12.06.20 Press Release

Combined Data from Multiple Phase 3 Studies of IMBRUVICA® (ibrutinib) Show Efficacy and Safety in High-Risk, Previously Untreated Chronic Lymphocytic Leukemia (CLL) and Real-World Data Indicating Low Biomarker Testing Rates for These Patients

NORTH CHICAGO, Ill., December 6, 2020 – AbbVie (NYSE: ABBV), today announced results from a long-term integrated analysis of two Phase 3 clinical studies and additional pooled analysis evaluating the effect of IMBRUVICA (ibrutinib) based therapies for the first-line treatment of high-risk patients with chronic lymphocytic leukemia (CLL). The totality of data featured at the virtual 2020 American Society of Hematology (ASH) Annual Meeting continues to establish the treatment benefit of IMBRUVICA for CLL patients with or without high-risk disease.

Results from an integrated analysis of two Phase 3 clinical trials (RESONATE-2 and iLLUMINATE) with up to 6.5 years of long-term follow-up investigating the use of IMBRUVICA-based therapies in patients with CLL/small lymphocytic lymphoma (SLL) with first-line treatment showed similar progression-free survival (PFS) and overall response rates (ORR) in patients with or without high-risk genomic features (Abstract #2220).1

"We’re excited to present long-term follow-up results at the ASH congress across multiple studies, including our pivotal Phase 3 clinical trials RESONATE-2 and iLLUMINATE, which showed continued PFS and ORR benefits across high-risk patients with previously untreated CLL,” said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company.

Additionally, a pooled analysis across four clinical trials with up to 8 years of follow-up, including three Phase 3 studies (RESONATE-2, iLLUMINATE,  E1912), and the Phase 2 PCYC-1122e study - sponsored by the National Heart, Lung, and Blood Institute (NHLBI) - showed that first-line treatment with IMBRUVICA-based therapies resulted in sustained, long-term efficacy with high 4-year PFS rates in high-risk CLL patients, defined as del(17p) or TP53 gene mutations (Abstract 2219).2

“The presence of del(17p) or TP53 gene mutation is a strong negative predictor of survival in patients with CLL, and testing for these markers is important so patients receive optimal therapy,” said John Allan, M.D., assistant professor of medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and principal study investigator of the pooled analysis. “Although these patients remain at risk for disease progression, first-line treatment with ibrutinib based therapy may meaningfully improve the poor prognosis in this high-risk population.”

The informCLL™ real-world prospective observational registry assessing treatment patterns will be featured in an oral presentation. Data from this real-world evidence study showed low testing rates for prognostic and biomarker features among patients with CLL.3 Further, when biomarker testing was performed, the selection of chemo-immunotherapy (CIT) continued for a considerable proportion of patients with del(17p)/TP53 mutational status, which is inconsistent with current guidelines (Abstract 547).4As well, a retrospective, chart review study of real world patients featured as an oral presentation examined treatment patterns and time to next treatment (TTNT) in patients with CLL. Results showed high-risk patients with CLL treated with IMBRUVICA monotherapy had longer TTNT than those treated with CIT, and that IMBRUVICA therapy showed similar results in high risk and non-high-risk patients (Abstract 372).4


Abstract #2220: Outcomes of First-Line Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and High-Risk Genomic Features With up to 6.5 Years Follow-up: Integrated Analysis of Two Phase 3 Studies (RESONATE-2 and iLLUMINATE)

Poster Presentation: Sunday, December 6, 2020 at 7:00 a.m. PST

Data were presented from an integrated analysis of two Phase 3 studies evaluating IMBRUVICA-based therapy in the first-line treatment of CLL/SLL (RESONATE-2 and iLLUMINATE) to better understand outcomes in patients with various high-risk genomic features, including integrated fluorescence in situ hybridization (FISH) cytogenetics and single gene mutations.

