Sometimes, Pulling Your Punches is a Good Thing To Do
It is a bit counter intuitive to treat an incurable cancer with kindness and gentleness. After all, CLL is our mortal enemy, it is an incurable cancer – should we not be looking to eradicate it by hitting it with every weapon in our arsenal? Once “Watch & Wait” is over, conventional wisdom in the past few years when treating CLL patients has been to try and achieve MRD (minimum residual disease) negative status at almost any cost – hence the interest in exploring therapy options such as CFAR and a host of other overkill combinations. CLL is a nuanced cancer and we need to treat it with equally nuanced therapy options.
The problem is, CLL does not exactly track other more familiar solid cancers. I would not go as far as calling it a “good” cancer, but for the most part it is an indolent cancer. With the exception of a percentage of patients cursed with very aggressive version of it, CLL is a bit of a drama queen that drags on and on. Patients suffer B-symptoms, autoimmune disease, secondary infections and secondary cancers etc during their CLL career – a long and depressing list of nasty stuff. Sometimes, I wonder if this death due to a thousand cuts is not more frustrating and hurtful than other cancers which finish their jobs quickly and efficiently. Not really, of course.
I think you would agree, it does not help if we succeed in getting deep remissions and the coveted MRD negative status if in the process of getting there we kill the patient too. “Death due to therapy” is not all that uncommon. Since our guys also tend to be older, how much therapy they can tolerate is an important question. Are six cycles of full strength FCR the slam dunk gold standard therapy option – even for elderly patients?
At the other end of the spectrum, chlorambucil (“Leukeran”) is often prescribed as a no-brainer choice for older patients. This drug certainly does not pose as much toxicity as FCR. It is popular drug of choice by many oncologists and in many countries because (1) it is a cheap and off patent drug (2) it is an oral pill, which means the old dear does not have to deal with nasty needles or intravenous infusions (3) the physical side effects are quite mild and easily tolerated by most people (4) no one is going to get sued for prescribing chlorambucil as a safe choice for older patients. But unfortunately chlorambucil does not pack much of a punch, especially in patients with poor prognostic indicators. Responses are not very deep and remissions are shorter than one would like. After awhile patients develop resistance to the drug.
Is there a better choice? Something that packs a bit more of a wallop than chlorambucil but at the same time has less toxicity than FCR – and while we are making up our wish list – something that is hopefully able to deal with high risk FISH abnormalities? As you might guess, we have not yet reached the promised land of great efficacy and next to zero toxicity, not by any stretch of the imagination. But we are making some progress and I think you ought to take the time to read the details of one promising approach.
Revlimid (lenalidomide) for Elderly Patients
The latest issue of Blood has a very interesting study from M. D. Anderson. Below is the abstract of the article, send me a personal email if you wish to read the full text of the article.
Blood. 2011 Jul 1. [Epub ahead of print]
Lenalidomide (REVLIMID) as initial therapy of elderly patients with chronic lymphocytic leukemia.
Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O’Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A.
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States;
The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL age 65 years and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg per day as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65% including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3-4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 12% of patients. When compared with baseline levels we noted an increase in serum Immunoglobulin levels across all classes and a reduction in CCL3 and CCL4 plasma levels were noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered in www.ClinicalTrials.gov (ID# NCT00535873).
An Expert Speaks Out
Before I give you my take on this important paper, I thought I would share with you comments from a far more credible source than yours truly. Dr. Kanti Rai is one of our best CLL experts. This is what he had to say about this study:
“This paper presents extremely positive evidence in favor of lenalidomide. Previously published results from studies of successful chemo-immunotherapies tend to exclude elderly patients because elderly patients have comorbidities and often cannot meet eligibility requirements. This study looks at this population directly and comes up with evidence that lenalidomide has efficacy. I particularly like that the investigators identified that, when dealing with elderly people, the classic objectives of complete remission or minimal disease negativity are not very realistic. These investigators instead focused on what impact lenalidomide had on daily activity level, need for the patient to return to the clinic, duration of response and time to next treatment. Badoux et al had very practical goals and I laud them for it. I would like to see more studies with these types of objectives to furter our quest for better treatment strategies for elderly patients with CLL”.
Clinical Trial Design
This study recruited 60 previously untreated patients who were 65 years or older. We are talking about frontline therapy, but clearly all the patients were past W&W and needed to start therapy.
They started the patients with a small dose of only 5 mg of lenalidomide (Revlimid) each day. Each cycle was 28 days long. After completion of 2 cycles (8 weeks), dosage was increased by 5mg increments every 28 days, provided the patient tolerated the higher dose. The highest dose aimed for was 25 mg/day, but dosing was adjusted to the highest tolerated dose for each individual patient.
