Written by: Tammy McClellan, PharmD
The purpose of this PQI is to expand on therapy management of ibrutinib (Imbruvica®) when used in combination with obinutuzumab (Gazyva®).
This latest FDA approval extends the indications for Ibrutinib; already approved as a single agent OR in combination with bendamustine and rituximab. Ibrutinib is indicated for Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) at doses of 560 mg daily. Ibrutinib is also indicated for Waldenstrom’s Macroglobulinemia (WM), chronic Graft versus Host disease (cGVHD) and CLL/SLL at doses of 420 mg daily.
Ibrutinib in combination with Obinutuzumab has been approved for adult patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This latest indication is the first non-chemotherapy option for treatment naïve patients diagnosed with CLL/SLL, which may further help reduce the need for chemotherapy. As an oral and IV combination therapy, coordination of the medically integrated pharmacy team is critical.
The Illuminate Trial:4
Results: Ibrutinib and Obinutuzumab is a proven efficacious, first-line, non-chemotherapy regimen in CLL/SLL patients regardless of age or disease status. The median follow-up was 31.3 months and the most common grade 3 or 4 adverse effect was neutropenia and thrombocytopenia. After a median follow-up of 31.3 months (IQR 29.4–33.2), median progression-free survival was significantly longer in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33.6–non-estimable]) than in the chlorambucil plus obinutuzumab group (19.0 months [15.1–22.1]; hazard ratio 0.23; 95% CI 0.15–0.37; p<0.0001). Estimated 30-month progression-free survival was 79% (95% CI 70–85) in the ibrutinib plus obinutuzumab group and 31% (23–40) in the chlorambucil plus obinutuzumab group.
Upon receiving a new prescription for Ibrutinib for specific use in combination with obinutuzumab
- Verify an Established CLL/SLL diagnosis (independent of patient’s del(17p) status, comorbidities and age) in the treatment naive patient and relevant dosing.
- Assess patients risk for Tumor Lysis Syndrome (laboratory abnormalities of potassium, uric acid, phosphate, serum creatinine) which commonly occurs during the first cycle.
- Ibrutinib 420 mg Daily with:
- Obinutuzumab 100 mg on Day 1
- then Obinutuzumab 900 mg on Day 2
- then Obinutuzumab 1000 mg on Day 8 and Day 15 every 28 days for 1 Cycle
- Followed by Ibrutinib 420 mg Daily with:
- Obinutuzumab 1000 mg on Day 1 every 28 Days for 5 Cycles
- Ibrutinib 420 mg Daily with:
- When administering Ibrutinib in combination with Obinutuzumab, consider administering Ibrutinib prior to Obinutuzumab when given on the same day.
- Consider if a dose modification for ibrutinib is warranted (hypertension, dermatologic toxicities, risk of bleeding, hepatic impairment, fluid retention, cardiac arrhythmias or abnormalities).
PQI Process continued:
- Verify scheduling of premedications for Obinutuzumab:
- Acetaminophen 650 mg – 1000 mg at least 30 minutes prior
- Antihistamine (example: Diphenhydramine 50 mg at least 30 minutes prior)
- IV glucocorticoid (example: Dexamethasone 20 mg, methylprednisolone 80 mg) at least 60 minutes prior
- Review standard laboratory findings (CBC, CMP, Hepatitis, LDH, and Quantitative Immunoglobulins) monthly and as indicated.
- Verify recommended antiviral (herpes and varicella virus) and pneumocystis prophylaxis are initiated. Consider antibacterial and antifungal prophylaxis for at risk patients.
- Confirm baseline EKG has been obtained.
Patient Centered Activities:
- Provide ibrutinib Oncology Chemotherapy Education (OCE) sheet
- Counsel patient on disease state, treatment regimen, what to expect (ex. fatigue) and verify patient understanding.
- Ibrutinib should be taken at the same time each day with a glass of water and always prior to Obinutuzumab.
- Swallow medication whole. Avoid grapefruit products and Seville oranges.
- Advise patient to take a missed dose as soon as possible on the same day and to resume normal dosing schedule for the next day.
Ibrutinib has been deemed first-line therapy for CLL/SLL patients but is also considered as an option for the following populations as well:
- Patients with and without del(17p)/TP53 mutation who are:
- 64 years old and younger without significant comorbidities
- 65 years old and older with significant comorbidities
- IMBRUVICA (Package Insert). Pharmacyclics LLC in conjunction with Janssen Biotech INC, Sunnyvale, CA; 2019. Assessed at: https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing-information.pdf
- Gazyva (Package Insert). Genetech, South San Fransico, CA; 2019. Assessed at: https://www.gene.com/download/pdf/gazyva_prescribing.pdf
- Micromedex Online, Ann Arbor, MI: IBM Watson Health, Inc.; updated 6/18/19; accessed 6/18/19. https://www.micromedexsolutions.com/micromedex2/librarian/
- Moreno C, Greil R, Demirkan F, et al: Ibrutunib plus Obintuzumab versus Chlorambucil plus Obintuzumab in first-line treatment of chronic lymphocytic leukemia (ILLUMINATE): A multicenter, randomized, open-label, phase 3 trial. Lancet Oncol 20:43-56,2019.
- U.S National Library of Medicine (clinicaltrials.gov). Ibrutunib in Treating patients with Relapsed Hairy Cell Leukemia. Assessed at: https://clinicaltrials.gov/ct2/show/NCT01841723. 6-28-19
- Younes A, Sehn LH, Johnson P, et al. Randomized phase III trial of Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma [published online March 22, 2019]. J Clin Oncol. Doi:10.1200/jco.18.02403
- Cancer Therapy Advisor Online, New York, NY: Haymarket Media, Inc.; Revised 11/2016; accessed 8/19/19. https://www.cancertherapyadvisor.com/home/cancer-topics/hematologic-cancers/chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-cll-sll/?utm_source=newsletter&utm_medium=email&utm_campaign=cta-spotlight-
- Cancer Therapy Advisor Online, New York, NY: Haymarket Media, Inc.; Published August 6, 2019; accessed 8/19/19. Use of MRD status following Obinutuzumab/Ibrutinib therapy to Guide in Subsequent Therapy Selection in CLL. https://www.cancertherapyadvisor.com/home/cancer-topics/chronic-lymphocytic-leukemia/chronic-leukemia-cll-obinutuzumab-ibrutinib-mrd-status-guide-treatment
- Targeted Oncology. Ibrutinib Plus Obinutuzumab Approved by FDA as Frontline CLL/SLL Treatment. Assessed at: https://www.targetedonc.com/news/ibrutinib-plus-obinutuzumab-approved-by-fda-as-frontline-cllsll-treatment. 8-19-19