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. 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: 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.

PCI-32765 or Ibrutininb and why the great responses in CLL

I almost never just have a strictly medical post, but I thought this was such a clear and concise explanation of how ibrutinib (I better get used to PCI-32765's new name) and GS-1101 (another new name, this time for for CAL-101) that it needed to be shared by those considering one of these new agents for treating their CLL.

Dr. Rai has more experience than anyone in treating CLL and he has no time or tolerance for bogus claims or hype, so I deeply respect his opinion.

That doesn't stop me from questioning his argument in favor of combination therapy.

First. it is too early to know what is best. Dr. Wiestner at the NIH is looking at a single agent therapy and others including Dr Byrd at OSU and Dr. O'Brien at MDACC at combinations.

Second, I worry about powerful chemo selecting out the most refractory clone.

And third and most importantly, I believe that these new small molecules portent a sea change in how we treat CLL with the depth of remission not being the measure of success, but rather the duration of the response.

Let me know what you think.

The original article in Blood can be found here:BLOOD article on ibrutinib.

Thanks to Blood and HemOnc Today.

It is an exciting time in the world of CLL.

9 0Posted March 25, 2012

BTK inhibitor linked to CLL regression

de Rooij MF. Blood. 2012;doi:10.1182/blood-2011-11-390989.

The Bruton’s tyrosine kinase inhibitor PCI-32765 demonstrated inhibitive properties in primary chronic

lymphocytic leukemia, according to recent results.

The researchers based their hypothesis on the premise that small molecule drugs that target the B-cell antigen receptor (BCR) signalosome demonstrate efficacy in B-cell non-Hodgkin’s lymphoma. One such drug, the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765, also demonstrates a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis in CLL. This reduction is reversible upon temporary drug deprivation, according to the researchers↓ The researchers hypothesized that the clinical response induced by PCI-32765 reflects impaired integrin- mediated adhesion and/or migration.

In the current study, it is demonstrated that the drug strongly inhibits BCR-controlled signaling and integrin alpha-4 beta-1–mediated adhesion to fibronectin and vascular cell adhesion molecule-1 of lymphoma cell lines and primary CLL cells, according to the results.

It also has been shown that the drug is an inhibitor to CXCL12-, CXCL13- and CCL19-induced signaling, adhesion and migration of primary CLL cells.

“Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of the malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, resulting in the clinically evident CLL regression,” the researchers concluded.

PERSPECTIVE

Two important new drugs have attracted the attention of colleagues all over the world who treat patients with CLL. Both PCI-32765 and GS-1101 demonstrated an extraordinary level of activity when each was used as a single agent in previously treated CLL patients who had bulky lymphadenopathy, and had relapsed or refractory disease. PCI-32765 is an inhibitor of BTK, while GS-1101 is an inhibitor of PI-3 kinase delta isoform. These kinases are considered to be highly active inhibitors of BCR signalling and chemokine networks. The paper by de Rooij and colleagues provides clear and convincing evidence as to how PCI-32765 actually works. These researchers,by meticulous and disciplined work, demonstrate that this drug acts on the micro- environment of lymph nodes and bone marrow where the leukemic cells can live safely and proliferate, an important mechanism for maintenance and progression of the disease. When exposed to PCI-32765, the leukemic cells can no longer hide in their safe harbors of lymph nodes and bone marrow, and they also can no longer continue to proliferate. Being deprived of adhesion-capabilities, these leukemic cells must, therefore, migrate into the circulating blood. That explains why the bulky lymph nodes shrink in size dramatically and rapidly when the patient starts taking this oral medication. This paper also makes it clear as to why the numbers of lymphocytes in the circulating blood increase equally dramatically,at least initially, while the lymph nodes are shrinking. Finally, this paper explains why it will be important to move from using PCI-32765 as a single agent and toward combining it with a monoclonal antibody or chemotherapy, if a lasting and good-quality remission is the desired objective. The leukemic cells pushed out from the lymph nodes and other tissues are eminently killable by cytocidal agents while they are in the blood circulation, where they no longer have the protective chemokines that allowed them to resist while they resided in the lymph nodes. In my view, this is an important contribution that explains the mechanism of action of the exciting and promising new drugs in the treatment of CLL.

– Kanti Rai, MD

HemOnc Today Editorial Board member Disclosure: Dr. Rai reports no relevant financial disclosures.

Copyright © 2012 HemOnc Today. All rights reserved.

More from Brooklyn- Kinase Inhibitors for CLL

Except maybe for a transplant, a cure for CLL is still not around the corner and is not likely going to be a single magic bullet. Progress is rapid and exciting, but clinical application is slow and very very expensive.

What is more likely is that a series of lower toxicity, higher specificity, more personalized therapy will be coming our way.

If we choose wisely, and are on the happy side of the survival curves AND meet the strict entry criteria for a trial (set up to insure approval of the drug and not to help the patients in the study) or the very limited FDA indications for our therapy (established among other reasons to give insurance companies coverage to say no to our needs) AND can afford the possible calamitous expenses of these new approaches either through insurance or our savings, we may be able to keep going for a long long time.

Some of the options include the new generation of small molecules that inhibit pathways that are preferentially expressed in CLL cells. Often these drugs block the cross talk (BCR) with other supporting cells, making the cancer clone more vulnerable.

I didn't see any data in Brooklyn, but I heard reassurance that these oral drugs like PCI 32765 (as the manufacturer's web site says: "As a Btk inhibitor, PCI-32765 blocks BCR signaling in human B cells but does not affect T cell receptor (TCR) signaling") and CAL 101 (a selective PI3 kinase inhibitor) and others in the pipeline not only shrink the nodes, but that the rise in the white count when the clonal cancer cells are run out the nodes is only temporary and it too falls to normal, AND even the bone marrow gets cleaned up.

Few side effects, but the risk of infection is significant and seems to me is a bit underplayed.

These drugs are going to big part of the future of CLL management, but now they are only available in trials, and it seems that you need to stay on them very long term or the leukemia quickly flares up again. Nodes can flare up again almost overnight to bigger than they were before therapy But the argument on the other side, is that if they are so safe, no worries, why not stay on them forever. The drug companies love this logic, but that is true with a ton of other therapies from insulin to blood pressure meds.

To their credit, the drug companies are allowing patients to continue (for free) on the meds after the trials are closed.

Not close to a cure, still they are a big step forward.

For that I am grateful.