Here is something interesting: the study initially kicked off with a starting dose of 10mg/day followed by rapid dose escalation to 25mg/day in just 21 days. Of the first two patients treated by this rather aggressive dosing scheme, one died of sepsis and the second one had severe tumor lysis syndrome. This in spite of the fact that patients got allopurinol as prophylaxis against tumor lysis. Based on these early results, I am pleased to say the dosing regimen was significantly scaled back.
The chart below describes the patient characteristics. Age at therapy is the one feature that jumps out. Most of the other lenalidomide clinical trials I have seen thus far treated significantly younger patients. Like it or not, age is an important criteria and it is a shame that so many trials use younger patients than is the norm in CLL patient population.
These are pretty mature results, in the sense that patients received daily doses of Revlimid for a median of 27 cycles (that is a little more than 2 years!) Majority of the patients made it up to the 10mg/day dose level. None made it all the way up to 25 mg/day. Right there is an important lesson to learn and remember. Age and dosage matters. If you are considering frontline Revlimid therapy and you are in the age group this study recruited, it may be a smart idea to start with a low dose (5mg or even 2.5mg per day) and increase the dose very slowly. You don’t want the fate of the first two patients in this study that had much more aggressive dosing schedule and paid for it.
The table below gives the usual response statistics. Notice that the responses got better as the patients got more cycles of Revlimid under their belt. The accompanying graph shows how many people were still alive and how many were alive and still in remission.
The full paper has a lot more details about who responded and who did not. Not that all the detailed parsing is of much use, when you slice and dice these statistics into many different groups, before long the numbers are too small to be of any statistical significance. But it is worth noting a few details that are not captured in the charts and graphs.
- It did not make a statistical difference whether patients were in early or late Rai stage – but that could be due to the relatively small sample size of this study.
- Patients with 17p deletions identified by FISH test were less likely to achieve a response. That was disappointing, I was really hoping that since the mechanism of Revlimid was thought to bypass the 17p pathway, these folks would not have to a penalty in terms of response.
- There was no statistical difference between IgVH mutated and unmutated folks, in terms of their ability to achieve a response.
- Maximum tolerated dose did make a difference. Higher average daily dose during the first 6 cycles was associated with higher chance of response.
- There were 7 deaths. Of these, 3 died more than 18 months after start of therapy and subsequent discontinuation shortly thereafter. One death was due to Richter’s transformation 10 months after therapy. Two patients died of unrelated cancers that may have been present even before start of this study.
- Now for some very encouraging news: as most of you know, CLL patients are prone to low immunoglobulin levels and these levels drop as the disease progresses. Low immunoglobulin levels are one reason why our guys are more prone to infections. Lenalidomide therapy seems to be unique in reversing this trend in immunoglobulin levels. In patients who finished atleast 15 cycles of therapy, immunoglobulin levels increased across all Ig classes (IgG, IgA and IgM).
Anyone who thinks Revlimid therapy is a walk in the park are going to be sadly surprised. Especially in older patients with less bone marrow and stem cell reserves, blood toxicity is likely to be high. But even with that caveat, I was surprised by the very high percentage of patients who had high grade 3-4 neutropenia. The chart below describes the hematological toxicity as well as the level of infections. Once again, you should be aware that grades 1-2 are not so severe. Grades 3-4 are a lot more serious.
It cannot be disputed that a large majority of CLL patients are ready for Social Security. True, there is a smaller group of patients who are much younger, people in their forties or even younger, stricken with this awful disease. I will address their special needs in a later article. But for now, let us focus on the majority of CLL patients who are 65 or older, as this article does.
Older patients have additional medical needs. For starters, they have significantly reduced immune function and bone marrow function than younger folks – even in the absence of CLL diagnosis. T-cells become less efficient as the thymus decays – part of the aging process – and a healthy thymus is necessary for training of newly minted T-cells. Immunoglobulin counts drift downward and certainly the repertoire of immunoglobulin variety decreases, meaning it is harder to fight all the zillions of pathogens that test our defenses. Stem cell counts decrease and the ability of stem cells to regenerate themselves as well as create new blood cells decreases. All in all, older folks are more prone to infections, more likely to have anemia, fewer immune defenses, and less robust stem cell reservoir in their bone marrow.
