Biologic and Immune Therapies for CLL (chronic lymphocytic leukemia)

Hi Friends,

This week’s update on the CLL Society website http://cllsociety.org is my unscripted recordings on biologic or immunotherapies.

I start by reviewing my take on the good and bad of the well known and novel antibodies directed against our B cells by targeting its surface marker CD20. These include rituximab (Rituxan), ofatuzumab (Arzerra), and obinituzumab (Gazyva). Among other topics,  I discuss the difference between type I and type II monoclonal antibodies.

I also cover other antibodies, new and old, IMIDS (immune modulating drugs) such as lenalidomide (Revlimid) vaccines, and more.

To listen please, visit the treatment section (found under the Basics tab) of the CLL website by clicking here: http://cllsociety.org/cll-101/treatment/

Please let us know if this helps. I am particularly proud of this recording as it was done live and spontaneously with no notes. I think is ends up being more focused, ironically similar to the drugs discussed.

We plan on bringing more of this type of content. Your feedback on the website or to me by email informs what we add and how we will grow the website. Although there is only myself, my wife (both unpaid) and a wonderful RN, Betsy Dennison as the team, we listen carefully to all comments to help brings what’s needed to best manage our cancer. 

Smart patients get smart care™.

As always, all our content is free and easily accessible to anyone but if you want you may sign up for our weekly alerts to know when we post new content, 1 to 3 x a week, and for our inaugural newsletters which will be amazing. We understand the importance of privacy and don’t share any personal info.

Our website traffic has grown phenomenally in its first 10 weeks. Over a 1000 page views on our busy days. We also hope it will be a launching site for anyone with CLL as we have links to nearly all the quality sites on our front page.

The artwork in the background of the video is again my son, Will Koffman’s tribute to Durer’s Four Horsemen of the Apocalypse.  Will rendered the entire work using only bleach on black cotton.

Nothing much new to report on the personal level with my CLL. Still get tired. Still traveling way too much (over the next 2 weeks I will be in Dallas, Seattle, Las Vegas and Poland to teach and to learn) and still doing too much and getting too sleep. Really it is a bit crazy.

I am waiting on my more granular lab results from OSU. Despite my best intentions, I always worry when I am waiting for my results.

Thanks.

Stay strong.

We are all in this together.

Brian

Volunteer Medical Director, CLL Society Inc.

http://cllsociety.org

BKOFFMANMD@GMAIL.COM

One more Weapon in Our Arsenal: Obinutuzumab is Approved for Treatment Naive Patients

That was pretty fast.

Obinutuzumab is a third generation monoclonal antibody (mAb) directed against a marker (CD20) sitting on the surface of B cells, including our cancerous CLL cells. Rituximab was the first generation, and it has proven to be a great boon to all of us with CLL. I believe that obinutuzumab will prove to be even more of a friend. It is a type of immunotherapy that has shown its value when added to a chemo backbone to treat CLL. Think of the huge improvement FCR was over FC. The addition of that antibody demonstrated for the first time that we finally had a therapy that could prolong our lives.

A couple of thing to note about the FDA new release that follows.

The approval was based on comparison to chlorambucil alone or chlorambucil with obinutuzumab. That seems like a bit of a fixed race. Single agent chlorambucil is a commonly chosen competitor as it one that is easily beaten. Other drugs such as bendamustine have won approval using a similar trial design. It is rarely used in the USA, especially as a single agent, but might be a good choice for some more fragile elderly patients.

Second,  obinutuzumab was approved for frontline therapy in combination with chlorambucil in treatment naive patients. That was the way it was studied, and that's what was okayed. Period.

The much bigger issue is that if this is only way its use will be covered by insurance plans, then we are leaving the real power of this potent medication in many other life saving setting sorely neglected. That would be a real disservice to us patients. It remains to be seen how this will play out, but I am dismayed about the limited indication granted by the FDA and frankly worried about how that bodes for ibrutinib and idelalisib. Will their indications also be as tightly focused? 

The reality is that many cancer drugs are widely or even mostly used off label, and if there is evidence, usually in the form of published research, then insurance can often be arm wrestled into paying. Once a drug is approved, the options for patients should greatly expand beyond the narrow boundaries of the inclusion/exclusion criteria set forth in a clinical trial. But they are no guarantees. 

Does this make pharmaceutical companies rethink how they design trials if the indications approved by the FDA will only reflect the exact manner in which the drug was studied? Those more expert than me in knowing how these processes unfold will need to answer that thorny question. I suspect we will have some more approval news soon on ibrutinib that should give us a clearer indication of how the FDA is handling these issues.

Finally, a reminder that at least to the the FDA's eyes, the concerns with hepatitis B reactivation and the very rare but devastating brain infection, progressive multifocal leukoencephalopathy, are risks for all the CD20 monoclonal antibodies (mAb) such as rituximab and ofatumumab. I am not sure that those unusual complications were even seen in the trials with obinutuzumab, but the black box warning is there nevertheless. I am OK with that. Logically it makes sense, and it is better to err on the side of safety, though I doubt this is an error.

