Large Granular Lymphocytic Leukemia: What We CLL Patients Can Learn from a Novel Therapy for a T Cell Cancer

This week in Blood there was a very interesting article published on a very rare form of blood cancer, LGLL or large granular lymphocytic leukemia.

The abstract stated:

T-cell large granular lymphocyte leukemia (LGLL) is a rare clonal disease often associated with rheumatoid arthritis (RA) and manifests chiefly as neutropenia and recurrent infections. Immunosuppressive agents are the mainstay of treatment, but long-term remissions are rare. We report 2 cases of LGLL in patients with RA successfully treated with rituximab, a monoclonal antibody specific of B cells and approved for treating RA. The first patient experienced a complete LGLL remission that was sustained during the 8-year follow-up after the first rituximab infusion. In the second patient, rituximab therapy was followed by immediate neutropenia recovery and then by marked shrinkage of the LGLL clone 1 year later. The paradoxical efficacy of this specific anti–B-cell drug on a monoclonal T-cell disease suggests that some cases of LGLL may be reactive manifestations of chronic autoantigen stimulation rather than true malignancies.

I added the bold because this jamming on of reactive pathways with all its nasty downstream consequences is similar to what we are trying to block with BTK and PI3K inhibitors in CLL. In CLL, we are trying to shut down the constitutively stimulated B cells by blocking their pro-survival communication, proliferative, and homing instincts.

Further down is the report we find:

As illustrated by our first patient, T-cell LGLL is frequently associated with concomitant low-grade B-cell dyscrasias, such as monoclonal gammopathy of unknown significance or chronic lymphocytic leukemia, suggesting that a common antigen may drive both T- and B-cell proliferation.

That is powerful talk. Yet to be proven, but worthy of more research.

Maybe that is why anti-T cells therapies such as ciclosporin help some in CLL, yours truly included. 

Everything in the complex immune system is so connected.

The whole Blood article is short and I recommend it.

This type of creative systemic thinking is exactly what will be needed to completely and finally shut done the monoclonal B cell factory that is CLL. We may need to read the green tea leaves in more than our CLL teacups to find our answers. We need to look at the research being done in other liquid and solid cancers. Some of the fantastic new immune therapies in metastatic melanoma as detailed in my prior post from ASCO 2013 immediately come to mind as future paths to pursue. 

Last, but not least, and while the issue may be just semantic and this is only two cases, all of us with  CLL would much prefer to live with a "reactive manifestations of chronic autoantigen stimulation rather than true malignancies", especially if such labeling leads to better therapeutic approaches and better outcomes.

I am off to Germany on Monday for iwCLL. Send me your burning thoughts and questions that I might share with all the CLL gurus gathered in Cologne.

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ASCO 2013: Dr. Jeff Sharman on Mantle Cell Lymphoma (MCL) and Coffee and Road Map.

Dr. Sharman is a great educator with a super blog on CLL and NHL (Non-Hodgkin's Lymphoma) talks about MCL.

He points out the specific challenges with MCL and why the changes coming to treatment for other B cell lymphomas such as CLL might be even more helpful in this particular nasty cancer.

While not speaking specifically on CLL, the drugs he discusses should be familiar and his explanations of mechanism of action are both clear and creative- like coffee and road maps.

I will be interviewing Dr. Sharman and many others at iwCLL, a CLL specific conference in Cologne, Germany in a few weeks, so stay tuned. Please let me know if you have any burning questions.

Here is the short ASCO interview:

Again my thanks to the team at Patient Power with whom I worked at ASCO. Andrew Schorr and his team do important work for the CLL and cancer community, and it has been a pleasure to pool our energies and resources.

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 on Prognostic Factors in CLL (Chronic Lymphocytic Leukemia)

The whole arena of prognostic factors in CLL is constantly evolving, but a few principles have remained constant over the years.

1: Most, if not nearly all the data is retrospective.

