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.
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!
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
French
German
Spanish
Italian
12 comments on "Planning for Success"
Follow-up comment rss or Leave a TrackbackA couple of comments on the MDA study on reponse to RFC based on previous therapies:
1. The number of patients in the Rituxan category was very small. I’m wondering how much one can glean from 7 patients?
2. There is no prognostic data on the patients. I would think that favorable/unfavorable prognostics would have had a significant impact on response rates aside from previous therapies.
My thanks to “Harvey and Serena” for sharing this journey with us. I wish them strength and good luck.
Kathleen
True, as Kathleen correctly points out the subset of patients with previous Rituxan monotherapy was small in the M. D. Anderson study. Unfortunately, we have to make-do with the published information we have to date. While the sample size is small, the difference in response rates between truly therapy naive patients and just Rituxan treated patients was pretty substantial and therefore worthy of note.
If the new CLL guidelines we talked about in a recent Topics Alert are followed by researchers in the future, we will have prognostic information on all clinical trial participants. That has not been the case in most trials up to now.
Making judgment calls in the absence of complete information is what makes it all so challenging.
CHAYRA,GLAD TO HEAR THAT HARVEY HAS ACHEIVED A CR.I DO HAVE A FEW QUESTIONS.CAN YOU PLEASE DESCRIBE THE REVASSIST PROGRAM AND DO YOU KNOW IF THE MEDICARE PROGRAM COVERS A MINI ALLO TRANSPLANT FOR A CLL
PATIENT.THANKS
You can find the official program description at http://www.revassist.com.
Before you can take Revlimid as a patient outside of clinical trials, you and your physician must enroll in the Revassist program. Having gone through it personally, Harvey’s impression is that it is a mechanism set up to avoid any possibility of fetal exposure to Revlimid. Given the historical experience with thalidomide use in pregnant women and the risk of birth defects, you can understand the caution for this thalidomide-related drug.
In reality, complying with the Revassist requirements is very simple. You have to swear you are not now pregnant, and you have no intentions of ever getting pregnant while you are taking Revlimid. If you are a guy, you have to promise you will not get anyone else pregnant during this period.
Celgene also has a Patient Support Coordinator to help with reimbursement issues: http://www.revlimid.com/hcp/hcp-psc.aspx.
They have a patient help program to mitigate the cost of the drug for patients whose insurance does not cover the cost of the drug. You will find contact information at the link provided.
Medicare programs seem to be different in different states, and in any case neither Harvey nor I are experts on this subject. If stem cell transplant and insurance coverage is an issue, we suggest you review the articles we published recently on http://clltopics.org on the subject of heavily subsidized (as in almost completely free of charge) transplant protocols at the NCI. Your tax dollars at work. I am amazed more patients don’t know about this terrific “deal”.
It became apparent some time during 1996 that I had some form of lymphoma by the enlarged nodes on my neck and arm pits. I finally had a biopsy in 2024 that diagnosed me with SLL/CLL which I received Chemo for in 2024. The Chemo was RF with something else on the day of the Retuxin. I finished the six cycles and am still in remission but not CR since I still have some lynph nodes that have appeared. It will be six years in Novemeber 2024 since the Chemo.
My case sounds similar to Harvey’s that is why I am very interested in the journal.
I want to thank you for the imformation that you have been providing and I wish a complete remission for Harvey.
Sincerely,
Joan McEnery
My pre-transplant nodes were about 2-3 cm so my midi-allo sibling transplant was iffy for relapse. I’m happy to say after 2 years post SCT my nodes are normal and no sign of SLL/CLL. My regimen was Bu/Flu R with 1 day TBI but previously I had CHOP,F, FRC,R,and high dose steroids. I wish “Harvey” the best for the cord blood SCT-Make sure he doesn’t trip with IV attached-wash hands,get all horizontal surfaces cleaned by housekeeping,get the shower disinfected routinely-small things but very important. I found that patients who rolled their IV poles around and fell was a big problem in the transplant unit. I’ve heard very good things about Minn. Regards, Carol Rhoades
This new information/ Rituxan therapy is quite startling, and of course gives me chills since Mark is 5 years into Rituxan maintenance. Still, it is better to know what we may be facing. I look forward to more posts on this important subject. Looks like we may have a very hard time getting a good CR for a transplant too, this puts so many things in a different light. Time to rethink the five year plan. Thanks Chaya for bringing this important information.
Beth
Thanks chaya for this update, I had a conversation with my consultant yesterday and she said that patients my age that have had Rituximab and Campath (which I will have as part of the 4th line salvage therapy) have more GVHD problems.
Is there any where one can find out how many transplants have been done worldwide on patients with CLL?
The Royal Free Hospital in London has only done 19 CLL transplants, I should be the 20th, of course they have done many in other heamatology conditions, provably all young people as I noticed when I was on the waiting room last week, I was the only person without a transplant, all others had and were all younger people.
Thanks for sharing your path with us
Chonette
During my last treatment, the first round of Fluradabine and Rituximab did absolutely nothing to my nodes or even my numbers, we decided to change the strategy and add HDMP to the combo for the second round, nodes and counts went on the right direction fast after that round, and continued for 3 more rounds, then all stopped, so we did not do the 6th round of HDMP though we did 6 of Fluradabine if we include the first one. Treatment finished in September and nodes are on the growing again.
I had had little treatment before that mainly Rituximab and low doses Chlorambucil one treatment, I was actually surprised how little effect fluradabine had had on me having a good FISH test even I am unmutated.
As HDMP is the only thing I seem to respond, we will be doing that for the salvage therapy (HDMP and Campath) locally and then other chemo in London.
I am not looking forwards to the road ahead.
Chonette
Chaya - You said that truly therapy-naive patients achieved 70% CR rate. I can’t see in the chart where that information is. Can you help me understand where you get the 70% CR rate from? Thanks! Aditi
Aditi:
The 70% response rate for truly chemo naive patients comes from another MDA article in the JCO. Here is the PubMed citation for th article, write if you want help locating the full text of it.
Chaya
Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H.
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030, USA. mkeating@mdanderson.org
PURPOSE: Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%.
PATIENTS AND METHODS: We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC.
RESULTS: The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin.
CONCLUSION: FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).
PMID: 15767648
Hi Chaya,
I send you best wishes and my prayers and love for the journey ahead. I am very interested in your experience with Revlimid, as I am considering that for the same reasons. I am in partial remission after PCR, but still have some nodes in the 3cm range. Any information you can post on “tumor flare reactions” and other side effects of Revlimid would be very helpful in making this difficult choice. Thanks so much.