Dr. Terry Hamblin’s third installment of his “What is the aim of treatment?” series has created quite a stir among patients. Many of us, after all, have been assured by our doctors that chemotherapy is pretty harmless, perhaps even desirable, and certainly inevitable. Essentially, Hamblin posits that when it comes to chemo and CLL, we are often putting the cart before the horse. Here is a lengthy but important excerpt:
"Except in the most virulent cases I prefer to take the long view. I’m not much interested in treating a blood count. Treating a blood count is like polishing the bodywork while the engine is disintegrating. I have two concerns. I want the bone marrow to go on making blood cells, and I want to stop the immune system falling apart. So unless the bone marrow is threatened I prefer to avoid treatment. The CLL will eat away at the immune system, but it will do it slowly. Every treatment that I know will make the immune system worse. There is now way of treating the CLL that will restore the damaged immune system.
"So, supportive care is the first thing. Blood transfusion or erythropoietin to keep the haemoglobin high. Surgery for an uncomfortable spleen or one that is consuming red cells or platelets. Irradiation of large or uncomfortable peripheral lymph nodes. Antibiotics for infections. And when infections are caused by low serum immunoglobulins then intravenous immunoglobulin infusions on a regular basis. Do what you can to avoid having to have treatment.
"If treatment is inevitable, my choice would be the treatment that is least harmful. At the moment this is rituximab. It only works in about half the patients, and it does lower the levels of normal B cells, but this is transient and they quickly return. Rituximab plus a growth factor like G-CSF or GM-CSF may well be more effective. So if it works for you and gives you a year off treatment then go for it, and don’t be afraid to repeat it. True rituximab resistance is very rare. In some patients increasing the dose will turn a non-responder into a responder.
"It’s after that that you have to think about chemotherapy, and that is the subject of another article."
I am in general agreement with the doctor and am grateful that he is saying what a lot of us patients have been concluding for a long time: the best course is to play for time and avoid chemo until absolutely, positively necessary.
As we wait for Hamblin’s next article, I do want to make a point about supportive or palliative care followed by the use of single-agent Rituxan. My argument is that Rituxan can be part of that palliative care and should be considered for that purpose before the disease gets so out of control that Rituxan is rendered pretty much useless.
If you just let things go and the marrow gets to the point that one needs transfusions of red blood cells, it is unlikely that Rituxan will be very effective as a next step. Indeed, in a Stage IV type of condition, there may be other factors, especially involving nodes, spleen, or unusual conditions, that might require a more powerful drug response. The value of single-agent Rituxan in such a case may be limited, even with the addition of a growth factor such as G-CSF or GM-CSF.
For one, Rituxan doesn't work too well in the marrow, though anecdotal evidence from the MD Anderson R + GM-CSF trial seems to indicate that it might have a minor beneficial effect. One patient I’ve spoken to, who had bone marrow biopsies both before and after treatment in this trial, reported a small but decent improvement in the marrow -- from 45% CLL cells before treatment to 25% afterwards. (Adding a steroid such as methylprednisolone to the Rituxan would help reduce CLL in the marrow further, as well as reduce the nodes and spleen.)
The finer points of when to palliate and how obviously depend upon one's case of CLL. In my desire to avoid chemo, I am gambling that Rituxan will stave off disease progression -- or at least slow it down -- for as long as possible. (I have had three courses of Rituxan during the past two years.) My plan, then, barring an unforeseen monkey wrench or the arrival of important new drugs on the market, would be 1) Rituxan, 2) palliation when Rituxan fails, then 3) chemo. I am guessing that this will buy me more time than 1) letting the disease progress to the point where palliation is needed and Rituxan may be rather ineffective, then 2) palliation, then 3) chemo. (All these well-laid plans assume, of course, that I don't develop some sort of complication that demands stronger treatment sooner; in the same way that jumping into chemo early can be a mistake, so can avoiding it at all costs when it really is needed.)
I had a baseline BMB done after diagnosis two years ago. It showed 44% CLL cells and 50 to 60% cellularity (the percentage of my bone marrow being used to create cell lines; the rest of the marrow is kept in storage, as it were). This means I have, or had then, a majority of healthy non-CLL cells and a great deal of space for my marrow to make room for cell production. There are patients who don’t have a problem with red blood cell and/or platelet production crashing until their marrow is more than 90% compromised at 100% cellularity. I am hoping that my Rituxan maintenance at the very least will allow me to tread cellular-production water for quite some time.
In addition, there are splenic complications to consider. My spleen balloons between treatments, trapping platelets as it gets clogged with CLL cells and expands. My platelets have been in the normal range but on a gentle decline, and they are always boosted after I have Rituxan, which is working to palliate the symptoms. Would I be better off letting things go and just having the spleen removed? Or are the problems born of Rituxan a better risk than the problems associated with having no spleen?
As to nodes, mine have been reasonably cooperative, numerous but relatively small at their biggest (3 cm or so). There are patients with much bigger nodes. Since some drugs do not work well on large nodes -- notably Rituxan and Campath, the latter being fairly ineffective at the 5 cm level -- I think patients need to think about the implications of leaving them to fester, as it were. Once again, Rituxan can perform a palliative role, reducing the nodes in size for a time and therefore keeping them at bay.
CLL patients face unexpected complications, such as clonal evolution of the disease. The more CLL cells floating around, and the longer you have the disease, the more likely you are to have one of them evolve into an even nastier clone. If Rituxan knocks the CLL population back, it may be a worthy ally here. (When it comes to clonal evolution, given what I know of chemo’s facility for selecting for treatment-resistant clones, I’d rather take my chances with mild treatment or supportive care.)
The whole argument that Rituxan is a suitable tool for palliation hinges on the fact that is is of very low toxicity, at least in most patients. Still, there is risk. Wiping out healthy B cells on a regular basis can contribute to declining immunoglobulins. Rituxan can lead to delayed-onset neutropenia. In rare cases, it can cause severe skin problems. And for the most part, the consequences of repeated re-use of Rituxan as a single agent in CLL are unknown. You have to take your chances.
There are no easy answers and no elegant solutions. The best we can probably hope for is two steps forward and one step back, and even one step forward and two steps back is better than nothing. As Gilda Radner’s Roseanne Rosannadanna used to say, “It’s always something. If it’s not one thing, it’s another.” But one school of thought is that for patients with all but the most aggressive disease, heavy-duty chemotherapy is the last thing to do, not the first.
From today's vantage point it is interesting that I wrote the following:
"My plan, then, barring an unforeseen monkey wrench or the arrival of important new drugs on the market, would be 1) Rituxan, 2) palliation when Rituxan fails, then 3) chemo. I am guessing that this will buy me more time than 1) letting the disease progress to the point where palliation is needed and Rituxan may be rather ineffective, then 2) palliation, then 3) chemo. (All these well-laid plans assume, of course, that I don't develop some sort of complication that demands stronger treatment sooner; in the same way that jumping into chemo early can be a mistake, so can avoiding it at all costs when it really is needed.)"
AIHA, which came a cropping in March 2007, was that complication. I should add that palliation may work in some cases, especially where there is little "bulk" in the nodes, spleen and/or liver. For any number of reasons a great many patients will not have the luxury of this approach. And there is no free lunch: living a transfusion-dependent life certainly diminishes its quality to some extent, and there are risks associated with blood transfusions. Besides viruses and bacteria, these include iron overload. Still, for a few this may be an option. One patient on the ACOR CLL List has done it for years now and with such success that doctors at the NIH want to study her. -- November 18, 2007
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