In RESONATE-2 (NCT01722487), patients aged ≥65 years without del(17p) were randomized to single-agent IMBRUVICA or chlorambucil. In iLLUMINATE (NCT02264574), patients aged ≥65 years, or <65 years with coexisting conditions or del(17p)/TP53 mutation, were randomized to IMBRUVICA plus obinutuzumab or chlorambucil plus obinutuzumab. The integrated analysis included 498 patients treated with first-line IMBRUVICA -based or chlorambucil-based therapy (n=249 each) with a median follow-up of 49.1 months. At 42 months, PFS rates were higher across high-risk genomic subgroups in patients treated with IMBRUVICA (63 to 82 percent) compared to those receiving chlorambucil with or without obinutuzumab (6 to 34 percent), and consistent PFS benefit with IMBRUVICA was observed across all high-risk genomic subgroups.1 When comparing IMBRUVICA-treated patients with specific high-risk genomic features versus those without, results showed that PFS and ORR were comparable in the different subgroups, including patients with unmutated versus mutated immunoglobin heavy chain variable (IGHV) (PFS Hazard Ratio [HR], 1.79, 95% Confidence Interval [CI] 0.99-3.24) or mutated versus not mutated NOTCH1 (PFS HR, 1.05, 95% CI 0.65-1.69).1 Results also showed improved outcomes for patients with del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category (HR 1.05, 95% CI 0.54-2.04).1,5

At a median duration of IMBRUVICAtreatment of 35.7 to 43.8 months across these high-risk subgroups, there were no meaningful differences in the rates of treatment-emergent AEs of any grade or Grade 3 or higher AEs compared to those of the overall population.1


Abstract #2219: Long-Term Efficacy of First-Line Ibrutinib Treatment for Chronic Lymphocytic Leukemia (CLL) With 4 Years of Follow-Up in Patients With TP53 Aberrations (del(17p) or TP53 mutation): a Pooled Analysis from 4 Clinical Trials

Poster Presentation: Sunday, December 6, 2020 at 7:00 a.m. PST

A pooled analysis of data across four studies to evaluate the long-term efficacy and safety of first-line IMBRUVICA-based therapy in patients with CLL bearing TP53 aberrations were presented. Eighty-nine patients with TP53 aberrations receiving first-line IMBRUVICA treatment were included in this pooled analysis. Median age was 65 years, and 69 percent of patients were male. Forty-five patients received IMBRUVICA as a single agent and 44 patients received IMBRUVICA in combination with an anti-CD20 agent.2

At 48 months, the PFS rate was 79 percent among these high-risk patients treated with IMBRUVICA-based therapy.2 Median duration of IMBRUVICA treatment was 46 months. With a median follow-up of 50 months, median PFS was not reached (95% CI: 67 months to not estimable).2

At the current follow-up, 46 percent of patients with TP53 aberrations remained on IMBRUVICA treatment. Reasons for treatment discontinuation were progressive disease (20 percent), study closure (12 percent), adverse events (AEs; 10 percent), withdrawal by patient (7 percent), death (3 percent), and other (1 percent).2

Grade 3 or greater AEs of clinical interest with up to 8 years of treatment with IMBRUVICAwere infection (22 percent), most commonly pneumonia (7 percent); hypertension (13 percent), atrial fibrillation (12 percent), and major hemorrhage (7 percent).2


Abstract #547: Real-World Prognostic Biomarker Testing, Treatment Patterns, and Dosing Among 1,461 Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) from the informCLL™ Prospective Observational Registry

Oral Presentation: Monday, December 7, 2020 at 8:15 a.m. PST

Results from the informCLL™ real-world prospective observational registry assessing treatment patterns in the era of novel agents were presented in an oral session.

The registry fully enrolled with 1,461 patients, of whom 855 (59 percent) were previously untreated and 606 (41 percent) were relapsed/refractory.4 Community-based practices enrolled 93 percent of the patients.4 Patient demographics include a median age of 71 years; majority were male (64 percent), and 88 percent had an ECOG performance statue of 0/1.4 Median follow-up for previously untreated patients was 14.9 months and 15.3 months for relapsed/refractory patients.4

Results showed the most common index treatment was IMBRUVICA; and CIT was the next most widely used treatment regimen for one-third of patients.4 Data also showed that prognostic biomarker testing rates were poor, especially for TP53 and IGHV mutational status.4 Data from the informCLL study also indicates a ‘knowledge gap’ in terms of importance of prognostic marker testing and appropriate selection of therapies for patients with high-risk disease.4


Abstract #372: Clinical Outcomes Among Real-World Patients with Chronic Lymphocytic Leukemia (CLL) Initiating First-Line Ibrutinib or Chemoimmunotherapy (CIT) Stratified by Risk Status: Results from a US Retrospective Chart Review Study

Oral Presentation: Sunday, December 6, 2020 at 10:00 a.m. PST

Results from a retrospective study comparing clinical outcomes in high-risk and non-high-risk patients with CLL receiving IMBRUVICA compared to those receiving chemoimmunotherapy (CIT) as first-line therapy were presented.

