Friday, August 1, 2014

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)


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.

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Blogger Unknown said...

Good news is always welcome. Seems like a baby step in the direction of Personalized medicine.

Serbian article on distinguishing differences between CLL and SLL prompted me to poke around in the research articles and found this paper on targeting CD22. The researchers did not mention SLL as it only stated CLL in the article. Wonder if this will be a further step in isolating subtypes of CLL/SLL for specific therapies? or


August 2, 2014 at 11:51 AM  

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