Zydelig: The Black Box Warnings for use in CLL (Chronic Lymphocytic Leukemia), SLL (Small Lymphocytic Lymphoma), and Follicular Lymphoma

Before you get very far into the Zydelig (CAL 101 or GS 1101 or idelasilib) label,  you come across a big bold black box warning.

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION

See full prescribing information for complete boxed warning.

• Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig- treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig. (5.1)
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig. (5.2)
• Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig. (5.3)
• Fatal and serious intestinal perforation can occur in Zydelig- treated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected. (5.4) 
  
  
  

That kind of warning should and does give most patients and doctors pause before proceeding. And that's a good thing. But we also need some perspective.

While black box warnings are the strongest language that the FDA can put on a label, it is focused on the worst of the worst and not necessarily on common problems.

Our old friend, the rather gentle giant in the CLL world, rituximab has multiple black box warnings (as it should):

From the Rituxan label:

WARNING: FATAL INFUSION REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
See full prescribing information for complete boxed warning.

•   Fatal infusion reactions within 24 hours of Rituxan infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor patients and discontinue Rituxan infusion for severe reactions (5.1).
  
•   Severe mucocutaneous reactions, some with fatal outcomes (5.2).
  
•   Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death (5.3).
  
•   Progressive multifocal leukoencephalopathy (PML) resulting in death (5.4).

Each one of those problems can kill us (PML has a 90% mortality rate, worse than Ebola) and if it doesn't cause our demise, leave us badly shaken and permanently damaged. But those concerns are thankfully relatively rare and it hasn't stop me or many others from enjoying the real benefits of rituximab.

Black boxes are found on many labels. Even common antidepressant medications come with a black box warning for the rare but obviously critically important issue of increased risk of suicide in those patients younger than 24.

For Zydelig, the serious liver issues and severe diarrhea and colitis occurred in one out of every seven patients in their trials. Not so rare. Colitis is miserable and can be fatal. Fortunately, the other, generally more life threatening, adverse events are less common.

Gilead have instituted a FDA mandated REMS (Risk Evaluation and Mitigation Strategy) program. Using this link and further links found on that webpage, you can see how serious the FDA and Gilead are about staying ahead of these potential problems for us patients.

They are being proactive. The fine print in the package insert gives strict guidelines on monitoring and what do based on what the patient's conditions and the lab test are telling the doctor. And most problems can be reversed if the patient and clinician are on their game and respond quickly and appropriately when there's a signal of an emerging problem. After a period off the drug, many of us can safely restart it at a reduced dose and continue to do get the benefits.

This is yet another reason to be choosy about who is managing your CLL. Please pick a doctor who is experienced with CLL and with the new medications so that he or she is on top of all the good and all the possible bad associated with them.

CLL is itself risky. Doing nothing is not an option for many of us.

FCR is no cakewalk. BR is not much better. Lenalidomide comes with a host of its own unique nasty issues.

But all of these drugs and and other drug combinations have saved lives. We can not afford to be therapeutic nihilists because we have no guaranteed safe choices.

Carefully read the label. Ask your doctor. Insist on the correct monitoring. Report any and all problems promptly.

Odds are heavily in our favor. Have perspective.

One place I do see as an advantage for idelalisib at this time is that there it has no warning on the label about bleeding in association with anticoagulants as there is with ibrutinib. By the way, Imbruvica has no black box warnings. The bleeding issues with Imbruvica are being studied more as they are not presently fully understood. Time will tell, but there is reason to believe that most of the bleeding/bruising problems may be simply increased bruising that is more a cosmetic than a health issue. Still, at this time, Zydelig has no such caution and Imbruvica does.

As I said in my last post, we are so lucky to have this choice of two new potent oral medicines that are targeted at our cancer.

To borrow from my dear friend and patient advocate, WWW: May our paths be well chosen.

FDA Approval of Idelalisib (or CAL-101 or GS-1101 or now Zydelig) for CLL (chronic lymphocytic leukemia), SLL (small lymphocytic lymphoma) and FL (follicular lymphoma)

ME AND A GIANT TREE

SEQUOIA NATIONAL PARK

It was another good week for those of us with CLL/SLL and our friends with Follicular Lymphoma (FL).

CAL-101 AKA GS-1101 AKA idelalisib AKA Zydelig (See Dr. Sharman's post on the name game and his positive early experience with the drug) was approved last week by the FDA for relapsed CLL patients who would be consider candidates for rituximab (R) and for FL and SLL patients who have had 2 prior therapies.

