Learning From Experience of Others

ChoicesExperts often use case histories as a way of illustrating their points in CME (continuing medical education) seminars for physicians. Abstract concepts are a lot easier to understand when presented in the format of a concrete case history. I think the approach works very well for patients too. For starters, it is hard to concentrate and learn much of anything when you are personally in the cross hairs. It is a lot easier to absorb the information and understand the nuances, when it is not so personal. Learn now, use later.

In this article I would like to present the case history of a recently relapsed CLL patient. We will go through her medical background, concerns, choices, risks and rewards. I will present my personal take on her best option(s), with the full expectation that many of you will have other opinions and perspectives. In fact, I am counting on it to generate a vibrant discussion! We learn best when we get personally involved in the discussion.

Meet Sarah

Sarah (not her real name, of course – but the details of her case history are entirely true-to-life) is one of my most cherished CLL friends. She is a bright and vivacious lady with a lot to live for. Her 65th birthday is around the corner.

Sarah was diagnosed with CLL in the summer of 2000, when she was 54 years old. She has pretty good prognostics, mutated IgVH and 13q deletion (what used to be single allele deletion has recently evolved into deletion of 13q on both alleles).

Sarah’s Frontline Therapy

After four years of watch and wait, Sarah opted to participate in the PCR (pentostatin, cyclophosphamide and Rituxan) clinical trial. (Thank you, Sarah!) As most of you know, PCR is very similar to the present day gold standard FCR, with the difference that the purine analog used in PCR is pentostatin versus fludarabine. Pentostatin is thought to be kinder and gentler by some experts. I am not so sure I buy into that. You can read our earlier review comparing the two regimens.

Sarah got a long remission, just about 6 years. It was not entirely worry free remission since Sarah developed significant pulmonary problems after the PCR. Looking at this slender woman who led an active life, played tennis etc earlier on, it shocked me how out of breath she was just climbing stairs or even talking animatedly on the phone. There is some literature suggesting that one of the less lovely side effects of pentostatin is lung injury. Zillions of tests and visits to experts did not really resolve her problems. Physical therapy seemed to help some.

Relapse!

All chemotherapy induced remissions end eventually and Sarah’s 6 year long remission is now history. Her white blood count is increasing, but not galloping at any great pace and there do not seem to be any obvious swollen lymph nodes, yet.  At this stage of the game, it is reasonable to expect her tumor load is still quite low. Platelet counts have dropped a little bit, possibly indicating increase in bone marrow infiltration with CLL cells. But the most worrisome aspect of her relapse is the frequency of various infections over the last 4-6 months, in spite of her taking every possible precaution to avoid getting infected. Regularly scheduled IVIG (intravenous immunoglobulin) infusions seem to help somewhat.

Family History

Sarah’s mother was also a CLL patient, diagnosed when she was 85 years old. I am not sure she was ever treated for her CLL. But a few years later she was also diagnosed with a second cancer, ovarian cancer. She died at the ripe old age of 92, in 2005.

There is a concept called “anticipation” in family clusters of CLL. It seems that CLL shows its ugly face earlier in life and it may be a more aggressive variety in succeeding generations. As far as Sarah and her mother are concerned, that certainly seems to be the case. Sarah’s diagnosis was a full three decades sooner than her mother’s. While her mother lived out her natural life span (even with a second cancer!) without needing treatment for the CLL, Sarah has already been through PCR therapy, relapsed, and now looking at her best salvage options.

Cancer does seem to be a common theme in Sarah’s family. Her father had skin cancer and eventually died of brain cancer. Her grandmother died of stomach cancer. 

Two Additional Complications

There are a couple of other interesting points about Sarah’s background. First, Sarah is of Ashkenazi Jewish background. Second, at the age of 18 she was clinically diagnosed with full fledged mononucleosis (Glandular Fever, for our British readers). And oh, by the way, continuing the family tradition Sarah’s daughter too had mononucleosis as a youngster.