Still is very good news to have this new and more potent option. There are many reasons to believe that this third generation monoclonal antibody obinutuzumab will prove to be a much better CLL killer than rituximab. It got 30% of the patients to MRD (minimal residual disease, that is an important surrogate marker for length and depth of remission) negativity in combination with chlorambucil in the trial that got it approved. And you can bet it did the heavy lifting, because in the arm with chlorambucil alone, the MRD rate was zero.No surprise there. Image what magic it will wrought when matched with an equally potent fighter such as ibrutinib or idelalisib. And now that it is approved, setting up such trials will be much easier. it is already being studied with ABT-199, a trial that I have recommended for many to consider.

Side effects were generally pretty minimal. Except for the nasty infusion reactions common with many mAbs, most of those listed below in the news release were more likely from the effects of chlorambucil on the bone marrow than from the obinutuzumab.

Here is my prayer: That this powerful and important new mAb will be available to all those who might benefit and that means many more than those specified in the narrow indication.

I plan to be at ASH 2013 to hear the details of the phase 3 trial data and will share it all here.

Here's the FDA news release:

FDA NEWS RELEASE

For Immediate Release: Nov. 1, 2013
Media Inquiries: Tara Goodin, 240-402-3157, tara.goodin@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA 

FDA approves Gazyva for chronic lymphocytic leukemia

Drug is first with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

CLL is a blood and bone marrow disease that usually gets worse slowly. According to the National Cancer Institute, 15,680 Americans will be diagnosed and 4,580 will die from the disease this year.

Gazyva works by helping certain cells in the immune system attack cancer cells. Gazyva is intended to be used with chlorambucil, another drug used to treat patients with CLL.

Gazyva is the first drug with breakthrough therapy designation to receive FDA approval. This designation was requested by the sponsor and granted soon after the biologic license application to support marketing approval was submitted to the FDA. The FDA can designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.

The FDA also granted Gazyva priority review because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. And the FDA granted Gazyva orphan product designation because it is intended to treat a rare disease.

“Today’s approval represents an important new addition to the treatments for patients with CLL,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval reflects the promise of the Breakthrough Therapy Designation program, allowing us to work collaboratively with companies to expedite the development, review and availability of important new drugs.”

Gazyva’s approval for CLL is based on a study of 356 participants in a randomized open-label multicenter trial comparing Gazyva in combination with chlorambucil to chlorambucil alone in participants with previously untreated CLL. Participants receiving Gazyva in combination with chlorambucil demonstrated a significant improvement in progression free survival: an average of 23 months compared with 11.1 months with chlorambucil alone.

The most common side effects observed in participants receiving Gazyva in combination with chlorambucil were infusion-related reactions, a decrease in infection-fighting white blood cells (neutropenia), a low level of platelets in the blood (thrombocytopenia), low red blood cells (anemia), pain in the muscles and bones (musculoskeletal pain), and fever (pyrexia). 

Gazyva is being approved with a boxed warning regarding Hepatitis B virus reactivation and a rare disorder that damages the material that covers and protects nerves in the white matter of the brain (progressive multifocal leukoencephalopathy). These are known risks with other monoclonal antibodies in this class and rare cases were identified in participants on other trials of Gazyva. Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk. 

Gazyva is marketed by Genentech, a member of the Roche Group, based in South San Francisco, Calif.

For more information:

• FDA: Office of Hematology and Oncology Products
• FDA: Breakthrough Therapies
• FDA: Drug Innovation
• FDA: Approved Drugs: Questions and Answers
• NCI: Chronic Lymphocytic Leukemia

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

ASCO 2013: Dr. Sharman on The Biology of CLL being Cracked with a Therapeutic Renaissance Underway

At the ASCO 2013 in Chicago, I had a chance to catch on camera some of the enthusiasm and optimism of Dr. Sharman.

Dr. Sharman is the director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, and a very creative and visionary doctor and a great blogger. His posts are always worth reading.

In this  interview, he clearly outlines the rationale of using the new small molecules that blocks BCR (b-cell receptor) or Bcl-2 (b-cell lymphoma-2).

He shares some of the development of third generation mAbs (monoclonal antibodies) such as obinutuzumab to turn on the immune system.  We learned in my earlier ASCO post with Dr. Wierda, immunotherapy, namely an allogeneic stem cell transplant is the only proven cure on CLL. And we have strong data from the German trial and others that adding a mAb such as rituximab to FC makes the chemotherapy better, so building a better antibody is an important step forward .

The swelling number of promising new molecules and treatment options needs to be met with an reciprocal swelling number of volunteers for clinical trials to keep the renaissance alive.

