Size Matters

Lymph node size that is. Why, were you thinking of the size of some other gland?

In this entry I want to discuss the importance of getting good tumor clearance ahead of the transplant. This is perhaps the single most important thing done ahead of going to the transplant center. In most late stage patients massive concentrations of CLL cells reside in their swollen lymph nodes (and spleen, liver, bone marrow). Unshrinking lymph nodes and clearing out the bone marrow is the name of the game. It does not help to have squeaky clean blood counts if you still sport a goodly collection of bulky lymph nodes.

Below is a graph from a recent Hutch (Fred Hutchinson Cancer Center, Seattle) paper that shows the risk of post transplant CLL relapse depending on the size of the lymph nodes patients have going into mini-allo transplants. Lymph nodes larger than 5 cm are often used as the cut-off between “bulky” disease and “non-bulky” disease, and the same cut-off is used in this graph as well. As you can see, the risk of relapse is much higher for patients going in with bulky disease.

Bulky disease in the mini-allo transplant setting sets up a scenario of out-numbered armies, where the good guys (newly minted defenders such as T-cells, NK cells, macrophages etc) are out-gunned and out-numbered by the bad guys (hordes of CLL cells still infesting your body). Moral of the story – you are really well served going into a mini-allo transplant with as good a remission as you can get. Waiting too long may close that window of opportunity, especially if you have used up most of the therapy bullets available to you, or if your CLL becomes a particularly nasty and refractory variety.

Tumor Load vs Relapse Risk

Improving the Efficacy of Reduced Intensity Allogeneic Transplantations for Lymphoma using Radioimmunotherapy.
Biology of Blood and Marrow Transplantation 12:697-702(2006)
Ajay K. Gopal, John M. Pagel, Joseph G. Rajendran, David G. Maloney, Frederick R. Appelbaum, Mohamed L. Sorror, Brenda M. Sandmaier, Rainer Storb, Oliver W. Press

As you can see, at the two year mark only 14% of patients with lymph nodes less than 5 cm had relapsed, compared to a whopping 52% that relapsed as a result of having bulky disease with too many CLL cells packed in there. But even the 14% relapse rate is too high for my taste. How about patients who go in for the mini-allo transplant with a full honest-to-goodness CR? In other words, if the lymph nodes are no where close to 5 cm, if there are basically no swollen nodes at all, what does that merit?

Another Hutch paper addresses that question. The risk of relapse in CLL patients going into the transplant with full blown CR was zero, none, nada. While the sample size was small and therefore I would not take this “zero relapse risk” as cast in concrete statistics, there is absolutely no doubt about the trend, giving your new immune system a chance to settle down without having to fight large numbers of CLL cells right upfront is a very good thing to do. Why would anyone want to go through the significant hassle and risk of a transplant, only to have the darn CLL raise its ugly head a short while later?

But getting that CR ahead of the transplant may prove to be more difficult than you thought. Waiting too long to make the transplant decision may end up costing you. If you become a truly refractory “salvage” case, it may not be possible for you to get a good remission no matter what you try. Too few bullets left, and too strong an enemy, the window of opportunity to get a successful transplant may not last forever. Some of you have followed Greg’s Story, another of our patients who opted for the transplant route. Greg may have left it too late. He needed to go through massive amounts of chemotherapy before he was even eligible for the mini-allo transplant. All that extra therapy took its toll on him. I am deeply saddened to report that Greg did not make it. I heard from his father recently, Greg died of uncontrollable infections a few months after finishing his mini-allo transplant.

Harvey thought he would have no problem getting the pesky nodes under control. After all, he was still “chemo-naive”! All he had ever had was Rituxan and HuMax-CD20. Both are monoclonal antibodies, and not deemed to be ‘chemo’. He did have small amounts of prednisone as premedication ahead of the Rituxan and HuMax-CD20 infusions, but heck that is just a little bit of steroids, and that is not considered to be chemo either, right? With his “chemo-virgin” status, he had high hopes that his lymph nodes will melt away like butter on a sunny summer day in Sedona at first exposure to real chemo drugs.

HuMax-CD20 + Fludarabine

His choice was HF (HuMax-CD20 + fludarabine), closely patterned after the better known combo RF (Rituxan + fludarabine) pioneered at Ohio State. In his case, Rituxan had to be substituted with HuMax-CD20 since he had developed hypersensitivity to Rituxan earlier. He went through five of the six monthly cycles of HF before it became clear that this big gun was not doing much for him at all. Bummer! What went wrong?

For starters, wrong assumptions. Many people assume that Rituxan (and HuMax-CD20) monotherapy is the proverbial free lunch. Since it is not “chemo” as such, the wishful thinking goes, the hope is that it lets the patient keep his chemo-naive status and therefore eligible for the terrific response stats seen in the chemo naive subset of patients. Wrong!