2: Dr. Wierda and many others are refining algorithms that will weight the many variables to better predict our future including such helpful information as the expected time to first treatment or our chances of a durable remission or ultimately our chances to live long and prosper.

3: The markers predict for groups, not individuals, but that doesn't mean we should be therapeutic nihilist and ignore what our FISH tests tell us about what options improve our odds.

4: Bad prognostics are not in themselves an indication for treatment (outside a clinical trial).

5: Good prognostics doesn't always mean that our CLL will be a non-event.

6: New prognostic factors are being discovered all the time, but few will be of much clinical import.

Here is the second part of my interview with Dr. Wierda from ASCO 2013.

I will let him fill in the details on all these topics and other aspects of this moving target.

Again my thanks to  my friends at Patient Power for sharing the work and supporting the effort to get the important news about CLL from ASCO out and available to all those of us who need it to inform our choices about how we handle our disease. Check in on their website on a regular basis as Andrew Schorr is frequently update his informative site.



In fairness, I must add that other researchers have published data supporting a possible relationship between Notch1 and Richter's Transformation (or Syndrome),

I quote from a letter in the British Journal of Haematology, 2012, 158, 415–429


"NOTCH1 mutations were associated with a ~5·8-fold increase in the crude hazard of transformation into a clonally related RS (Richter's Syndrome) "

This is from an editorial from haematologica | 2012; 97(3)

"In fact, the first studies reported a high frequency of NOTCH1 mutations in .... disease progression towards transformation into Richter’s syndrome."

Now this is not the same level of evidence as in a full article, and as such might not pass mustard for Dr. Wierda and others as proof positive of the correlation, but it convinced me that it is worthy of further study.

There is just too much data out there for anyone of us to be aware of it all.

And that's OK.

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

ASCO 2013: The increasing numbers with Ibrutinib

As many of you know I have done very well on ibrutinib for the last year. When I started on PCI-32765 on May 7, 2012, there had been just a little more than a hundred patients who had been on the exciting new oral drug. Many of those early adapters are well known members of the CLL online community. Many are friends.

Personally, I am continuing to do great with near normal counts and no palpable nodes. CT next month in Ohio. All good. Off to Stockholm next week before EHA and just home from ASCO.

Now the community of ibrutinib users including those taking it for other B cell cancers including MCL, WM, and others now exceeds 1500 brave volunteers. Remember that the first trials were only begun in 2009. Many of those phase 1 trial patients are still on drug that tells us something about the durability of the responses, albeit in very small numbers. Still that makes the longest experience with ibrutinib something short of 4 years.

And as with many other biological treatments, the longer we stay on ibrutinib, the more responses, the more complete responses.

One of the nice problems is that when over 200 patients from the early trials were consolidated to look for those who had relapsed after more than a year on therapy, there was only a handful patients to study in more depth. Leaving aside the expected number of Richter's Transformation, about  only 1 out of 20 patients had relapsed with CLL. Most were 17p deleted but one was 11q deleted with a history of nasty auto-immune hemolytic anemia. I refer you to Dr. Sharman's nice review of the subject.

Whenever ibrutinib is approved (and hopefully that will be soon), the number of patients taking the medicine will swell. Other oral drugs may quickly follow. We will need to remain vigilant to see if rarer side effects become apparent post approval. And watch for long term surprises.

Many questions unanswered, but we have come so far in so few years.

And this is just the beginning of a new wave of targeted therapy. Ibrutinib and idelalisib and ABT-199 and GA101 are just the beginning of new wave of game changing therapies. Second and third generations of mAB and TKIs are following on their heels. We patients are needed for the trials to maintain the forward progress.

But let's celebrate the progress that we have made.

These are good times.

ASCO 2013: A Call for New Ways of Thinking

LIVE from ASCO 2013

It's huge.
It's crazy.
It's crowded.

But boy is there a ton of new research to share.

While ibrutinib and idelalisib have kicked open the door to explore new less toxic pathways to control not just CLL, not other B cell cancer, they did not close the door behind them.

