Treating Refractory or Relapsed CLL
Making the right therapy choices at each point in your CLL journey are probably the most important decisions you and your medical team will face. How long to stay in “Watch & Wait“? Should you bring out the big guns right away, perhaps start out with the ‘gold standard’ FCR? Would you be better off with a lower impact regimen such as single agent Rituxan, ofatumumab, even if remissions are likely to be short? Who is best served by regimens such as FCR-Lite? Is there a risk in pulling your punches early on, will you wake up to find the window of opportunity has closed while you fiddled with ineffective therapy options? How about an early stage clinical trial using a sexy new drug, or is that too much like buying a lottery ticket and hoping for the best? None of these are easy questions. A lot depends on your clinical history, your prognostic indicators, your overall health situation and age, and not to forget, your own personality. And your oncologist’s level of comfort with thinking outside the box.
If making front line therapy decisions is tough, making the right choices when you have been around the block a couple of times and relapsed is even harder. What are some of the criteria that should go into making smart therapy choices in the case of relapsed or refractory CLL patients?
Right upfront, I would like to highlight the difference between “relapsed” and “refractory” patients. A relapsed patient is someone who had a reasonable remission to his prior therapy, reasonable being defined by the nature of the therapy chosen. Relapse 6-12 months after single agent Rituxan is reasonable. Majority of patients fall into this bracket and they would be classified as merely “relapsed”. Chances are pretty good that they will respond again to re-treatment by the same drug. But a one year remission after completion of a higher impact regimen such as FCR is not good news. Most chemo naive patients respond with longer remissions than that. There are grounds for expecting such patients will not respond again to re-treatment with FCR (or similar combinations), that they are in fact “refractory” to one or more drugs in the combination.
So, what are the choices available to relapsed and /or refractory CLL patients? Clearly, in such patients the disease is tougher to treat. It might have learned a trick or two during its prior exposure to therapy, it may be a tougher nut to crack. However, it is important to remember that during this process the patient has changed too. He is older. His immune system has absorbed some body blows as he went through his prior therapies. He may have experienced cytopenias (anemia, neutropenia, low platelets) during his prior therapies, perhaps an infection of two as a consequence of the resulting immune suppression. Another consequence of poorer immune surveillance, does he now have more issues with skin cancer? Chemotherapy drugs are not friendly to bone marrow function or the precious stem cells that live there. Very likely the patient has less “bone marrow reserve” after going through prior rounds of therapy.
When treating relapsed / refractory patients, should we focus on treating the disease, hit it harder than we did before, because it is now a tougher clone to kill? Or should we pull our punches, treat the patient who is now likely not in as good shape and therefore pay more attention to minimizing toxicity of the next regimen? These are two very different approaches. In this first of this set of two articles, I would like to highlight what happens when the focus is on treating relapsed/refractory disease. The second one will look at the other side of the coin, making therapy choices based on the condition of the patient.
I also need to point out that I am a strong believer in treating the patient, the whole patient, and nothing but the patient. Does this color how I review these two different approaches? You betcha. In other words, there is a lot more editorial content in these two articles, not “just the facts ma’am” approach I try to present most of the time. Remember that caveat as you read and make up your own mind.
CFAR
This “cute’ acronym is pronounced “See Far” and stands for cyclophosphamide, fludarabine, alemtuzumab (also known as Campath) and Rituxan. In other words, using far more familiar terminology, it stands for FCR + Campath – administered concurrently. Too bad the cleverness of the acronym is not matched by clinical results, CFAR does not see far reaching remissions for its patients.
As most of you know, I am not a big fan of Campath consolidation after initial induction with combinations such as FR or FCR or even R+HDMP (Rituxan + high dose methyl prednisolone). “Consolidation” is the term used to drive the number of cancer cells left in the body to even lower levels, after the initial “induction” regimen has taken care of the bulk of the disease. Several studies have shown that Campath consolidation started too soon after completion of FCR or FR induction may have more toxicity than most patients can tolerate.
CFAR kicks it up a notch, delivering the Campath right along with FCR. Why bother with waiting, an induction phase followed by a consolidation phase, why not do it all in one massive concurrent administration of all drugs? CFAR is definitely not-for-sissies type of drug combination. The idea is very simple. These are heavily pre-treated patients. Chances are good that their CLL has grown fangs and become a tougher beast to kill. How do you kill a cancer that has grown fangs? You increase your fire power too. (Seems to be based on logic similar to that in the movie “Untouchables“: You wanna get Capone? Here’s how you get him. He pulls a knife, you pull a gun. He sends one of yours to the hospital, you send one of his to the morgue!)