FCR response in previously treated patients

Above is a chart from M. D. Anderson’s paper on how previously treated patients fared using their signature FCR therapy(fludarabine + cyclophosphamide + Rituxan). Notice, under prior treatment they list single agent Rituxan, as well as more conventional chemotherapy agents. 29% of these Rituxan-virgins got the coveted CR response. Compare that with the 70% CR rate achieved in truly therapy-naive patients, and you can see that even single agent Rituxan therapy is no free lunch, it too takes away some of the oomph of later therapy choices. While these statistics are for FCR therapy, the same trends are seen in FR therapy as well. Harvey had multiple rounds of Rituxan and HuMax-CD20. While these monoclonals gave him a chance to control the CLL for a good many years (6 years to be precise), he paid the price for it in terms of becoming less responsive to HF therapy.

Five monthly cycles of heavy duty HF therapy and little to show for it – that was not good news. Now the scary phrase “fludarabine refractory” applied to him. Since he had several lymph nodes that were quite bulky, Campath was not a good fallback option either. Campath is a very powerful monoclonal, but it does not deal with bulky nodes; and Harvey still had bulky nodes. Fludarabine refractory, and Campath ineligible – where have we heard that phrase before? We reviewed the options open to this high risk group of patients in an earlier article on our website: Refractory CLL. None of them were good options, none of them had terrific response statistics or long term remissions associated with them.

Harvey had a FISH test done prior to starting on the HF therapy. It still showed ‘only’ double allele 13q deletion and single allele 11q deletions. No 17p (p53) deletions were noted. So, how come he flunked HF? surely patients without the nasty 17p (p53) deletions should have better response to chemoimmunotherapy? Aha. Good question, and one that I will attempt to answer in a future post. Like the oracles of mythology, FISH test answers only the specific questions you ask of it. It can be maddeningly silent about stuff you don’t ask.

If Campath is not an option, what remained? Well, there was still the sledgehammer option, combination of Campath with high dose steroids. Flavopiridol is another one, but it required that he go to OSU for therapy since this experimental drug is still in clinical trials and cannot be obtained outside of them. The last choice was Revlimid. All the options were high risk, and none of them were going to be easy. Harvey opted for Revlimid. One of the reasons for his choice is that while Revlimid too is still undergoing clinical trials, it is possible to get it through Celgene’s “RevAssist” program – provided your local oncologist is willing to oblige.

Revlimid for Refractory Patients

Harvey sweet-talked his local oncologist to go along with this therapy option. It helped tremendously that his therapy choice had the backing of some of the best experts in the field. Harvey was truly fortunate that he had experts at Mayo, NCI and Roswell Park willing to guide him and his local oncologist on this unfamiliar journey. It is easy to become cynical about our health care system. But once in a while it pays to remember all the generous physicians and researchers out there, folks who answer urgent phone calls over the weekend and answer emails late into the night out of sheer generosity.

Revlimid is a strange drug. No one quite knows (yet) exactly how it works. Dr. Byrd is on record warning CLL patients that it is not an easy drug to deal with and at high doses it can have high grade adverse effects. Keeping that in mind Harvey opted for a modest dose of 10mg/day. The deal was that he took the drug at this dose for 21 days, then had a one week holiday from the drug. He repeated this 28 day cycle three times. On the 3rd and last cycle he increased the dose to 15mg/day.

“Tumor Flare” reaction is a well publicized side effect of Revlimid, and Harvey had it in spades. I will write more about Revlimid, tumor flare and how Harvey tolerated in in another post. Looking at the rewards side of the equation for now, I am happy to report most of the bulky lymph nodes gradually melted away during these three months of Revlimid use. They are still shrinking as I write this, since the effect of Revlimid seems to go one for a while even after the drug is stopped. None of the nodes that can be felt by physical examination were bigger than 1 cm, blood work was clean, making it a “CR” by the old NCI guidelines. But there were still a few nodes deep in his abdomen and chest that were in the 2cm range, clear indication that observable disease remained. Bottom line, Harvey did not quite make it to that squeaky clean CR remission he wanted ahead of his transplant, but he got awfully close to it. All the experts agreed it was not going to get much better than this and he had better not waste this opportunity. Given how hard he had to fight to get this remission, it is clear to Harvey and Serena that there may not be another equally good remission in his future, if he let this opportunity slip through his fingers.

Next stop, double cord blood mini allo transplant, and Harvey will settle for nothing less than a full cure of the CLL. Stay tuned, this roller coaster is speeding up and it is going to be an interesting ride. One of our members asked if we are going to name names, specify drugs, dosages, all the gory details. The answer in one word, yes. If you want just the human interest part of the story, skip these details. If you are looking for a detailed road map because there is a good chance you might have to make this journey yourself some day, you have found the right place for it.

Be well,

Chaya