Watch & Worry

One of the more infamous phrases that patients learn soon after the CLL diagnosis is “Watch & Wait”.  It is understandable that most of us chickens re-phrase the “W&W” to mean a more realistic “Watch & Worry”.  It is a hard concept to accept and seems counter intuitive at first blush.  The general understanding of cancer treatment is that it is better if the cancer is diagnosed early so that we can hit it right away with everything we got, from multiple fronts - surgery, radiation and chemotherapy.  Why is this not the recommended approach for CLL as well? 

Beast of a different color

Many solid cancers have a short fuse and you do have to hit them and hit them hard first chance you get, to increase your chances of a full cure. That is not the case with the majority of CLL patients.  While some patients do have aggressive CLL, majority of CLL patients have at least a little bit of time to think, learn, plan.  Oncologists who give patients the bum’s rush into therapy immediately after initial (often unconfirmed) diagnosis of CLL are not doing them any favors.

Another reason why solid cancers are treated as soon as they are discovered is to avoid metastasis of the cancer to other parts of the body.  When the cancer is localized to a specific region, say the breast, skin, liver or lungs or whatever, it is more vulnerable to therapy targeted to that specific region. Think of a small group of terrorists conveniently gathered in a single house, ripe for a well targeted attack by the good guys.  Metastasized cancer that has spread elsewhere is a lot harder to eradicate. Now we are talking of house-to-house searching, trying to take out bad guys that can blend in with the general population.  Guerrilla warfare is never as easy as surgical strikes, and it always costs a lot more innocent civilian lives.

CLL does not fit into this general understanding we have of solid cancers.  CLL is a blood cancer, and CLL cells circulate in the blood.  Where does blood go in your body?  Everywhere!  In other words, right from the get-go, CLL is present in every nook and cranny of your body, every place where blood flows.  CLL is 100% metastasized from the day it is diagnosed.  Worrying about CLL spreading through metastasis is a bit like bolting the barn door after the horse has gone over to the next county - no, make that the next state!

Making the case for waiting for as long as possible

Watch & Wait makes sense for CLL, most of the time.  It gives you a chance to get your ducks in a row:

  • Did you get that all important second opinion confirming the diagnosis?  Are you sure what you have is indeed CLL, not a kissing cousin like MCL, NHL, SLVL or some other bit of nasty alphabet soup? Your game plan depends on what you have.  Getting a rock-solid diagnosis is the first step. Most insurance companies are only too happy to cover the cost of a second opinion. Make sure you use that option!
  • May be you got lucky, you have the “smoldering CLL” variety that does not require treatment for a long time, if ever.  There is nothing to be gained by rattling a quiet and peaceful hornets nest with a long stick, is there?
  • Maybe you got unlucky, your CLL is an aggressive variety and you have the worst case FISH result - 17p deletion, with unmutated IgVH thrown in for bad luck.  If this is your profile, single agent fludarabine is not such a good idea, and you may want to be extra nice to all those siblings your parents were generous enough to give you.  One of them may be a perfect match for a mini-allo stem cell transplant down the road. No point rushing into therapy before you get a good fix on the lay of the land, no point in signing up for therapy options that are not going to do much for you, except deal with a lot of adverse effects.
  • Clonal evolution sometimes happens all by itself.  But more often, it is thought to happen after treatment with heavy duty chemotherapy drugs, many of which are mutagenic.  Why help your CLL cells learn new tricks, become that much more dangerous and hard to kill, before you have to?
  • Most therapy options leave patients with immune systems that become even more dysfunctional than they were to begin with.  For that lovely remission patients hope to get there is generally a price to pay -  anemia, neutropenia, increased susceptibility to infections to name a few possibilities.  Some folks luck out, but others report significant loss of quality of life.  Why bring on these problems sooner than you have to?

Is there risk in waiting too long?

Yes, there is such a thing as sticking your head in the sand and waiting ‘forever’. Remember, the phrase is Watch & Wait“, not just “Wait”.  The “Watch” part of the equation is equally important, and it rules out sticking-head-in-sand as a sound game plan. Taking a vacation from CLL is all good and fine. But there is a limit to it.  I had reason to read the riot act to a close friend recently on this subject.

