Campath Consolidation – Not What We Hoped For
I have never been much of a fan of Campath Consolidation. I wrote my earlier review back in December of 2009. The latest article published in the Journal of Clinical Oncology by some of our most respected CLL experts confirms my worst fears.
For those of you who are new to this game and not quite sure what “Campath consolidation” means, here is a quick explanation. The idea is to follow-up standard chemoimmunotherapy regimens such as FR, FCR, PCR or even R+HDMP (high dose methylprednisolone, a steroidal drug) with additional doses of Campath. Why do it? The hope is that if you got a so-so but not great remission with the chemoimmunotherapy regimen, and you did not get the coveted MRD negative remission (no traces of minimum residual disease) that you were hoping for, then additional therapy with Campath may put you over the top and give you the desired MRD negative status. The deeper the response, the longer the remission lasts and therefore the longer the patient lives – thus went the logic.
And sure enough, patients given Campath consolidation therapy after completion of their standard chemoimmunotherapy regimens do, in general, improve their response status. Many people with only partial responses (“PR”) or barely “CR” responses went on to get better grades. The percent of patients with MRD negative remissions (no trace of minimum residual disease, even when tested by the most sensitive pcr techniques) increased after Campath chaser. Sounds good, right? Better responses for more people – what is not to like?
Aha. Not so fast. Devil is in the details.
Below is the abstract of the latest article in JCO. My review follows. If you wish to read the full text article for yourself, send me a personal email and I will try to point you in the right direction of how to get hold of it. Don’t get confused by the use of the word “alemtuzumab” in the abstract. That is the scientific name for Campath (brand name).
J Clin Oncol. 2010 Aug 9. [Epub ahead of print]
Consolidation Therapy With Subcutaneous Alemtuzumab After Fludarabine and Rituximab Induction Therapy for Previously Untreated Chronic Lymphocytic Leukemia: Final Analysis of CALGB 10101.
Lin TS, Donohue KA, Byrd JC, Lucas MS, Hoke EE, Bengtson EM, Rai KR, Atkins JN, Link BK, Larson RA.The Ohio State University, Columbus, OH; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; Southeast Cancer Control Consortium, Goldsboro, NC; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Long Island Jewish Medical Center, New Hyde Park, NY; University of Iowa, Iowa City, IA; and University of Chicago, Chicago, IL.
Abstract
PURPOSE To determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS)after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia.PATIENTS AND METHODS Patients (n = 102) received fludarabine 25 mg/m(2) intravenously days 1 to 5 and rituximab 50 mg/m(2) day 1, 325 mg/m(2) day 3, and 375 mg/m(2) day 5 of cycle 1 and then 375 mg/m(2) day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks. Results Overall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection(viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab. CONCLUSION Alemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.PMID: 20697069
In a nut-shell, Campath chaser after conventional FR may improve your response grade, kick you from a mere“PR” or “CR” to an MRD negative CR. But you may not live longer to enjoy your better response grade. As this abstract points out, there were five deaths associated with Campath induced viral infections as much as 7 months after completion of therapy. Now for the details.
Details of this study
This study was conducted by participating centers of CALGB (Ohio State, Duke, Long Island Jewish, U of Iowa, U of Chicago – among others). These are some of our most credible research institutions. The patients were chemo-naive but had high Rai stage (generally III/IV stage) needing therapy. Patients received 6 cycles of conventional FR (fludarabine + Rituxan) therapy, following the protocol established at Ohio State University. Three months after completion of this FR “induction phase” therapy, patients who had at least stable disease got Campath consolidation using subcutaneous Campath for 5 weeks. Campath injections were given three times a week for a total dose of approximately 500 mg. The dosage details are spelled out in the article.
Full list of prophylactic precautions were taken, as established by earlier best practices. This included Pneumonia (PCP) and shingles protection through out therapy as well as for 6 months after completion of therapy. Good to hear they were loaded for bear, taking full precautions. There was some concern that unanticipated deaths and toxicity in earlier Campath consolidation studies was due to inadequate protection, or starting the Campath consolidation immediately after the FR induction. Not so in this trial. Researchers did things by the book, patients had to wait three months after completion of FR therapy before starting Campath consolidation.
