Keeping up with the times
A little while ago the FDA approved Campath as single agent in the frontline treatment of CLL. I thought this was a poor decision based on a tricked out clinical trial that pushed all the FDA hot buttons but failed to impress most CLL experts. Not that I am saying I am a CLL expert, but I do read this stuff till my eyes bug out. Here is the latest stuff about Campath in ASH2009. There is so much Campath news that I had to break it up into a couple of articles. Some of these are truly definitive clinical trials and I am sorry to say the news about Campath is not all that rosy.
Campath: what makes it tick
It must be acknowledged that Campath (scientific name “alemtuzumab”) is a very potent monoclonal antibody. Modern day patients are lucky to have this drug available to them, since it is one of very few drugs that works in poor prognosis patients with 17p deletions (FISH). The trick is to know when to use it, and when not to use it.
Before diving into the ASH information, here is a very short tutorial on how Campath works. Campath targets the CD52 marker on cells. Unlike CD20 (the marker targeted by Rituxan), CD52 is heavily expressed on B-cells. There are literally thousands of copies of CD52 per B-cell and that means the cells are festooned with many molecules of Campath when they are exposed to the drug. This in turn means cell kill is very efficient. Campath packs a lot more oomph when it comes to killing CLL cells and that is the good news.
Here is the problem in a nutshell. This monoclonal is not a very smart “bomb” because many different cell types express CD52, not just B-cells. Among the other cell lines that express CD52 are neutrophils, T-cells and macrophages. What that means is that when a patient is treated with Campath, the drug kills all of these cell types, not just B-cells. (For those of you guys who worry about such things, did you know human sperm cells also express CD52 marker and Campath therapy may not be all that smart if you are thinking about becoming a brand new daddy?)
Why is it important if neutrophils, T-cells and macrophages get killed? It is important because these are all cell lines that are the crucial frontline troops that protect us from infections of various sorts. Kill off all the defenders and patients are sitting ducks waiting for an opportunistic infection to take hold and grow out of control. Campath lingers in the body for a nice long time, trace amounts are measured for months in blood and tissue, which in turn means the breach in our defenses lasts for at least as long. Deep seated neutropenia, across the board T-cell deficits and resulting infections are measured for many months past end of Campath therapy.
Bottom line, while we are happy about the effectiveness of Campath (especially in 17p deleted tough cases), we must stay very vigilant about the risk of potential infections – including life threatening infections. It is hardly a consolation to roll back the CLL only to have the patient die of an opportunistic infection, if you get my drift.
If FCR is good, is FC + Campath even better?
Oncologists have a tendency to keep ratcheting up the potency of their drug combintions in an effort to get ever higher remission statistics. The longest string of drug combos I have come across had 10 different drugs in it. But hey, as long as there was “non-overlapping toxicity”, what is a couple of more drugs between friends?
FCR has been in the news a lot lately. There is little question it is now the gold standard of CLL therapy by which all other therapy options are judged. So, it is a logical question to ask: can we make chemoimmunotherapy even better by replacing the “R” (Rituxan) in FCR with Campath? After all, since Campath targets CD52 that is plentifully available on the surface of CLL cells, is that not a better target than the CD20 that Rituxan tags?
Below is the ASH2009 abstract of a very important Phase – III clinical trial that addressed the very question we posed above. These were previously untreated patients. Half of them were randomized to get conventional FCR. This was the control arm. The other half got FC + Campath, the experimental arm. The study was a collaboration at many different centers, so there is no room for biased results. This is a terrific study, it is about as credible as it gets. The French Cooperative group on CLL does some excellent work. This well conducted clinical trial is an example of their work.
