Rate of major bleeding with ibrutinib versus bendamustine-rituximab in chronic lymphocytic leukemia: A population-based cohort study

To the Editor:

The approval of ibrutinib, a Bruton’s Tyrosine Kinase (BTK) inhibitor, has revolutionized the treatment landscape for treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) patients. Forty-four percent of CLL patients enrolled in the informCLL registry received ibrutinib—making it the most commonly used CLL treatment in the current era of novel targeted therapies. Ibrutinib demonstrated a 6.5 year progression-free survival (PFS) of 61% in untreated CLL compared to 9% with chlorambucil (RESONATE-2 trial), and also improved PFS in both untreated (E1912 and A041202 trials) and previously treated (HELIOS trial) CLL compared to chemoimmunotherapy. However, bleeding was frequently observed in ibrutinib-treated patients and has become a notable safety concern.

Bleeding of any severity occurs in up to 50% of ibrutinib-treated patients,¹ due to ibrutinib’s on-target BTK and potentially off-target (Tec) effects on collagen-induced platelet aggregation. Major bleeding, however, was uncommonly observed in clinical trials, with incidences ranging from 2%–8%.^1,2 Although major bleeding was uncommon in these studies, it may occur more frequently in clinical practice due to its use in patients who were excluded from clinical trials, including those with renal dysfunction and/or those taking concomitant warfarin with or without cytochrome P450 3A4/5 (CYP3A4/5) inhibitors.¹ Indeed, higher incidences of major bleeding (8%–18%) have been reported in real-world populations compared to clinical trials.^3,4 Few studies have examined this topic, however, and those that have did not directly compare the rate of major bleeding between ibrutinib-treated individuals and individuals treated with therapeutic alternatives. Furthermore, many of these studies were limited to a single institution. Thus, the comparative rate of major bleeding with ibrutinib versus other CLL therapies in a population-based setting remains unknown. Given ibrutinib’s current widespread use and the life-threatening potential of major bleeds, a more robust assessment of ibrutinib-related major bleeding may inform its benefit-risk profile, which is particularly important as 2nd-generation BTK inhibitors (e.g., acalabrutinib and zanubrutinib) emerge.

We conducted an incident-user, active comparator retrospective cohort study using 2013–2020 Optum Clinformatics de-identified commercial health insurance data to compare incidence rates of real-world major and clinically-relevant bleeding between ibrutinib-and bendamustine-rituximab (BR)-treated individuals diagnosed with CLL. Additional details on Optum Clinformatics are described in Supplemental Methods 1.1.

We included individuals who were incident users of either ibrutinib or BR between November 1, 2013 and February 29, 2020 and were diagnosed with CLL. We excluded individuals who were co-exposed to an oral anticoagulant on the index date (date of incident exposure to ibrutinib or BR). Additional details on defining the study population are described in Supplemental Methods 1.2–1.5.

Potential confounders were identified during the 6-month baseline period preceding the index date and are listed in Supplementary Table 1. We also used the high-dimensional propensity score (hdPS) approach to empirically identify additional covariates with a high potential for confounding—which are hypothesized to be proxies for unmeasured confounders. This approach ranks and selects potential confounders based on their empiric association with either the exposure or both the exposure and outcome. Details on hdPS are described in Supplemental Methods 1.6.

The primary outcome was major bleeding, defined as bleeding resulting in inpatient hospitalization. We used a previously validated algorithm to identify outcomes, which demonstrated a positive predictive value of 89% in health insurance claims data⁵ (see Supplemental Methods 1.7). The secondary outcome was clinically-relevant bleeding, which was a composite of bleeding events resulting in inpatient hospitalization (i.e., major bleeding) and those resulting in emergency department presentation.

We calculated descriptive statistics for baseline variables, crude incidence rates, and unadjusted association measures, the latter using Cox proportional hazards models. We included pre-specified covariates, along with hdPS-identified covariates, into a logistic regression model to calculate propensity scores. We calculated the stabilized inverse probability of treatment weight (sIPTW) for each individual based on propensity scores. We then estimated hazard ratios (HRs) using Cox proportional hazards regression, weighted based on sIPTW. Additional statistical details on the primary analysis as well as sensitivity and effect modification analyses are described in Supplemental Methods 1.8. The University of Pennsylvania institutional review board deemed research using this dataset to be exempt from review.

We identified 2423 and 1102 incident users of ibrutinib and BR respectively (Supplementary Figure 2). Individuals in the overall cohort were predominantly male (61.6%) and White (70.4%), with a median age of 72 years and a median frailty score of 0.135 (i.e., pre-frail category per frailty index). The majority of ibrutinib-treated individuals (88.1%) received an average daily dose of 420 mg at cohort entry. Differences in unweighted baseline characteristics between groups are highlighted in Supplemental Results 2.1. All weighted baseline characteristics that were included in the propensity score were well-balanced except for geographic region of residence (absolute standardized difference = 0.14) (Supplementary Tables 5 and 6).

Crude incidence rates for major and clinically-relevant bleeding are presented in Table 1. Major bleeding events in ibrutinib-treated individuals were predominantly gastrointestinal (47.6%), followed by cerebral (19.0%), genitourinary (14.3%), other (14.3%), and unspecified (4.8%) (Supplementary Table 7). Ibrutinib (vs. BR) had an elevated, yet statistically compatible with the null, hazard of major bleeding (sIPTW-adjusted HR: 1.61, 95% confidence interval [95% CI]: 0.67–3.84), and an elevated and statistically significant hazard of clinically-relevant bleeding (sIPTW-adjusted HR: 2.66, 95% CI: 1.29–5.49) (Table 1 and Supplementary Figure 4). Results from sensitivity analyses were consistent with our primary findings; additional details on sensitivity analysis and effect modification results can be found in Supplemental Results 2.2.