The results of this clinical trial are just published in “Blood”. Some of the big names at M. D. Anderson that many of you may recognize are on the author list. The abstract is below. Do send me a personal email if you need help locating the full text of this paper.
Blood. 2011 Jun 13. [Epub ahead of print]
Cyclophosphamide, fludarabine, rituximab and alemtuzumab (CFAR) as salvage therapy for heavily pre-treated patients with chronic lymphocytic leukemia.
Badoux XC, Keating MJ, Wang X, O’Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG.
Department of Leukemia, U.T. M.D. Anderson Cancer Center, Houston, TX, United States;
Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features such as fludarabine refractoriness, complex karyotype or abnormalities of chromosome 17p experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase II study of cyclophosphamide, fludarabine, alemtuzumab and rituximab (CFAR). All patients were assessed for response and progression according to 1996 CLL-working group criteria. For the intention to treat analysis, the overall response rate (ORR) was 65%, including 29% CR. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher CR in high-risk patients following CFAR compared to a similar population who had received FCR as salvage therapy, there was no significant improvement in PFS and OS appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pre-treated high-risk group of patients there was no benefit in survival outcomes.
PMID: 21670470
CFAR Clinical Trial Design
- This was a single arm trial, at a single institution. But what is interesting is that M. D. Anderson compared this group getting CFAR with an exactly matched group of prior patients that they had treated with just FCR. The hope was that addition of Campath to FCR would improve things.
- 80 patients with relapsed or refractory CLL participated in this study, between Dec 2002 and October 2006.
- Patients had adequate liver and kidney function; no uncontrolled infections; HIV or carriers of hepatitis B and C were excluded.
- Treatment consisted of standard drug dosages of FCR, in addition to 30mg of Campath on days 1,3 and 5 of each 28 day cycle. Campath was administered intravenously, not a subcutaneous injection. Allopurinol was given for 1 week prior to start of therapy.
- Standard premeds of Tylenol, Benadryl prior to Rituxan infusion and hydrocortisone prior to Campath infusion.
- I guess they knew better than to tempt fate, all the patients were on infection prophylaxis: Bactrim twice daily (to prevent bacterial infections, especially bacterial pneumonia) and valacyclovir daily for prevention of Herpes infections.
All this is pretty standard, no punches were pulled on dosages and all protective pre-medications and prophylaxis medications were given. All patients who entered the trial were in need of therapy, as defined by the NCIWG guidelines. Below is a chart that describes more detailed profile of the patients. No question about it, these were indeed a tough crowd to treat. What you would expect given the fact they all had an average of three sets of therapy under their belt.
FCR is no walk in the park and here we have added the other big drug, Campath to create the new acronym CFAR. How bad was the hematological toxicity for this four string combo? Funny you should ask. Here are the scary statistics.
As always, it is important to pay attention to the grade of the toxicity. Grade 1 is easy stuff. Grade 2 is a little more note-worthy. It is grade 3 or grade 4 that are worrisome (just so you know, Grade 5 means the patient died). A substantial percentage of patients experienced Grade 3 or higher hematological toxicity.
How about infections? Remember, these patients all got the recommended protective medications (Bactrim for bacterial infections, especially bacterial pneumonia; and valacyclovir for prevention of Herpes infections). Once again, the infections are broken down by grades, so we can better judge the seriousness of the infection. The grim news is that roughly half the patients experienced a serious Grade 3 or Grade 4 infection. Even with Bactrim prophylaxis, the number of patients with pneumonia was surprisingly high.
Well, nobody said this was a therapy combo for sissies, the patients were all heavily pre-treated and they were a tough crowd to treat. We knew that going in. As always, the $64,000 question is what did we get for this high price? Did the patients get longer remissions than just garden variety FCR without Campath? Did patients who went through the tough love of CFAR live longer?
22 patients died while they were undergoing CFAR therapy or while they were still being followed after conclusion of therapy. That is 22 out of 80 patients recruited for this study. Here is the sad break-down.
22 patients died, starting from a cohort of 80 patients. 13 patients were still undergoing CFAR when they died, and another 9 died during the post therapy monitoring program. The authors also report many more deaths that occurred after the end of the monitoring period. I just did not have the heart to report those numbers as well. Send me a personal email if you wish to read the full text of the article, it has all the gory details.