I quote from the label:

----INDICATIONS AND USAGE---------------------------

Zydelig is a kinase inhibitor indicated for the treatment of patients with:

            􏰅  Relapsed chronic lymphocytic leukemia (CLL), in combination with 
rituximab, in patients for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities. (1.1)

            􏰅  Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients 
who have received at least two prior systemic therapies. (1.2)

            􏰅  Relapsed small lymphocytic lymphoma (SLL) in patients who have 
received at least two prior systemic therapies. (1.3)

Let’s pause and consider this.

A few things should catch our attention and this post is about parsing this first part of the label..

First idelalisib is approved as mono-therapy for SLL or small lymphocytic lymphoma (and FL), but not CLL. With CLL it is only approved for use with rituximab. Moreover, for CLL we can use it on label if we have relapsed after one treatment, but for SLL (and FL), idelalisib must be at least our third therapy.

But aren’t CLL and SLL essentially the same disease? Though we may be starting to tease apart the biology of this pairing (see this article expectedly from Serbia: (Possible role of CD22, CD79b andCD20 expression in distinguishing small lymphocytic lymphoma from chroniclymphocytic leukemia; Danijela Jovanovic, Predrag Djurdjevic, Nebojsa Andjelkovic, LjubicaZivic Contemp Oncol (Pozn) 2014; 18 (1): 29–33 DOI: 10.5114/wo.2013.38570), in almost all practical circumstances, there is no distinction between CLL and SLL and we treat the two diseases as one entity. Until now, with perhaps the one exception to consider possibly curative surgery and/or local radiation for SLL when it is only found in a single node, treatment was the same whether our malignant B cell clone was strictly nodal or it had spilled over into the peripheral blood and marrow.

Now, if we are going to strictly follow the language on the Zydelig label, we will have for the first time both a different indication for treatment and a different treatment protocol for CLL and SLL.

While this is an interesting point, it is probably of little clinical import as SLL recurring three times as strictly nodal would be rare. Idelalisib might be a good choice, but ironically this is exactly where I personally would want to use it in combination, likely with antibody or even chemotherapy.

Next point.

For those of us with CLL, idelalisib is approved after our first relapse. This is different than the CLL indication for ibrutinib, where we only need to have received a single prior therapy and due perhaps to an adverse reaction or intolerance, are now looking for another treatment options but may not have relapsed. (The label says: IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.) Although the most common circumstance leading to a prescription of Imbruvica would still be relapse, it is possible that some of us couldn’t tolerate FCR or Chlorambucil or other treatments and then still needing some sort of therapy for our progressive CLL, but not having relapsed, would now qualify for Imbruvica but not for Zydelig.

This too would be a rare but possible occurrence.

The last item to be considered in the “Indications and Usage” of Zydelig quoting the label again is indicated, for relapsed CLL in combination with Rituximab:

….in patients for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities.

Who are these patients? What relapsed patient would ever be offered single agent R? Hard to imagine mono-therapy with rituximab where the response rate as a single agent in relapsed disease is dismal, ironically confirmed in the idelalisib pivotal trial where only 13% of those in the rituximab plus placebo arm got any benefit from treatment.

Before dismissing out of hand this possibility, there are several realities to consider.

First and foremost, the FDA approved the drug based on the trial data it was presented.

The FL and SLL gang were two subpopulations of a larger pool of patients with Non Hodgkins Lymphoma (NHL) that were studied. The data that the FDA used was from that lymphoma patient trial where everyone had to have received at least two prior therapies to be included. Of all those studied, these two subgroups, FL and SLL, responded very nicely to single agent idelalisib, hence the language of the approval.

For the CLL trial group, the phase III study was for patients who were considered too frail based on their co-morbidities (chronic kidney disease and others) for chemo-immunotherapy and thus would be considered for rituximab alone. The results of idelalisb with rituximab versus rituximab alone were, as we all would expect, very impressive.

Are the “Indications and Usage” starting to make sense?  This is the same reasoning that that explains why we have Gazyva only approved for use with Chlorambucil.  That's the way it was studied.


The FDA approvals tend to stick pretty closely to the exact way the drug was studied and thus the pharmaceutical companies tend to reap what they sow.

This is not as crazy as it seems on first blush. It can be dangerous to extrapolate data and the FDA has been burnt too often not be conservative. I am in fact impressed with the speed and the use of the new breakthrough pathways has allowed these important novel drugs to get to market so quickly.