I must have one of the largest anecdotal databases on CLL. I hear from literally thousands of patients from all over the world, describing their particular situation.  Once in a while the letters give me a perspective that I think is important to share with the general patient community. I heard from “Greg”, a smart and detail oriented software engineer a couple of weeks ago. It is not his real name or profession - we are very careful to protect patient confidentiality - but the case history I report is true. This is what Greg had to say (published with his permission):

My experience with the “good kind of cancer” began 4 years ago (December 2024) when I noticed a lymph node under my chin while shaving one morning.  I was officially diagnosed with CLL / SLL soon after.  Although my FISH test said I had “normal” results, I did have elevated CD38 and ZAP70.  My absolute lymphocyte count was in the normal range, bone marrow was 30 to 40% infiltrated with lymphocytes, and my initial CT scan showed only 1-2 cm lymph nodes. I was reassured there was not much to worry about and that sometimes these nodes may even melt away by themselves.

Later I noticed other small nodes in my arm pit but these and the nodes under my chin stayed pretty much stable over the next two and one half years of W&W. I had no symptoms and I remained in good physical condition.

Sometime towards the end of 2024 the white count had increased to 39 thousand. Not all that high compared to some patients I had heard about, and I drew comfort from the stable size of the lymph nodes under my chin, the ones I tracked each day while I shaved. They were my “sentinel nodes”, the canary in the mine I hoped would give me advance notice of progressive disease.

My doctor ordered a CT scan anyway. I was not too thrilled about that.  Why get all that radiation exposure if things were stable? But I went along with his recommendation.  CT scan of the abdomen showed it was basically a solid mass of swollen lymph nodes packed together tightly. The whole mass was 20 cm x 17 cm x 13 cm. I feel I have been betrayed / fooled by the small and deceptively stable nodes under my chin and in my armpit. I had no way of knowing what was going on deep in my abdomen where it was impossible to “feel” anything in just a physical examination.  Even my belt size stayed the same!

Now with a better awareness of the aggressive nature of my brand of CLL/SLL, I am trying to decide my best therapy choices. Most likely I will go for a stem cell transplant sooner rather than later. The first step is to get a good remission ahead of the transplant. The bulky nodes are proving to be tough to eradicate.

Greg did what most of us do, believe the evidence he could see (stable size of nodes under his chin and armpit, reasonably low white blood count), and not worry too much about what he could not see - the abdominal nodes that could only be detected by CT scans.  Now he faces tough choices and not a lot of time to get his ducks in a row.  As most of you know, “bulky” disease (usually defined as bigger than 5 cm) is a lot harder to treat.  Drugs like Campath do not work very well on large lymph nodes - in fact these patients are described as “Campath ineligible”.  If fludarabine does not work, or contra-indicated for some reason (as in 17p (p53) deletion, or autoimmune disease such as AIHA), we are looking at a patient with significant similarities to the “Double Refractory” folks we discussed in the earlier article on Humax-CD20.  For perfectly understandable reasons, Greg waited too long, it would seem.

Most of us are squeamish about getting CT scans.  Who wants to get a dose of radiation for no good reason?  There are now tentative links between CLL and radiation exposure, which makes this decision to scan or not scan all the more tricky - but more about that in another article I have on the drawing board.  For now, the take home message is that while you don’t want to over-indulge in unnecessary CT scans, it might be a good idea to consider getting a scan and bite the bullet once in a couple of years. 

This is particularly true for people who tend to have most of their disease in bulky lymph nodes, folks whose disease is more like SLL than CLL.  Do you have 12 Trisomy or 11q or 17p deletions?  Bulky disease is more of an issue for patients with these FISH abnormalities. Placing your bets on relatively low and stable blood counts may not be sufficient insurance for you, if you are in this group. You may need more frequent CT scans to keep an eye on things, do justice to the “Watch” part of W&W.  I will be the first to admit this is a tough call to make, no black or white slam-dunk choices.  I have come to appreciate how many of the decisions we have to make in CLL arena fall into grey areas.

