J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://jh.elmerpub.com

Review

Volume 15, Number 5, October 2026, pages 219-224

Heterogeneity in Infection Reporting Across Covalent Bruton Tyrosine Kinase Inhibitor Studies in B-Cell Malignancies: A Systematic Review

↓ Figure 1. PRISMA flow diagram of study selection. Flow diagram showing identification, screening, eligibility assessment, and inclusion of studies evaluating infectious outcomes among patients with B-cell malignancies receiving covalent Bruton tyrosine kinase inhibitors (BTKis). PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

↓ **Table 1.** Characteristics of Included BTKi Studies
Characteristic	All studies (n = 40)	Phase 1 (n = 21)	Phase 3 (n = 14)
Percentages represent the proportion of included studies reporting each characteristic rather than the proportion of individual patients. BTKi: Bruton’s tyrosine kinase inhibitor; CLL: chronic lymphocytic leukemia; MCL: mantle cell lymphoma.
BTKi evaluated
Ibrutinib	21 (52.5%)	13	6
Zanubrutinib	10 (25.0%)	4	5
Acalabrutinib	7 (17.5%)	3	3
Other BTKi	2 (5.0%)	1	0
Primary disease
CLL	25 (62.5%)	13	9
MCL	10 (25.0%)	6	3
Other B-cell cancers	5 (12.5%)	2	2
Concomitant therapy
None	29 (72.5%)	14	11
Anti-CD20 antibody	11 (27.5%)	7	3
Antimicrobial prophylaxis	11 (27.5%)	7	3

↓ Table 1. Characteristics of Included BTKi Studies

Characteristic

All studies (n = 40)

Phase 1 (n = 21)

Phase 3 (n = 14)

Percentages represent the proportion of included studies reporting each characteristic rather than the proportion of individual patients. BTKi: Bruton’s tyrosine kinase inhibitor; CLL: chronic lymphocytic leukemia; MCL: mantle cell lymphoma.

BTKi evaluated

Ibrutinib

21 (52.5%)

Zanubrutinib

10 (25.0%)

Acalabrutinib

7 (17.5%)

Other BTKi

2 (5.0%)

Primary disease

CLL

25 (62.5%)

MCL

10 (25.0%)

Other B-cell cancers

5 (12.5%)

Concomitant therapy

None

29 (72.5%)

Anti-CD20 antibody

11 (27.5%)

Antimicrobial prophylaxis

11 (27.5%)

↓ **Table 2.** Reported Infectious Complications Across BTKi Studies, Stratified by Study Phase
Infection category	All studies n (%)	Phase 1 n (%)	Phase 3 n (%)
Values represent the number and percentage of studies reporting each outcome and should not be interpreted as pooled patient-level infection incidence. HSV: herpes simplex virus; VZV: varicella zoster virus; HBV: hepatitis-B virus; BTKi: Bruton’s tyrosine kinase inhibitor.
Pneumonia	31 (77.5)	18 (85.7)	9 (64.3)
Upper respiratory tract infection	29 (72.5)	17 (81.0)	9 (64.3)
Urinary tract infection	19 (47.5)	12 (57.1)	5 (35.7)
Skin/soft-tissue infection	10 (25.0)	7 (33.3)	2 (14.3)
Opportunistic infections
Aspergillosis	9 (22.5)	7 (33.3)	1 (7.1)
Cryptococcosis	6 (15.0)	5 (23.8)	1 (7.1)
Viral reactivation (HSV, VZV, or HBV)	9 (22.5)	6 (28.6)	2 (14.3)
Grade ≥ 3 infections (any)	27 (67.5)	17 (81.0)	7 (50.0)
Infection-related mortality	25 (62.5)	14 (66.7)	8 (57.1)

↓ Table 2. Reported Infectious Complications Across BTKi Studies, Stratified by Study Phase

Infection category

All studies n (%)

Phase 1 n (%)

Phase 3 n (%)

Values represent the number and percentage of studies reporting each outcome and should not be interpreted as pooled patient-level infection incidence. HSV: herpes simplex virus; VZV: varicella zoster virus; HBV: hepatitis-B virus; BTKi: Bruton’s tyrosine kinase inhibitor.

Pneumonia

31 (77.5)

18 (85.7)

9 (64.3)

Upper respiratory tract infection

29 (72.5)

17 (81.0)

9 (64.3)

Urinary tract infection

19 (47.5)

12 (57.1)

5 (35.7)

Skin/soft-tissue infection

10 (25.0)

7 (33.3)

2 (14.3)

Opportunistic infections

Aspergillosis

9 (22.5)

7 (33.3)

1 (7.1)

Cryptococcosis

6 (15.0)

5 (23.8)

1 (7.1)

Viral reactivation (HSV, VZV, or HBV)

9 (22.5)

6 (28.6)

2 (14.3)

Grade ≥ 3 infections (any)

27 (67.5)

17 (81.0)

7 (50.0)

Infection-related mortality

25 (62.5)

14 (66.7)

8 (57.1)

↓ **Table 3.** Recommended Reporting of Infectious Outcomes in Future BTKi Trials
Reporting domain	Information to report
BTKi: Bruton’s tyrosine kinase inhibitor.
Infection ascertainment	Define each infection outcome; state whether infections were actively sought or passively reported, how they were diagnosed, and the period during which they were recorded.
Infection type and severity	Report all-grade and grade ≥ 3 infections; name the infection site and organism when known; identify opportunistic infections; specify the grading system and its version.
Denominators and timing	Give the number of BTKi-exposed patients at risk in each treatment group, number of patients affected, and number of events where relevant. Report treatment duration, follow-up, and timing of infections relative to BTKi initiation.
Patient and treatment context	Report underlying malignancy and treatment setting, prior anticancer therapy and transplant history, baseline immune status where available, corticosteroid use, and concurrent anticancer or other immunosuppressive treatment.
Infection prevention	Describe antibacterial, antiviral, and antifungal prophylaxis, including who received it and when; report relevant vaccination or infection-prevention policies.
Infection-related mortality	Report deaths attributed to infection separately from all-cause deaths and describe how infection attribution was determined.

↓ Table 3. Recommended Reporting of Infectious Outcomes in Future BTKi Trials

Reporting domain

Information to report

BTKi: Bruton’s tyrosine kinase inhibitor.

Infection ascertainment

Define each infection outcome; state whether infections were actively sought or passively reported, how they were diagnosed, and the period during which they were recorded.

Infection type and severity

Report all-grade and grade ≥ 3 infections; name the infection site and organism when known; identify opportunistic infections; specify the grading system and its version.

Denominators and timing

Give the number of BTKi-exposed patients at risk in each treatment group, number of patients affected, and number of events where relevant. Report treatment duration, follow-up, and timing of infections relative to BTKi initiation.

Patient and treatment context

Report underlying malignancy and treatment setting, prior anticancer therapy and transplant history, baseline immune status where available, corticosteroid use, and concurrent anticancer or other immunosuppressive treatment.

Infection prevention

Describe antibacterial, antiviral, and antifungal prophylaxis, including who received it and when; report relevant vaccination or infection-prevention policies.

Infection-related mortality

Report deaths attributed to infection separately from all-cause deaths and describe how infection attribution was determined.