How did the CFAR statistics for remission duration and overall survival compare against garden variety FCR? The authors matched the patients in this group against an exactly matched group of patients who had undergone FCR therapy at their institution. They say a picture is worth a thousand words. Below is the chart for overall survival, for a subset of the CFAR group that was considered high risk – because of their clinical situation and prognostic background. These were particularly the group that the researchers hoped would benefit from CFAR, as compared to FCR.
The dark line is for CFAR, the light line is for FCR. As the authors themselves pointed out in their abstract there was no significant improvement in progression free survival (i.e., remission length) and overall survival appeared worse for CFAR. The median survival was 31 months for FCR, but only 14 months for CFAR. One does not have to look hard to find the reasons for this disappointing result. CFAR caused a lot more toxicity, a lot more infections. For a significant number of patients, this was a case of death due to therapy.
Editorial
OK, there was no way you could have missed my personal bias in the analysis above. I think CFAR is far too toxic for majority of relapsed / refractory patients. True, there may be a few unfortunate folks here and there that may have no other choice – though I find it hard guessing exactly who they are likely to be. But for the majority of relapsed / refractory patients, there does not seem to be much to be gained by the addition of Campath therapy, concurrently with FCR therapy – namely, CFAR.
Which brings me to a question that I cannot answer to my satisfaction. Prior studies have shown that Campath consolidation after completion of FCR therapy resulted in too many deaths if the waiting period between completion of FCR and start of Campath consolidation was not long enough. We are talking of a waiting period of several months between FCR induction and Campath consolidation. And these studies were done in chemo naive patients to begin with.
If a short wait between FCR and Campath was not good enough, what ever convinced these researchers that no wait at all was safe? The patients in the CFAR trial were heavily pre-treated. They had already absorbed quite a lot of toxicity from earlier therapies. Their bone marrow reserves were already depleted. And this study put them through full strength FCR along with concurrently administered Campath. I wish someone will explain the logic of doing this trial. I expect they were looking at the fact that these patients probably had very tough to kill CLL varieties – looking at the disease and not the patients – and decided to bring out the biggest guns they had at their disposal. They were treating the disease and not necessarily giving sufficient weight to the nature of the patients.
I guess we should be relieved the researchers themselves declared the trial a failure: the intent was to see if relapsed / refractory patients got longer remissions or lived longer with CFAR compared to FCR. The sad answer is that they did not, on both counts.
The end of the M. D. Anderson paper lists the usual author contributions, acknowledgements and conflicts of interest. But no “thank you” to the patient volunteers that suffered and died for this study. Surely they deserved that?! Please join me in thanking these brave but unfortunate volunteers – and their families.
30 comments on "Treating Relapsed or Refractory Patients – Part 1"
I find it hard to imagine choosing to participate in such a trial even while acknowledging how strong the survival instinct may be in one who has tried ‘everything’ else.
There surely must be very explicit guidelines for what must be disclosed to gain informed consent, so I cannot help wondering what motivated the 80 participants.
For me,”I wish someone will explain the logic of doing this trial” says it all.
I’m more on the sll side, m/48, dx stage 4 Oct. 2008. I’ve got all the bad prognostic markers.
I completed RCHOP in Feb. 2009.
Refractory less than 6 months later.
Completed FCR, April 2010…so it’s been a little over a year now, and things have been stable so far.
I’m starting to have some minor nightsweats….and having some itchiness in my feet, which was definitely a symptom when this whole thing started. My hands are not itching…so I’m getting mixed signals.
Maybe I’m just being paranoid. But being suspicious about this is never really out of my mind at the moment.
If thing comes back in the near future, I think I need to jump into a SCT, instead of trying another round of chemo.
And those CFAR statistics are scary.
I’m not going anywhere near Campath.
The thought of a SCT doesn’t thrill me either.