In fact the Zydelig label also adds:

Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

As to the actual reasons for the pivotal CLL trial design, I discussed with Dr. Sharman and Dr. Furman in this and this past post about the strong trial data that lead to approval for CLL published in the NEJM and presented at ASH 2013. There are times when single agent rituximab might be considered for relapsed disease in the elderly or frail “slow-go” patients that could not tolerate chemo-immunotherapy. While most if not all CLL gurus that you see interviewed here on my blog and quoted elsewhere on the web, would rarely, if ever use single agent R, it is the real world treatment of choice for about 8% of all relapsed patient in the community. Rituximab maintenance which I discussed a few years back in this post, is also frowned upon by most experts, but is used 9% of the time. 

So again, what seems at first to be a strange qualifier on the relapsed CLL indication label, I suspect won’t prove to be much problem to us patients.

Moreover, how the doctors prescribe them and how insurance pays for them is a whole other topic.

Once it is approved, remember that a doctor can use it however he or she wishes.

Which is a good segue to my final subjects for this post.

Before I finish on this very good news, I wanted to share even more good news by means of this link to the Gilead website that will assist any one considering this important new drug. As does Pharmacyclics, Gilead is offering to help commercial and uninsured patients with practical and generous financial support to make this expensive breakthrough drug more affordable. It is also priced a full $1,000 lower per month that ibrutinib, but that doesn’t consider the additional cost of rituximab. Still cheaper is better.

Unfortunately, like all pharmaceutical companies, even if they wanted to, Gilead cannot directly help Medicare Part D patients. They do nice job explaining the financial hit a Medicare patient faces on their website here.

What they can do is support independent non-profit organizations such as LLS that can then offer financial assistance for both eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs. On the LLS site, the income must be below 500% of the federal poverty guidelines, but for a family of four, that is anything below $119,250. 

For more details from Gilead and a number to call on how those of us with government insurance might qualify for financial aid, check here: There is of course no guarantee that help will be provided. Resources are limited, but it is certainly worth investigating.

And here is a link to active idelalisib trials. The expanded access program closed for new enrollees in the USA with Zydelig's approval, but will continue for those already enrolled. 

So in the end, good news. We all need more options, and now we have two great oral medications, both with strong help for most of us from their manufacturers to offset the considerable cost.

I will post more soon on how I see Zydelig fitting in, the the black box warnings and its strength and weakness, but for now I am just so happy we have this new weapon in our arsenal.

Thanks to all of you who volunteered for the trials that helped speed its approval. If appropriate, don't forget to consider trials for these two drugs and for several others existing antibodies and TKIs in the pipeline.

It is a good time in the CLL world and it will only continue to get better, quickly.

Only a few days later after this good news, Imbruvica was approved for front line therapy for those of us with 17p deletion. That is giant. More on that important expanded indication in another post soon. 

Much reason to celebrate as we now have two new powerful oral medications to help us live longer and better.

ASH 2013: Dr. John Pagel Speculates on the Future of CLL (chronic lymphocytic leukemia) Therapies including the late breaking data on Idelalisib

In the second part of our interview at ASH 2013 we shift from discussing radio-immune therapy and listen as Dr. John Pagel starts by agreeing with many of us patients that our future could and should see less and less chemotherapy and more and more combinations of targeted therapies.

He then gives his perspective on the late breaking abstract at ASH on idelalisib (AKA CAL 101 AKA GS-1101) plus rituximab versus placebo plus rituximab that Dr. Furman and I also discussed in this prior post that also contains a link to the ASH abstract and the NEJM where it indeed did get published. This trial has been well reviewed in the past, but it was nice to note the agreement among the researchers involved in this large trial.

Here's part two of the three part interview.



More to come soon with the last section of Dr. Pagel's interview and a long three part interview with Dr. Byrd from the same ASH annual conference.

Then all the attention turns to ASCO 2014. ASCO covers all cancers, so CLL is a minor player compared to the big four of breast, colon, lung, and prostate, but there will be important new data on ibrutinib, idelalisib, ABT-199, ONO-4059, a new SYK inhibitor from Gilead and others.

I have several exciting interviews scheduled both in video and simple audio format that I will be posting and sharing with my friend Andrew Schorr on his patient friendly cancer website Patient Power as Andrew made the sensible decision not to fly from Barcelona to Chicago. Andrew's team will also be posting the latest news on several other types of cancer, some of which may have directly relevance to those of us with CLL.