538 Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine (F), Cyclophosphamide (C) and MabCampath (Cam) (FCCam) in Previously Untreated Patients (pts) with Advanced B-Chronic Lymphocytic Leukemia (B-CLL) : Experience On Safety and Efficacy within a Randomised Multicenter Phase III Trial of the french Cooperative Group On CLL and WM (FCGCLL/MW) and the “Groupe Ouest-Est d’Etudes Des Leucémies Aigües Et Autres Maladies Du sang” (GOELAMS) : CLL2007FMP (for fit medically patients)
Stephane Lepretre1*, Therese Aurran2*, Beatrice Mahe3*, Bruno Cazin4*, Olivier Tournihlac5*, Hervé Maisonneuve6*, Olivier Casasnovas7*, Alain Delmer8*, Veronique Leblond9*, Bruno Royer10*, Brigitte Corront11*, Sylvie Chevret12*, Roselyne Delepine13*, Sandrine Vaudaux1*, Eric Van Den Neste14*, marie-Christine Béné15*, Florence Cymbalista16 and Pierre Feugier15*
Introduction : Recent data suggest that FCR immunochemotherapy improves response rates and Progression-Free Survival (PFS) of previously untreated CLL pts. The monoclonal antibody alemtuzumab, a humanized anti-CD52 antibody (Campath), has shown activity alone and in combination in CLL pts. In order to validate the place of Campath in combination with the synergic association FC, the FCGCLL/MW and the GOELAMS conducted a multicenter French and Belgian phase III trial, CLL2007FMP, to evaluate the efficacy and toxicity of FCCam versus FCR in previously untreated patients with advanced CLL. PFS was the primary-end-point of this trial.
Methods and Patients : A cohort of 178 fit medically pts (cumulative illness rating scale (CIRS) score of up to 6), less than 65 years old, without 17p deletion, were enrolled between November 2007 and January 2009. Pts were randomly assigned to receive 6 oral courses of FC (F 40mg/m2 d1-3 and C 250 mg/m2 d1–3; q 28 days) in combination with either R (N=83; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or Cam (N=82; 30 mg s/cut d1-3; q 28 days). Patients were stratified according to IgVH mutational status and 11q deletion. Anti-infective prophylaxis included trimethoprim-sulfamethoxazole and valaciclovir during immunochemotherapy and until the CD4-positive lymphocyte count reached 0,2 109/l. In the FCCAm arm, CMV monitoring was monthly performed by either PCR or antigenemia. The use of GSCF was recommended. The trial’s recruitment was stopped in January 2009 after 165 pts had been randomized (83 and 82 respectively in the FCR and FCCam arms) because of an excess of mortality in the FCCam arm, while 13 patients were enrolled but not randomized because of this decision.
Results : We reported here a preliminary analysis including baseline characteristics and response rates in the first 100 included pts but safety analysis of the whole cohort ; among the first 100 pts, 81% were Binet B, 19 % Binet C ; median age was 56.8 years (range 52.8 to 60.6). Percentages of pts with 11q deletion, unmutated IgVH status, and elevated β2m, were 18.5%, 48.4%, and 77.6%, respectively. A number of 76.5% (FCR arm) and 71.4% (FCCam arm) of pts received 6 cycles. Reasons for discontinuation were mainly related to persistent grade 3-4 neutropenia. Safety analysis data were available for 165 pts. Number of patients reported with Common Toxicity Criteria (CTC) grade 3-4 adverse events were observed in 87.8% (FCCam arm) versus 90.2% (FCR arm) (p = 0.76). Grade 3-4 neutropenia was the most frequently reported adverse event (79.6% with FCCam and 74.6% with FCR arm). Interestingly, percentage of observed grade 4 neutropenia was stable during FCR treatment (17.6% for cycle 1 and 17.9% for cycle 6) but increased during FCCam treatment (28.4% for cycle 1 and 45.5% for cycle 6). A total of 63 Serious Adverse events (SAE) were declared (19 with 18 pts in FCR arm, and 44 with 35 pts in FCCam arm) consisting mostly of the cases in febrile neutropenia (13 with FCR arm, 27 with FCCam arm); 7 patients died, all in the FCCam arm : 3 of B diffuse large B-cell lymphoma (one of them EBV positive), 1 of mucormycosis, 1 of septic shock due to P.aeruginosae and 2 of heart failure during neutropenia. The Overall Response Rate ( ORR) in the first 100 patients was 96% in the FCR arm compared to 85% in the FCCam arm (p=0.086). The Complete Response rate was 78% (FCR arm) versus 58% (FCCam arm) (p=0.072). PFS and OS are not yet evaluable.
Conclusion: the FCCam regimen for the treatment of advanced CLL appeared to be associated with an unfavourable safety profile representing a significant limitation of its use in this indication. Other combinations with Alemtuzumab may be studied.
Discussion
This was a good sized study using 178 patients. While they clearly needed treatment for their CLL, they were relatively young and fit patients. None had the dreaded 17p deletion since the researchers were looking to see if FC + Campath was viable for the general run of the mill CLL patient, not the special 17p deleted cases where Campath has special advantage.