The analysis was performed by evaluating medical records from more than 40 U.S. clinical practices, included 271 patients with high-risk disease and 245 patients with non-high-risk CLL.3 Baseline demographics and clinical characteristics were balanced within each pair of comparison groups.3 The median (range) follow-up for high-risk patients treated with IMBRUVICA compared to CIT was 33.3 versus 35.3 months, respectively.3Additionally, the median (range) duration of first-line therapy for patients treated with IMBRUVICA was 28.6 months compared to 5.5 months for patients treated with CIT.3

The weighted analysis showed that high-risk patients treated with IMBRUVICA had significantly longer median TTNT and were 54 percent less likely to start a new treatment compared to high-risk patients treated with CIT (HR [95% CI]: 0.46 [0.34-0.62], p<0.01).3 During the available follow-up, more weighted high-risk patients treated with IMBRUVICA had only one line of treatment compared to weighted high-risk patients treated with CIT (74.7% vs 47.2%, respectively); more non-high-risk CIT patients had only one line of treatment compared to high-risk CIT patients (69.9% vs 45.8%, respectively); and more non-high-risk IMBRUVICA patients had only one line of treatment compared to high-risk IMBRUVICA patients (91.5% vs 81.7%, respectively).

Additionally, the majority of patients received a small molecular inhibitor therapy as second-line treatment. The most common second-line agents were IMBRUVICA monotherapy in the CIT groups (high-risk: 86.5%; non-HR: 83.7%) and venetoclax in the patients treated with first-line IMBRUVICA, either as monotherapy (high-risk: 37.5%; non-high-risk: 28.6%) or in combination with rituximab (high-risk: 28.1%; non-high-risk: 28.6%).

Results from the Kaplan-Meyer analysis showed that weighted high-risk IMBRUVICA patients had significantly longer median TTNT and were 54 percent less likely to start a new treatment compared to high-risk CIT patients (HR 95% CI: 0.46 [0.34-0.62]; p<0.01). For the high-risk patients receiving CIT versus non-high-risk patients receiving CIT, high-risk patients had a significantly shorter median TTNT and were 2.43 times more likely to start a new treatment (HR [95% CI]: 2.43 [1.58-3.47]; p<0.01).3 No significant differences were noted in TTNT between high-risk and non-high-risk groups receiving IMBRUVICA, with median TTNT not reached (HR [95% CI]: 2.2 [0.96-4.96]; p=0.06).3

About IMBRUVICA

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton's tyrosine kinase (BTK). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.6,7 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.8

Since its launch in 2013, IMBRUVICA has received 11 FDA approvals across six disease areas:

chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.9

IMBRUVICA is now approved in more than 100 countries and has been used to treat more than 200,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

In early 2019, the National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL. In February 2020, the NCCN Guidelines® were updated to elevate IMBRUVICA with or without rituximab from other recommended regimens to a preferred regimen for the treatment of relapsed/refractory MCL. In September 2020, the NCCN guidelines were updated to elevate IMBRUVICA with or without rituximab as the only Category 1 preferred regimen for treatment-naïve WM patients.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 10 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

What is IMBRUVICA® (ibrutinib)?

IMBRUVICA® (ibrutinib) is a prescription medicine used to treat adults with:

  • Mantle cell lymphoma (MCL) who have received at least one prior treatment
  • 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 a medicine by mouth or injection (systemic therapy) and have received a certain type of prior treatment
  • Chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy

It is not known if IMBRUVICA® is safe and effective in children.

Important Side Effect Information

Before taking IMBRUVICA®, tell your healthcare provider about all of your medical conditions, including if you:

  • have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA® for any planned medical, surgical, or dental procedure.
  • have bleeding problems.
  • have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes.
  • have an infection.
  • have liver problems.
  • are pregnant or plan to become pregnant. IMBRUVICA® can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA®. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA®.
    • Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA® and for 1 month after the last dose.
    • Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA®and for 1 month after the last dose.
  • are breastfeeding or plan to breastfeed.Do not breastfeed during treatment with IMBRUVICA® and for 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA® with certain other medicines may affect how IMBRUVICA® works and can cause side effects.

How should I take IMBRUVICA®?

