Dose modifications can help optimize patient management to enable continued treatment when appropriate

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DOSE MODIFICATIONS
GUIDANCE
AE OUTCOMES IN POOLED
ANALYSIS
LONG-TERM FOLLOW-UP
DOSE MODIFICATION DATA
ADDITIONAL MEDIAN
TREATMENT DURATION DATA
RELATED RESOURCES

Dose modifications for adverse reactions1*

If an adverse reaction (AR) listed here occurs, interrupt IMBRUVICA® therapy at each occurrence of the same AR.
Once the AR has improved to Grade 1 or baseline, follow the recommended dose modifications.1

IMBRUVICA® (ibrutinib) dose modification chart based on adverse reactions for CLL/SLL patients

Certain types and severity of cardiac ARs require discontinuation after first occurrence for only IMBRUVICA®.

†See full Prescribing Information for Warnings and Precautions.

‡Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematological toxicities in CLL/SLL.

§Evaluate the benefit-risk before resuming treatment.

For Grade 4 non-hematological toxicities, evaluate the benefit-risk before resuming treatment.

For use with CYP3A inhibitors and inducers, and in patients with hepatic impairment, please see the full Prescribing Information. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA®. Monitor for signs and symptoms of bleeding. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and risk of bleeding.

Eddie discussed his side effects with his doctor, who decided to reduce his dose.
We were able 
to reduce my dosage...and it helped with my side effects.”
Eddie, an IMBRUVICA® patient living with CLL
Patient experiences may vary.

Starting & staying on IMBRUVICA® when appropriate

Click below to watch a video including IMBRUVICA® dosing guidance, dose modifications for ARs, and data, including dose modifications outcomes data.

Discontinuation may be appropriate for some patients.

Dose Modification for ARs Flashcard

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Guidance on ibrutinib (IMBRUVICA®) Dose Modifications* for Certain ARs2

In patients with no intolerance, cBTKi can be continued until disease progression, while following recommended dose modification guidance as needed

See NCCN Guidelines® for the complete list of recommendations.

What does this guidance mean for IMBRUVICA®?

  • NCCN Guidelines recommend continuation of the same cBTKi until progression and/or intolerance2
  • Ibrutinib (IMBRUVICA®) is the only cBTKi with recommended dose reductions for select ARs* after first occurrence for appropriate patients1
  • Ibrutinib (IMBRUVICA®) has exploratory outcomes data in patients following dose modification in 1L CLL3

Certain types and severity of cardiac ARs require discontinuation after first occurrence for only IMBRUVICA®.

NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.1.2025. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 1, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org

Dose modifications were designed to help manage ARs1

Initial dose modifications for pooled IMBRUVICA®-treated patients (cardiac and non-cardiac related)4

Study Designs

  • This analysis pooled data from the IMBRUVICA® arm of two multicenter studies of patients with treatment-naïve CLL/SLL. RESONATE™-2 included 136 patients who were 65 years or older and received single-agent IMBRUVICA®. iLLUMINATE™ included 113 patients who were 65 years or older or with coexisting medical conditions and received IMBRUVICA® in combination with obinutuzumab1
  • Median (range) follow-up times varied between studies as follows: 86 months (0-97) for RESONATE™-2 and 43 months (0-52) for iLLUMINATE™. Median follow-up was 41 months (range, 0-97 months) for the overall pool4
  • Dose modifications were defined in the study protocol; presented with outcomes are only those modified according to current recommendations

Pooled IMBRUVICA®-treated patients: N=248

Patients with any AE leading to a dose reduction per protocol = 48 (19%)

Dose modifications were per USPI and per study protocol.

Patients with an AE leading
to dose reduction per USPI*
21/248 (9%)

AE recurrence

  • No recurrence or recurred at lower grade: 16/21 (76%)
  • Recurred at the same or higher grade: 5/21 (24%)

Recurrence can take place after AE resolution.

Of the 21 patients who required a dose reduction†‡§

Initial AE resolution:

for pooled IMBRUVICA®-treated patients

95%
20/21

Initial AE that led to a dose modification was resolved in 95% of patients

Timing of AE outcomes was not part of the evaluation.

In patients who both did and did not dose modify over the entire course of the long-term follow-up phase 3 trials

22.9%
57/249

22.9% of patients discontinued IMBRUVICA® due to AEs5

Timing of AE outcomes, including resolution, recurrence, and discontinuation was not part of the evaluation. Dose modifications include a dose hold, followed by a dose reduction.

Results from this analysis are descriptive in nature and have no implications regarding efficacy.
These pooled analysis results are not included in the Prescribing Information for IMBRUVICA®.

From the USPI

  • Adverse reactions leading to dose reduction occurred in approximately 9% of patients
  • 4% to 10% of patients with CLL/SLL receiving IMBRUVICA® discontinued treatment due to adverse reactions

AEs for which dose reductions are recommended in the USPI (grade 2 cardiac failure, grade 3 cardiac arrhythmia, grade 3-4 non-hematological AEs [excluding cardiac failure and cardiac arrhythmia], grade 3-4 neutropenia with infection or fever, and grade 4 hematological AEs).

