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NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®) RECOMMENDATIONS FOR THE USE OF IBRUTINIB (IMBRUVICA®)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Recommendations

NCCN recommendations for the use of ibrutinib (IMBRUVICA®)

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.4.2020. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed December 20, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. 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.

Ibrutinib (IMBRUVICA®) is the only NCCN Category 1 Preferred Regimen in frontline CLL/SLL*

*As monotherapy for CLL/SLL without del 17p/TP53 mutation.

Frontline

Suggested Treatment Regimens for Frontline Therapy in CLL/SLL without del 17p/TP53 mutation (alphabetical by category)
  Preferred regimens Other recommended regimens
Frail patient with
significant comorbidity
OR Patients age ≥ 65 y and
younger patients with significant comorbidities
(creatinine clearance [CrCI] <70mL/min)

Ibrutinib (IMBRUVICA®) (category 1)
 

Acalabrutinib ± obinutuzumab (category 2A)
 

Venetoclax + obinutuzumab (category 2A)

  • Bendamustine + anti-CD20 monoclonal antibody (category 2A)
  • Chlorambucil + obinutuzumab (category 2A)
  • HDMP + rituximab (category 2B)
  • Ibrutinib + obinutuzumab (category 2B)
  • Obinutuzumab (category 2B)
  • Chlorambucil (category 3)
  • Rituximab (category 3)
Patients age <65 y without significant comorbidities

Ibrutinib (IMBRUVICA®) (category 1)
 

Acalabrutinib ± obinutuzumab (category 2A)
 

Venetoclax + obinutuzumab (category 2A)

  • Bendamustine + anti-CD20 monoclonal antibody (category 2A)
  • FCR (fludarabine, cyclophosphamide, rituximab) (preferred for patients with IGHV-mutated CLL) (category 2A)
  • FR (fludarabine, rituximab) (category 2A)§
  • HDMP + rituximab (category 2B)
  • Ibrutinib + rituximab (category 2B)
  • PCR (pentostatin, cyclophosphamide, rituximab) (category 3)
Suggested Treatment Regimens for Frontline Therapy in CLL/SLL with del 17p/TP53 mutation (alphabetical by category)
  Preferred regimens Other recommended regimens
All patients
  • Acalabrutinib ± obinutuzumab (category 2A)
  • Ibrutinib (IMBRUVICA®) (category 2A)
  • Venetoclax + obinutuzumab (category 2A)
  • Alemtuzumab ± rituximab (category 2A)
  • HDMP + rituximab (category 2A)
  • Obinutuzumab (category 2A)

Relapsed/Refractory

Suggested Treatment Regimens for Relapsed/Refractory Therapy in CLL/SLL without del(17p)/TP53 mutation (alphabetical by category)
  Preferred regimens Other recommended regimens
Frail patient with
significant comorbidity
OR Patients age ≥65 y
and younger patients with
significant comorbidities (creatinine clearance [CrCl] <70 mL/min
  • Acalabrutinib (category 1)
  • Ibrutinib (IMBRUVICA®) (category 1)
  • Venetoclax + rituximab (category 1)
  • Duvelisib (category 2A)
  • Idelalisib + rituximab (category 2A)
  • Alemtuzumab ± rituximab (category 2A)
  • Chlorambucil + rituximab (category 2A)
  • Reduced-dose FCR (category 2A)
  • HDMP + rituximab (category 2A)
  • Idelalisib (category 2A)
  • Lenalidomine ± rituximab (category 2A)
  • Obinutuzumab (category 2A)
  • Ofatumumab (category 2A)
  • Reduced-dose PCR (category 2A)
  • Venetoclax (category 2A)
  • Dose-dense rituximab (category 2B)
  • Bendamustine, rituximab ± ibrutinib, or idelalisib (category 2B for BR and BR + ibrutinib; category 3 for BR + idelalisib)

 

Patients age <65 y
without significant
comorbidities
  • Alemtuzumab ± rituximab (category 2A)
  • Bendamustine + rituximab (category 2A)
  • FC + ofatumumab (category 2A)
  • FCR (category 2A)
  • HDMP + rituximab (category 2A)
  • Idelalisib (category 2A)
  • Lenalidomine ± rituximab (category 2A)
  • Obinutuzumab (category 2A)
  • Ofatumumab (category 2A)
  • PCR (category 2A)
  • Venetoclax (category 2A)
  • Bendamustine, rituximab + ibrutinib (category 2B)
  • Bendamustine, rituximab + idelalisib (category 2B)
Suggested Treatment Regimens for Relapsed/Refractory Therapy in CLL/SLL with del 17p/TP53 mutation (alphabetical by category)
 
  • Acalabrutinib (category 1)
  • Ibrutinib (IMBRUVICA®) (category 1)
  • Venetoclax + rituximab (category 1)
  • Duvelisib (category 2A)
  • Idelalisib + rituximab (category 2A)
  • Venetoclax (category 2A)
  • Alemtuzumab ± rituximab (category 2A)
  • HDMP + rituximab (category 2A)
  • Idelalisib (category 2A)
  • Lenalidomide ± rituximab (category 2A)
  • Ofatumumab (category 2A)

See NCCN Guidelines® for complete list of regimens.

Bendamustine + anti-CD20 monoclonal antibody is not recommended for frail patients.

§

FR is not recommended for CLL with del 11q.

NCCN recommends testing for:

  • FISH for del 17p
  • TP53 mutation status
  • CpG-stimulated karyotype
  • IGHV mutation status||
||

IGHV mutation status evaluation/testing is necessary when considering treatment with chemoimmunotherapy.

NCCN Categories of Evidence and Consensus

  • Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate

  • Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate
  • Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate
  • Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate

NCCN Categories of Preference

  • Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability
  • Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes
  • Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation)

All recommendations in the NCCN Guidelines are considered appropriate.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.4.2020. © 2019 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. 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.

BR=bendamustine and rituximab, CLL=chronic lymphocytic leukemia, CrCl=creatinine clearance, del=deletion, FC=fludarabine and cyclophosphamide, FCR=fludarabine, cyclophosphamide, rituximab, FISH=fluorescence in situ hybridization, FR=fludarabine, rituximab, HDMP=high-dose methylprednisolone, IGHV=immunoglobulin heavy-chain variable region gene, PCR=pentostatin, cyclophosphamide, rituximab, SLL=small lymphocytic lymphoma.

IMPORTANT SAFETY INFORMATION

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, including bruising and petechiae, occurred in 39% of patients who received IMBRUVICA®.

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: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA®. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% 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.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias 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.

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

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.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe baseline 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.

 

INDICATIONS

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.
    • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
  • 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.
    • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

IMPORTANT SAFETY INFORMATION

INDICATIONS