Novel pathway inhibitors beyond PI3K and BTK and BCL-2 are being explored and being explored in novel ways with more open access.

New and potentially potent BTK and PI3K inhibitors are in trials now.

Combinations are being considered.

Dr. Wiestner said these new drugs offer us the opportunity to think in new ways.

Hence my disappointment when I hear speakers rightly celebrate the lack of bone marrow suppression with these new targeted therapies, but then got all excited about how that allows them to pile on the old school  bone marrow damaging chemotherapy. Maybe we do need to go in that direction, but can't we try to leverage the low toxicity of these drugs but adding other low toxicity agents to them, offering patients like us gentler and less risky control of our disease.

I like the idea of adding together more than one TKI or adding a monoclonal antibody or an IMID.

In my book, adding in bendamustine or fludarabine or chlorambucil or their ilk should make a significant difference in outcomes to justify the additional downside risk.  

I understand the temptation to revert to tried and true paths. And it might turn out to be the best call. Medicine must be both conservative and progressive.

But we have a sea change, a paradigm shift, happening in CLL. Let's try to keep innovating and exploring using the kind of thinking that got us the breakthroughs with  ibrutinib and idelalisb and ABT-199.

That is the next stage of research that has me excited.

That is the future that I want for all of us.

Doctor Turned Patient

I have commented before on the extra advantages and risks of being a healthcare provider, a doctor, facing any serious illness, in my case an indolent (slow) but incurable cancer with a host of nasty complications.

I have also touched on how, with my increased awareness and access, comes the added responsibility of sharing what I have learned and decoding it to make it more widely accessible and digestible.

I plan to discuss this topic over the next few months concerning how I have sailed these troubled waters, but let me start by saying that the more navigational tools I have (think knowledge and friends in high places), the more fellow CLLers in my boat or in sister boats in the convoy ahead and behind me in the race for a cure or at least a long and trouble free voyage, the more friends on the shore with their warning lights and their fog horns to cut through the mist of the unknown and the unseeable, the better are my chances to reach that promised land.  And I plan to bring as many along with me as possible.

Stay strong.

We are all in this together.

Next post will be live from ASCO.

Good News on the Home Front and Sad News at the Hospital

I have managed to stay out of the infusion center where I get my IVIG for a full five weeks and my lab results today were great.

My hemoglobin was the highest it has been in years (14.7) and finally well within the normal range, my platelets were over 400,000 and my ALC was about 1.3 and my WBC around 10.

Maybe it was my wife's Cajun gingerbread with all that blackstrap molasses boosting my iron while my ibrutinib controls my disease and keeps my counts in check, and my cyclosporin and IVIG shut down my ITP.

Whatever it is, it is good news.

As I have preached before, I mustn't get too excited by one blood count. It is the trend that matter. And for my mental health, it is best to smooth out the high and lows, but I wanted share this piece of good news before I head off to ASCO 2103.

With these encouraging results, I am now planning to stretch out my IVIG infusions to every six weeks with my doctor's blessing.  Not so long ago it was every three weeks that I was getting poked and infused. My veins are most thankful for the respite.

On a much more tragic note, last week I lost a colleague, a compassionate and talented surgeon from my local hospital with whom I had worked for decades. He had chosen to keep his CLL and other blood issues more private. We shared many confidence about our battles and I will miss him and the life he gave back to many of our mutual patients though his skilled interventions. 

His last few months were very difficult. Rest in peace, my friend.

This is a cancer that still plays for keeps. It picks no favorites. 

We need to decide wisely on our therapies. We need to get these new drugs to market soon. There are lives in the balance.

ASCO 2013 Abstract: ABT-199 in Relapsed and Refractory CLL Patients

I have posted before on ABT-199. I like this drug because it works. And it is a pill, not an IV.

It is clearly a very potent therapy.

We know that not just from the impressive 85% response rates, even for those difficult to treat 17p del and F refractory patients where an amazing 88% and 75% respectively achieved at least a partial response (PR), but we also know it from its dark's side, namely tumor lysis syndrome (TLS).