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.

ASH 2012: Dr. Richard Furman Discusses What is Known and What Isn't About the New Treatments in Trials

In the final part of Dr. Furman's interview from ASH 2012, the doctor who had the most early experience with GS-1101 (idelasilib) and ibrutinib discusses the still limited experience of disease progression with these new small molecules. He reminds of the real risks of bone marrow damage (MDS) and transformation to a more aggressive cancer (Richter's) and offers an interesting hypothesis on why Richter's might be found more often with these treatments.

He reviews the open pivotal for idelasilb (GS1101) and the associated crossovers, plus the trial for ibrutinib versus ofatumumab.

But there are other trials out there too that he didn't mention, especially for patients in special categories, such as 17p deletion or age  > 65.

So always remember to check what clinical trials might be a fit for you at http://clinicaltrials.gov when you are considering treatment. Don't count on your doctor to know all the latest. See my prior post on clinical trials.

Dr. Furman candidly outlines what is known and not known about how these drugs work.

What I really like is the strategy he outlines of using these drugs one after another as stepping stones to a normal life expectancy.



More to come from ASH 2012.

ASH 2012: Dr. John Byrd Discusses Possible Complications of the New Therapies and the New Trials

We pick up the interview at ASH 2012 with a perspective on the possible complications of the new therapies (ibrutinib and GS-1101 or Idelalisib), starting with infections in general in CLL and in the trials, bleeding problems, liver enzymes, and atypical pneumonia.

He reminds us that we are treating CLL, not a trivial disorder. I believe he is asking us patients to take a step back and consider our tolerance of adverse events against the often higher risks of the alternative therapies or the real dangers of doing nothing.

In the last half of the interview, Dr. Byrd discusses the RESONATE trial and a possible path to early access to ibrutinib, another trial of GS-1101 versus rituximab with a cross-over, a single arm relapsed 17p del trial of ibrutinib, and others with bendamustine.

Several of these trials offer real solid therapy with no chemo arm. That's special.



This post comes from a castle in the the cold and wet and wonderful Ballyfarnon in northern part of Ireland.

Below is a picture of my my bonnie lassie at the entrance to Kilronan Castle.

We are happy a splendid time, meeting brilliant people. You don't need to believe in the wee folk to recognize that Ireland is a magical place.

ASH 2012: Dr. John M. Pagel Part 2: Present Trials and Speculations on the Near Future of Ibutinib, GS-1101, ABT-199, GA-101, TRU-016 including Combinations and the Changing Role of Transplants

I am grateful for the thoughtful, caring and careful way Dr. John Pagel tells the evolving story of CLL treatment. But I am also grateful that he is willing to speculate about what the future might hold for us CLL patients and those yet to be diagnosed.

In the follow-up to Part 1 of my interview, Dr. Pagel hypothesizes a possible future of the "game changing" emerging therapies in CLL, their paths to probable approval, logical combinations, available and coming trials, the "boots on the ground" reality of how they will be used on and off label, and the reassessing of the time and place for allogeneic transplants.

His candid observation that drugs such as ibrutinib (PCI-32765) and GS-1101(now idelalisib and formerly CAL-101) will potentially be used extensively "off label" and upfront in therapy is in my opinion, a realistic take on what is coming to the next generation of CLL patients.

When he talks about the shifting role of allogeneic transplants, we hear his wisdom and experience gained from his years of helping patients in both the pre and post imatinib (Gleevec) eras.

He informs of us the logical combinations of agents, many with no cytotoxic chemotherapy to be found anywhere in the treatment protocol, that are available right now in clinical trials and will continue to be explored.

Please be sure to view Part 1 if you haven't already. It will help with the context of this continuation of the same interview. In Part 1, there is more indepth discussion of ABT-199. In Part 2, presented below, I start by asking him about the other two big names out there ibrutinib (PCI-32765) and idelalisib (GS-1101), and he picks up from there. 

There will be a brief Part 3 soon that will deal with transplants exclusively.

ASH 2012: Dr. John M. Pagel Part 1 Game changing medications including ABT-199, Ibrutinib, and GS-1101 for CLL

Here's a little New Year's Eve gift.

In the first of three segments of my interview with Dr. John Pagel,  he says some amazing things.

"this year from last year in CLL, it's game changing, it's night and day difference from where we're going and where we've come and what this field is evolving to, ...... evolving away from cytotoxic chemotherapy"

"this is an amazing wonderful time"

But enough of me quoting the scientist.