Great job Chaya….having done chorambucil/rituxin both concurrent and consecutively then fcr with a prudent 6 month wait for a campath chaser (recommended by a cll specialist who (or is that whom?)I still respect and consult with… I find myself with cll not well controlled…got less then a year remission before doing epoch-r (very nasty) as the lymphoma part of my cll was out of control along with chipping off blood clots to my lungs….am now doing ofatumamab with the hope of getting either a transplant(scary) or going into a clinical trial…all in the last 4 years…reading this site allowed me to make informed decisions tho the outcome so far has not been anywhere near as good as I hoped…I am more aware how doctors do care and give the best advice they can with the caveat that there are no guarantees…and there is so much we do not know about this disease…the best and brightest…Kipps…Rai…Keating…Hamblin et all are working diligently for our good…yet without your analysis and comments of others I would be lost…guess the message is be informed…live and love every day…don’t look back…be as healthy as you can as there is promise and hope in every sunrise…thanks chaya for all the good you do
romanbob—-you should check into the PCI or CAL101 trials—they are seeing excellent results with the PCI. SCT’s can be rough on those with the “lymphoma” or bulky node part of CLL.
Chaya–I guess there are times that the trial rats pay with their life’s so the rest of us know what NOT to do. As you know, Tom has always been a trial rat from one of the first 300 in FCR to Revlimid/Ofatumamab to PCI. Tom had MRD following his FCR treatment and I was already very against “mop up” with Campath after reading one of your articles about it. So, I was very relieved when Dr. Keating told Tom that he was not a candidate for Campath because he felt that it would be too invasive to his marrow. In this case, Tom was truly a patient and not a trial rat!
I always appreciate your ending these kind of articles thanking the trial participants. Thank you for the continuing recognition!
JLOU
The authors make a good point”The CFAR patient population was significantly higher risk than the population treated on our FCR salvage protocol” and “These two populations are therefore not
readily comparable” but it is a little late to blame their faulty trial design after the fact. What is the point of having a trial that compares apples and oranges? It is surprising that their mechanism for stopping to recruit did not kick in. After 14 months, the chances that CFAR could prove superior seem astronomical. The overall p=value of .0076 in the wrong direction is the widest I can recall. We would call that an F minus minus in school.
One chance to compare apples to apples is with the people who chose stem cell therapy, the so called “only cure” to CLL. Despite campath’s widely used role as a conditioning treatment for SCT, supposedly to clean out the bad guys, the people who chose SCT lived 10 months less than those who did nothing. They put a typical spin on these results: The CFAR regimen could be considered for high-risk relapsed patients who are candidates for transplantation; however since we could not demonstrate a significant improvement in survival in our transplanted patients, this hypothesis remains unconfirmed.”
Their figure 3 needs a correction, as it lists the overall survival backwards. It is correct in the text: There was no significant difference in survival for the 9 patients who had an objective response after CFAR and underwent a SCT compared to 36 patients who achieved a response but did not undergo SCT (Figure 3, OS: 17 versus 27 months, respectively; p=0.26). The figure is very clear on its own. Every person who underwent SCT died compared with about 2/3 of those who did not have SCT. How could anyone suggest CFAR be repeated as a pretreatment to SCT in these type patients after these results? Not only does it appear they are treating the CLL and ignoring the patients, it seems they are writing the paper for the drug companies instead of other clinicians, scientists and patients. Only 2 of the authors have taken any drug company money but one is the PI, although Wierda does have a good reputation and I am not trying to imply he was motivated by these payments. It just seems obvious there is spin on these results.
Finally, I wonder if there was any medical advice concerning all these antibiotics. Without replacement therapy with probiotics, this can be a very dangerous situation. The link below points out we have more bugs than cells in our body It can’t be a good thing to wipe them out.
Chaya, thank you for this informative article. The message seems clear – stay away from Campath. Cll patients need those T-cells to survive infections.
Thanks again Chaya – articles like this are very valuable for people who have been round the block ONCE and might face more in the future. I also had a conversation recently with my son, who has been round the block with a brain tumour. He reckons one of his most valuable assets is a mindset which says he was treated for cancer – NOT that he has it now. It holds out hope for him.
Likewise, I think that Romanbob’s summary is excellent and thank you Romanbob for that – I will just repeat it here: ” be informed…live and love every day…don’t look back…be as healthy as you can as there is promise and hope in every sunrise…thanks chaya for all the good you do”
I couldn’t have said it better myself.
Lawrence
(Cornwall, UK)
Definitely thank all people who volunteer for trials…they are braver than I am. I refused admission into a shingles vaccine trial for CLL patients here in Rochester. And a friend of mine in Pittsburgh who’s 8 year old son was diagnosed with ALL this week also refused to enter him in a trial. So not all of us have the guts to do what those brave few do.
