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RESONATE™-2: superior overall survival and progression-free survival VS CHLORAMBUCIL1

RESONATE™- 2 Study Design1,3

Phase 3, multicenter, open-label trial of 1L CLL/SLL patients (N=269) ≥65 years of age who were randomized 1:1 to IMBRUVICA® 420 mg once daily until disease progression or unacceptable toxicity (n=136) or chlorambucil (n=133) for up to 12 cycles. Patients with del 17p were excluded. The primary endpoint was PFS as assessed by an IRC per iwCLL criteria (primary analysis). OS was a secondary endpoint. Patients with IRC-confirmed disease progression were enrolled in an extension study (long-term follow-up) and second-line treatment per investigator’s choice (including IMBRUVICA® for patients progressing on chlorambucil). 

Primary Analysis

95% Overall Survival

Estimated 2-year OS rate with IMBRUVICA® 
(95% CI: 89, 97) vs 84% with chlorambucil
(95% CI: 77, 90)

  • Median follow-up of 28.1 months, HR=0.44 (95% CI: 0.21, 0.92) (secondary endpoint)1
  • 41% of chlorambucil-treated patients crossed over to IMBRUVICA® upon disease progression
90% Progression-Free Survival

Estimated PFS rate with IMBRUVICA®
at 18 months vs 52% with chlorambucil

  • Median follow-up of 18.4 months, HR=0.16 [95% CI: 0.09, 0.28]; P<0.0001) (IRC-assessed primary endpoint)1-3
  • Median PFS with IMBRUVICA® was not estimable vs 18.9 months (95% CI: 14.1, 22.0) with chlorambucil

5+ Years: long-term follow up

Long-term analysis: median follow-up of 60 months (range, 0.1-66)4

83% Overall Survival

Estimated 5-year OS rate with IMBRUVICA®
(95% CI: 75, 88) vs 68% with chlorambucil
(95% CI: 58, 75) 2,4,5


Estimated 5-year OS rate 83% with IMBRUVICA® 68% with chlorambucil
  • At 5 years, median OS was not reached for either the IMBRUVICA® or chlorambucil arms
  • In the chlorambucil arm, 57% (n=76) crossed over to IMBRUVICA®
70% Progression-Free Survival

Estimated 5-year PFS rate with IMBRUVICA®
(95% CI: 61, 78) vs 12% with chlorambucil
(95% CI: 6, 20) (investigator-assessed) 2,4

Estimated 5-year PFS rate 70% with IMBRUVICA® vs 12% with chlorambucil
  • At 5 years, median PFS with IMBRUVICA® was not reached vs 15.0 months (95% CI: 10.2, 19.4) with chlorambucil

5-year RESONATE™-2 long-term efficacy results are not included in the Prescribing Information for IMBRUVICA®. The timing for long-term follow-up was not prespecified and the analysis was descriptive in nature.

1L=frontline, CI=confidence interval, CLL=chronic lymphocytic leukemia, HR=hazard ratio, IRC=independent review committee, iwCLL=International Workshop on Chronic Lymphocytic Leukemia, OS=overall survival, PFS=progression-free survival, SLL=small lymphocytic lymphoma. 


  1. IMBRUVICA® (ibrutinib) Prescribing Information.
  2. Data on file.
  3. Burger JA, Tedeschi A, Barr PM, et al.; for the RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. 
  4. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. 
  5. Tedeschi A, Burger J, Barr PM, et al. Five-year follow-up of patients receiving ibrutinib for first-line treatment of chronic lymphocytic leukemia. Presented at: 24th Congress of The European Hematology Association (EHA); June 13–16, 2019; Amsterdam, The Netherlands. 


Warnings and Precautions

Hemorrhage: Fatal bleeding events have occurred in patients who received IMBRUVICA®. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA® in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA®, respectively.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA® increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. 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 the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients who received IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: In 645 patients with B-cell malignancies who received IMBRUVICA® as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 3%, based on laboratory measurements.

Monitor complete blood counts monthly.

Cardiac Arrhythmias and Cardiac Failure: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA®. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4%, and Grade 3 or greater cardiac failure occurred in 1% of 1,476 patients who received IMBRUVICA® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

At baseline and then periodically, monitor patients clinically for cardiac arrhythmias and cardiac failure. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias and cardiac failure appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.

Hypertension: Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA® and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate.

Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (4%), occurred among the 1,476 patients who received IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA®. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.  

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA® and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.


B-cell malignancies: The most common adverse reactions (≥30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (54.5%)*, diarrhea (43.8%), fatigue (39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%)*, rash (35.8%), anemia (35.0%)*, and bruising (32.0%).

The most common Grade ≥ 3 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (20.7%)*, thrombocytopenia (13.6%)*, pneumonia (8.2%), and hypertension (8.0%).

Approximately 9% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.


CYP3A Inhibitors: Co-administration of IMBRUVICA® with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA® may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA® if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.3 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.


Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA® dose and monitor more frequently for adverse reactions of IMBRUVICA®.

Please see full Prescribing Information.



IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with:

  • Mantle cell lymphoma (MCL) who have received at least one prior therapy.
    • This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.

  • Waldenström's macroglobulinemia (WM).
  • Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.
    • This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.