102 patients participated in this study, of whom 58 patients went on to have Campath consolidation to try and better their end of therapy response scores. Did Campath consolidation improve response statistics? Yes it did. Of 46 patients who had only a PR (partial remission) after the FR induction therapy and went on to get Campath consolidation, 28 of these patients (61%) improved their overall response to a CR. Three of seven patients who had a MRD positive CR after FR induction therapy converted to the better grade of MRD negative CR after doing Campath consolidation.
Did the better response statistics translate into longer/better remissions ? Here is how long the remissions lasted, with or without Campath consolidation.
People who had Campath consolidation (gold line, first graph above) stayed in remission just a tad longer – but not enough to meet statistical significance. In other words, the better response statistics did not translate to longer remissions. Campath consolidation improved response statistics but did not deliver longer remissions.
Since toxicity was the big news in this study, let us look at the level of toxicity in the group during FR “induction therapy” phase as well as during the Campath consolidation phase. Toxicity is generally reported as four grades with increasing level of seriousness. Grade 1 is nothing to write home about. Grade – 2 toxicity is worth reporting but not really anything to get too worried about. Grade-3 and Grade-4 toxicity is serious business. I did a double-take when I saw the “Grade-5” citation. This is not something that I see frequently, frankly I was not even aware there was a Grade-5 level toxicity. It turns out the researchers were being circumspect in their choice of words. Grade-5 toxicity in this case means death. As in the patient died. I think it would have been a bit more honest to report it as “death” rather than the euphemism of “Grade-5 toxicity”.
As you can see, 12 % of the patients died as a consequence of Campath consolidation therapy – ahem – they suffered from “Grade-5” toxicity.
Based on these disappointing results, the CALGB group has announced they will no longer carry out Campath consolidation. Chalk this up to experience, we owe the participants of this clinical trial a big thank you. How long will it take for this hard won piece of wisdom to trickle down from expert “best practices” to the local level where most patients are treated? If your local guy has not read the latest JCO article we reviewed here and recommends Campath consolidation to you, it might be a good idea to bring the CALGB article to his attention.
Editorial
This article proves once again the danger in depending on response statistics as the sole definition of therapy success. Most clinical trials stop short at looking at response statistics immediately at end of therapy. So many CRs, so many MRD negative CRs etc. The researchers congratulate themselves, publish glowing articles about their clinical trial and then go on to other things. Patients who participated in the clinical trial go home with little more than a pat on the back – if that. They are on their own, once the clinical trial is complete and researchers have the data they were looking for.
Long term follow-up of patients after completion of therapy is expensive business. Contacting patients and keeping up with their health situation for several years after completion of therapy becomes frustrating, tedious and costs many dollars. I also suspect most drug companies are not really all that interested in doing long term follow-up studies that may tarnish the bright glow of their response statistics immediately after completion of therapy. Why look a gift horse in the mouth?
But as patients and caregivers, our incentives are quite different. What do you care what acronym is tagged with your name as far as response statistics are concerned? What matters to you and your family is how long the remission lasts, the quality of your life during remission and in the final analysis, how long you will live because of the therapy you just had. Going the extra distance to get an MRD negative response is scant comfort if you pay for it with your life. Even garden variety infections that may land you in the hospital (but don’t quite kill you) surely take a toll on your quality of life.
No one should consider Campath therapy without due regard for its propensity for increased infections. Some of the infections are viral reactivations, traces of viral infections lurking in your body from your earlier life that come back to haunt you. Some are brand new infections that you may pick up from the general community.
Early in Campath trials researchers learned about protecting patients with prophylactic antiviral and antibacterial drugs during therapy, to protect patients from infections. Switching from Campath infusions to sub-cutaneous injections has minimized some of the infusion related side effects felt immediately by patients undergoing Campath therapy. But this is almost a cosmetic improvement. Infusion or injection, Campath has long-lasting effects on your immune system and that is pretty much baked in the cake.
Why is Campath so much worse than Rituxan when it comes to long term infection risk? It goes back to the CD markers the two drugs target. Rituxan targets CD20, the marker that is carried only by mature B-cells. No other cell lines are involved. A certain amount of mayhem is unavoidable even after Rituxan therapy (such as delayed onset neutropenia, possible allergic reactions to mouse protein in Rituxan), but in general Rituxan therapy is not associated with long lasting immune suppression – not counting loss of all B-cells, even healthy B-cells.
