EHA 2019: Dr. Susan O’Brien on Frontline Therapy in CLL
Take Away Points
- Chemotherapy used in chronic lymphocytic leukemia (CLL) mostly works by damaging the DNA of dividing cells.
- There are many short-term and long-term risks with chemotherapy and off-target damage.
- Without an intact p53 (cell suicide) pathway, which is missing with deletion 17p, chemotherapy doesn’t work well and should be avoided.
- When used in the right patients, a short duration of chemo-immunotherapy (CIT or the combination of chemotherapy with immunotherapy, usually a monoclonal antibody or mAb) has been shown to prolong life, and to provide deep remissions, even for more than a decade for some patients.
Chemotherapy
What is chemotherapy and why does it have such a bad rap?
After cancer itself, chemo is perhaps the other big C that we fear, but what is the reality behind that fear.
Let’s start by explaining what we mean when we say chemo.
Different doctors and patients use the term “chemo” differently and often imprecisely.
While the term chemotherapy or “chemo’ can loosely be understood to mean any drug that is anti-cancer, I will restrict our discussion to a more focused examination of cytotoxic agents.
What does cytotoxic mean?
“Cyto” means cell and “toxic” of course means poison.
So cytotoxic chemotherapy means drugs that poison cancer cells. They usually do so by messing with their DNA and with DNA that is damaged enough, cells can’t reproduce.
The good news is that cancers cells tend to divide rapidly and have lousy repair mechanisms for damaged DNA. This is the perfect target for these drugs, and the reason that they are so effective. Chemotherapy preferentially kills cancer cells and clearly has saved lives of many cancer survivors.
Types of Chemotherapy Used in CLL
In CLL, while many types of drugs have been used in rare circumstances, there are really only two commonly prescribed classes of chemotherapy drugs.
Most of the chemo used in CLL is rather gentle in comparison to the cocktails used to treat many other tumors.
The first and oldest class of drugs used in CLL are alkyating agents. These are direct descendants of the infamous World War I mustard gas. These include, chlorambucil, bendamustine (B) and cyclophosphamide(C). As the name implies, they substitute an alkyl group for a hydrogen atom on the DNA that ultimately leads to crosslinking in the DNA chain. This crosslinking causes misreading of the genetic code and hence lousy copying of the cell’s reproductive and repair information, ultimately alerting the cell to clean up the mess. If the damage is too extensive, the cell gets a message that it should commit suicide, known by its scientific name, as apoptosis or programmed cell death.
But therein lies the Achilles heel of all these therapies.
These drugs are dependent on an intact pathway within the cancer clone that carries out the suicide of the badly damaged cell. Both the p53 gene and ATM gene are critical to the integrity of the suicide pathway. If there is no p53 gene present as occurs with deletion 17p and less so if there is no ATM gene as occurs with deletion 11q, the efficacy of the drug is severely impaired.
The other big class of cytotoxic chemo drugs that changed the treatment of CLL for the better is called the anti-metabolites, specifically a subgroup called the purine analogs. Fludarabine (F) is the best known purine analog, followed by pentostatin (P). They mimic the structure of the nucleoside bases of DNA but aren’t functional hence they interfere with the cell’s ability to process DNA and replicate. The key fits, but the lock doesn’t turn.
Both alkylating agents and anti-metabolites can kill both reproducing and quiescent CLL cells, but again they don’t do nearly as well without an intact path to apoptosis, missing in those of us without a functional p53 protein.
And if only a small percentage of our cells are missing the p53, those will be the ones that preferentially survive the chemotherapy onslaught, and potentially leave us with a more aggressive clone to deal with at relapse.
The negative implication of this Darwinian survival of the fittest is the perfect segue to our next topic.
The Downside to Chemotherapy
Cancer cells are not the only ones susceptible to the type of damage caused by chemo.
The bad news is these drugs are not “targeted therapy” but rather indiscriminately affect any rapidly growing cells. This explains their side effects. Hair loss is just the tip of the iceberg. The real concerns are GI issues, bone marrow suppression and immunosuppression that are often part of the package. These are our body parts that are constantly dividing and renewing themselves.
Seeing as we are already immune suppressed and one reason that we might need therapy is due to our low blood counts, taking drugs to fix our cancer that further suppress our immunity and our marrow can be a bit of a head scratcher.