†The denominator is patients with AEs for which dose reductions are recommended in the IMBRUVICA® USPI.

‡Two patients had two different AESIs that led to dose reduction; for one patient, neither recurred, and for the other patient, one did not recur and the other (rash maculo-papular) recurred at a lower grade.

§Five patients had AEs that recurred at the same grade (grade 3 atrial fibrillation [n=1], grade 3 diarrhea [n=1], grade 3 headache [n=1], grade 4 neutropenia [n=1], and grade 3 pleural effusion [n=1]); all resolved without further dose reduction.

RESONATE™-2 long-term analysis: Dose modifications can help manage ARs so appropriate patients can continue to benefit1

RESONATE™-2 exploratory post hoc analysis:
PFS in IMBRUVICA®-treated patients with or without dose modifications due to AEs3

IMBRUVICA® (ibrutinib) RESONATE™-2 PFS graph in CLL patients with and without dose modifications

This exploratory analysis evaluated baseline demographics and clinical outcomes (PFS) in subgroups of patients with and without dose reductions due to AEs from the overall population of IMBRUVICA®-treated CLL patients.

Study Context

  • The median time to first dose reduction was 23.7 months (range, 1.6-78.4)6
  • Median PFS for IMBRUVICA®-treated patients with dose reductions was 87.7 months (95% CI: 56.9-NE) and was not reached (95% CI: 81.9-NE) for those without dose reductions3
  • Median follow-up was 82.7 months (range, 0.1-96.6 months). Results from the tail end of the Kaplan-Meier curve should be interpreted with caution due to low number of patients at risk3
  • AEs led to dose reductions in 23% (31/135) of all patients treated with IMBRUVICA®3
  • The median duration of IMBRUVICA® treatment was 74 months (range, 0.7-96.6 months)7
  • Results are based on a starting dosage of IMBRUVICA® 420 mg once daily. Kaplan-Meier curves ≥7.5 years have a limited sample size, potentially impacting PFS estimates​3
  • Subgroups of patients with and without dose modifications were not stratified for any baseline characteristics. Imbalances in baseline characteristics may exist between these groups3
  • Outcomes in the subgroup of patients with and without dose reductions in the overall population of all IMBRUVICA®-treated patients from RESONATE™-2 are from exploratory post hoc analyses and were not powered for significance; comparative statistics are provided for descriptive purposes only3
  • Dose modifications for any reason were per protocol based on the discretion of the physician3

8-year RESONATE™-2 long-term dosing results are not included in the Prescribing Information for IMBRUVICA®.

RESONATE™-2 8-year data: Dose modifications for ARs

Median overall treatment duration in RESONATE™-27

74
MONTHS

The median duration of IMBRUVICA® treatment was 74 months (range, 0.7-96.6 months; n=135)7

Median treatment duration following dose modifications3

36
MONTHS

In a subset of patients who had dose reductions due to adverse reactions (n=31), the median duration of treatment with IMBRUVICA® after the dose modification was 36.1 months (range, 0.0-84+ months)3*

Study Context

  • These data are descriptive in nature only and have no implications regarding efficacy or safety
  • Dose modifications were defined in the study protocol; patients may not have undergone ibrutinib dose reduction according to current recommendations
  • The data described below reflect exposure to IMBRUVICA® in one single-arm, open-label clinical trial (Study 1102) and 5 randomized controlled clinical trials (RESONATE™, RESONATE™-2, HELIOS, iLLUMINATE™, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA®)1
  • 4%-10% of patients with CLL/SLL receiving IMBRUVICA® discontinued treatment due to ARs. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia, arthralgia, rash, and thrombocytopenia. ARs leading to ibrutinib dose reduction occurred in approximately 9% of patients1

Duration of dose reduction to study drug discontinuation was calculated from first date of the earliest dose reduction to study drug discontinuation.3

Related resources

Abbreviations

AE=adverse event, AR=adverse reaction, cBTKi=covalent Bruton's tyrosine kinase inhibitor, CI=confidence interval, CLL=chronic lymphocytic leukemia, FDA=US Food and Drug Administration, HR=hazard ratio, SLL=small lymphocytic lymphoma.

References

1. IMBRUVICA® (ibrutinib) Prescribing Information. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.1.2025. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 1, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Woyach JA, Barr PM, Kipps TJ, et al. Characteristics and clinical outcomes of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma receiving ibrutinib for 5 years in the RESONATE-2 Study. Cancers (Basel). 2023;15(2):507. 4. Ghia P, Owen C, Barrientos JC, et al. Initiating first-line ibrutinib in patients with chronic lymphocytic leukemia improves overall survival outcomes to rates approximating an age-matched population of ≥65 years. Poster presented at: 64th Annual Meeting of the American Society of Hematology; December 10-13, 2022; New Orleans, LA. 5. Data on file ABVRRTI75538 6. Data on file ABVRRTI76430 7. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450.