Why are these two relevant to our discussion? If down the road Sarah wants to consider a mini-allo transplant, chances of finding a suitably well matched unrelated donor are not certain by any means. The stem cell donor banks are under-represented in all ethnic minorities. Compared to the higher incidence of CLL in Ashkenazi Jewish people, this low representation becomes a double whammy, something I wrote about a while back in an earlier article: “Does Ethnicity Matter?”

What About Her Bout of “Mono” as a Teenager?

As we have pointed out in several articles, once a person is infected with EBV (Epstein-Barr) virus, traces of the virus linger in the body for the rest of the life of the patient. Vast majority of our population are carriers of this virus. It is passed from person to person through saliva. But not everyone who has been infected with EBV goes on to develop full fledged, clinically diagnosed mononucleosis. That distinction is important to remember.

Researchers at M. D. Anderson reported that patients who have had full blown, clinically diagnosed mononucleosis in their youth are more likely to have reactivation of EBV infection. This is all the more likely in patients who have been through immune suppressive chemotherapy. More recently, M. D. Anderson also reported EBV reactivation might increase risk of Richter’s transformation. “Richter’s transformation occurs in approx 5% of CLL patients and may be associated with infection with Epstein-Barr virus (EBV).”

Given Sarah’s recent history of infections, it is obvious that her immune system is not quite able to nip potential infections in the bud, before they become dangerous. Viral reactivation is one of the hallmarks of reduced T-cell and NK cell function. In this context her medical history of mononucleosis becomes relevant. Is she at increased risk of EBV reactivation if the immune suppression becomes even more pronounced?

You can learn more about EBV by visiting our flagship website CLL Topics and browsing through our review article “EBV: the enemy within

Life After PCR: Similar to Life After FCR?

We discussed “Life after FCR” in a prior article. In general, patients who have relapsed after FCR have few good options. Salvage therapy is not all that effective and remissions are short lived. With the exception of mini-allo transplant, the survival statistics for post FCR relapse patients are bleak at best.

But does relapse after PCR signal the same kind of response to salvage therapy? The plain answer is that we do not know. The statistics are just not detailed enough for us to peer into the crystal ball. Since fludarabine and pentostatin are both purine analogs and have very similar methods of action, it might be reasonable to guess that therapy options after PCR relapse are similar to options after FCR relapse – but that is just an assumption. Also, patients who get reasonably long remissions after FCR seem to fare better in salvage therapy as well. Sarah got a very satisfactory 6 year remission from PCR, significantly longer than the average PCR patient. I hope this signals her response to salvage therapy in future will be equally robust, compared to the averages.

Sarah’s Concerns

  • Given her family history, Sarah worries about secondary cancers and would therefore like to avoid heavy duty chemotherapy, if she can. Alkylating agents such as chlorambucil and cyclophosphamide have long been known to be “genotoxic” (toxic to the genome) and therefore present increased risk of secondary cancers.
  • With all the infections she had to deal with in the recent past, and her history of mononucleosis as a teenager, she is reluctant to take on additional hits on her T-cell and NK cell function. That might rule out Campath containing therapy, since this monoclonal is justly infamous for destroying T-cell populations for many months. Viral reactivation is of real concern in patients undergoing regimens containing Campath.
  • Sarah is very fair skinned, and with the history of her father’s skin cancer as a wake-up call, she does not take skin cancer lightly. Many experts think that  immune surveillance by effective T-cell and NK-cell troops is one of the ways the body protects itself from skin cancer, killing off micro clusters of skin cancer cells before they get a chance to grow and establish themselves as full fledged cancers. One more reason why therapy options that kill of T-cells and NK-cells may not be in her best interest.
  • Will additional doses of purine analogs (most likely fludarabine) cause further pulmonary issues? In fact, there is strong guidance that patients should not use pentostatin and fludarabine concurrently. No such guidance about using them 6 years apart, however.
  • What about a mini-allo transplant? It would be a very tough call for her to opt for a transplant right now. After all, her relapse is just a few months old, her counts are still very low – and she has four wonderful grand kids she wants to play with! In any case, given her ethnicity it is not going to be all that easy finding a well matched and unrelated donor.
  • The other side of the transplant coin, if she decides against a transplant right now and opts instead for a salvage therapy that gives her a good second remission of say, 3-4 years, she will be a lot closer to 70 years the next time she has to consider a mini-allo transplant. True, the age restrictions for mini-allo transplants are a lot less strict than they used to be, but age does influence outcome – especially if there are complicating co-morbidities, such as Sarah’s poor lung function.