TABLE 1.

Rate of major bleeding and clinically-relevant bleeding in ibrutinib-treated compared to bendamustine-rituximab-treated individuals

	Ibrutinib	Bendamustine-Rituximab
Follow-up time
Follow-up, sum, in person-years	687	361
Follow-up, median per individual, in days	95	137
Outcomes during follow-up	N
Major bleeding	21	9
Clinically-relevant bleeding	40	15
Measure of outcome occurrence	Crude Incidence Rate, per 100 person-years (95% Confidence Interval)
Major bleeding	3.1 (2.0–4.7)	2.5 (1.3–4.8)
Clinically-relevant bleeding	5.8 (4.3–7.9)	4.2 (2.5–6.8)
Relative effect estimate for outcome	Hazard Ratio (95% Confidence Interval)
Major bleeding
Unadjusteda	1.16 (0.53–2.54)	1.00 (reference)
Adjustedb,c	1.61 (0.67–3.84)	1.00 (reference)
Clinically-relevant bleeding
Unadjustedd	1.34 (0.74–2.43)	1.00 (reference)
Adjustedc,e	2.66 (1.29–5.49)	1.00 (reference)

^aDid not fail a test for non-proportional hazards (p = .42).

^bDid not fail a test for non-proportional hazards (p = .23).

^cModel weighted based on stabilized inverse probability of treatment weights and adjusted for cohort entry year and geographic region of residence.

^dDid not fail a test for non-proportional hazards (p = .22).

^eDid not fail a test for non-proportional hazards (p = .11).

This population-based cohort study compared the rates of real-world major and clinically-relevant bleeding in ibrutinib-treated individuals versus individuals treated with chemoimmunotherapy. Ibrutinib had an elevated hazard of major bleeding compared to BR, although this finding was compatible with the null. Ibrutinib was associated with a 2.6-fold hazard of clinically relevant bleeding compared to BR, suggesting a potential risk of clinically-relevant bleeding events in patients treated with ibrutinib in routine clinical practice.

The crude incidence rate of major bleeding among ibrutinib-treated individuals in our study (3.1 per 100 person-years [p-y], 95% CI: 2.0–4.7) is comparable to that found in a meta-analysis of ibrutinib clinical trials,¹ which reported a pooled major bleeding incidence rate of 2.8 per 100 p-y. Though prior real-world observational studies did not report incidence rates, their crude incidence proportions (8%–18%)^3,4 were notably higher than that of our study (0.87%). Potential reasons for this difference are described in Supplemental Discussion 3.1.

Our adjusted primary outcome analysis found an elevated, yet consistent with the null, rate of major bleeding with ibrutinib compared to BR. It is likely that our study was underpowered due to the low number of outcomes; however, a lack of a difference in the rate of major bleeding between ibrutinib and BR cannot be excluded. Using Austin’s method for obtaining the number needed to harm (NNH) from adjusted survival models, we calculated an NNH of 252 for major bleeding. Caron et al. and Wang et al. also found increased pooled relative risks of major bleeding versus comparator therapies in clinical trials ranging from 1.66–2.46.^1,2 Our adjusted secondary outcome analysis showed a positive association of ibrutinib (vs. BR) with clinically-relevant bleeding (i.e., bleeding resulting in inpatient admission or emergency department presentation). We calculated an NNH of 58 for clinically-relevant bleeding. Though prior studies did not examine a similarly defined outcome, comparative rates of lower-severity bleeding were reported. Caron et al. and Wang et al. both observed a larger relative risk with all-severity bleeding in clinical trials (pooled relative risks ranging from 2.72–3.08)^1,2 than with major bleeding. Abdel-Qadir et al. conducted a population-based cohort study and observed a similar association with hospital-diagnosed bleeding in ibrutinib-exposed patients compared to chemotherapy-exposed patients (HR 2.58, 95% CI 1.76–3.78).⁶ Overall, these findings support current recommendations to consider ibrutinib’s potential bleeding risk when assessing it as a treatment option.

This study is the largest to date to investigate major bleeding with ibrutinib in real-world practice. A limitation is that we were unable to obtain CLL characteristics like Rai staging and high-risk genomic features such as the presence of deletion 17p or immunoglobulin heavy-chain gene mutation. However, we included CLL complications that may affect bleeding occurrence (e.g., thrombocytopenia) in the propensity score. Also, though we used a rigorous study design and adjustment method to address confounding, residual differences between ibrutinib- and BR-treated individuals may remain. Additional strengths and limitations are detailed in Supplemental Discussion 3.2–3.3.

Ibrutinib is currently the most commonly used CLL therapy in the United States. Our study found that, though the rate of major bleeding with ibrutinib in a real-world population was comparable to clinical trial populations, an increased rate of clinically-relevant bleeding compared to BR is evident. As the use of 2nd-generation BTK inhibitors increases, clinicians will require information on the real-world risks with individual agents within the therapy class. Furthermore, given the unique antiplatelet mechanism of BTK inhibitors through glycoprotein VI inhibition, research is warranted on their potential protective effect against thrombotic events, especially in patients experiencing BTK inhibitor-related atrial fibrillation. This study will help serve as a benchmark for ibrutinib-related bleeding until such post-market studies among all available BTK inhibitors can be conducted.

DATA AVAILABILITY STATEMENT

The data that support the findings of these studies are available from Optum Inc., but restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available.