The trial design was a prudent one. Patients got antibiotic (trimethoprim-sulfamethoxazole) and antiviral (valacyclovir) prophylaxis for the duration of therapy, and this was continued until T-cell counts had a chance to recover. GCSF (granulocyte colony stimulating factor, brand name Neupogen) was recommended to help neutrophil counts recover quicker. The patients getting Campath were carefully monitored for reactivation of CMV (cytomegalovirus) since we now know this is a common opportunistic infection in Campath treated patients.
Trials like this one cost a lot of time, money and effort, one reason why so few of them get done. So, you can imagine it is a big deal when one of these trials stops recruiting patients prematurely – because too many patients were dying in the Campath arm! That was quite a bombshell. Now for the deadly details.
The level of toxicity was quite high in both arms of the study. Not a big surprise, we know these chemoimmunotherapy regimens are no walk in the park. But I must confess the level of toxicity came as a bit of a shock to me. Of the seven patients who died on the FC + Campath arm (there were no deaths on the FCR arm), three died because their CLL became much more aggressive lymphoma. One of these lymphoma conversions was triggered by uncontrolled Epstein-Barr viral reactivation. Two died of infections. Two died due to heart attacks during high grade neutropenia. Wow.
Things like toxicity, neutropenia etc are graded on a scale of 1-4. Grade 1 is no big deal. Grade 2 is a bit more serious, but nothing to get too excited about. Grades 3-4, now we are talking big time problems that no one can pooh-pooh. As you can see, the level of high grade toxicity and neutropenia was roughly the same in both groups. The authors point out that the most serious Grade 4 neutropenia was stable in the FCR group but increased over time as patients went through additional cycles of FC+Campath. This too is to be expected, given the well understood and direct risk of neutropenia due to Campath exposure.
The million dollar details that caused premature shut down of the trial are highlighted in red. Serious Adverse Effects as well as the number of patients who were involved in such adverse effects are very important measures of the safety of therapy regimens. There were more than twice as many SAE in the FC+Campath arm and just about twice as many patients had serious adverse effects, compared to the FCR arm. This is a big deal, especially in view of the fact that the researchers tried their best to protect the patients with ongoing antibacterial and antiviral prophylaxis, as well as Neupogen shots.
Seven patients died in this study, all of them in the FC+Campath arm. There is no way of sugar-coating this one stark fact. Once again it points out the courage and sacrifice made by the patients who volunteered for this clinical trial. Half of them, the ones that got randomized to the FC+Campath arm, took on the additional risk of this untested combination. Seven of them paid with their lives so that you and other patients like you can make smarter choices down the road. How do we say “THANK YOU” to these brave souls and their families? This is high priced information indeed, purchased at the expense of 7 lives that would not have ended so abruptly but for FC+Campath.
How about the rewards side of the equation? After all, it is all about weighing the risks and rewards in this harsh game we play. Did FC + Campath group get higher overall remissions? Were there more complete responses (CRs) in this experimental group compared to the FCR control group? The answer to both questions is NO. The overall response rate was lower in the FC + Campath arm and there were significantly lower percentage of people who got a CR. All pain and no gain. I am amazed these crucial clinical trial results have not seen much broader publicity in the lay press or on patient chat rooms. Hello!? Anyone out there paying attention besides little old me?
If you are as yet untreated CLL patient that fits the profile of the patients in this clinical trial and your oncologist suggests FC+Campath as the frontline therapy, be sure to bring the results of this important trial to his / her attention. If he still insists FC+Campath is your best choice, find yourself another doctor. Stay smart guys. What you don’t know is dangerous. What your oncologist does not know can be downright lethal.
How about other roles for Campath? How about Campath consolidation after FR? How about FC+Camopath for relapsed or high risk patients? Last but not least, how about use of Campath in the preconditioning therapy prior to a stem cell transplant? I will be discussing each of these possible roles for Campath in the next couple of weeks.
32 comments on "Role of Campath in CLL: FC + Campath"
Wow, I am humbled by the actions of the brave people who volunteer for medical trials. Thank you, thank you Chaya, for sharing this information with us – although I am still in Stage 0 I know my time will come to consider treatment options. Your information fills me with hope and courage.
Beverley, Australia
Chaya,
A very interesting and helpful report for first line therapy patients.
