Managing Untreated CLL - When the patient does not want chemotherapy.
(frontline ibrutinib pt here)
(frontline GA-101 pt here or here)
(frontline ibrutinib pt here)
(frontline GA-101 pt here or here)
Who wants chemotherapy? Well, virtually nobody would ever sign up for a dose just for the fun of it. Yet for quite a few years, nothing has come close to the disease control offered by chemotherapy for patients with CLL. While six months of FCR/FR may be one of life’s less pleasant experiences (see my FCR post here), durable disease control is something many would want. Furthermore, in favorable risk CLL, there are some patients that remain without detectable disease for over 10 years. Some thought leaders are even starting to wonder if a small proportion of CLL patients have been cured by aggressive therapy. Fortunately the standard paradigm is beginning to change.
I did my residency at Harvard, my fellowship at Stanford, and now I practice in Oregon. Furthermore, my research efforts have me continually in contact with the well-known investigators from Texas, Ohio, New York and beyond. I am amazed by the geographic variation in both physician and patient attitudes toward treatment options. While generalizations always have limitations, I’ve seen Northeastern / Southern patients enter chemotherapy more willingly than my Stanford / Oregon patients who want just about anything other than chemotherapy. In fact, the “anti-chemotherapy” attitude is so strong in my area I’ve seen numerous patients willing to turn down potentially lifesaving therapies to pursue “alternative care” over my strenuous objections in some cases.
At this point, chemo-immunotherapy rules the day but a handful of other investigators are eagerly trying to advance the idea of avoiding chemotherapy in CLL. Please read the following with considerable skepticism as any deviation from “standard of care” should prove itself before it is offered widely. While different aspects of the science are generally agreed upon, putting it into one entire narrative needs to be directly tested to determine if it is true. I strongly vote for clinical trials in this setting as it is the only way we are really going to make progress against the disease! Fortunately, there is an explosion of trials attempting to go after this exact question.
Modern day chemo-immunotherapy regimens (FCR, FR, BR, R-CVP, R-CHOP) are what we call “geno-toxic.” The best example I can think that illustrates this is a study that came out of the Human Cancer Genome Project looking at brain tumors. In this project, they took samples of patients brain tumors and carefully examined the DNA in just about every technical way they could. In a few cases, they had samples from patients both before and after a treatment called temodar (similar to the “C” in FCR/R-CVP/R-CHOP or the “B” in BR). What they found was unsettling to me. After treatment, tumors contained more than 5x the number of mutations than were present before therapy started.
This should actually not be surprising. “Alkalator” therapy works by binding to DNA and triggering DNA damage. It really shouldn’t be a surprise if we find that our treatment overwhelms the normal DNA repair machinery and leaves cancer cells with more mutations than before. Fludarabine also causes DNA damage but through a different mechanism. While the old adage, “Chemotherapy is more damaging to rapidly dividing cells than stationary ones” has truth, I worry that this sort of approach is like hitting a wasp nest with a baseball bat and killing half the wasps. While that could definitely be considered progress, you put yourself in danger if you’re not prepared for a bunch of angry wasps.
In just about every type of cancer that has been looked at with the full power of modern sequencing technology, there are some alterations in the cancer cells DNA repair machinery. Whether that is BRCA in breast cancer, microsatellite instability in colon cancer, ATM deficiencies like those found in 11q minus CLL, or the old enemy p53 (located on 17p in CLL) that is one of the most commonly mutated proteins in all of cancer. That means that cancer cells are not fixing their DNA as well as normal cells (which is probably how they became cancerous in the first place).
Therefore, we are causing genomic disruption in a genomically unstable environment. This is likely one of the reasons our CLL patients with 11q/17p alterations do not experience the same magnitude of benefit from FCR (ok, 11q respond about as well, but durations don’t last as long). Furthermore, 1/5 patients treated with for CLL will relapse with one of these high risk markers. If you utilize ultra-sensitive tests you find that those high risk cells were probably there from the beginning at a very low level, but now they are the ones that take over as the more “benign” cells have been killed off (sort of like the angry wasps from the nest you smacked above).
So what are the alternatives?
In patients who walk in the door with CLL that contains a high proportion of 17p deletion at baseline, many English or European docs would utilize therapy that relies less upon DNA damage and more upon immune strategies or other mechanisms of cell killing. High dose steroids and Campath has become the standard for many such patients. Interestingly that has not seemed caught on as much in the US. To extend this further, patients with molecular high risk disease are often offered stem cell transplants (the mother of all immune-therapies) provided they are have adequate disease control, are young enough, fit enough, etc.
Other therapies that exert their effectiveness through “non-genotoxic” mechanisms include rituxan, ofatumumab, and revlimid. The first two are antibodies against the cancer cells. Unfortunately, they have their own weaknesses and come nowhere close to matching the effectiveness of FCR, BR, etc.
Revlimid is an interesting molecule and must be carefully considered. It is known as an “immunomodulator” or IMID. Revlimid has a very peculiar activity in CLL that is far from predictable. It is not uncommon to get a “tumor flare” reaction as healthy lymphocytes come flooding into lymph nodes. It can be moderately painful and even require some pain medications. More worrisome however is the occasional patient who experiences “tumor lysis syndrome” in which all the cells die off at once which can cause serious damage to the kidneys or worse. This appears to be loosely related to dose so it is important to start at a low dose and work your way up slowly. This treatment is NOT approved in CLL and access to the drug can be very difficult – though studies are currently ongoing seeking to gain approval in this disease. Some docs who treat a lot of CLL are comfortable using this drug in this disease but many are not.
“Enhancing immunity” is the goal of several new approaches to cancer. T-Cells can be engineered to fight of cancerous B cells. This exciting new technology remains a number of years away and will likely be reserved for patients with refractory disease long before it is given to patients in front line. In solid tumors, new approaches to modify the immune system are definitely turning heads. Anti-CTLA-4 antibodies or PDL-1 antibodies are able to “turn on” parts of the immune system that the cancer has “turned off.” In melanoma this has led to the approval of ipilumimab. Other antibodies are demonstrating efficacy where very little progress has been made in years. There has only been very limited evaluation of the effects of these treatments in NHL/CLL.
Many of the “novel agents” in CLL would be considered “non-genotoxic” and seek to exploit either enhanced immune mediated / antibody based cell killing or target key aspects of the cancer cells survival. Preliminary reports indicate patients with 11q/17p abnormalities respond to a number of these agents. These molecules are currently the subject of numerous ongoing studies.
My hope is that we will be able to utilize therapies in CLL/NHL that do not damage DNA in order to kill off the cancer cells. With a host of therapies working their way through the system, the trick will be to figure out how to combine different treatments to maximize response and minimize side effects (and protect DNA). We currently have the drugs in trials today that could make this a possible reality very soon.
With the average age of 71 at diagnosis for CLL, imagine if we could delay chemotherapy for 5-10 years with effective “targeted” or “immune” therapies. We might find that some patients would never even need chemotherapy. Honestly, I don’t think that is too far off. This approach will need to be intensively studied in the context of clinical trials. When you consider that major research groups are going to begin front line studies in which FCR is directly compared to non-genotoxic targeted therapies – we may be only a few years away.