Until the dosing was adjusted after the first cohort, the first three patients all had TLS, a life threatening complication (and one die did in this trial) from the massive killing of the cancer overloading the liver and especially the kidneys' ability to prevent all that toxic waste from cell death from building up to dangerous levels.

We need to move carefully, but I am glad that ABT-199 is back in trial after the studies were suspended due to deaths from TLS.

The present approved options for F-refractory and 17p deleted patients are severely limited and these results are very promising.

Complete responses (CR) are only 13%, but that's not bad for any mono therapy, especially in these tough patients.

Our future depends on the researchers taming both the disease and the drugs that we use to treat it.

We also need to constantly recognize the sacrifice of those who bravely jumped into this "first-in-human" phase 1 trials. CLL is not for wimps.

The question I am asking myself is will ABT-199 offer enough of a therapeutic potency edge over the other novel oral therapies such as the gentler inhibitors of BTK and PI3K∂ that will justify its risks and earn a place in our therapeutic arsenal.

Or will its risks become acceptably manageable? Whatever that means.

Still is nice to have more viable choice options for those of us with bad disease.

I hope it move forward. I imagine a time that we will take a cocktail of oral pathway blockers to completely slay our dragon, much as is done today with HIV. Blocking BCL-2 is part of that vision.

Here is the abstract.

Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
John Francis Seymour, Matthew Steven Davids, John M. Pagel, Brad S. Kahl, William G. Wierda, Thomas P. Miller, John F. Gerecitano, Thomas J. Kipps, Mary Ann Anderson, David C.S. Huang, David E. Darden, Lori A. Gressick, Cathy E. Nolan, Jianning Yang, Todd A. Busman, Alison M. Graham, Elisa Cerri, Sari H. Enschede, Rod A. Humerickhouse, Andrew Warwick Roberts; Peter MacCallum Cancer Center, Melbourne, Australia; Dana-Farber Cancer Institute, Boston, MA; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Wisconsin Carbone Cancer Center, Madison, WI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Arizona Cancer Center, Tucson, AZ; Memorial Sloan-Kettering Cancer Center, New York, NY; UC San Diego Moores Cancer Center, La Jolla, CA; Royal Melbourne Hospital; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; AbbVie, Inc, North Chicago, IL; Royal Melbourne Hospital, Melbourne, Australia
Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki< 0.10 nM) than for BCL-XL (Ki = 48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose- escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626. 

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ASCO 2013: Press Release and Abstract about Idelalisib (CAL-101 or GS1101) in Treatment Naive CLL Patients

This is why I go to ASCO and ASH and hope to get to Europe for IWCLL. To get the inside scoop on these studies. To talk to the investigators about the data between the lines in their abstracts.

And to hear the good news.

I can't wait to push the presenters to get more of the details, but the overview in the press release is certainly impressive. 

All nine patients with 17p del or mutated P53 responded and three had a CR (complete response).

93% progression-free survival at two years. And I love the fast disappearing B symptoms.  Us patients just seem to feel so much better very quickly on most of these new small molecules.

Now admittedly this is an easy group to treat, all treatment-naive so the number should be good.

The 17% with significant pneumonia is more worrisome to me than the 1 in 4 with elevated liver enzymes. That usually resolves with stopping meds, and one can usually restart at a lower level without recurrent liver issues, but pneumonia can be fatal in CLL.

What I want is more information on those not still on the trial?

Why did the 17 of 64 drop out? What was the cause of the death in the three brave patients?

Why does the abstract say 18 drop outs and four deaths?  I have pasted it at the end

Why are the CR levels so low with this and with ibrutinib? FCR has better numbers, admittedly at a much higher cost.

Does  it really matter that a low level of disease is hanging around? Maybe not? Only time will tell.

Still I am glad to see such strong results with another very active tyrosine kinase inhibitor.

The more potent yet gentle treatment options the better.

The future is looking brighter and brighter for those of us with CLL.

