Treating Older CLL Patients

Time takes a toll on all of us

Rummaging through some of my mom’s papers I came across snapshots of when I was in high school.  I could hardly recognize myself.  How things have changed, and almost none of the changes are  for the better.

But it is not wrinkles, an extra pound or two and faded hair that I want to discuss.  None of them are welcome, but they are only cosmetic.  What I want to talk about are health conditions that creep in as we age that may impact how your CLL should be treated.  Dr. John Gribben is a recognized CLL expert and I would like to review for you his latest article on the subject of CLL and elderly patients.

One shoe does not fit all

And that is particularly true when making right therapy decisions for older CLL patients.  I confess I had not really thought about it before, but many of the clinical trials that we depend upon to set the stage are just not representative of real life CLL patients.  The exclusion criteria usually rule out anyone with kidney or liver issues, anyone with serious co-morbidities such as heart disease, lung disease, on-going infections, secondary cancers etc.  It follows, many of the clinical trial results discussed on this and other websites are not really relevant when we consider elderly patients with other health issues.

Researchers would like to test their drugs in pristine patients with nothing else wrong with them except CLL.  It kind of makes sense.  Researchers want to figure out how a particular drug or combination works on CLL, with nothing else to complicate evaluation of the results.  But that is not real life.  In real life, we deal with a host of complications all the time.  Life is unfair, it does not throw at us just one curve ball at a time. More often than not, our patients are dealing with multiple problems and CLL is just one of them. This is particularly true as our patients age.  Just because you have CLL  does not mean you get a free pass from heart disease, emphysema, high blood pressure, diabetes, Alzheimer’s, kidney or liver disease, skin / breast / prostate cancer etc.  ALL of these medical issues become more common in an aging population and CLL patients are not exempt.  In fact, our guys are more likely to have second cancers and long lasting infections, courtesy of CLL.

If you are barely “40 something” CLL patient who is otherwise in perfect health, you can skip reading this article.  But for the majority 95% or so of CLL patients, Dr. Gribben has something worth considering.  Here is the abstract of his paper.  Send me a personal email if you would like help locating the full text article.

Expert Rev Anticancer Ther. 2010 Sep;10(9):1389-94.

Chronic lymphocytic leukemia: planning for an aging population.

Gribben JG.

Barts Institute of Cancer, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. j.gribben@qmul.ac.uk

Abstract

Chronic lymphocytic leukemia (CLL) remains incurable, but over the past decade there have been major advances in the understanding of the pathophysiology of CLL and in the treatment of this disease. This has led to greatly increased response rates and durations of response, as well as improved survival. CLL is a disease of the elderly and not all patients are eligible for the aggressive upfront chemoimmunotherapy regimens that are resulting in improved response rates and survival, so what is the optimal treatment approach for more frail elderly patients? It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released. The age range of patients involved in clinical trials is not representative of this disease, and more research is required in patients who are representative of the majority of CLL patients seen in practice before we will see outcome improvements in these more elderly and often more frail patient populations.

PMID: 20836674

Age distribution of CLL patients

Below is a chart that spells it out quite clearly. Chances of being diagnosed with CLL increase as people age.  True, there are a small percentage of very young CLL patients barely in their 40’s.  But the incidence statistics are quite clear, odds of being diagnosed with CLL increase with age.

Dr. Gribben reports roughly 15,500 new CLL patients were diagnosed in 2009.  As you can see from the graph above, chances of being diagnosed with CLL increases with age.  Almost 70% of patients are older than 65 at the time of diagnosis. Less than 2% are younger than 45 years.  (I wonder how many of the really young  CLL patients are part of family clusters where an older blood relative in their families had CLL.  CLL is clearly known to be a familial cancer.  Some evidence points to younger members of family clusters getting the disease at an earlier age, the technical term for it is “anticipation”).  Below is a chart showing age at diagnosis for CLL patients.

Just a couple of decades ago..