I’m highly interested in getting your next information Alemtuzumab as preconditioning therapy prior to a stem cell transplant.
Two years ago I was member of a first line FC Humax-CD20 trial and got a complete remission.
Meanwhile I relapsed, got a PRCA and 17p- deletion so my doctors recommended to start an Alemtuzumab, Dexamethasone therapy within the CLL2O trial. Included is a lot of co-medication and examination to avoid opportunistic infections. The goal of this therapy is to get a best possible remission for a hopefully successful sct. Alemtuzumab within this study will be applied with subcutaneous injections this shall avoid most of undesired side effects without touching the efficiency in killing the cancer.
My therapy should start in about three weeks. Do you think you will be able to provide your next articles within this time?
Maxi
Maxi:
I plan to complete the Campath series in the next week to ten days (after which I will be traveling from India back to USA and unhooked from my laptop for a while). I will send you the Campath in transplant setting abstract – just in case I do not meet your timeframe.
Chaya,
Thanks again for your advocacy and excellent summaries. The results of the Campath part of the trial are very scary. It would be good to hear an analysis of how and when, what circumstances in which Campath should be used. If it has a role, it looks like it should be a well defined one and perhaps limited. I hope heme/oncs in the field are paying attention to this study.
Please travel safely and I hope you were able to get the H1N1 vaccine.
Chris R.
Hi Chaya.
This series could not be more timely for my 11q husband. He obtained PR on fludarabine-rituxan (our center doesn’t use the C), but has SUFFERED with shingles since September (no prophylactic valtex). Although currently stable, the other “C” word has been mentioned in passing. We are so grateful to those whose made the ultimate sacrifice in good faith. It is a debt that can never be repaid in full.
Lupner9:
There is a definite role for Campath in the treatment of CLL. We will be talking about that too in the next couple of articles.
Getting H1N1 vaccines in India before I leave for USA. You are kidding, right? They do not even have the beginnings of a program for country wide annual flu vaccinations in this country. Never been done here. The flight from Mumbai to Newark is 18 hours long, non-stop. Wish me luck that the guy sitting next to me in the sardine can is not hacking away.
Truly, how DO we say “thank you”? Would it cause more pain to the families of these brave folks if we actually could and did? Tough question. But we are so in debt to them.
Thank you Chaya……..to answer your question — No – I don’t think anyone is paying attention but YOU !! and thank the lord you are! I as a previously treated person with FR will be looking forward to your upcoming information regarding Campath after…..
And thank you to those that are brave enough to go into these trials. I just hope that their Doctor’s were not ones that ‘strongly encouraged’ them rather than just put it out there for their choice.
We are so vulnerable at that point that we do not know what we should do and can be so easily nudged into something that we might should not have done.
I concur with your assessment of the study reported on, which is sound and which should serve as a warning for all. As you know, I think that alemtuzumab is a drug whose use can be of value when applied under appropriate circumstances.
The most frightening thing to me (just from reading the few comments already posted) is that “best practices” are still not carried out routinely as demonstrated by the use of FR WITHOUT antiviral prophylaxis AND that other seemingly rational drug combinations may still lead to unwanted results. The development of pure red cell aplasia and 17p deletion is a heavy price to pay, although, I suppose that the same result may have occurred following FCR as happened to Maxi following FC”H”.
The most important thing for all of us with skin in the game is to make decisions after careful consideration of all possible outcomes and to plan our follow up moves with the same strategy. It is most important for people to have faith in their physicians, but at the same time they must avoid falling into the trap of what I shall label “new drug exuberance”. By that I mean simply that the biodiversity of the human species is so great that there is no realistic way to predict how things that work well in the test tube and then in small groups will work when applied “in the field”.
There is a natural tendency for researchers as well as patients to share in this excitement. It is not necessarily a bad thing; lord knows we need to obtain data using therapies in real patients. My only concern is that people evaluate what they are doing and have realistic expectations before embarking on any therapy, inside or outside of any trial.
I have already witnessed any number of new therapies come on the medical scene with great promise, only to see them removed from general use after unanticipated results accrued. In some instances the therapies remained available for judicious use in the appropriate circumstances; in others the unanticipated problems were too great to justify continued use of the therapy. We now know enough about ofatumumab (for example) to conclude that it is “reasonably” safe, but the data available do not indicate that it is a “game changer” as many had hoped. Of course, there may be new information garnered as it’s use becomes more widespread and, perhaps, as higher dosages are utilized. Ongoing critical evaluation of any particular therapy and reasoned approaches by the physicians treating the disease in question result in the best outcomes over time.