Remember this is a press release from the maker of the drug, so please take a critical look at  what Gilead had to say about their promising new agent and send me your comments on what you like and what  gives you pause:

Gilead Announces Response Data from Phase 2 Study of Idelalisib for Previously Untreated Chronic Lymphocytic Leukemia

-- Regimen Achieves 97 Percent Overall Response Rate with Estimated Progression-Free Survival at 24 Months of 93 Percent --
-- Results from Study 101-08 and Other Idelalisib Clinical Studies to Be Presented at American Society of Clinical Oncology Annual Meeting --

FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 15, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from a Phase 2 study (Study 101-08) evaluating idelalisib (formerly GS-1101), an investigational, targeted, oral inhibitor of PI3K delta, in combination with rituximab for older patients with treatment-naïve chronic lymphocytic leukemia (CLL). This regimen achieved a complete response (CR) rate of 19 percent and an overall response rate (ORR) of 97 percent, with estimated progression-free survival (PFS) at 24 months of 93 percent. Detailed results will be presented during an oral session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract #7005).

CLL is a slow-growing cancer that induces the production of too many mature white blood cells. It is the second most common type of leukemia in the United States and can lead to life-threatening complications, including serious infection. Currently, patients with CLL are usually treated first with rituximab in combination with one or more chemotherapy agents.

“New therapies that can drive CLL into remission while potentially avoiding or delaying the need for chemotherapy would represent a much needed clinical advance,” said Susan M. O’Brien, MD, Ashbel Smith Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston and a principal investigator of the study. “The high overall response rate and durable disease control observed in this Phase 2 study suggest that idelalisib in combination with rituximab could become an important therapeutic option for CLL patients new to treatment.”

Among the 64 patients in the study, Kaplan-Meier estimated PFS at 24 months was 93 percent. The median time on treatment was 14 months, with 33 patients remaining on treatment. The median time to response was two months. No relapses on study have been reported. The nine patients with chromosome 17p deletion (del 17p) (n=6) or mutation in the TP53 gene (n=3), which have been linked to poor prognosis, all responded to therapy including three with a complete response. Ninety-four percent of patients with thrombocytopenia at baseline responded to treatment (16/17), as did all patients with anemia at baseline (17/17). Of patients with systemic symptoms such as extreme fatigue, fever, night sweats or weight loss (known as “B symptoms”) at baseline, 77 percent (20/26) were asymptomatic by eight weeks.

Patients completing 48 weeks of therapy without progression could continue to receive idelalisib in an extension study. Forty-three patients completed 48 weeks of treatment (21 discontinued – 17 due to adverse events, three due to death and one due to other reasons); 40 patients entered the extension study and 33 remain on treatment.

During the primary and extension study, Grade 3 diarrhea and/or colitis was reported in 33 percent of patients, Grade ≥3 pneumonia in 17 percent and Grade ≥3 transaminase elevations (measure of liver function) in 23 percent of patients.

“These results demonstrate for the first time idelalisib’s potential benefit for patients with a previously untreated hematological malignancy,” said Roy D. Baynes, MD, PhD, Senior Vice President of Oncology and Inflammation Therapeutics at Gilead Sciences. “Based on these promising data, we are now evaluating Phase 3 study designs for idelalisib as part of a frontline treatment regimen for CLL patients.”

Idelalisib’s clinical and safety profile for a number of blood cancers will be characterized in six additional oral or poster presentations at ASCO 2013:

Chronic Lymphocytic Leukemia (CLL)
Final results of a Phase 1 study of idelalisib in patients with relapsed or refractory CLL (Abstract #7003; oral session).
Update on a Phase 1 study of idelalisib in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL (Abstract #7017; poster session).

Indolent Non-Hodgkin’s Lymphoma (iNHL)
Combinations of the PI3K delta inhibitor idelalisib with rituximab and/or bendamustine are tolerable and highly active in patients with previously treated, indolent non-Hodgkin lymphoma: Updated results from a Phase 1 study (Abstract #8500; oral session).
Final results of a Phase 1 study of idelalisib, a selective inhibitor of PI3K delta, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (Abstract #8526; poster session).