Back in the 70’s and earlier, the only realistic option for treating CLL was good old chlorambucil (“Leukeran”).  Since it became clear that patients treated right away with single agent chlorambucil did not live any longer than patients who were treated with this drug only after their CLL had developed significant “B symptoms”, there was no point in treating patients as soon as they were diagnosed.  “Watch & Wait” became the name of the game.   Few patients got “CR” (complete response) or long lasting remissions from single agent chlorambucil treatments.  The aim of therapy was palliative, to reduce symptoms so that patients had better quality of life.

How things have changed in the last decade or so.  Now, palliation is not good enough.  Now, we want to see high response rates, high percentage of complete responses, and most important from patients’ perspective, longer remissions and overall survival. Chemoimmunotherapy combinations such as FCR have been shown to extend overall life, something that is truly worth celebrating.  Just for comparison, it is interesting to note that CR rates went from about 7% in patients treated with single agent chlorambucil to 44-70% among patients treated with FCR.  Dr. Gribben puts it in unequivocal terms: chemoimmunotherapy is the treatment of choice today.  If it is not contra-indicated in your case, that is.

When CLL is just one of many problems

But FCR may not be a slam dunk front-line choice for older patients.  Since the bulk of newly diagnosed CLL patients are in their late 60’s to early 70’s, and then there is typically a couple of years of Watch & Wait before therapy becomes necessary, majority of patients considering therapy options are no spring chickens.  We are talking of people closer to 70 years old than otherwise.

Advancing age is invariably associated with age related health problems.  Every single system in our bodies takes a hit as we age.  Virtuous living and  terrific genes may mean you lucked out and have none of the obvious medical problems of your age cohort.  But it is only a matter of degree. Over 1,000 newly diagnosed patients at Mayo Clinic were evaluated for other major health issues besides CLL. 89% of the patients had at least one additional major co-morbidity, 46% had more than one.

How about you?  Is CLL your only health problem?  Here is a list of the various systems in our bodies that take a hit as we age.  Be honest with yourself as you go down the list and check the ones that may present a problem for you now or down the road as you go through CLL therapy.

It is interesting to see that Dr. Gribben included psychiatric problems in his list.  That does not mean he is only talking about people in late stage dementia or Alzheimer’s disease.  How about garden variety depression?  Going through something like FCR is tough enough, with a long list of potential adverse effects that can gang up on you.  It is never a dull day, and sometimes the relentless march of therapy related side effects (that can last many months even after completion of the 6 months of therapy) can bring even macho men to their knees.  Dealing with these problems day in and day out is not easy, if you are also dealing with depression at the same time.

Do co-morbidities influence outcome?

I have seen no back-to-back clinical trials with chemoimmunotherapy regimens such as FCR where the role of co-morbidities are considered. However, there is information available on survival statistics for patients undergoing mini-allo stem cell transplants.  As you would expect, people with extra medical problems don’t do as well after a mini-allo stem cell transplant. But how much of an effect is there?  Here a graph from none other than the “Hutch” (Fred Hutchinson cancer center, Seattle, WA) that spells it out.  Each major medical issue (other than CLL) is a penalty point.  As you can see, 75% patients with zero penalty points are alive at the two year and 4 year mark.  At the other end of the spectrum, only 30% of  patients with 3 or more penalty points are alive over the same time periods.  Please be aware these survival statistics are based on transplant outcomes done 5-10 years ago and the good news is that the statistics keep improving each and every year.

Moral of the story, just because they have extended the age cut-off for mini-allo transplants does not mean every 75 year old is a good transplant candidate.  If you have more than your share of medical problems associated with a 75 year old, you may want to take a careful look at the value of quality of life versus quantity of life. Going through a stem cell transplant is no picnic, far from it.  If your chances of coming out of it with significantly prolonged life expectancy are not all that good, why put yourself through the loss of quality of life?  Only you can make that call, after discussing the pros and cons with your medical team.

