More on Halting the Lenalidomide Trial

Please read my immediate prior post on this trial first if you have not already to best understand the context of this post.

I heard from a respected investigator and my person physician in my ibrutinib trial, Dr. John Byrd, involved in the halted trial of Revlimid (lenalidomide) versus Leukeran (chlorambucil) in the elderly with CLL. 

He said the Kaplan Meir curves were narrowing. Deaths are now 28 versus 36, but still with more in the lenalidomide arm. He also said "The cause of death was interspersed among many different causes." And he reiterated "We are very excited about lenalidomide as an immune modulating agent at lower doses" suggesting that we might find use for it at a low dose by not only considering its potential to control the CLL, but also to rebuild our damaged immunity. 

This is completely consistent with the additional information presented below from the well balanced reporting of the Myeloma Beacon News.

I have pasted the last half of their article on the topic, the part that is most pertinent to CLL.

Lessons learned?

1. Don't rush to judgement: Analyze all the data and don't generalize.
2. Don't throw out the baby with the bathwater: Immune modulating drugs may be an important piece in solving the CLL puzzle.
3. Expect the unexpected: Be prepared for something that you are are completely unprepared for.

Here is the last half  on the article. The full  article is available at this link but I jumped to the part that is more focused on CLL

As I said in my prior post, this is an evolving story.

Revlimid Leukemia Trial Halted – No Immediate Impact On Drug’s Use In Myeloma Expected

By Julie Shilane

Published: Jul 19, 2013 4:52 pm

The decision to halt the ORIGIN study was based on an analysis conducted in March that showed CLL pa­tients treated with Revlimid had a 92 percent increased risk of dying compared to those treated with chlor­am­bucil.  Specifically, 16 percent of patients treated with Revlimid had died at that point, compared to 9 percent of patients treated with chlorambucil.

Click on image to view a larger version of it.

The results from the March analysis show that a dif­ference between the overall survival curves started to emerge around 6 months after the start of treatment (see graph on the right).

Celgene told The Beacon that the gap in the sur­viv­al curves has since grown smaller, but has not closed, and that the death rates are currently 18 percent for Revlimid and 13 percent for chlor­am­bucil.  These findings, however, have not yet been reviewed or confirmed by the FDA.

The FDA also has not yet released any information about what factors may have increased the risk of death among Revlimid-treated patients.  A spokes­per­son from the agency told The Beacon, “The FDA is working with [Celgene] to gather the infor­ma­tion needed to better understand the nature of the deaths.”

Greg Geissman, a spokesperson from Celgene, provided some additional information to The Beacon.  He explained that secondary cancers have not contributed to the increased risk of death among patients treated with Revlimid in this study.  He added that secondary cancers were balanced between the two treatment groups, both in terms of the rate of patients developing secondary cancers and the number of deaths at­trib­ut­able to secondary cancers.

Geissman also stated, “As we understand, a preliminary observation shows a greater imbalance in deaths in patients over the age of 80 who have co-morbidities [additional medical conditions]. Our analysis will now look to understand further some of these dynamics and how they may have contributed to the imbalance.”

In addition to analyzing the potential impact of age and co-morbidities on the survival imbalance, Celgene stated that the company will analyze differences in how the patients were cared for at the various centers involved in the study.  The company indicated that the results from these analyses will be presented at an upcoming medical meeting.

The Mayo Clinic’s Dr. Kumar also explained that “Other studies of Revlimid in CLL have shown that these patients can have unique side effects compared to myeloma patients, such as tumor flare.”

A tumor flare reaction is a temporary worsening of symptoms soon after treatment begins.  It can be a sign that treatment is working, but it requires that patients be monitored closely during the first few weeks of treat­ment.

“Given that the [survival] curves start separating out close to a year, it is unlikely that [tumor flare] explains the increased mortality, but it clearly would be one of the aspects to be examined in the future,” explained Dr. Kumar.

“As we know more details about the cause of deaths in the Revlimid arm in the CLL study,” added Dr. Kumar, “we should certainly evaluate if there are specific patients with myeloma where there might be a concern.”

Lenalidomide (Revlimid) Associated with Excess Deaths in the Elderly

Honestly, I didn't see this coming. The IMIDs (immuno-modulating drugs such as lenalidomide or Revlimid) are touted as kinder gentler and safer therapy for the elderly.

Not so says this trial. 

What it found instead in an interim analysis was a significant increase in the number of deaths for those taking lenalidomide compared to those on the old school chemo drug, chlorambucil, an oral alkylating agent.

Now of course the details on the causes of the excessive deaths will help unravel this story, but for now it is a cautionary tale as why we need trials to test what seem to be safe and logical assumptions.

Does this mean if you are in another trial with lenalidomide, you should stop? Absolutely not, but you should discuss with your doctor what this means in your particular circumstance. Probably nothing if you are doing well.

Now this is a newsflash, and the full story is far from told, but since it is a popular non-chemo option out there, I wanted to share this ASAP.

Personally, I still believe there is a role for IMIDs in CLL (too many patients have done well with them), but my bigger belief is that we really have a very primitive understanding of how they work.

We have begun to crack the biology on B cell receptors pathways and BCL-2, but what exactly Revlimid is doing is murky. 