These drugs can also damage fertility and perhaps most ironically, they are carcinogenic or cancer causing, especially regarding blood cancers. FCR (fludarabine, cyclophosphamide, and rituximab) probably carries a 5-10% risk of MDS (myelodysplastic syndromes). Since we already are at a high-risk for secondary cancers, this is an inconvenient truth that we need to face and weigh-in on when making treatment decisions.
There’s more bad news. Because chemo damages our DNA, it may increase the risk of our cancer further mutating and becoming more aggressive and refractory to therapy.
So why do we use these drugs with all their baggage?
The Upside to Chemotherapy
So far, I have only shared one side of the story.
The short answer is that we use them because they work.
There is strong data to support their efficacy, although they haven’t proven to cure us yet.
These drugs are most often used in sensible and well-studied combinations with immunotherapies, usually a monoclonal antibody (mAb) such a rituximab, known as chemo-immunotherapy or CIT for short. Cocktails such as FCR (fludarabine, cyclophosphamide, and rituximab) or BR (bendamustine and rituximab) or chlorambucil and obinutuzumab, can offer some of us a very tolerable path to very long remissions.
In fact, all of the above combinations have been proven to improve our progression free survival (PFS).
FCR combination was the first therapy in CLL shown to significantly prolong our lives or overall survival (OS). This was the big news at ASH just a few years ago. And so it should have been. Before FCR, nothing, and I mean nothing, had been shown to help us to live longer. Now many CIT combinations come with that promise.
Another point in their favor is that these compounds have been around for many years and most oncologists are very familiar with them and are competent in their use. They know what to expect and can prepare for it. They have a track record.
Many are now available in generic form and so are often much less costly than most of the new targeted agents.
Due their long history of proven success and their lower cost, most insurance insists on them being used as frontline therapy.
The duration of therapy is finite with CIT, usually 6 months or less, and then hopefully we are on a glide path with a very long remission. In contrast, many targeted therapies may need to be continued lifelong. This is not a trivial difference for us or for society as a whole.
Nearly all the short-term toxicities of chemo are manageable. The vast majority of us survive our chemotherapy. We have drugs and prophylactic strategies to handle the low blood counts, infection risks and other complications. Even our hair grows back, often curlier and thicker. Actually hair loss is very rare with most CIT used for CLL.
Finally, the long-term effects, while more concerning, are still relatively rare. And they can sometimes occur in those who have had no chemotherapy, so the cause and effect with chemo is not a lock.
Summary
If we look to the history of any and all prior cancer cures, we are going to need well-conceived combination therapies that may very well include CIT to get to us to cure. No single drug, no matter how targeted or potent is likely to carry that ball over the goal line. It hasn’t worked that way in solid tumors or other blood cancers. For reaching that elusive goal of a cure, we will almost certainly need a team of drugs. Single agent chemo is rarely indicated. Cytotoxic agents today are being used in creative combinations, often with a novel targeted agent or with immunotherapy or both (as an example, see the Helios trial from ASCO 2015 that attempts to improve on BR by adding ibrutinib). CIT has already proven not only to prolong our overall survival. For some subgroups of us CLL patients, six months of treatment with FCR can bring more than a dozen years of no CLL. As an example, a friend is more than a decade out, alive and well with his CLL under control after FCR and no further CLL therapies in all those years. However recently he has been dealing with myelofibrosis, a rare and serious blood marrow cancer that may or may not be secondary to his CIT. Robin Roberts is another cancer patient who has been public about developing MDS secondary to her chemotherapy for breast cancer.
Before we throw out all these agents, let’s take a hard look at who might best benefit from them, how and when they should be used, what combinations make the most sense, what might get to CURE, and what we can do to enjoy the most benefit with the least risk.
Our decision to use or not to use chemo-immunotherapy (CIT) as part of our treatment is one that involves weighing many complex factors and should be discussed with our treating doctors and us.
Final word is that this is not the final word. The CLL therapeutic landscape is rapidly changing and the role of CIT is likely to be much different in the future. It has already shrunken dramatically in the last few years. It should no longer be used in those of us with deletion 17p or nonfunctional p53. Its role is becoming more restricted to frontline use, or as the chemo backbone of a combo trial with a novel therapy, or more rarely, when novel agents and clinical trials are no longer helpful, as a last ditch salvage therapy prior to transplant.
If you prefer to look and listen, here is a video of me reading a much shorter version of this discussion.
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Brian Koffman 6/1/15
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