Mantle Cell Lymphoma (MCL)
Final results of a Phase 1 study of idelalisib, a selective inhibitor of PI3K delta in patients with relapsed or refractory mantle cell lymphoma (Abstract #8519; clinical science symposium).
Preliminary results of PI3K delta inhibitor idelalisib treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma (Abstract #8501; oral session).

About Study 101-08
Study 101-08 is an open-label, single-arm Phase 2 trial that enrolled 64 treatment- naïve patients ≥65 years old with CLL or small lymphocytic lymphoma (SLL), a less common form of the disease. Patients received intravenous rituximab 375 mg/m2 weekly for eight weeks and oral idelalisib 150 mg twice daily for 48 weeks. The primary endpoint of the study is overall response rate, defined as the proportion of patients achieving a complete or partial response with this regimen (response definitions based on standard criteria). Patients completing 48 weeks of therapy without progression could continue to receive idelalisib in an extension study.

About Idelalisib
Idelalisib is an investigational, targeted, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a molecular target that is critical for the activation, proliferation and survival of B lymphocytes. PI3K delta signaling is hyperactive in many B-cell leukemias and lymphomas and drives proliferation, survival and trafficking to lymphoid tissue. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.
Gilead’s clinical development program for idelalisib includes three Phase 3 studies evaluating the drug in combination with approved therapies for patients with previously treated CLL, and two Phase 3 studies of idelalisib in combination with approved therapies for patients with previously treated indolent non-Hodgkin’s lymphoma (iNHL). In addition, combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, is being studied in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid and hematological malignancies.
Additional information about clinical studies of idelalisib and Gilead’s other investigational cancer agents can be found at www.clinicaltrials.gov. Idelalisib and GS- 9973 are investigational products and their safety and efficacy have not yet been established.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific. 

Abstract # 7005

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective oral inhibitor of PI3Kδ. When combined with R in 19 relapsed/refractory patients with CLL, the ORR was 78% (Coutre, ASH 2012). Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m² weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 wks w/o progression could continue to receive idelalisib on an extension study. Responses and progression were based on investigator assessment using IWCLL criteria (Hallek, Blood 2008). Results: Data is presented here on the first 50 of 64 pts enrolled, 48 CLL/2 SLL, median age 71 yrs (range: 65-89), M/F 70/30 (%), Rai stage III/IV 10/32 (%), nodes ≥5 cm in 16%, WHO 0/1/2 in 34/64/2 (%); del(17p) in 6 pts and del(11q) in 13 pts. 32 pts completed 48 wks (18 discontinued, 11 due to AE, 4 due to death and 3 other); 30 pts entered the extension study and 26 remain on treatment. The median time on treatment was 16 months (range 0.8-27.5). The ORR was 96% with 4% nonevaluable; median time to response was 1.9 mos (range 1.0-6.5). There have been no on-study relapses. The Kaplan-Meier estimated PFS is 91% at 24 mos. Of note, 6/6 pts with del(17p) responded (1 CR, 5 PR) and 3 remain on treatment for more than 21 months. 13/14 (93%) pts with thrombocytopenia and 12/12 (100%) pts with anemia at baseline responded. Of 20 pts with B symptoms at baseline, 13 (65%) were asymptomatic by 8 wks. Most frequent AEs (total%/ ≥G3%) were diarrhea (including reported as colitis) (46/16), pyrexia (42/4), chills (34/0), fatigue (34/2), rash (34/10), pneumonia (30/20) and nausea (28/0). Elevated ALT/AST was seen in 60%, Gr ≥3 in 22%. Conclusions:Idelalisib + R is highly active, resulting in durable disease control in treatment-naïve older pts with CLL. These results support the further development of idelalisib in frontline CLL. Clinical trial information: NCT01203930.