FCR is not everyone’s best therapy option

Below is a list of items to consider in Dr. Gribben’s article, if you are in the market for chemoimmunotherapy regimens such as FCR or FR.  I added a few of mine own as well; all of this is stuff that you should know by now, if you have been a frequent reader of CLL Topics and Updates.  All of them are good recommendations for any CLL patient.  They are particularly important to consider in the case of elderly patients.

Did you know that there is a steady and irreversible decline in thymus function as we age, which in turn decreases the number and effectiveness of T-cells we have available to fight infections and second cancers?  That is because the thymus is where T-cells mature and learn their trade.  “T” in T-cells stands for “Thymus”.  A seventy year old is handicapped in this sense, compared to a 50 year old – even if he feels just fine.  Older people have a harder time fighting infections – plain and simple.  Eating a good diet, exercising etc are good for you for other reasons.  But they don’t do one bit to prolong and improve the function of your thymus.

• Discuss all of your medical problems with your physicians.  Often they do not have access to all of your medical history and in any case it seems to me most physicians have only short term memory. Of particular importance, any recent history of shingles (herpes zoster), hepatitis (HCV, HBV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections.   The reason why these viral infections are important to consider is that fludarabine is justly infamous for killing off what few T-cell defenses you have, making viral reactivation a real possibility to guard against.
• Prophylactic medications such as Valtrex and Famvir may provide much needed protection against shingles. Have you been hospitalized for pneumonia (pneumocystis carinii) recently?   Bactrim is standard prophylaxis to protect against pneumocystis carini.
• I will have more to say about Rituxan and hepatitis in my next article, please bear with me.
• Fortunately for us, most of the drugs used to treat CLL are not particularly toxic to the heart. The “H” in the popular therapy regimen called CHOP stands for  hydroxydaunorubicin (also called doxorubicin or Adriamycin) has significant cardiac toxicity, but this combo is rarely used in straightforward CLL.  It is used a lot more in NHL and also for treating CLL patients who have undergone Richter’s transformation.  An analog of doxorubicin called mitoxantrone (with cardiac toxicity to match) has been used in some CLL clinical trials, along with FCR.  I have a poor opinion of adding ever more toxic drugs to an already high impact regimen such as FCR.
• Renal (kidney) toxicity is the one to watch for.  Both fludarabine and cyclophosphamide have kidney toxicity.  If you have had problems with your kidneys in the past, it is important that your doctor knows about it ahead of initiating FCR or similar regimen.  It is also important to discuss use of allopurinol as prophylaxis to protect against kidney damage and “tumor lysis syndrome“.  You can do your bit by staying well hydrated and visiting the facilities frequently, so that your bladder does not take a hit either.
• Make sure the nurse does not rush the administration of Rituxan.  Infusion related adverse effects of Rituxan and significantly reduced if the drug is given very, very slowly – especially the first time you get it.  Make it a point to get your appointment for early in the morning, so the nursing staff are not in a hurry to quit work and go home for the day, therefore rushing the rate of infusion.
• If there is concern that your health does not permit use of full strength FCR, it may be time to consider lower doses.  “FCR Lite“, for example, reduces the “F” and “C” contributions while dramatically increasing the amount of “R”.  Does it work as well as full strength FCR?  Hard to tell, since there is no back-to-back comparison of the two versions.  Along the same lines, does FR work as well as FCR? Dropping the “C” in FCR surely reduces the toxicity of the combination, but it is probably at the expense of reducing the efficacy of the therapy as well. People with 11q deletion (FISH) are better off using FCR rather than FR.
• Old fashioned chlorambucil is not that popular in the USA, but it is still used quite often in Europe – rightly so in my opinion.  It has the advantage of being a cheap drug (off patent), you just fill a prescription and swallow a pill in the comfort of your own home.  It has relatively easy to take, no nausea, GI distress etc.  But make no bones about it, chlorambucil is every bit an alkylating agent as is cyclophosphamide, with all the toxicities associated with that classification.  Neither chlorambucil nor cyclophosphamide as single agents give deep or lasting remissions.  You get what you pay for.  But for an elderly and frail CLL patient with limited physical and financial resources, chlorambucil may still be a good option.  It is a good palliative drug, improving quality of life by reducing B-symptoms such as fatigue, night sweats etc.
• Keep your fingers (and toes, and eyes) crossed that the new fangled kinase inhibitors such as CAL-101 continue to look good and that they get approved quickly for general use.  I like the low adverse effect profile seen thus far, I like the fact that they are oral drugs and do not require a trip to the infusion chair, they seem to work by entirely different mechanisms than standard chemotherapy drugs such as fludarabine and cyclophosphamide.  No doubt they will cost an arm and a leg – what else is new.
• Do NOT assume that just because Revlimid (lenalidomide) is an oral drug, a daily pill you swallow each night, that it has a  low adverse effect profile.  Revlimid has a long list of possible side effects, not the least of which is the infamous “Tumor flare reaction“.  It can also cause deep hematological toxicity, with reduced counts of neutrophils, red blood cells and platelets.  Another thing to be aware of is its propensity to cause blood clots and possibly deep vein thrombosis (DVT).  Revlimid should not be administered except by physicians familiar with its peculiar toxicity profile.
• R+ HDMP (Rituxan + high dose methylprednisolone) is often recommended to elderly and frail CLL  patients.  We are talking of really high dose methylprednisolone.  If you have diabetes, this is something to discuss with your doctor before starting on R+HDMP, since the high dose of corticosteroidal drugs can play havoc with your blood sugar level.
• Another combination that was studied at M. D. Anderson a couple of years ago (but I have not seen it followed up any place else) is combination of Rituxan + GMCSF (granulocyte-macrophage colony stimulating factor – a growth factor similar to Neupogen and Neulasta, except that it also stimulates production of macrophages in addition to neutrophils).  For a while this was the recommended therapy for elderly patients treated at M. D. Anderson; perhaps it still is.  If you went through this regimen, do tell us how it worked for you.
• I am sure there are a bunch more issues to consider before signing up for FCR.  If you can think of any that I have forgotten, do write about them in the discussion section.  My reviews are just a way of getting the discussion going, your comments add significantly to the overall value of these articles.