Got stem cells?

Hematopoietic stem cells (HSC) are a precious resource.  These cells live in specialized niches within your bone marrow.  When called upon they can produce all the various cell lines in your blood, important cell lines such as red blood cells, platelets, neutrophils etc.  Each and everyday blood stem cells give birth to and replace the zillions of blood cells lost to wear and tear. Think of your bone marrow as a factory, and the stem cells as vital machinery that churns out the necessary red blood cells, platelets, neutrophils etc.  simplifying things just a little, three things can get in the way of proper functioning of the factory, bringing the production of life giving red blood cells, platelets and neutrophils to a grinding halt. 

First, if the factory floor gets cluttered to the rafters with garbage so that there is little room for the machinery to work properly, you can imagine this would get in the way of producing the needed cell lines.  When your bone marrow gets increasingly infiltrated with useless CLL cells, this is exactly what happens.  As the disease burden in the bone marrow increases, this congestion is reflected in increasing anemia (reduced red blood cell production), easy bruising (reduced platelet production, increased risk of infections (reduced production of neutrophils).  The only way to fix this problem is to do a hefty job of spring cleaning, free up space in the factory floor - namely, initiate therapy to reduce the number of CLL cells infiltrating the bone marrow.

A second reason why stem cells stop producing the needed cell lines in sufficient quantities is if for some reason they do not get the right signals.  Our bone marrow invented the concept of “just in time manufacturing” long before we discovered it as an efficient way of controlling manufacture of widgets on factory floors in the real world. The signals to stem cells to get off their behind and produce more cells come in the form of growth factor cytokines.  And yes, cancer can interfere with the proper levels of these production signals. 

Fortunately, we now have man-made versions of these production signals. Most of you are familiar with drugs such as Procrit (man-made epoietin, the signal calling for production of more red blood cells), Neupogen (man-made GCSF demanding goosed up neutrophil production), Leukine (GM-CSF calling for more macrophages and neutrophils). Provided the stem cells are in good shape and the factory floor is not too crammed with junk, giving patients these emergency orders to increase production has the desired effect.  There are dangers associated with using man-made growth factors indiscriminately, as we identified in the dark side of epo. More is not necessarily better. Several CLL “opinion leaders” who swore by double and triple shots of epo as a therapy strategy were very upset with me when I started writing about the risk of excessive growth factor use.  I think time has proven I was right on issuing this warning at a time few people were aware of the risks.

But the third reason why production may come to a grinding halt is the most dangerous one of them all, because we do not have an easy fix for solving the problem.  What if the precious stem cells gradually die off?  After all, it is no use sending emergency order for increased production, and /or making sure the factory floor is pristine clean, if the stem cell machinery is busted once and for all.  If the stem cells are dead or dying, we have no way of fixing it.  Patients with stem cell aplasia (fancy words for dead and dying stem cells) become transfusion dependent.  They will need regular infusions of red blood cells, platelets etc just to stay alive. The only long term viable option is to bring in brand new machinery, a new batch of stem cells from the outside - namely, a stem cell transplant with stem cells donated by a willing donor.

What kills stem cells?

Just like other cells in our body, stem cells too die if they are burned by radiation, poisoned by chemotherapy drugs etc.  That is why getting the drug dosages right is so important and it is such an integral part of every clinical trial. Drugs (and radiation) have to be carefully titrated; just enough to kill cancer cells but not so much that irreversible damage is done to other parts of the body - most importantly not so much that the precious stem cells in our bone marrow are damaged. 

But how about CLL cells?  Do CLL cells kill stem cells?  Does increasing level of bone marrow infiltration by CLL cells do more than just clutter up the works? Are we looking at more than just sidelining the stem cells for a while, easily fixed by giving the bone marrow a good spring cleanout? Do CLL cells damage the machinery to the point where it cannot be fixed? The abstract below sheds some light on this important issue.  It seems there is reason to worry that increasing hordes of CLL cells in the bone marrow can cause irreversible damage to stem cells, one more reason why waiting too long can be a self-defeating strategy.