I will let the good doctor introduce himself and share some details about his personal experience and excitement concerning ABT199, ibrubinib, and GS1101.



As I attended more of the ASH science and education sessions, and as I interviewed more of the CLL champions, a more mature full screen story develops about the changes that are coming to the world of treatment.

Even a vegan can say that this isn't a case of too much sizzle, not enough steak. These changes are mighty and meaty.

This is really happening and it's happening fast.

In an upcoming post, I will outline some possible tactics for those of us whose urgent present need for treatment doesn't allow the luxury of waiting for the day in the not too distant future when we can go to our local pharmacy and pick up our bottle of pills to control our cancer along with our toothpaste and shampoo.

But first more, we have much more to learn from Dr. Pagel.

One More Sunset

We walked up the beach at Crystal Cove and snapped this photo.

We are back home briefly, where we are getting ready for the family visiting tomorrow for the traditional Christmas meal of latkes (potato pancakes).

One small CLL Christmas present. Something special got a new official moniker. Her new name is Idelalisib but she called herself GS-1101 but everyone knew her as CAL-101. Reminds me of the Beatles' song Rocky Raccoon.

You heard it here first, though I am loathe to try to actually pronounce it or sing it.

I will have some interviews up my the end of the week and plan to review the good news from ASH on ABT-199 next.

To all those celebrating,

Merry Christmas 

ASH 2012: Combinations of the PI3K∂ Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory CLL

GS1101(formerly CAL101) was the first oral, exciting small molecule to show outstanding results in CLL after the failure of many other small pathway blockers.

It had about an 18 month head start on ibrutinib (formerly PCI-32765), but its lead has shrunk considerably in the race to FDA approval.

It too blocks the pathway downstream from the BCR (B cell receptor) that tells the clone to survive and proliferate. Bench research presented at ASH seems to suggest that in some clones of aggressive CLL with a higher tendency to Richter's Transformation, BCR is promiscuous (couples and responses with any old stimulating antigen) or in another poster presentation, may be self stimulating, perpetually turned on and driving the disease with no outside help. Quoting from the conclusions in that paper " These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. "

Either way, turned on BCR is not our friend.

This basic science work applies to any and all drugs that effect the BCR pathway, and it was work such as this that lead to the idea that compounds such as GS1101 and ibrutinib might someday have a major role to play in controlling CLL. We now know that PI3K∂ drives survival and proliferation of the cancers cells, so blocking it with GS1101 makes good sense. 

That kind of hard work leads to an understanding  of the basic cell biology that leads to a treatment hypothesis that leads to animal studies that leads to human trials that leads to a usable drug.  I am way oversimplifying the story and this ideal path is aborted 99% of the time long before it gives birth to a helpful medical compound, but I wanted to share some of the mostly unseen effort that makes these breakthroughs possible.  The medicine bottle at the pharmacy is just the tip of the iceberg. We owed so much to the medical chemists.

So what were the clinical results with GS1101 that were presented at ASH? 

The important  abstract 191:Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study reported more good news: high response rates.

Here I am sharing an executive summary of the findings but you have a link to all the details included in the abstract. We must wait for the peer reviewed published paper as that is the true test of the validity of the research.

51 patients were studied in three different arms. These were not the easiest  of us to treat. All had relapsed after up to 10 prior therapies, 27 had refractory disease, more that half had bulky nodes, and nearly all had had prior B/R (bendamustine/rituximab).

In the group that was randomized to get B (bendamustine) with the GS1101, the intent to treat overall response rate (ORR) was 82%. Adding rituximab (the BR group) raised that to 87%.

But here is the number that excites me. Leave out the chemo (bendamustine) completely, and use only biological therapies with the combination of CD20 antibody, rituximab, and the new PI3K∂ inhibitor, the response rate was a very respectable 78% in these tough patients. 

Minimum follow-up was 40 weeks for each arm with the one year progression free survival numbers being very similar to the ORR.

Nodes shrunk rapidly in almost everyone. Disease related cytokines, elevated at the start of therapy fell, and that may explain why we feel so much better with these treatments. Elevated cytokines make us feel sick.

In the GS1101 + R (rituximab) group (only 19 patients), 21% (6 patients) got pneumonia, 32% had low neutrophils ( and 11% or two patients had febrile neutropenia) and 21% had low platelets. Only one patient had elevation of the liver enzymes. As expected, the blood work was considerably worse in the  two groups that received bendamustine. Surprising infections were lower in the BR group, but the sample was small with only 15 patients being followed.

