Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options: Lots of Good Stuff on CLL

This Saturday in Manhattan Beach, Lymphoma Research Foundation (LRF) is putting on a patient education meeting.

Try to make it.

Dr. Herb Eradat out of UCLA is doing the CLL breakout session so that session is sure to be great.  He is very sharp, totally dedicated to CLL, and a nice guy too.

Dr. Sven De Vos is chairing the meeting- another good reason to attend. I guarantee you will walk away with valuable information from his sessions.

In fact all the speakers are top notch.

I and other volunteers from the CLL Society will be there to share information about our online services and survey the interest in starting new CLL support and education groups in LA and Ventura Counties.

And it's in a beautiful setting.

And it's free.

More than enough reasons to make the drive.

For more information and to register, please check out: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=9357081#location

The meeting will be at:

Manhattan Beach Marriott
1400 Parkview Avenue
Manhattan Beach, CA 90266

Saturday, April 2, 2016
7:30 AM - 3:30 PM

If you do come, please say hello and drop by our CLL Society table.

So remember:

Smart Patients Get Smart Care™

And join us this Saturday in Manhattan Beach.

Venetoclax in refractory CLL (chronic lymphocytic leukemia) patients with deletion 17p And News about Upcoming Support and Education Opportunities

Friends,

This week in the 2015 Conference Coverage section of the CLLSociety.org we have posted my final interview with Dr. Stephan Stilgenbauer while we were at the American Society of Hematology (ASH) annual meeting in December 2015 in Orlando. We discussed his late breaking abstract on venetoclax in refractory CLL patients with deletion 17p. You can see a summary and view our interview here. [http://cllsociety.org/2016/03/ash-2015-dr-stephan-stilgenbauer-dramatic-responses-venetoclax-relapsed-refractory-rr-17p-deleted-cll/]

Last Saturday, it was my privilege to speak at The Southern California Blood Cancer Conference sponsored by the Leukemia and Lymphoma Society in Anaheim, California on being your own advocate. The CLL Society team was in attendance at our booth and it was great to meet all of you who were there. It was a super meeting.

Our first satellite support and education group launched yesterday at City of Hope, Duarte CA and I believe the 15 patients and caregivers shared and learned together. We will be meeting the third Monday of each month at 7 PM of every month. For more information, view the flyer. [http://www.cllsociety.org/docs/cohmarch2016.pdf] There is no charge to attend.

We are also forming a new patient and caregiver support meeting in Charlotte, NC. If you are interested, please complete the online survey to indicate your preferences for days and times. [https://charlottegroup.questionpro.com/] We look forward to getting started. 

There is another educational meeting coming up, this time by LRF.

April 2^nd at 7:30 AM: The Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options hosted by the Lymphoma Research Foundation will be held in Manhattan Beach, California. It will be held at the Manhattan Beach Marriott from 7:30 AM to 3:30 PM. You can find out more information and register here. [http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=9357081#location] There is no charge to attend.

In the meantime….

Stay strong.

We are all in this together.

Brian Koffman

Volunteer Medical Director of the CLL Society

ASH 2015: Dr. John M Pagel on Idelalisib as Frontline Therapy in CLL (chronic lymphocytic leukemia)

We have just learned of the good news of the broad FDA approval in the USA of ibrutinib in the frontline setting for CLL.  

This step forward in CLL therapy only comes after years of research and is due in no small part to the brave patients who volunteered for these trials including the pivotal RESONATE-2 trial.

As a reminder, ibrutinib is a small molecule taken orally, a tyrosine kinase inhibitor or TKI, that inhibits the BTK pathway that is so important for  B cell communication. By doing so, it blocks a critical pro-survival signal in our CLL cells and helps control our disease. 

I will comment more on the significance of this frontline approval in a coming post, but to give some perspective, I want to reflect on the only other approved oral TKI for CLL, namely idelalisib that inhibits the PI3Kδ pathway. This pathway is also important for B-cell signaling in our CLL cells and blocking it also blocks the same strong survival signal. That is a big part of the reason why both these drugs work as well as they do. 

Researchers want to discover which CLL patient will get the most benefits with the least risks from these new therapies.

At ASH 2015 in December, many researcher were initially surprised by the amount of toxicity discovered when idelalisib was studied frontline or in the treatment-naive CLL population. 

Keep in mind that it is currently only approved for use in combination with rituximab in the relapsed and refractory CLL population, not frontline. This trial was to look at its safety and efficacy in this new setting.

I interviewed Dr. John Pagel of Swedish Hospital in Seattle, WA on the importance of this negative findings.  

It is a truism in science that we often learn as much or more from the trials that don't go as planned as from those that do.