These crucial differences between younger and older patients must be taken into account when making therapy decisions. An otherwise healthy 45 year old can well tolerate 6 cycles of FCR. Cytopenias (anemia, neutropenia, thrombocytopenia) due to therapy are reasonably quickly reversed as bone marrow and stem cells kick into high gear. Infections are easier to fight with a younger immune system, even with CLL. You saw older patients did not do very well with higher doses of Revlimid, the toxicity of higher doses was just too much for this older patient cohort. Younger patients can probably afford to start at a higher dose and escalate the dose more quickly than older patients. Unfortunately, there is a correlation between Revlimid dose and the depth of remission obtained. Lower doses pack smaller punch.
What is a realistic goal in treating elderly CLL patients, especially if they have other medical conditions to complicate matters? The answer depends on what the patient wants, his particular medical situation and what he is willing to risk in order to try and get what he wants. Here are some choices in increasing order of aggressiveness, when W&W ends and B-symptoms raise their ugly heads
- Do nothing. Go gently into that long good night. Untreated CLL that has gone past the W&W stage will not go away by ignoring it. The most likely outcome is uncontrollable infection of some sort, most often pneumonia. How about quality of life? Not so good, I am afraid. Anemia may make you feel tired and dispirited all the time. Hospitalizations for frequent infections are no fun. While CLL is generally not associated with massive amounts of pain, swollen lymph nodes and spleen are hardly comfortable to live with. B-symptoms are a bitch. Frankly, I am not a fan of the do-nothing option when treatment time rolls around.
- Treat with chlorambucil. It is cheap, it is an oral pill, and it will likely roll back the B-symptoms as the tumor burden decreases. It won’t work very well in people with poor prognostic indicators. And in any case, people will develop resistance to it sooner or later. Remissions are not very deep and responses do not last very long.
- Lower dose Revlimid therapy, as outlined in this paper. It too is an orally taken pill, but by no means cheap. It has significantly more adverse effects than good old chlorambucil, but there is a much better chance of getting durable remissions. Increased immunoglobulin levels and improved health of T-cells and NK-cells may help thwart infections down the line. Not quite the fountain of youth, but this feature of Revlimid sure beats a kick in the head.
- FCR “Lite” type approaches may work in older patients – something worth exploring. But the decisions have to be made on a case by case basis, depending on the specific medical needs of individual patients.
- Full strength FCR, all 6 cycles of it, may be more than most elderly patients can tolerate. If the therapy does not finish them off first, they may get nice remissions. But the risk is hard to evaluate. It may be possible to go the FCR route, without reducing the dosages as in FCR Lite, if the number of cycles is reduced. Four color flow cytometry is a wonderful invention. This is a simple blood test and it may give the physician a way of finessing the issue, stop short of the 6 cycles if he thinks the remission is good enough for government work, in view of the toxicity penalty that increases with each cycle.
- Stem cell transplant. In this era of mini-allo (non-myeloablative) stem cell transplants, the protocols have become a lot less aggressive and therefore the inclusion criteria have become more flexible. Older patients can now opt for a mini-allo stem cell transplant, where as they would have been excluded before. But just because an option is available does not mean it is the best option. Age at transplant is a clear indicator of likelihood of successful transplant – especially if the patient has other age related medical issues such as cardiac disease, high blood pressure, diabetes, kidney or liver issues etc. Transplant related mortality and morbidity is clearly influenced by age and health of the patient.
- Wild cards such as participation in early stage clinical trials. Drugs such as CAL-101 and PCI-32765 are attractive options for those who are not happy with any of the options listed above and would like to test their luck with less well understood therapy options.
There are many other options that fit at different points on this scale of low to high aggressive choices. R+HDMP (Rituxan + high dose methylprednisolone) and single agent monoclonal antibody regimens (Rituxan, Campath, Arzerra) come to mind. I am sure you can come up with other variations on the theme as well.
Where do you fit on this scale? What is your best choice? Those are decisions only you can make, after thoughtful discussions with your physicians. Your input into these discussions is essential. How do you weigh the need for quality of life versus sticking around for a few more Christmases? How good are your social support systems? Insurance? Finances? Willingness to fight and put up with the consequences? Who can make these decisions without your input?
Once again, in order to makeup for the oversight of the researchers, please join me in a sincere round of applause and thanks for the patients who volunteered for this clinical trial.
Site News (please read)
For a variety of reasons mostly having to do with my own health issues and work load, I am sorry to announce I will not be able to hold the Fall workshop on August 13, as originally planned. I know many of you were planning to attend and I apologize for any inconvenience I might have caused you. Hopefully I can pick up the pace again in the future.