The data are very encouraging, but we need much bigger numbers and longer time frames. That is the why we have the phase 3 trials, accruing right now. Check out clinicaltrials.gov for the details. My favorite would be the trial that offers either ofatumumab with or without GS1101 as a way to avoid a chemo arm.

But wait and discuss with your doctors the ibrutinib and ABT-199 trials too if you need to consider therapy soon. I will be reviewing those and some of the related important ASH abstracts here soon. Videos of my interviews with the experts at ASH are being rendered and prepared.

It is good to have choices. Not so long ago, we had almost none. 

Many reasons to be thankful and hopeful.

Randy Shirley: Another CLL Warrior Passes

I had hope to post the good news on GS-1101 from ASH 2012, but life and death have a way of intervening. I will get back to my sharing of the science tomorrow, but my blog has always also been about the journey, the wins and the losses. And sometimes I need to share the bad news too. Sometimes I need to mourn the loss of a friend. Randy Shirley, a fellow CLL battler, passed away yesterday at the age of 55.

Randy Shirley

From my friend Nancy O'Brien Simpson:

Randy Shirley has my kind of leukemia which is currently considered incurable. He was diagnosed October of 2009. Married to his best friend, Debbie, for 33 years with three daughters. He was an awesome poster on my FB leukemia support group. So happy, and brave, and cool! He was young and relatively healthy when he volunteered for a clinical trial (ABT-199). He unexpectedly passed away this morning. Devastating news. The volunteers in the clinical trials pave the way for the rest of us. Sometimes with their very lives. RIP Randy Shirley and thank you. Your presence will be missed so very much.

From me:

I was blindsided by the sudden death of this brave and good man. So sad to lose another CLL warrior. Rest in peace, Randy. The memory of your hope and generosity is a blessing to all of us who were lucky enough to know you. My deepest condolences to his family and friends.

From my friend, Pat Kennedy:

The CLL community has lost a great warrior. Like everyone else I was blindsided by this news. Randy was participating in a clinical trial and had just posted yesterday about how well he was doing. His motto, which you know if you knew Randy, was "Never,Ever Give Up!" and he never did, right to the end. RIP Randy!

From another person in the same trial:

I am not sure you are aware yet but Randy Shirley has passed away.  I just met him and his wife on Monday when I was in Seattle for my monthly blood draw at SCCA.  He said he felt better than he had in years. He was on 300 mg of the drug at the time.  Tuesday AM he began taking 1200 mg of ABT-199.  Sometime on Wednesday he passed away.  I contacted the clinical trial coordinator and they are completely shocked and do not have any information that they are releasing at this point.  So no details.  I am stunned with this news but I know you and Randy have been in contact and he spoke to me Monday about how helpful you had been to him.  Thought you would want to know.  I am lost for words.

Randy and I were in regular contact. He was so upbeat about his trial and his disease. It is way too premature to draw any conclusion about the cause of his death or its possible relationship to the trial drug ABT-199. We know nothing about what led to his unexpected demise. Believe me that in these tragic cases, there will be careful probing into what happened and what can be learned. Believe me that nothing will be swept under the carpet. Trials don't work like that. If there is an issue, it will be outed. The safety profile has been excellent for many others and I would still recommend this drug.

But first I need to mourn the loss of another friend.

ASH 2012: CLL Highlights

I am still traveling, now in Ohio staying with friends for my OSU clinic visit with Dr. Byrd tomorrow. I am expecting that my mildly elevated neutrophils on my last blood draw will turn out just be an unexplained blip. I have other results from that prior visit that I need to discuss here too, but my personal story needs to take a backseat to the wonderful news from ASH for now.

I also have a photo shoot with the doctor, so I need my rest to look my best. More on that later.

When I am home, I will report in much greater detail on ASH 2012, Atlanta, GA, but I want to rush the news out about the big picture as soon as possible, so let me share some overarching highlights as I see them without the stats and scientific explanations behind them.