As you can see, Sarah’s list of concerns put a big red warning flag on just about all chemotherapy agents out there, as well as Campath. If this is not the time for a mini-allo transplant, what are her remaining choices?

Sarah’s Options Going Forward

Here is are the game-plans that Sarah and her doctors can consider:

  • Do nothing right now, wait for better choices to become available down the road. After all, she has relapsed only a few months ago and her counts are still pretty low. No lymph adenopathy by physical examination.  What is the rush?
  • But her history of frequent infections in recent months is a real worry. Remember, majority of CLL patients die from infections. Especially pulmonary infections. Can Sarah afford to wait while her CLL continues to grow and her immune function gets progressively worse? Her pulmonary function is already compromised.
  • The other approach is to treat the CLL before the tumor load gets large. If I were in her shoes, this would be my preference. Without huge armies of cancer cells to deal with, Sarah may have the option of lower dose chemoimmunotherapy combinations such as FCR Lite. Lower dosage of chemotherapy drugs may translate into lower toxicity, we hope.

But my best advice to her is to avoid chemotherapy all together, use only immunotherapy drugs instead.

Immunotherapy, as Maintenance

Aha. I bet that got your attention. I cannot claim to be the inventor of this concept. In a recent article on chemoprevention we discussed some of the background of this new think. The latest issue of “Blood” has an excellent editorial by John Gribben on the subject of immunotherapy. Here is the link, you can read the full editorial for free by clicking on it. Here is what Dr. Gribben had to say, translated into plain English.

  • Response rates are increasing using modern drug cocktails such as FCR. But the few CLL cells that survive are likely to be drug resistant clones, and they are the ones that grow back during relapse. This makes treating post relapse patients difficult.
  • Immune suppression is also increased in relapsed patients.
  • Mini-allo transplants have the ability to really CURE patients because we can harness the power of graft-versus-leukemia (GVL) effect. This is immunotherapy, plain and simple. When everything goes right, the newly grafted immune system cells go after the CLL cells and kill them.
  • Expanding immunotherapy options should help us find new ways of CURING CLL and other cancers.

I like the sound of that!

Why is it that immune systems of cancer patients cannot fight off the cancer by themselves? Because in CLL patients their immune system is defective, that is why they got CLL in the first place. For starters, CLL cells develop “stealth technology”, whereby they can slink around and not be “seen” by the immune system cells. Second, some of the most powerful troops whose job it is to provide constant surveillance as well as killing of potentially cancerous cells – T-cells and NK cells – are either in short supply or asleep on the job. Anything we can do to paint a big red bull’s-eye on CLL cells, and increase the number and effectiveness of T-cells and NK cells is going to be helpful.

Standard chemotherapy drugs are a lot more blunt in how they work. Many of them mash up the DNA of the cell to the point where the cell’s own internal mechanisms take over and cause the cell to die. Problem is that in cancerous cells these internal mechanisms may not always work the way they should and then the result is an even more mangled cell that continues to live and reproduce! In patients with 17p deletion, the crucial p53 gene is missing. This gene is necessary for most of the cell death mechanisms. That is why standard chemotherapy does not work very well in patients with this FISH deletion. The percentage of patients with defective p53 function goes up sharply after they have relapsed following chemotherapy.