Have a safe trip and best of luck to Maxi in the CLL2O trial and subsequent HSCT,
Rick
People who go into clinical trials should get free and guaranteed life insurance from the conductors of the trials so as to ease the burden on their families. At the moment, volunteers are so desperate to get in trials that one might say they are being exploited
Patrick
Chaya
Because I have the many lymph nodes problem, Campath is not in the future for me. I read this update with a heavy heart as a friend of mine was given campath. We both had the same oncologist at that time. He was allergic to campath and was never the same. He had many, many problems including CMV. He died two years ago in a nursing home.
Campath scares me. It should be handled very carefully with a very knowledgeable oncologist.
My best to you and many Blessings
Rita
Rita
Chaya,
Thank you for your summary. I have a family member who died after a Richter Transformation, and I noted your comment about FC and Campath leading to an aggressive lymphoma from CLL in several patients. Are you referring to a Richter Transformation in your comments? Is there medical research which indicates that the FC and Campath combo can reactivate the Epstein Barr virus, which causes the Richters, or is the Richters caused by the treatment itself by the wiping out of other cells and the immune system (or the triggering of Richters by some other means). Thanks.
Ojibwak
Excuse me if I am a little ignorant here & I do not mean to change the subject, but has it ever been conclusively proved that FCR extends overall survival? I know MDAnderson has pushed this protocol very hard the last 10 years. Are we diagnosing CLL earlier and starting FCR treatment sooner? If so, the books would seem to be cooked. The long-term side effects of FCR & FC+Campath seem extreme to me. Until more targeted therapies come along, I question the progress we are really making. I don’t want to be a pessimist and I know that for many extreme measures are the only hope.
Patrick…I understand where you are coming from, but please understand 2 things:
1. No one is going to issue new life insurance coverage to cancer patients, especially not when they are undergoing “experimental” therapy.
2. The researchers and the patients had every reason going in to believe that the addition of Campath to FC would be superior to FCR. The appropriate precautions that were taken show that the researchers respected the potential for opportunistic and secondary infections. Unfortunately the results were worse than could have been predicted, but that is why research is done in the first place. To their credit they stopped the study in a timely manner.
I do agree with you on one point…desperate patients may easily be misled by overzealous researchers which is why it behooves all of us to remember that all clinical researchers, of necessity, wear two hats; this makes it imperative that we perform due diligence and employ very critical thinking before making personal decisions as to therapy, whether in trials or not.
mschwalm48:
No one really knows the absolute answers to these questions, but we all recognize that if one watches a forest fire for too long or simply tries to extinguish it with a squirt gun it will likely soon reach a stage where it cannot easily be dealt with and greater overall damage may occur than was necessary.
Chaya:
Safe travels, N92 mask all the way if you took one with you. Thank you for the most valuable heads up!
Rick:
Thank you for the insightful comments. We appreciate your knowledge and thoughtful guidance.
Our deepest thanks to all who participate in trials (I tried to get in the FC-HumaxCD20 trial two years ago, but was not accepted. My oncologist then opted for FCR. I am doing very well.)
I’m a 17p-deleted individual who elected single-agent Campath frontline, partly because my understanding was FCR could be counterproductive for people like me. (I’d have to go back into my decision-time research for the detailed reasons.) Obviously I’m curious how Campath alone compares with FCR and FCCamp. I’m in my 10th month post-treatment, in partial remission. Treatment itself proceeded with zero problems. Blood numbers good and stable for several months (T-cells adequate for discontinuation of prophylactics). Downsides: 2 bouts of thrombocytopenia, 1 mid-severity pneumonia.
Terrel
mschwalm48:
We have discussed “Do patients live longer with FCR” just a week or two ago. Please read the cited article. There is now credible information that FCR does extend overall life in the cohort of patients studied in this trial. It pays to be cautious, but suspicion without detailed knowledge of the facts is not helpful. None of us will take any chemo if we can help it, if we did not need it. But when the choice an aggresive cancer that needs treatment or early death, I think it is prudent to become an informed patient. If the patient is facing the Devil-or-the-deep-blue-sea, would it not be better to learn swimming ahead of time?