1. There has never been a year like this for those of us with CLL.
2. There is a palpable excitement and consensus among all the CLL doctors that treatment is radically changing for the better: a paradigm shift in therapy with the end of most chemotherapy possible in the next few years.
3. These new players are mostly oral therapies and are NOT traditional killers of rapidly dividing cells as is traditional chemo, but rather targeted biological drugs.
4. The stars of this sea change are GS1101 (formerly CAL-101), ibrutinib (formerly PCI-32765). and probably the least publicized member of this triumvirate, ABT-199 (a Bcl-2 blocker with amazing but less mature results).
5. Responses rates with these drugs in all comers, including the worst of the worst (think 17p del and refractory patients), are nothing short of astounding with progression free survivals in some treatment naive cohorts at 96% at about two years.
6. Responses get better, not worse, the longer we take these meds.The Kaplan-Meir curves are not falling. Relapses are remaining rare events, al least in the short term. We need longer follow-up for sure, but there is no signal that trouble is brewing,
7. Side effects are minimal and may actually decrease the longer we are on the medications.
8. The bone marrow is spared and infections at least with ibrutinib are not increased. Blood counts may actually improve with treatment.
9. With ibrutinib, there is some reason to believe immunity might improve
10. The data keeps just keeps getting better and better.

Much more to share about CAR-T, "off the shelf" CAR-T, GA-101, lenalinomide, the benefits of ASA and curcumin, and new encouraging data on 11q del, but I am badly sleep deprived so I am quitting here. Plus I need my beauty sleep for my photos.

Trust me that when I do fill in the details you will feel the same excitement that I felt humming in the air in Atlanta.

There is never a good time to get CLL, but there has never been a better time to get CLL.

Clinical Trials: Ibrutinib (PCI 32765), GS1101, ABT199, AVL 292, CAR-T, GA101 and all the Others

At the very engaging, patient education oriented, annual Lymphoma Research Foundation Meeting earlier this month in Manhattan Beach, CLL was among the invited guest, the only leukemia with a place at the table in the three days event, because CLL is at once both a lymphoma and a leukemia. In fact the official name, CLL/SLL or Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, recognizes that dual nature. The clonal fingerprints are identical for both disease. It is just that in SLL none of the cancer has spilled out into the blood stream. Yet. This dual labeling is a good thing as it allows us with CLL/SLL access to more meds (some that are used for leukemias and some that are used for lymphomas) and more importantly, access to more clinical trials.

One of the big pushes at the meeting was to encourage those attending to consider those clinical trials. Pharmacyclics and other pharmaceutical supporters had booths and brochures explaining the trials that they are running.

Speeches from happy patients in deep and durable remissions and from cutting edge researchers told us why clinical trials.gov should be a dog-eared bookmark on our web browser.

The poster boys for selling the risks and benefits of the trials to all patients with lymphomas were two early studies involving new CLL drugs (Ibrutinib and GS 1101) using the visually powerful waterfall plots that tell you about shrinking tumor burden.

Here is some of the early data on ibrutinib (PCI-32765) similar to what was presented.  I could show similarly impressive data for GS-1101(CAL 101).

Every picture tells a story. It's easy to see at a glance that for the vast majority of the patients their tumor burden shrank dramatically.

For many of the attendees this was their first exposure to both the brave new world of tyrosine kinase inhibitors and to what could a trial do for you. I was approached by a few with questions about what was this magical  medicine and how could they get in on the action.

So here is my take on clinical trials.

Now I am not talking about letting your doctor pull off a few extra tubes of blood at each visit to bank for studies down the line. Everyone should say yes to those research requests. 

I am talking about therapeutic trials.

First and foremost, you must need therapy. No matter how excited you are about a new medication, the guidelines as to when to initiate or resume treatment do not change if the therapy is tried and true, cutting edge, or experimental. Maybe 30% of us will never ever need any treatment and remissions  from standard chemo-immunotherapy such as FCR can be remarkably durable. If we don't need treatment, we don't need treatment.

Let's say we do need therapy and we are doing the research to find our therapy choice. Here is where my advice about picking our team of experts becomes so critical, because without a CLL guru at the helm of our ship, we may never know or have easy access to all our options. Each of the top guns in CLL aspires to be the one who discovers the next big thing, and so expect there to be some bias towards his or her own trials. This is not entirely sinister as it is what they know best, and if we are seeing that doctor already, odds are a trial at his or her facility is going to make a lot more sense than traveling across the country for a similar option with all the risks of infections, and all the expense, stress, and just inconvenience that flying and hotel rooms entails. Ask me, I am an expert with trips from Orange County to Columbus Ohio every 3 and 1/2 weeks (and there are no direct flights). 