Rituxan is perhaps the most famous of our modern immunotherapy drugs. It does very little direct damage to the cell by itself. Most of what it does is attach itself to the CD20 marker on CLL cells (all mature B-cells express some level of CD20 marker). With enough Rituxan molecules tagged on, the CLL cell can no longer hide, it looses its “stealth” ability as it were. Immune system cells (such as T-cells, NK-cells) can no longer ignore this monstrosity and therefore the CLL cell is killed. Unfortunately for us, CLL cells do not express a lot of CD20 markers. The relatively sparse tagging of CLL cells means many of them can still escape death. Another problem is that without adequate T-cells and NK-cells to do the actual killing, response is going to be poor. That is why single agent Rituxan does not work very well, especially in previously treated patients with poor T-cell and NK cell function.

The more recent ofatumumab (Arzerra, Humax-CD20) adds a little extra oomph (we think), because it is also able to use another part of the immune system to deliver the death blow, namely complement.

Immunotherapy as Maintenance Regimen

Now we come to the exciting development, the reason why I pounded away on my laptop writing this very long review. Lenalidomide (Revlimid) seems to be able to achieve both parts of the immunotherapy game. As we pointed out in our earlier Chemoprevention article, it increases the visibility of CLL cells. Revlimid takes away their stealth advantage by increased expression of CD154, a danger marker for the immune system. Second, it heals some of the defects in T-cell function, increases the numbers of T-cells and NK cells needed to do the job of hunting and killing CLL cells.

Revlimid is not an easy drug – there is no disputing that. In patients with bulky lymph adenopathy, with heavy tumor load, it is very important to start Revlimid therapy gradually, at low doses and build up slowly to higher doses. Otherwise, the swelling of the lymph nodes –what is called “tumor flare” – can be very painful and downright dangerous. Most experts now agree that extra precautions should be taken in treating patients with high tumor load with Revlimid. Starting dosages can be as low as 2.5mg per day in such cases. Jumping right in with high doses of Revlimid in patients with heavy tumor load can be dangerous.

Many experts are beginning to think that Revlimid therapy is best initiated in patients with low tumor burden, when the troops of the enemy are still small. Tumor flare is likely to be less of a problem in such patients. Hopefully the increased T-cell and NK-cell function as a result of Revlimid therapy will bring about an effective response, effective cell kill. Hopefully the low tumor load means the immune system troops are not overwhelmed by very large armies of the enemy.  Unlike standard chemotherapy drugs, there is no mashing up of DNA of the target cells and therefore less chance of secondary cancers – we hope. 

While immune suppression in terms of destruction of T-cells and NK-cells does not happen with Revlimid therapy, it is important to remember that a very large majority of patietns treated with Revlimid develop neutropenia.  Monitoring and controlling neutropenia with drugs such as Neupogen and Neulasta is an important thing to remember while on Revlimid therapy.

A couple of unanswered questions that I find very interesting are these:  does the improved effectiveness of T-cell and NK-cell function due to Revlimid therapy also result in increased ability to fight general viral infections and reactivations? Does it also protect patients from micro clusters of secondary cancers (think skin cancer spots) from gaining a foothold and becoming full fledged monsters?

Many clinical trials are going on to see if the ability of Revlimid to increase T-cell and NK-cell function means it can give Rituxan or Arzerra a more effective helping hand. Remember, we said both Rituxan and Arzerra depend on the immune system to do the actual cell kill of CLL cells. They do the tagging, Revlimid supplies the T-cell and NK-cell troops to do the actual killing. Sweet concept, I hope it proves to be the case.

So, that is my advice to Sarah; that she should talk to her doctors about low dose Revlimid therapy, either by itself or in combination with Rituxan (or Arzerra). And that she should consider starting sooner rather than later, in order to possibly avoid massive tumor flare reactions. Unlike Campath and fludarabine which will further demolish her T-cells and NK-cells, Revlimid may actually build up these immune defenses, give her additional protection against opportunistic infections, especially viral infections. The neutropenia that seems to be built into the cake with Revlimid therapy can be controlled with prudent use of Neupogen or Neulasta shots.  Staying away from standard chemotherapy drugs may also increase her chances of avoiding secondary cancers.

What say you?

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