However, I guess I’m one of the exceptions to the Campath rule…fairly poor prognosis…pos CD38 and ZAP70, unmutated and 11Q. February 1st of 2008 they started me on Campath, following my last PCR treatment on December 4th 2007…about 2 months later. Of course, my treatment was the initial one, not a second or third, but it apparently worked well the first time.
The BMB after the PCR and before the Campath indicated 20% of CLL cells still present, and another after the Campath, 10 weeks later, produced 0 cll cells.
And that’s the way I’ve remained. Still in remission over 3 years later, although my lymphocytes have yet to recover and remain around 500 (.5). Still taking Valtrex and Bactrim. Everything else is normal. No swollen lymph nodes yet and feel healthier and am doing more than I have in the last 20 years. Haven’t even had a cold in the last three years!
Guess Campath can work for some people, if all conditions are right. Just wanted to put a light side on this relatively dark news….
Harley
Azzy raises a good point that I should have commented on in my review. About a year out from start of the clinical trial, it was crystal clear that CFAR was not helping patients any more than plain vanilla FCR – quite the contrary. Just look at the survival curves I included in my review. CFAR patients were dying at a much faster clip than their comparison FCR patients.
So, why did M. D. Anderson continue recruiting patients into their CFAR trial? They recruited volunteers to participate in the CFAR trial for almost 4 years, from December 2002 through October 2006. Why did their internal ethics committee not step in and stop recruitment after the first year? after the second year?
In a 2004 article I published on CLL Topics, I compared Campath consolidation studies done at M. D. Anderson and in Germany. The German study saw more deaths and morbidity (probably because they had shorter wait between the induction phase and the Campath consolidation phase). But they also had a trigger point for shutting down the trial when the deaths and morbidity got to be more than they expected. Not so the Anderson study. They went the distance, their study was not shut down. I expect different institutions have different “personalities” in how they view patient deaths. The researchers at MDA seem to be made of sterner stuff, when it comes to dealing with patient deaths. You can read my 2004 review here:
http://www.clltopics.org/Campath/campath_consolidation.htm
I wonder how the families of the patients recruited for the CFAR study late in 2005 and 2006 feel about it. The trend in the results was already quite clear by that time.
Chaya,
Thank you for a valuable and honest study. I am now 78 years old and have for years stayed away from campath especially with my lymph nodes.
Dx in 1994 at age 61 and in W&W for 8 years, when I had chemo, RF. I am not sure I ever recuperated from that.
“Listen to the patient.” is my mantra. “I am too old for all those high powered meds.”
Rita
“I wonder how the families of the patients recruited for the CFAR study late in 2005 and 2006 feel about it.”
and I wonder what information and/or other options the patients were offered in 2006? Were they told the results to date?
For me this confirms why sites like CLL Topics are critical to patient knowledge, advocacy and protection. One can get the information necessary to make an informed decision on treatment for a disease that much is still not known.
Chaya,
Does the journal Blood publish comments on studies? Maybe you can write a commentary asking the questions you lay out and also thanking the patients who participated?
Someone needs to keep raising these questions- can’t wait for part II.
Having had FC twice, Campath and then FCR (with AIHA,failed splenectomy as well as being unmutated), I am now 12 years on and nearing the end of my ‘CLL career’. When I first needed treatment, I chose trial CLL4 (FC)and was happy to be part of that trial. However, even if I had been eligible for CFAR I would not have participated. At this stage I feel quality of life is more important than quantity and am trying a half dose of chlorambucil (Leukeran) which is a old drug and Prednisolone. I am living out my life and trying a gentler route. I salute the people who participated in this trial. More so since I have been read The Emporor of All Maladies (as recommended by Chaya). After reading much of this book (I have not finished it yet), I salute all the patients who have ever participated in drug trials. Speaking for myself, when I joined CLL4 trial, I did it for me and only me and would have accepted the consequences. When I did Campath, I was grateful for the patients who went before me on earlier stage trials so I was more informed than they were. I would never have tried CFAR knowing how toxic my body found FC, FCR and Campath separately. The company running the CFAR trial should not have continued once the trend showed that the CFAR patients were dying at a much faster clip than their FCR comparisons.
Sylvie
Marathon:
Blood does publish comments, but only from professional oncologists and hematologists, not riff-raff patient advocates like me. Did you know mere patients cannot even attend the annual ASH (American Society of Hematology) meetings? PC and I attended by getting Press credentials because we were publishers of CLL Topics. I hope ASH has changed their policies since then.