Campath is another story all together. This monoclonal targets CD52, a marker carried by many cell lines, including crucial T-cells. So, Campath consolidation following FR, FCR or whatever may do a good job of mopping up remaining CLL cells and vault you into a better response grade, but Campath will also do a real number on your T-cell counts. Several authors have pointed out that patients’ T-cell counts are mere ghosts of their former selves even a year after completion of Campath therapy.
Why are T-cells important? Because they are the absolutely crucial frontline troops that fight viral infections. Think of it this way and you will get the seriousness of it: Late stage CLL patients in general and especially those that have undergone T-cell depleting therapy are in the same boat as full blown AIDS patients as far as their immune function goes. The HIV virus attacks T-cells. Campath does the same thing. Without adequate number of properly functioning T-cells, you are at the mercy of any viral “old friend” your body has been harboring for decades, and of course any new virus out there.
Why are viral infections so much harder to treat than bacterial infections? I am not trying to make light of bacterial infections, especially the scary ones such as MRSA and NDM-1 that have developed serious drug resistance. But in general, most bacterial infections respond to antibiotic treatment. You may need extra powerful antibiotics, or you may need intravenous antibiotic therapy rather than swallowing a few pills, but by and large there are several good options and broad spectrum antibiotics that doctors can use to try and cure bacterial infections.
That is not the case when it comes to viral or fungal infections. First, it is not always possible to diagnose exactly what particular virus or fungus is causing the symptoms. It may take weeks to identify the culprit, if ever. The second problem is that we just do not have broad spectrum anti-viral medications. The few anti-viral medications we do have (such as Valtrex etc) are specific to only one type of virus, not all its close kissing cousins.
The general approach to controlling viral infections is using vaccines, which work by helping the body’s own defenses (T-cells) learn about the particular virus and therefore better able to resolve infection by that particular virus. A good example is the annual flu shot. That pathway of protecting against viral infections does not work for CLL patients since our guys do not respond to vaccines. So, our main defense is our innate T-cell armies to protect us, with or without the additional education of theses smart troops by means of vaccines.
Campath therapy compromises precisely this important line of defense. Let’s see if you got the picture. Campath kills your remaining T-cell defenses. Vaccines will not work for you since you have CLL to begin with. There are no broad-spectrum viral medications that will work across whole families of viruses. You may be screwed. Oh, before I forget, many experts feel proper T-cell function is also involved in prevention of garden variety squamous cell and basal cell carcinoma from becoming full fledged skin cancer that can kill you sooner than the CLL. Ever heard of AIDS patients and their increased risk of variety of skin cancers? Below are links to earlier articles I have written on the subject of Campath and of how T-cells work. I suggest you come up the learning curve on this important subject.
Campath Consolidation – home run?
CLL and Infectious Complications
I would like to close this long-winded editorial with one point. Once in a while I see a patient who becomes ardent supporter or virulent hater of a particular therapy based solely on how that therapy worked in his particular case. A strong supporter of FCR may come to hate it – because it did not work as well as hoped for him. But that does not justify strident calls for complete removal of FCR from therapy options open to CLL patients. This is a bit like individual post-purchase regrets. It is important to remember single individual responses are nothing more than anecdotes. Good or bad, they are specific to that particular individual. Interesting to read, and when presented as well chosen case histories they may even prove to be of educational value. But very vocal patients with individual agendas and personal disappointments driving their less than logical positions do a lot of harm by scaring off other patients from needed therapy options.
That is why large scale clinical trials are important, to take out personal and anecdotal bias. We are not talking of a single John Doe patient who had increased risk of infections after Campath therapy. Neither are we talking about glowing testimonials from a single patient who did well after Campath consolidation. We are talking about study after study underlining this fact, credible research done by our best experts. It is now confirmed beyond doubt that Campath causes long term immune suppression, long term T-cell deficits that leave patients vulnerable to infections – especially viral infections. Protecting patients during Campath therapy helps. But what about long term risk? How long does the risk last? How do we protect patients for the long term? Can we even do it?
Is consolidation with Campath – an attempt to improve response to initial chemoimmunotherapy – worth the risk? This patient advocate does not think so, and very grateful to the researchers reviewed here for pointing out the same thing with far greater authority.
20 comments on "Campath Consolidation – the Jury is in."
Dear Chaya
Thank you so much for this important and informative article. You are doing a superb work helping all of us.
Jorge/Ana
I consider this trial flawed because of the 5 ‘grade 5’ toxicities. No one else has had so many deaths in such a clinical trial and therefore this small trial is an outlier. That is why it is in JCO and not Blood.