  • Take IMBRUVICA® exactly as your healthcare provider tells you to take it.
  • Take IMBRUVICA® 1 time a day.
  • Swallow IMBRUVICA® capsules or tablets whole with a glass of water.
  • Do not open, break or chew IMBRUVICA® capsules.
  • Do not cut, crush or chew IMBRUVICA® tablets.
  • Take IMBRUVICA® at about the same time each day.
  • If you miss a dose of IMBRUVICA® take it as soon as you remember on the same day. Take your next dose of IMBRUVICA® at your regular time on the next day. Do not take extra doses of IMBRUVICA® to make up for a missed dose.
  • If you take too much IMBRUVICA® call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking IMBRUVICA®?

  • You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA®. These products may increase the amount of IMBRUVICA® in your blood.

What are the possible side effects of IMBRUVICA®?

IMBRUVICA® may cause serious side effects, including:

  • Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA®, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache. 
  • Infections can happen during treatment with IMBRUVICA®.  These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA®.
  • Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA®, but can also be severe.  Your healthcare provider should do monthly blood tests to check your blood counts.
  • Heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter). Serious heart rhythm problems and death have happened in people treated with IMBRUVICA®, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint.  If you develop any of these symptoms, your healthcare provider may do a test to check your heart (ECG) and may change your IMBRUVICA® dose.
  • High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA®. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
  • Second primary cancers. New cancers have happened during treatment with IMBRUVICA®, including cancers of the skin or other organs.
  • Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.

The most common side effects of IMBRUVICA® in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:

  • diarrhea
  • tiredness
  • muscle and bone pain
  • rash
  • bruising

 

The most common side effects of IMBRUVICA® in adults with cGVHD include:

  • tiredness
  • bruising
  • diarrhea
  • mouth sores (stomatitis)
  • muscle spasms
  • ·nausea
  • pneumonia

Diarrhea is a common side effect in people who take IMBRUVICA®. Drink plenty of fluids during treatment with IMBRUVICA® to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.

These are not all the possible side effects of IMBRUVICA®. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of IMBRUVICA®

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA® for a condition for which it was not prescribed. Do not give IMBRUVICA® to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA® that is written for health professionals.

Please click here forfullPrescribingInformation.

About AbbVie in Oncology

At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit http://www.abbvie.com/oncology

About AbbVie

AbbVie is a global, research and development-based biopharmaceutical company committed to developing innovative advanced therapies for some of the world’s most complex and critical conditions. The company’s mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, FacebookLinkedIn or Instagram.


Forward-Looking Statements

Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words “believe,” “expect,” “anticipate,” “project” and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, “Risk Factors,” in AbbVie's 2015 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

Dr. John Allan has been a paid speaker and advisory board member for AbbVie, and a paid speaker for Janssen Pharmaceutical Company and Pharmacyclics.

Contacts:

Media
Eric Anderson
Phone: 650-788-7327

Investors 
Liz Shea
Phone: 847-935-2211

Physicians
U.S. Medical Information
Phone: 877-877-3536

Dr. John Allan has been a paid speaker and advisory board member for AbbVie, and a paid speaker for Janssen Pharmaceutical Company and Pharmacyclics.

IMBRUVICA is a registered trademark of Pharmacyclics LLC.

SOURCE AbbVie Inc.

 

1. Burger JA. et al. Outcomes of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and high-risk genomic features with up to 6.5 years follow-up: integrated analysis of two phase 3 studies (RESONATE-2 and iLLUMINATE). 2020 American Society of Hematology Annual Meeting. December 2020.

2. Allan JN. et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del(17p) or TP53 mutation): a pooled analysis from 4 clinical trials. 2020 American Society of Hematology Annual Meeting. December 2020.

3. Mato A. et al. Real-world prognostic biomarker testing, treatment patterns and dosing among 1461 patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the informCLL™ prospective observational registry. 2020American Society of Hematology Annual Meeting. December 2020.

4. Huang Q. et al. Clinical outcomes among real-world patients with chronic lymphocytic leukemia (CLL) initiating first-line ibrutinib or chemoimmunotherapy stratified by risk status: results from a US retrospective chart review study. 2020 American Society of Hematology Annual Meeting. December 2020.

5. Rossi, D. et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121(8):1403–1412.

6. Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed January 2020.

7. Turetsky, et al. Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor. Scientific Reports. volume 4, Article number: 4782 (2014).

8. de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.

9. IMBRUVICA U.S. Prescribing Information, April 2020.