibrutinib | 2 | ||
Prior treatments ≥ 2 | 1 | ||
COPD (1) | 1 | ||
RiskGroup | Risk Score | % Patients(n) | % Patients with Infections(n) |
Low | 0–1 | 71.2 (352) | 23.0 (81) |
Intermediate | 2 | 13.6 (67) | 41.8 (28) |
High | ≥3 | 15.2 (75) | 62.7 (47) |
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Mauro, F.R.; Giannarelli, D.; Visentin, A.; Reda, G.; Sportoletti, P.; Frustaci, A.M.; Chiarenza, A.; Ciolli, S.; Vitale, C.; Laurenti, L.; et al. Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib. Cancers 2021, 13, 3240. https://doi.org/10.3390/cancers13133240
Mauro FR, Giannarelli D, Visentin A, Reda G, Sportoletti P, Frustaci AM, Chiarenza A, Ciolli S, Vitale C, Laurenti L, et al. Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib. Cancers. 2021; 13(13):3240. https://doi.org/10.3390/cancers13133240
Chicago/Turabian StyleMauro, Francesca Romana, Diana Giannarelli, Andrea Visentin, Gianluigi Reda, Paolo Sportoletti, Anna Maria Frustaci, Annalisa Chiarenza, Stefania Ciolli, Candida Vitale, Luca Laurenti, and et al. 2021. "Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib" Cancers 13, no. 13: 3240. https://doi.org/10.3390/cancers13133240