Science. 2024 Dec 19;322(5909):1861-5.

Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells.

Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue MC 2115, Chicago, IL 60637, USA.

The host tissue microenvironment influences malignant cell proliferation and metastasis, but little is known about how tumor-induced changes in the microenvironment affect benign cellular ecosystems. Applying dynamic in vivo imaging to a mouse model, we show that leukemic cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments that sequester transplanted human CD34+ (HPC-enriched) cells. CD34+ cells in leukemic mice declined in number over time and failed to mobilize into the peripheral circulation in response to cytokine stimulation. Neutralization of stem cell factor (SCF) secreted by leukemic cells inhibited CD34+ cell migration into malignant niches, normalized CD34+ cell numbers, and restored CD34+ cell mobilization in leukemic mice. These data suggest that the tumor microenvironment causes HPC (blood stem cells) dysfunction by usurping normal HPC niches and that therapeutic inhibition of HPC interaction with tumor niches may help maintain normal progenitor cell function in the setting of malignancy.

PMID: 19095944

OK, I admit this abstract is not the easiest to read and understand. Some of these researchers need to get remedial writing courses, lean how to contstruct sentences in English that native speakers can understand. Fortunately, a more user-friendly version of the same information is written up in the article below. Think of this as Darwinian fight to the death at the cellular level.  CLL cells in the bone marrow and stem cells compete for the same resources, the same niches in which to grow and thrive.  Kicking out the stem cells and making it hard for them to come back home is a classic survival strategy adopted by cancer cells. It is as if drug dealers and mobsters move into a nice neighborhood.  If allowed to get out of hand the bad guys get the upper hand and law abiding families start moving out.  In no time at all once lovely homes and streets become home to dope peddlers and thugs and the old neighborhood that we cherished starts dying.  Yes, there is such a thing as waiting too long.  “CLL holidays” that last too long can be expensive affairs, as I told my friend.

 

http://www.medicalnewstoday.com/articles/133633.html

Stem Cells And Leukemia Battle For Marrow Microenvironment

Medical News Today

20 Dec 2024 - 1:00 PST

Learning how leukemia takes over privileged “niches” within the bone marrow is helping researchers develop treatment strategies that could protect healthy blood-forming stem cells and improve the outcomes of bone marrow transplantation for leukemia and other types of cancer.

In a paper in the journal Science, available early online Dec. 19, 2024, researchers from the University of Chicago Medical Center show that by blocking one of the chemical signals that leukemic cells release, they could help prevent the cells that mature to become red and white blood cells from being shut down by the cancerous invader.

“We found an approach, in our mouse model, that could help protect the cells that give rise to healthy blood cells, and improve their accessibility for use in autologous transplantation,” said study author Dorothy Sipkins, MD, PhD, assistant professor of medicine at the University of Chicago Medical Center. “The next step is to confirm this in human studies.”

Sipkins and colleagues study the molecular characteristics of tissue microenvironments, or “niches,” within the bone marrow where normal, healthy bone marrow stem cells divide and mature. From these niches, the stem cells produce all the different types of blood cells involved in transporting oxygen from the lungs to the rest of the body, fighting off infections and controlling blood clotting.

In patients with leukemia, however, these stem cells lose their powers. Part of the problem is that they are being crowded out by the rapid multiplication and spread of diseased cells as they take over the bone marrow, but this isn’t always the explanation.

Sipkins and colleagues have shown that the process is far more complicated, and focused, than simply overcrowding. Using sophisticated microscopy tools, they developed systems to monitor the movements of leukemia cells and hematopoietic progenitor cells (HPCs)-a group of cells that includes stem cells as well as more differentiated, though still primitive, progenitor cells that give rise to the various kinds of blood cells-as they struggled for these coveted niche sites.