Guys, please let us not throw out the baby with the bathwater. Campath is a very potent and powerful drug. It has its role to play, and I for one am glad we have access to it. Without Campath we would be minus one of few drugs that work in 17p deleted cases. Should it be used without due consideration and without prudent protection of the patient against infections? Obviously not.
The FCR versus FC+Campath was a good trial. It was based on good logic, conducted with due diligence for patient safety, trail design was sufficient to give credible answers to important questions. The results could have turned out the other way just as well, with spectacular responses and long lasting remissions, and we would have been cheering the development of this new combo. Simply put, we did not know how it would pan out. That was the point of doing the trial, to find answers. The decision to stop recruiting additional patietns was taken when the results showed that was the correct thing to do, and I have respect for the researchers who made that tough call. I regret very much the patients who died during the course of this trial. Let us not trivialize their sacrifice by misunderstanding or misinterpreting the true meaning of the results of this trial.
Well conducted trials and honest evaluation of critical information obtained from them is the life blood of clinical research. Without such research, you can kiss goodbye any chance that this incurable cancer will ever be cured, that patients suffering from it today will ever find better therapy options. I am very serious about this folks. We would not have Rituxan today if patients had not volunteered for Rituxan containing trials in the years gone by. I suppose it is human nature to wish for the results without having to “pay” for them, or wish some one else would pay for them while we get a free ride. But I doubt any of us would feel good about such selfishness. When push comes to shove I think most of us do the generous thing, pick up our share of the tab. Noblesse Oblige. If not you, then who?
ojibwak:
Three of the patients in this trial died due to diffuse large B-cell lymphoma – an aggressive lymphoma. Richter’s transformation too is a type of aggressive lymphoma. Wether these three case were exactly Richter’s or not cannot be determined with the information given in the abstract. Some cases of Richter’s are driven by EBV, and viral reactivation (EBV, CMV, Hepatitis etc) during periods of deep immune suppression is well known. The take home message here is that FC+Camptha was found to be very deeply immune suppressive. These types of conversion to more aggressive lymphomas are invariably triggered by combination of deep immune suppression and viral reactivation in a susceptible host.
Another off specific discussion question. Does anyone have info on Rituxan alone as a front line therapy? Or is there a way to search this site for an answer to such a question?
Yes, this is likely in my future, but not as part of a controlled study.
I saw an earlier piece on Campath alone as a front line therapy.
Thank you, Chaya, for keeping the cll population inform.
Monique
Response to tsvieps. I am currently having Rituxan as a front line therapy. Six months ago, I had 8 weeks of treatment, once a week. I had no problems and have been in remission since. All of my blood counts are great. I will begin another session consisting of 4 weeks of therapy. They call it a maintenance program. This therapy will continue every 6 months for 2 years if all goes well. Good luck.
Ojibwak
Thank you, Chaya, for the answer to my question. Deep immune suppression, be it with Campath or any other chemo or monoclonal antibody, seems key to Richters Transformation. I guess this will also “let loose” the EBV which is latent in most of us. I would imagine either one treatment that significantly suppresses the immune system or several years of chemo (as in my family member’s case) and recurrent immune suppression may lead to transformations or secondary cancers. We experienced both the secondary cancer (skin) and the transformation, both at about the same time. That a transformation can occur in a previously untreated patient, as a result of one clinical trial, is somewhat of a concern to me. The balance between killing the cancer and compromising patient well being or lifespan is what we often ponder.
ojibwak
CLL patients have a higher incidence of secondary cancers than the general population. Skin cancer is the most common second cancer, which is why I write so often about limiting uv exposure.
Our present understanding is that as we age all of us develop microscopically small clusters of cancer cells on our skin, in our lungs, breast, prostate etc. But a healthy immune system that is vigilant and on the look out can spot these tiny clusters of cancerous cells and kill them before they can grow up and become clinically diagnosable cancers.
You know the saying, when the cat is away, the mice will play. CLL Patients, even chemo naive patients, are dealing with less than perfect immune surveillance – hence increased risk of infections, secondary cancers. The more advanced CLL gets, the more dysfunctional the immune system and therefore increased risk of infections, secondary cancers, autoimmune disease.
While potent chemotherapy regimens can make the patient even more immune suppressed for a while, the root cause of the immune dysfunction in our patients is CLL. Our guys have a cancer of the very immune system that is supposed to protect us from other cancers! A corrupted police force that is sleeping on the job, letting the crooks flourish. I would not attribute all of your family member’s problems to the chemo, the underlying CLL had a lot to do with it as well.