Still, there might be a better option at a distance. It is incumbent on us to do our own research on the web and at clinical trials.gov. That was certainly the circumstances in my case where my only option for an ibrutinib trial was across the country. Is it fun? NO. Is it worth it? YOU BETCHA!

When we are considering a trial, understand this is not a DIY therapeutic tour, but a tightly scripted and heavily escorted guided tour. This is important. Our appointments, biopsies, and CT scans are part of a rigid schedule, and if we don't like it, well, we can always leave the trial. We shouldn't enter a trial expecting it to change to meet our particular needs. When change comes though the IRB (Institutional Review Board), it is never quick and is always very conservative. They are watching out for our safety, but are also very sensitive to not corrupt the data by changing the rules midstream.

Understand what our insurance will pay and what it will not. Often the only costs covered by the trial sponsor is the medication and special blood tests that monitor its levels. How they get away with saying that a CT scan every three months is usually and customary care for CLL and that we and/or our insurance are responsible for the costs is beyond me, but somehow they do .

Look at what doors this trial might open, and what it might close. Having had a transplant as I have shuts off a lot of options. Will the treatment in the trial preclude further treatments or trials?

If it is a multiple arm trial, we need to be comfortable with all the possible options. Are they all realistic for our circumstances or is one arm a straw man chosen because it will be easy to best and represents nothing that we would ever consider? Can we live with letting a computer program randomly decide whatever treatment we will get?

Does it offer a cross-over if we don't respond to the arm to which we are randomly assigned? I believe that less CT sans and more cross-overs would go a long way to increasing the dismal rate of enrollment in most cancer trials in the USA. Why these are persistent sore issues will be a topic for a follow-up post.

Remember we are starting with the premise that we need treatment, so we can't compare the trial option to doing nothing. We must compare it to what we would do if we weren't in the trial. And that's the rub.

Honestly, despite these caveats, for many relapsed and most refractory CLL patients and for nearly all those with 17p deletion (like me), a trial is often our very best option. It is what I chose. And I am sure glad that I did. My circumstances would likely be very different if it weren't for Clinical Trial NCT01217749 at OSU and my daily 420 mg of ibrutinib.

Another point. We should not think of trials just as a last resort when we are knocking at heaven's gate. It is sadly so rare that such a miracle save happens. Trials are much more likely to be helpful at earlier stages of the disease.

Let's be honest. If the existing therapies were so great, the pharmaceutical companies, the universities, the NIH and all the researchers would not be trying so hard to come up with new ones and there wouldn't be the 1274 CLL trials listed on clinicaltrials.gov. For comparison, strep throat is an illness we nailed decades ago with penicillin and there are only 31 trials listed, nearly all dealing with special populations such as HIV. Most of us with CLL need more research to get us better help, but for the vast majority of us with a strep throat, there are already easy cures.

What I am saying here is that is a desperate need to move the therapy ball forward, to improve our story. As Dr. Susan O'Brien succinctly said: "Those who need treatment for CLL will die of CLL."  Maybe not the cold truth we wanted, but if we are ever going to change that reality, it will be through clinical trials. Conventional therapies, as good as they are, will never change that paradigm. New treatments or protocols are our only hope for a cure.

That's why small phase 1 trials, where there has been an encouraging signal from animal and cell line studies, and now we need to know about dosing and toxicities, make more sense in CLL than in CML where options are already pretty good.

Phase 2 trials are great as there is more experience with the new drug, and now the research is looking at efficacy as well as adverse events. Sometimes the new therapies are used on their own or combined with other standard medications and sometimes new dosing schedules or combos of only already approved drug are tried.

The phase 3 trials are usually the ones that compare the new therapy to standard care and often involves hundreds and hundreds of patients from multiple sites. These are the easiest to find and enroll as they are usually big, but there can be very strict inclusion and exclusion criteria.

Truth is that we help with advancing knowledge whether or not the trial brings us any direct clinical benefit. While it's a good feeling to be beneficent, it is a much better feeling to be beneficent and healthy. Choose carefully. Ask for help.

Today, in CLL, they are so many promising choices in trials. The late Dr. Hamblin implored us to think laterally and trials are one of our best way to do that. 

Last point. With the increased understanding of the biology and structure of the cancerous CLL cells, the new targeted therapies that today are only available in clinical trials are often a better bet or at least an equivalent option when compared to the less specific existing chemo-immunotherapies. In other words, while we are lab rats when we enter a trial these days, odds are improving that we will be long lived lab rats.