Editorial

Doctors and researchers don’t often get involved in individual patient’s personal problems.  This may be because there are no real good answers, nothing that the physician can do to solve the problem. Nevertheless, individual patient concerns (over and beyond the body systems listed in the chart above) do have a role to play in making therapy choices.  We are more than the sum total of our purely medical problems.

I suppose money (lack thereof) and inadequate medical insurance are not systematic health issues, but they may as well be.  Without financial resources and robust medical insurance to back you up, chemoimmunotherapy options such as FCR are a lot more expensive than old fashioned chlorambucil.  I am always depressed and at a loss as to what to suggest when I hear from people with these particular “co-morbidities”.

Another related issue is lack of social network.  This too is a “co-morbidity” that is increasingly likely as we age.  Spouses die, children move away, old friends are under the weather themselves.  We get more isolated and lonely as we age.  Who will drive you to the many infusions you need for six months of FCR therapy?  Who will take care of things that need to be taken care of in your daily life, if you are among the unlucky with deep seated anemia and resulting fatigue? What if you need to be hospitalized for pneumonia? Who will take care of your cats or dog when you are not there to take care of them?

There are really no good answers, certainly none that fit every situation.  All I can suggest is that you evaluate your own situation as honestly as you can, so that you can make therapy decisions that are right for you. They say misery loves company.  If that is true, it might help to know that each and everyone of us is aging at the same rate, all of us face many of the same issues as we age.  You are not alone. Finding emotional balance is not easy, especially when we face health issues. Hopefully websites such as this one will help you to reach out to others that can understand what you are going through. Do the best you can, and remember that no one can be expected to do more than that.