Though most of the research on idelalisib presented at the ASH meeting was positive, the title of this abstract tells us there were significant issues:  Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities.

Three quarters of the patients had grade 3 toxicities or severe problems. For 56% of them this was liver toxicities where the blood tests that measure liver inflammation were 5 to 10 times the upper limit of normal. These are much higher levels than generally seen when idelalisib is used in patients who have had prior treatments.

The good news is that with immune suppressive therapies including steroids, all the patients recovered.

The details of the trial are here.

Why then when ibrutinib is relatively benign in the frontline setting, did a somewhat similar drug have such unexpected problems.

Any drug may have effects on cells that are not their therapeutic target, resulting in unwanted side effects. One theory is that idelalisib lowered the balancing activity of the regulatory T cells or Tregs that are important in preventing auto-immunity. The PI3Kδ pathway is critical to the function not just of CLL cells but of the Tregs too. 

This is why we need to do research. This is why we need to laud the brave subjects who jump into these trials. Without them, we make no progress.

Here is my interview with Dr. Pagel on this subject from ASH 2015.



As Dr. Pagel emphasizes, idelasilib is a powerful drug that helps many patients with CLL. How and when to best use it is a matter of ongoing research.

Stay strong

Brian

This Changes Everything: Approval of Imbruvica (ibrutinib) for Frontline Use in CLL (chronic lymphocytic leukemia)

This is big news in stark contrast to the preliminary NICE recommendation to note approve ibrutininb  for relapsed and refractory patients in the UK despite approval in almost 50 other countries.

Here is one of the many links on this story. Here's another.

On the other side of the ocean in the USA, in stark contrast,  there was good news of FDA frontline approval of ibrutinib. This changes everything. I will comment more on this later.

Here is the official press release from Abbvie for your review and appraisal:

PRESS RELEASE

IMBRUVICA® (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia

         ·  Approval based on data from the Phase 3 RESONATETM-2 trial showing an 84% reduction in the risk of progression or death with IMBRUVICA compared to chlorambucil 


         ·  First FDA-approved chemotherapy-free treatment option for first-line CLL patients 


         ·  This is the 5th treatment indication for IMBRUVICA 
NORTH CHICAGO, Ill., Mar. 4, 2016 – AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) approved IMBRUVICA® (ibrutinib) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).1 The approval is based on data from the randomized, multi-center, open-label Phase 3 RESONATETM-2 (PCYC-1115) trial, which evaluated the use of IMBRUVICA versus chlorambucil in 269 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. The RESONATE-2 data were previously presented at the American Society of Hematology (ASH) Annual Meeting in December 2015 and also simultaneously published in The New England Journal of Medicine. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc. 
“This approval represents a significant leap forward for patients diagnosed with CLL who may want to consider an alternative first-line treatment to traditional chemotherapy,” said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. “AbbVie is committed to making significant improvements in the lives of patients with hematologic malignancies and will continue to explore ways to improve treatment options for patients.” 
The prevalence of CLL is approximately 115,000 patients in the U.S.2 with approximately 15,000 newly diagnosed patients every year.3 CLL is a disease of elderly patients, with an average diagnosis age of 71.3 
The National Comprehensive Cancer Network (NCCN) recently published an update to its clinical practice guidelines for non-Hodgkin’s lymphomas, granting IMBRUVICA a category 1 recommendation for certain CLL patients, the highest recommendation assigned by the organization. Specifically, NCCN recommends IMBRUVICA as a first-line treatment option for frail CLL patients with significant comorbidities, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant comorbidities. The NCCN guidelines inform prescribing and reimbursement practices in many institutions in the U.S. and internationally. 
AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064 


“The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging,” said Dr. Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and the RESONATE-2 lead study investigator.* “This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients.”

IMBRUVICA is now approved to treat CLL patients regardless of their treatment history (treatment-naïve and previously-treated patients). In addition, IMBRUVICA is approved to treat high-risk CLL patients with del 17p,1 a genetic aberration that occurs when part of chromosome 17, the location of the tumor suppressor gene `

IMBRUVICA significantly prolonged progression-free survival (PFS; primary endpoint) as determined by an Independent Review Committee (IRC), reducing the risk of progression or death by 84% versus chlorambucil (hazard ratio [HR], 0.161 [95% confidence interval: 0.091, 0.283]; median PFS: not reached for IMBRUVICA vs. 18.9 months [95% confidence interval: 14.1, 22.0] for chlorambucil).1 IMBRUVICA was also associated with a significantly higher IRC-assessed overall response rate (ORR: a composite of complete and partial responses; 82.4% vs. 35.3%; P<0 .0001="" chlorambucil.="" span="" versus="">1 Five patients (3.7 percent) in the IMBRUVICA arm achieved a complete response, compared to two patients (1.5 percent) in the chlorambucil arm.1