And usually our best results come when we have nailed the underlying basic science. Some drugs have come to us in the past from plain dumb luck, but most of the breakthrough today are based on meticulous pre-clinical basic research.

Here's the news:

GEN News Highlights : Jul 18, 2013

Celgene Halts a Phase III B-Cell CLL Trial Because of Deaths

Celgene today said that after a consultation with the FDA it will stop administering Revlimid® (lenalidomide) in its open-label, Phase III ORIGIN® trial because of patient deaths.

“An imbalance was observed in the number of deaths in patients treated with lenalidomide versus patients treated with chlorambucil,” Celgene said.

The trial, which FDA placed on clinical hold July 12, was intended to evaluate the efficacy and safety of lenalidomide versus chlorambucil as single agent in elderly patients 65 and older with B-cell chronic lymphocytic leukemia (CLL), plus comorbidities that precluded treatment with more aggressive standard chemo-immunotherapies.

The firm noted that, in this particular trial, there were 34 deaths out of 210 patients in the lenalidomide arm compared with 18 deaths out of 211 patients in the chlorambucil group. It added that “all other Celgene-sponsored chronic lymphocytic leukemia clinical trials with lenalidomide are continuing in accordance with their respective protocols.”

Revlimid is approved in the US for the treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies. The drug is also approved in the US, Canada Switzerland, Australia, and New Zealand, Malaysia, Israel, and “several Latin American countries”—according to Celgene—for the treatment of transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. In Europe, the drug is also approved for the treatment of similar patients with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. Revlimid is not approved as a CLL treatment.

Non-Chemo Approaches to CLL in and out of Trials: Lenalidomide

Avoiding chemo, especially when it doesn't cure any of us with CLL/SLL, has always made good sense. My readers know my mantra of protecting our bone marrow and immune defenses for the long term battles aheads again against infections and secondary cancers.

Now with the promise of the approval of all these new agents in sight, many CLL gurus (Kipps, Keating, Byrd and others) hail the twilight of chemo as frontline treatment. Today there are even more reasons to consider non-chemo " bridge therapies" to buy us time until the magic CLL slayers are approved or there is a trial open that accepts someone with our profile (not always easy).

Besides the short term misery of the side effects in the infusion center and for the weeks that follow, why put ourselves at increased risk for secondary cancers (especially other hematological malignancies), bone marrow damage with resulting cytopenias (low blood counts), infections, and maybe even an increased risk of auto-immune issues. If we can hang on for a year or two, we can get a much less toxic therapy from our drugstore, assuming we can find a way to pay the $10,000 or more a month cost, but that's another subject. See my friend, Dr. Jeff Sharman's blog at http://www.cll-nhl.com/2013/05/how-expensive-are-new-drugs.html?m=0 for a nice discussion of that issue.

The good news is that there are already several good non-chemo options available in trials or in the clinic, for use as single agents or in combinations.

Over the next few weeks I will offer up several for your consideration.

I will start with an old friend, one of the choices that is both on the market already and available in some interesting trials.

Lenalidomide (Revlimid), an immunomodulator, is approved for multiple myeloma (MM) and some special cases of myelodysplastic syndrome (MDS). In CLL, the NCCN recommends it as 1st line therapy for those over 70 or sicker younger patients with co-morbidities. That can help you get it off label and with a little bit of effort, have your insurance to help pay for it. At an estimated $425 for each daily 10 mg tablet at Walmart that translates to more than $150,000 per year, we all need some help.

That is one real unsung advantage to a clinical trial: the trial drugs are free.

And Revlimid is also available in several promising trials for CLL. There are two in particular that are very much alike that have me excited: NCT01766583 and NCT01732861 where it is combined with a very specific BTK inhibitor (CC-292 AKA AVI-292 or AVL-292) that is behind the leader of that pack in development, ibrutinib.  More on that drug later. Both of these trials are for those with relapsed or refractory disease.  Read the details. Call the co-ordinator. Become your own expert.

If you go on to http://clinicaltrials.gov/ct2/results?term=lenalidomide+CLL&Search=Search you'll find an impressive list of 75 different trials with lenalidomide for CLLers. Many of these are closed or not recruiting, many are in combo with chemo, and many have restrictive inclusion and exclusion criteria, but take a look and you may find something that fits your need to control the CLL.

Lenalidomide has several advantages. It is an oral medication. It may work better the longer you take it. It is an IMiD that modulates the immune system, and CLL is a disease of the immune system. It doesn't damage DNA or target rapidly dividing cells as does most chemo. It make sense that it might boost the efficacy of other therapies from vaccines to rituximab (AKA R+R), steroids and more.

And as I said, it's not "chemo.

Not that it a free ride. It can suppress blood counts especially neutrophils and platelets, increase infection risk, cause a nasty and potentially dangerous tumor flare and tumor lysis syndrome, make us very sleepy, increases the risk of dangerous blood clots, should never be taken if you could get pregnant (it is closely related to thalidomide that also works in CLL) and it has been associated with more secondary cancers.

Still, today, I definitely sees many circumstances where I would take it ahead of the gold standard, FCR or the new hottie, BR.


Do your homework and check it out.

More soon on other non-chemo options including new and old TKIs and the next generation of MaBs and others.

Also part two of the Wiestner interview from ASH and more details on my recent visit to OSU.