Heck, they don’t thank their own patients who made the study possible, at great cost to themselves and their families. Why would they care to pay attention to what I have to say?
But we do have veto power, if only we choose to exercise it. We are the consumers of healthcare. We pay for all of it, every last single dollar. As informed and involved patients, we can make huge differences to how we are treated.
A small request: the next time your physician or CLL expert asks you to participate in a clinical trial, ask them this. ” Mr. Expert, do you thank the patients who participate in your trials, when you write up the reports?” The answer to that will speak volumes about how patients are viewed and how their agendas are honored in the institution conducting the trial.
One researcher told me that journals like Blood have page charges, the author (his institution, in actual practice) has to pay dollars for every page of the paper. I wonder how many dollars it would cost to include one sentence: “We thank the patients who participated in this clinical trial and made it possible”. There is a lot of self-serving language hiding behind opaque jargon in these papers. Surely one sentence thanking the volunteers is justified? Especially since the study could not have been done in the first place without these brave folks?
It is the sheer lack of respect that gets to me. Sorry for the venting.
Harponner
in my short involvement in the whole CLL treatment process, it is clear that most of the Drs, especially the ones at the big research clinics, tend to consider pts as statistics….another data point. These guys are hard to get a hold of, have maybe one clinic a week, travel the world giving scientific papers, etc. they get paid and promoted based on doing hot research. they are what i call ‘research physicians’, and the MDA scientists whose article you describe are of this ilk. i had one such dr. and after a lot of frustrating encounters, moved on to what i hope will be a ‘pts physician’; one who cares about me and my situation and who is not a STC trog. we’ll see. but already i know most people’s hearts will align with your forth coming Part 2.
keep up the good work!!!
Keep venting!
Maybe CLL Topics can purchase an advertisement in the magazine. We could thank all the patients who made the clinical studies published in the magazine since 1946 possible. Then the 16,461 subscribers could be asked to take “Thank You Pledge”. I checked and they do take advertisements but all are subject to acceptance by the Editor. I am sure many of us would be happy to help pay for the advertisement (rates did not look too bad).
Anyone else ready to contribute and see if they will accept a “patient” focused advertisement???
Jlou…in dec had seen coutre at stanford on cal 101…used a wheelchair as could not go 10 feet without losing breath and completed necessary paperwork…next day in hospital as blood clots and nodes exploded…am presently considering one of those trials if I can find one close or even revilimed (concerned about tumor flare) yet it seems to heal up the bone marrow…need to wrap my head around it more…waiting for part two of this to explain more treatment options…thanks…bob
marathon:
CLL Topics is no longer a non-profit, and I do not have enough money personally to take out such an advertisement and pay for it out of my pocket. The money I can spare goes to maintaining these sites and paying for the two workshops I conduct each year.
But we have thousands of registered members on this “Updates” site. No doubt some of them are quite wealthy. Any of you interested in getting together and publishing such a patient centered advertisement in “Blood”, “Journal of Clinical Oncology”, “British Journal of Hematology” etc?
I wonder how may researchers would take such a “Thank You Pledge”. I suggested it at a Mayo conference back in 2006. To say the least, many of the big name experts were offended and horrified at the concept. And the Mayo folks are among the best and brightest, many of them are the go-to experts I recommend to patients because they are more patient friendly.
Patient advocacy works best when the whole community gets involved. How many of you think the AIDS community could have gotten the level of attention they got, if all they had going for them are a few patient advocates speaking for them? I am just another voice in the wilderness, and without your support I would be unheard and unwanted. You are the wind beneath my wings.
This trial was a horrible disaster! It had a death rate of well over 25%. That they kept those unfortunate people on the trial when the researchers knew that the CFAR could likely kill them is beyond unconscionable. It almost seems as though the goal became how many people WOULDN’T die.
Dr. Wierda was the lead researcher on this trial. He had done a prior trial on previously untreated patients, so he should have been extra watchful for poor results as they developed from this refractory group.
I don’t understand the mechanics and responsibilities regarding co-researchers on trials. But to see such heavy hitters as Keating and O’Brien involved in this travesty puts up a red flag for me.
I’m heading over to MDACC next week for an appointment with Keating, hoping to get on the CAL-101 + RTX trial. O’Brien is the lead researcher. I may ask Keating for insights about the disastrous CFAR trial. But you can be sure that I won’t participate in any trials where Wierda has any responsibilities.