One of the first actions of cancer cells, they found, is to settle into these niches, taking over the specialized supportive environments that HPCs need to perform their crucial role.

Within days of taking over a niche, leukemia cells began releasing a chemical signal, called stem cell factor (SCF), which attracts normal stem cells back to sites near their now-captive niche. Within one month, the leukemic cells could induce HPCs to leave even tumor-free niches and migrate to malignant sites.

But when the HPCs arrive, other signals released by leukemic cells interfere with the production of healthy new blood cells. As their microenvironments were taken over, the number of HPCs declined. HPCs also stopped responding to drugs designed to coax them out of the bone marrow and into the blood stream, where they could be harvested and used for transplantation.

Sipkins’ team was able to blunt this effect by blocking the release of stem cell factor by tumor cells. When the researchers inhibited stem cell factor, the number of HPCs went back up, as did their ability to migrate out of the bone marrow.

“Our data suggest that therapeutic targeting of SCF may increase the hematopoietic reserve and improve outcomes for bone marrow transplantation and autologous stem cell harvest in the setting of hematopoietic malignancy,” the authors conclude.

“This is not a cure for leukemia,” Sipkins said, “but it’s one more tool. We like to hit cancer from all sides. This approach could potentially boost the immune system’s response to the cancer by protecting the HPCs that are the source of mature immune cells. It could also maintain the patient’s ability to tolerate treatment and to remain active.”

“If human stem cells respond in the same way as mouse cells do, it could buy us time to apply other therapies,” Sipkins added. “By preserving the activity of HPCs and potentially boosting the immune system, the body’s own weapon again leukemia, we support the patient and take away one of the disease’s weapons.”

It could also make transplantation an option for more patients, enabling physicians to collect stem cells from the peripheral blood, which could be banked for bone marrow “rescue,” a technique that restores the patient’s marrow after it was damaged by high-dose chemotherapy targeted at the leukemia.”

Editorial

Anyone looking for easy answers or short sound bites that give us the perfect game plan is in for disappointment.  CLL is a confusing and complicated disease.  So are most cancers, but for cancers with very short fuses patients don’t have a chance to get confused before time runs out and things can get complicated awfully quickly.  There is not enough time to dither, patients are up to their ahem knees in alligators before there is a chance to understand, get the lay of the land and actually hope to influence the outcome with a good game plan.  Most that patients can do is find a good doctor and punt, hoping they made the right choice.

CLL is a “good” cancer because most patients do have time to come to grips with it.  But that is also what makes it so scary and frustrating.  As with all things that go bump in the night, you have the option of pulling the bed sheets over your head and pretend you never heard that “thump” and try to go back to sleep  Or, you can get out of bed, get the flash light from the night stand and go out to investigate.  What you do depends on your personality, your way of doing things. There are no absolute right answers, the “right” answer is the one that is right for you and your family.  My job? Make sure the batteries are working in the flashlight, in case you want to go out and investigate.  The choice is yours, as it should be.

I will not pretend to you that any of these are easy slam-dunk choices.  The devil is indeed in the details, and there are no guarantees.  My husband PC was fully aware of the risks of his aggressive “Bucket C” type CLL; he was perhaps one of the most informed CLL patients in the world.  He and I made the best choices we could, given the cards we were dealt.

The half-empty glass view is that he did not survive the cord blood transplant.  The half-full glass perspective is that knowing about his risk of infections and skin cancer kept him healthy and out of hospitals.  Being proactive about keeping his galloping CLL under control with the least damaging drugs we could find meant he had terrific quality of life for the seven years between his diagnosis and death. 

Was it worth it?  Would I recommend the same strategy to him again if I had a choice?  You bet!  I miss my husband more than words can say.  But I do not have the added agony of woulda, coulda, shoulda eating away at my gut.  I wish he never had CLL, I wish he had a more indolent variety of it.  But given that he did have CLL and it was a Bucket C variety, we played the hand we were dealt to the best of our ability.  And no one can ask more of themselves than that.  Cold comfort, but as they say, it beats a kick in the backside.