Are we already in a therapeutic renaissance for CLL?  I believe we are just in the very earliest stages of the coming change to the treatment paradigm, but we need many more bright lights to guide our way and that will only be produced by the hard work of the bench scientists and the valour of the volunteers  who enroll in well designed and patent friendly clinical research. Only then will we able to say that we have turned the corner on the "dark ages" of CLL

Thanks again to Andrew Schorr and the great team at Patient Power for helping make these interviews possible.

More soon.

ASCO 2013: Dr. Wierda Discusses Immune Therapies in CLL

In this first of several interviews from ASCO 2013, Dr. Bill Wierda of MDACC discusses immunity in general (or lack there of) in CLL and how that relates to the coming immune therapies.

He starts by explaining the basic difference between passive and active immune therapies.

His candid review of the trials so far points out the recurrent disappointments in the attempts to develop active immune therapies.

The story with passive immunity has had more success.

Monoclonal antibodies (mAb) such as rituximab or alemtuzumab were the pioneers of targeted immune therapy and have in many cases improved outcomes when added to chemotherapy without significantly increasing toxicity. Newer mAbs hold the promise of even deeper responses with few of the downsides of traditional chemotherapy and may even prove to work well without the addition of cytotoxic chemotherapy. Already useful examples include Rituximab and Revlimid or lenalidomide (R2) and the combo of HDMP (high dose methylprednisilone) + Ofatumumab. Powerful therapies with no chemo.

GA101 or obinutuzumab, a third generation anti CD20 mAB had received breakthrough status at the FDA and may be approved before the end of the year. The early data suggest this is both a potent and well tolerated treatment, hence the rush to get it to the clinic.

Passive immunity also includes the exciting CAR-T therapies that Dr. Wierda discusses. These are still in very early trials, but a few cases such as those out of U. Penn have seen spectacular saves when patients had all but ran out of all conventional options.

Immune modulating drugs (IMIDS) such as lenalidomide are in the early days of studies to figure out how they fit into the therapeutic landscape, but are clearly active in CLL and may improve some aspects of our impaired immunity,

This segues to another topic that gets Dr. Wierda really excited.

He tells of his research into ways to improve our immunity, to reconstitute our lost ability to fight off infections and to search and destroy the earliest microscopic cancers before they can grab hold and cause problems. Infections and secondary cancers are what kill those of us with CLL, and Dr. Wierda is fighting for ways not only to knock out our blood malignancy, but to also prevent us from dying not from our cancer itself, but from the damage the CLL (and its treatment) have already done to our ability to protect ourselves from infections and secondary malignancies.

This interview is from ASCO 2013 in June in Chicago.

It was great fun working with Andrew Schorr and the dedicated team from Patient Power in doing these interviews. I am grateful for their efforts and support and the willingness of the doctors to share their work at such a busy conference.

Look for more CLL interviews here over the next few weeks and keep checking Patient Power for other interviews that Andrew and I did on other cutting edge treatments for different cancers at ASCO in Chicago. Many of these have direct implications for how CLL may be treated in the future.

Here is Dr. Wierda:


Tomorrow it will be a full six weeks since my last IVIG infusion and blood draw. This is the longest I have gone without IVIG in the last six years and the longest I have gone without lab test since my first year with CLL.

I will report from the infusion center tomorrow.

Immunotherapy for Metastatic Melanoma

The big news out of ASCO 2013 was not about CLL, but about metastatic melanoma.

ASCO is well known to be more of a solid tumor meeting and it lived up to its reputation.

The big buzz is that now oncologists are using a new class of immune therapies that takes the brakes off the immune system so that it can aggressively attack the cancer.

Harnessing the immune system has long been an elusive goal in cancer therapy.

Until recently the best durable response rate in advanced melanoma was about 5% with a very difficult interleukin 2 protocol that made patients feel just awful.

Now it is over 70% and quite durable with simple combination of two separate immune therapy. And with a manageable side effect profile.

Moreover, the breakthrough PD- L1 antibody drugs discussed may have potential in a broad range of cancers, including blood cancers. It is important that those of us with CLL follow the developments in other tumor therapy so that we can be aware of any possible application or parallel research for our particular malignancy.

Exciting and hopeful times for those of us with cancer.

I am grateful to Andrew Schorr and the dedicated professional team at Patient Power for providing the support to do these fun interviews with these pioneering doctors. Please check out Patient Power over the next few weeks for more interviews from ASCO 2013.

Here's a link to Patient Power for the the first part of this same interview on the tremendous parallel progress in targeted therapy for advanced melanoma with a specific mutation that until recently had been well known as a fast working assassin for most victims.

Targeted therapy.

Immunotherapy.

Logical and complementary drug combinations.

This is the future not just for the treatment of melanoma, but for all of oncology.

Soon I will be posting my interviews with several CLL experts done in partnership with Patient Power.

Dr. Lynn Mara Schuchter on the Latest News on Immunotherapy for Advanced Melanoma from ASCO 2013