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.

ASH Abstract: Long-Lasting Responses with Lenalidomide As Initial Therapy of Elderly Patients with Chronic Lymphocytic Leukemia (CLL)

Here's another abstract from ASH, # 3932.

I need to be reminded that most patients with CLL are elderly. The median age at time of diagnosis is about 71 or 72. I tend to be in touch with a skewed population sample as I suspect that those who follow my blog and are active on a list serve or Yahoo group might be a younger bunch. There are of course many many exceptions.

Our bone marrow becomes less resilient as we age (doesn't everything), so the standard approach of FCR can be hard and persistently dangerous low blood counts can delay or even prevent a full course the chemo-immunotherapy. And some elderly may not tolerate the adverse events as well, especially those who have picked up co-morbidities during their long lives.

That is why it is encouraging to see non chemo approaches to CLL, this time with the immune modulator, lenalidomide (the son of the infamous thalidomide that caused so many birth defects).

No-one is quite sure how it works, but that is a topic for another post.

The old good news is that it is a pill (no infusion needed) and the response rate is high with two out of three patients responding and a whopping 88% alive at two years. What is new this year that is being presented at ASH 2012 is that the researchers continued to follow this cohort and now three full years out (or longer) 31 of 60 are still responding. 29 of those 31 are in a CR (complete remission) with 4 MRD negative (minimal residual disease negative) CR. Very nice durable responses in a little over half of the patients for  at least 36 months! 

The median dose was low, only 5 mg a day, with a range of 2.5-10. That's good. This is one drug that is cheaper and safer at lower doses. Side effects that led to stopping the drug were the usual suspects: DVT (deep vein thrombosis) fatigue, secondary cancers (skin), and neuropathy.

Neutropenia resolved in 83% patients within a year. Hgb (100%), platelets (77%) and even immune globulin (IGG, IGM and IGA levels were higher than baseline in those who were long term survivors. T cell counts increased, More good news and a very different story than told by most chemo drugs.

The bad news is that it doesn't work for those who need it the most. Long term survivors "were more likely to have lower baseline levels of beta2-microglobulin, IL6, IL8, IFNγ and MIP1α and intermediate or favorable cytogenetic abnormalities."

In other words, those whom are favorable to treat, are favorable to treat. Those of us with poor prognostic factor live up to our billing, at least with this drug.

Remember also that everything has its price Lenalidomide is associated with potentially fatal blood clots, tumor lysis syndrome, painful and potentially fatal tumor flares, secondary cancers, suppressed blood counts, profound fatigue, diarrhea, neuropathies, and serious infections, so use with caution.

Still for half the population, this looks like a fine option. Better than chemo.

For the others. let's check for the news of trials of the tyrosine kinase inhibitors in the elderly.

On a personal note, my blood chemistries remain remarkably unremarkable with kidney and liver function all in the very healthy range. Low LDH and uric acid are also reassuring that nothing sinister is brewing in my blood.

Tonight, I am off to the beach, where there is no WIFI, but my cell phone works. I have mixed feeling about that.

From there I leave for ASH in Atlanta on Friday.  Much to share.

Life is good.