Chaya,
Thanks so much for the powerful analysis of one of the most difficult of dilemmas faced by our community.
Some of the variables I had to consider before opting to participate in a Clinical Trial (PCI-32765 monotherapy) after relapse from 2nd TX with Rituxan HD-monotherapy were:
1) which of the non-Trial therapy drugs were available to me that were not likely to produce the severe life threatening reactions of previous treatments.
2) Do I want Alkylating agents with a family background of my father and his 1st cousin having bladder cancer and my recent discovery/removal of a squamos cell carcinoma?
3) When to treat? as I am currently without “B” symptoms. My history from DX in ’06 shows clearly that the cancer, prior to any therapy, was causing kidney function to be impaired and that my two previous attempts at treatment failed in part due to acceleration of, as yet to be identified mechanisms, of kidney failure and further loss of renal function. Can’t keep doing that.
The criticality of What & When narrows the choices due to the renal-Achilles-heel in my otherwise very fit and healthy profile. Past history of blood work indicated increasing renal impairment with higher tumor load so Wait & Watch for me is not the best option. Choices of drugs are Chlorambucil, Revlimid and Bendamustine. I have issues with those three and due to a “Gambler’s Gene” in my personality I am opting to treat early with PCI-32765 as the cancer is just ramping up.
What also helped me in my decision was a history of consulting and 1st treatment under Dr. John Byrd at OSU. While nobody has enough answers when it comes to CLL I have confidence in John. His staff and assistants are great. Columbus has some great restaurants so life doesn’t get any better than that.
I am philosophically comfortable with my decision though I must add that I am not happy about the frequency of CT scans that are a part of the Trial protocol. I understand the importance of obtaining data but every three months appears excessive and presents us guinea pigs with additional risk.
Last thoughts: All treatment should be evaluated against the current time of rapidly changing therapy protocols and knowledge. Treatment with some gold standard therapies like FCR can lead to dramatic failures and classical successes as Andrew Schorr is known for (12yr CR) but it is still a guessing game.
WWW
I can comment on Blood’s policy. They have a strict word limit at 5000 and footnote limit of 50. Hoever, by my count they only used 4883, so there was plenty of words left to thank the patients.
There are always ways to make the words less for a few sentences. I agree, this should be standard policy to thank the patients. Here it is clear many months of life were lost on this poorly designed, unstopped fishing expedition.
Chaya, thank you for another great article.
Be well,
Monique
I’m saddened by this. And it’s not only from the researchers who continued a trial when it was obvious that the drug combination wasn’t the miracle that they were perhaps hoping for. It’s for the patients and their families who were victimized by the trial when it should have been more than obvious to the researchers that the drug cocktail was doing more harm than good.
If the trial was conducted like many other trials, the patients had to pay (either with their own insurance or out of pocket) for many of the procedures, drugs, hospitalizations, labs, and other medical costs not directly related to the specific drugs being tested. So, when the grade 3 and 4 complications arose, the patients were on their own to cover those expenses. If the patient had traveled to MD Anderson to participate in the trial the lodging/food expense for family members could have been outragously high should the patient have been hospitalized for a lengthy infection. (I’m kindly avoiding adding funeral expenses but CFAR certainly didn’t add any months to survival time…)
And the out-of-pocket monetary expense doesn’t even begin to cover the emotional toll on the patient and patient’s family. Having been the sole caregiver for a spouse with terminal cancer, I’ve been in the trenches. I’m sure that the caregivers of the patients in the trial felt like their loved one was going to be receiving the best medical care that treatment might actually help the CLL. Most importantly, they entrusted the researchers with the lives of their loved ones. The researchers might not like it but that’s what it comes down to. (And we willingly trust our lives with our doctors because we believe they have our best interests at heart. How foolish are we, the naive?…)
The researchers might have gotten a pass on the first couple of years of the trial when the data might not have borne out the cold statistics. But later in the trial I couldn’t have imagined looking in the pleading/hopeful eyes of patients & their families and shining them on so they’d join the trial knowing full well what fate awaited them.
The final insult from the researchers? Not a single thank you to these patients nor their families for their sacrifices. These brave souls gave more than anyone should ever ask a person to give.
Unfortunately, research trials like this will make many prospective participants do some very deep soul searching before they’d ever sign on the dotted line. It’s definitely made me rethink my participation in any drug trial. Trial participants should be treated with dignity, respect, dealt with honestly and be thanked publically for their participation – they deserve nothing less.