Chaya,
I certainly agree with all you have to say. The FC vs FCR study was very well done. However, playing the devils advocate here- is 84% survival vs 79% survival at 37.7 months statistically that significant?
My other concern is whether these trials play more to lab results than over all survival. Intuitively I have trouble understanding how indiscriminately hammering the entire immune system and not completely eliminating all CLL will ever produce great results for overall survival. We all know the limited options for those that become F refractory and the many bad things that can turn up much later when the immune system has been severely compromised. My doubling rate was every 20 months for 8 years and when my WBC hit 200 & platelets 100, several MDs suggested treatment. For reasons no one knows, I suddenly have stabilized at WBC 220 and platelets 100 for 2 years (I did participate in the failed MyVax trial). My question is this: how can you compare overall survival of doing nothing vs FCR treatment? No one would participate in such a trial. There is no question that routine blood counts are far more common & cheaper today than they were 10 years ago. If we are diagnosing earlier and treating sooner, then it may only look like survival times are increasing. There is a big fear factor here. Billions are made off treatments; is there a bias for some of these treatment protocols? I simply have not seen any dramatic proof that FCR is the right track. I sincerely hope I am wrong and do not mean to upset the thousands who are vested and believe that this protocol is giving them many good years. These are fair skeptical questions. I would like to hear your expert opinion. Convince me I am all wet.
I’m sure Chaya will discuss the more positive outcomes involving campath in the future, but let me provide my own experience.
I was treated with FCR in 2005 and relapsed in 2007. I began campath in 2008. My blood counts were closely monitored and the campath was terminated after 9 injections due to low neutrophils. The nine shots resulted in a six-month remission. I then completed a full course (36 injections) between March and May of 2009. I had no adverse side effects at all, though I did need neupogen (for neutrophils) and platelet and RBC infusions. This course of Campath cleared my bone marrow down to 4% leukemia cells, but did very little to shrink my moderately-large lymph nodes. To get my node-size ready for a transplant (<5cm), I was then given two 5-day cycles of r-ESHAP, a fairly common drug used for lymphoma but apparently not for CLL. The r-ESHAP (July and August 2009) was exhausting because you have to be hospitalized for 5 consecutive days. But it reduced my lymph nodes to under 0.5 cm and further cleared my marrow to under 1% leukemia cells.
I then had the transplant September 16 at OHSU in Portland, Oregon. After two months, there is no evidence of leukemia in my marrow and the chimerism analysis showed 100% donor T-cells. My primary oncologist suggested that one reason for such a fast engraftment was the use of campath, which disabled my T-cells and thereby made it easier for the donor T-cells to take over. Such early engraftment predicts longer survival and PFS, presumably by supporting a stronger graft-versus-leukemia effect. It's unclear, however, whether it also promotes a stronger graft-versus-host effect,
I wanted to share this because it is, I believe, one positive example of what campath can do. Of course all of our diseases are probably different (I only had the 13 deletion but all other indicators were negative). And also, it's worth noting that my oncologists were wary and very careful in administering the campath. Finally, I'm sorry to make things more complicated given our current drug choices, but the r-ESHAP worked very well in preparing me for the transplant. Unfortunately, there doesn't seem to be much research, if any, regarding its use in CLL.
mschwalm48
You are not all wet, and in any case it is not my business to convince you or anyone for that matter. I see my responsibility as providing credible information. It is up to you to convince yourself, or not, as you please.
By the way, the reason why the FCR study was so important is that it showed improved overall survival with FCR and this was indeed statistically significant.
Way back when a study was done to see if W&W was better or earlier treatment with the then available drug, chlorambucil. There was no advantage to either regimen. It was a draw. Now we have moved several generations ahead to FCR. And for the first time we have staatistically valid results that say FCR improves overall survival compared to the next best, FC. I have no doubt that the same would be true of FCR versus Chlorambucil.
All of these results are applicable to the CLL patient population in general, not to the single individual. Statistics works on large sample sizes, not on individual cases. CLL comes in many flavors. For some, those with very indolent variety of CLL, Watch & Wait is the smart thing to do. Others may not have that option. Indefinite W&W in the case of aggressive CLL will surely not prove to be the key to longer life, not when the disease calls for treatment. My husband did not have that option either. For the sake of these patients with progressive disease, I am very thankful FCR has come along.