The safety of IMBRUVICA in this patient population was consistent with previously reported studies. The adverse reactions (AR) reported in the U.S. Prescribing Information reflect exposure to IMBRUVICA with a median duration of 17.4 months versus a median exposure to chlorambucil of 7.1 months: nearly 2.5 times longer exposure for IMBRUVICA. Warnings and Precautions include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, embryo-fetal toxicity and tumor lysis syndrome. The most commonly occurring adverse reactions of all Grades in CLL patients treated with IMBRUVICA in the RESONATE-2 trial (>20%) were diarrhea, musculoskeletal pain, cough and rash.

Please see the Important Safety Information section below.

About the RESONATE-2 Study

RESONATE-2 is a Pharmacyclics-sponsored study which enrolled 269 treatment-naïve patients with CLL or SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The primary endpoint of the study was PFS as assessed by an IRC according to the International Workshop on

AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064

Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included ORR (based on the same iWCLL criteria), overall survival (OS) and safety.

Patient Access to IMBRUVICA

AbbVie and Janssen strive to make access to IMBRUVICA easy by helping patients understand their insurance benefits for IMBRUVICA. The YOU&iTM Support Program is a personalized program that includes information on access and affordability, nurse call support and resources for patients being treated with IMBRUVICA. This includes the YOU&iTM Instant Savings program, which provides co-pay support to eligible commercially insured IMBRUVICA patients. Patients can access the program by contacting 1-877-877-3536, option 1 or by visiting http://www.IMBRUVICA.com.

The YOU&iTM Instant Savings program is not available for patients enrolled in Medicare or Medicaid. For a list of patient support organizations that may be able to provide financial support please visit: http://www.cancer.net/navigating-cancer-care/financial-considerations/financial-resources.

About IMBRUVICA

IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).1 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.1,4 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.1

IMBRUVICA is approved to treat patients with CLL, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.1

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS

AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064

Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICAÒ. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICAÒ.

The mechanism for the bleeding events is not well understood. IMBRUVICAÒ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICAÒ for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and nonfatal infections have occurred with IMBRUVICAÒ therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICAÒ. Evaluate patients for fever and infections and treat appropriately.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) occurred in patients treated with IMBRUVICAÒ. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICAÒ, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICAÒ treatment and dose modification.

Hypertension - Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA® with a median time to onset of 4.5 months (range, 0.03 to 18.40 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA®. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies - Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICAÒ. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064

Tumor Lysis Syndrome - Tumor lysis syndrome has been infrequently reported with IMBRUVICAÒ therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICAÒ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICAÒ and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 53%, 43%), diarrhea (51%, 48%, 37%), anemia* (41%, 37%, 13%), neutropenia* (47%, 46%, 44%), musculoskeletal pain (37%, 32%†, NA‡), fatigue (41%, 29%, 21%), bruising (30%, 25%†, 16%†), nausea (31%, 24%, 21%), rash (25%, 23%†, 22%†), and upper respiratory tract infection (34%, 19%, 19%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased). †Includes multiple ADR terms.
‡Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 4% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, subdural hematomas, and atrial fibrillation (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS
CYP3A Inhibitors - Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A

inhibitor must be used, reduce the IMBRUVICAÒ dose.
CYP3A Inducers - Avoid coadministration with strong CYP3A inducers.

AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064

SPECIFIC POPULATIONS
Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients

with mild impairment, reduce IMBRUVICAÒ dose.
Please see Full Prescribing Information: http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company’s mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world’s most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

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, the likelihood that the transaction is consummated, the expected benefits of the transaction, 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 2014 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.

*Disclaimer: Dr. Jan Burger served as the primary investigator of this Pharmacyclics-sponsored clinical study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. Dr. Burger does not have a financial interest in either company.

AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064

Contacts:

Media

Erica Jefferson

Investors

Liz Shea

Physicians

U.S. Medical Information

Phone: 408-990-7313

IMBRUVICA is a registered trademark of Pharmacyclics LLC SOURCE AbbVie Inc.

Phone: 847-935-2211

American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Available

from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed March 2016.

4 Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated- growth-hormone-deficiency. Accessed March 2016.

Phone: 877-877-3536

1 IMBRUVICA US Prescribing Information, March 2016.

2 IMS Database [Data on File] 3

AbbVie Inc. +1 (847) 938-9190 1 North Waukegan Road abbvie.com
North Chicago, IL 60064