From Mutations of Mortality..Terry Hamblin’s Outstanding Blog on a wide range of topics!
Marathon said…
Speaking of trials, I am curious as to your thoughts on whether patients should be thanked in journal articles publishing trial results.
Something as simple as:
We would like to thank all the patients in this trial for participating.
25 June, 2011 23:28
Blogger Terry Hamblin said…
Absolutely!
25 June, 2011 23:29
Chaya, Thank you for all that you do to help us stay informed of what going on out there.
Patients should definitely be THANKED for participating in trials…it should be a standard protocol.
My dad is 71; dx in august 2009 with AIHA…underlying cause was CLL with 17p deletion. Saw a local hem/onc. Was immediately started on FR for 4 cycles and stopped due to cytopenia and neutropenic fevers; then started on bendamustine for 4 cycles and stopped due to neutropenic fevers (June 2010); then consulted with Dr.Kipps in September 2010. He recommend Campath consolidation…he had about 30% cll cells. Started Campath in November 2010…had netropenic fever after 2nd day of campath…was hospitalized and discharged home. Restarted in January 2011 to March 2011…he is in complete remission and acheived negative MRD….however he has been transfusion dependent since then. He’s local hem/onc is City of Hope and we consult with Dr.Kipps. On top of being transfusion dependent more so with platelets then red blood….he has had oral herpes..in his mouth…and now has a fungal pneumonia and influenza…he goes in to COH 3 times a week for possible transfusions…he is still pretty active and walks daily. He has no other co- morbidities. He did have CMV reactivation during campath therapy…but everything else was ok. His WBC was always low and needs neupogen/neulasta, but hemoglobin and platelets were pretty normal until his last does not campath in March.
I really hope his bone marrow recovers and he gets better. I feel bad because I don’t know if I helped my dad make the wrong decision. He does not speak English and I’m the primary interpreter and I’m a nurse. I just want my dad to be better.
Thank you for everyone’s input. It helps to be able to read about what others go through.
Tiffany
Question; since the research community does not appreciate trial participants enough to express their thanks will we have accomplished anything if we get them to automatically print a thank you note?
Elek
epuskas:
You are right, an automatic thank you note attached to papers is just another way of side-stepping the issue.
What we hope to accomplish is a change in attitude. I do not know how to achieve that. I see no way of improving the clinical trial process until patients are treated with respect, as equal partners in the process and not just lab rats or statistical data points.
I have recently been thru a clinical trial at NIH. Originally, I had entered the History of CLL clinical study after Chaya mentioned it. Within a year I needed treatment. Chaya again mentioned another clinical trial of FCO at NIH. What timing! The doctors asked me if I would be interested and of course after emailing Chaya, I decided to try it.
First, let me say everybody at NIH has been super. The doctors involved are Dr. Wiestner, Dr. Aue, and Dr. Farooqui. Janet Valdez is a PA involved and Susan Soto is the clinical nurse. The infusion nurses are excellent. Dr. Farooqui’s bedside manner and communication skills are wonderful. He is a very patient man. I always felt he wanted what was best for me, the patient. The trial paid for all meds, airfare for me and $60 a day. Now, for the best part-I just had restaging last week. The CT scan showed spleen and nodes normal and the bone marrow showed NO MRD!!!!!
Fortunately, this was one clinical trial that proved very worthy and I would have to say that the cll team involved at NIH are wonderful people to work with.
Linniesd ..
Congratulations !!! That is fabulous news.
Lynn, considering the same trial
Chaya,Thank you for keep us so well informed and for yours important articles.
We hope you are better about your knee problem.
Also our thank you for those volunteers and their families.
Chaya,
Nice review and great discussion. I’ve been gone from the CLL world due to family issues
I wonder what is the basis of your statement that a relapse only six months after rituximab is considered adequate to give it a try again?
My nodes seem to start growing about six months after my last dose of rituximab, which I believe was related to the R finally being gone from the blood.
I am on my third cycle of R now. and my palpable nodes are responding, but the truth lies in my gut. One year and two courses of R, my mesenteric nodes were about the same size as where I started (largest slightly >6 cm). They shrunk in between. I am now following them with MRI rather that CT. CBC and especially my platelets with my history of ITP are great. Still on a low dose of cyclosporin.
Be well
Happy 4th
Brian
bkoffman.blogspot.com
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