I was not an early fan of FCR. It took many years of slow dribble of clinical trial results to convince me. Another member of the sceptics club was Dr. Terry Hamblin. As his recent blog entry shows, he too is pleased to acknowledge the validity of the latest results. That is the hallmark of a good scientist, not hanging on to notions that are not supported by most recent and credible facts.
Will FCR be better than W&W in your case? I do not know. In any case, it is your decision to make, not mine.
Chaya,
I absolutely know that it is not your position to recommend individual treatment protocols. What you say is very reasoned and tempered with experience and many years of turning over every rock and reading vast amounts of information. There is not another person I can think of who looks at all the claims and hopes more objectively than you. I have complete faith in your realism and honesty as a patient’s advocate along with a scientifically trained mind. We all appreciate your dedication immensely. Nevertheless,I am uneasy with the lack of specificity & bad side effects of so many treatment protocols; I also know statistical truths can be elusive. Do not mind me- I am a born skeptic and full of frustration at the snails pace of understanding and treating this disease. Thank you for all you do!
mschwalm48;
You have caught me in a rare sleepless night occasioned by family issues and I find that your concerns are real and hard to deal with objectively.
I am not a game theorist, but agree that your course to date is a bit atypical. No one can predict the future. I have practiced medicine for many years and remain frustrated that I rarely feel that I have the absolute answers. As i’ve said many times…statistics do not matter in individual cases.
My suspicion is that you are at the brink of needing to do something for your CLL before you cross the line where theraoies will offer less hope of a good outcome, but no one can predict this with any certainty.
I have not seen any true miracles, but I have seen most curious unpredictable courses of disease where patient’s outcomes far exceeded our expectations and where the refusal to undergo recommended therapy proved no worse (if not a better decision) that would have been the decision to proceed with the ‘tried and true” therapy of the day. The opposite occurs as well…early demise preceded by an unglamorous end of days.
There are many cases of what I term “death by therapy” so these answers are never crystal clear.
More that 30 years ago a young man (27 yoa) with what was then termed Stage D colon cancer was under my care. He had definitive surgery, but declined chemotherapy and pursued a macrobiotic diet which I thought was foolish. He continued to have periodic follow up colonoscopies for almost 25 years before concluding that this was a waste of his time and resources. Insofar as I know he remains well. I can not explain this and would not recommend such a course of action to a similar patient if seen tomorrow, though it is undeniable that he did quite well.
There are some things in this world which defy rational explanation. Ultimately you must digest the available information and follow your heart. FCR in large cohorts prolongs survival Is it the correct course of action for you…who can say.
Good luck whatever you choose to do. Remember…no one escapes this earth alive,
Rick
Thanks Rick.
It is truly sad for Forrest Bump and all those other patients who had to make a choice on limited information. Thanks for the warning about campath!
Chaya,
Your article on Campath is so timely and I do appreciate your efforts and the sacrifices made by those patients and families of those participating in this trial.
I know a trial including Campath will be encouraged on my next MD visit Dec. 2 as frontline therapy. I was already hesitant because of the downside of the Campath complications. Your article has confirmed my thoughts. I look forward to reading what is next in the series.
This doctor down play’s Humax CD-20, if one were able to be given a choice as front line how to you feel the two stack up?
debroberts:
The devil is in the details.
This article and the results I discussed here are with reference to this particular trial of FC+Campath versus FCR in this cohort of patients.
It does not mean all Campath containing regimens are to be shunned, or that Campath is an unreasonable choice for all sorts of patients in all kinds of situations.
I do not know your situation, or what your doctor is recommending. I get worried when patients extrapolate my carefully written reviews well past their legitimacy boundaries.
Deb, please don’t go off the deep end. If your doctor is recommending Campath, and you are concerned, the thing to do is sit down and have a nice long conversation with him. Ask him why he is recommending Campath; share your concerns with him. Then come to a smart and informed decision that is right for you as an individual patient.
Thanks for more brain food. With all the information, I admit to feeling overwhelmed much of the time. This was a good read and though most still clear as mud, I, at least, am feeling more informed.
I have not had any treatments yet, but there is talk of an Arzerra combo trail in a few months. Not sure what it is combo’d with, but hope to read all I can find on these when I learn so I can try to make a better informed decision.
Chaya, have a wonderful journey and away time.
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