Thank you, Dr. Hamblin, for weighing in on this. We in the patient community tend to think of all peer-reviewed articles as gospel. You obviously know differently. Is “Blood” the 500 lb gorilla of hematology? Isn’t “Journal of Clinicial Oncology” good enough? I was kind of surprised at the small number in the study (n=102), but it is hard to know/understand just how many counts as a “big trial.” This is Campath in just one application, right? As consolidation, meaning after the big guns (FR or FCR)? As mop up? What about Campath as therapy prior to non-myeloablative stem cell transplant? Is this study a black and white condemnation of Campath, or just in this group of chemo naive first-time treated and for this purpose?
Dear Chaya,
I participated in the Campath 1-H trial al UCDS back in 2002 after 8 rounds of Fludara and I have been MRD, PCR negative ever since. Dr. Kipps kept me very well protected during and after the study, had no infections and my T cells fully recovered after a little longer than two years. I am still doing a BMB every year and this Wednesday will have what I think is number 19 but who’s counting?
Thanks for everythng that you do for us CLLers, it is greatly appreciated,
Patricia.
Excellent follow-up information. Another priority item to include on ones check list when reviewing/evaluating treatment and options.
Chaya, a good heads-up on this one.
Thx,
William Bates
Chaya, I would like to ask several questions regarding CLL patients getting the annual flu shot:
Is it a complete waste of time and money for us to get the shot?
Does it, perhaps, work for early stage CLL folks but not for those in stages 3 and 4?
Is it, perhaps, effective for chemo-naive patients or is this irrelevant and/or based on one’s stage.
Finally, CDC has made a flu vaccine for the age 65+ crowd. Supposedly, it is 4 times more potent than the regular shot. Might it, therefore, be helpful for CLL patients? How thoroughly it was tested, I don’t know.
Thanks so much.
I wonder what will happen with the PCR + Campath trial that is getting underway with this news. I also read last week that a clinic in Switzerland has stopped consolidation therapy with Campath due to toxity events they have experienced. Maybe it’s part of the same trial.
I have CLL for the past 10 years plus. I have been treated with FR, Campath, Rituxan alone and currently, with Treanda. My response with Treanda, so far, is the best. My Cat Scan results show a great improvement of all of my organs and lymph nodes and spleen. I wanted to share my good news to help others who might be facing treatment decisions.
Ronald Isaacson
Ronald
Are you doing Treanda on its own, or in combination?
Peter Lewin
Chaya,
Thank you for this important update.
Stay well,
Monique
Very interesting indeed. I would tend to agree with Terry, the study comes under some deserved scrutiny. Tip-toeing around the truth puts it in its best possible light. Let’s hope grade 5 toxicity is shelved. clinical reports are confusing enough without having to understand a new vocabulary.
The 1st issue seems blatantly obvious. Why would anyone treat someone in complete remission with anything?
” The initial patient participating in this study died as a result of meningitis 7 months after completion of alemtuzumab therapy. …the second and third deaths not related to disease progression were noted; all three deaths occurred in patients who had received alemtuzumab after achieving CR to induction.”
Removing these deaths to create a study of people who actually needed to improve their “clinical score” brightens the numbers on the surface, but then we see that there were 2 other deaths, which they employ more fancy vocabulary to write off.
In addition (to the 5 deaths blamed on campath infections), “two patients who had achieved PR after induction and received alemtuzumab died as a result of causes unrelated to progressive CLL (Table 2). The first patient died as a result of fulminant Epstein-Barr virus viremia and hepatitis 4 weeks after alemtuzumab, and the second patient died as a result of transfusion-associated graftversus-host disease (TA-GVHD) 8 months after alemtuzumab after receiving nonirradiated blood products after surgery.”
Is EBV and Hep now not considered infections? Where was the communication between the oncologist and surgeon in case 2? It would be very useful, but never will happen, to see which institutions were responsible for this unusually high level of deaths/grade 5.
On one hand it seems easy to argue that treating only the patients in need of CR would make a study worth doing, 7 deaths out of 100 due to complications from treatment would not make me suggest anyone to sign up. Perhaps campath deserved a better effort.
Chris
I completed FR and achieved a PR – I then had campath for 12 weeks- 3 times a week- sub q. I did not have any infections or illnesses during the 12 weeks. I achieved a CR with MRD neg. It has been almost two years since campath treatment ended. I still have a lymph count of .4 and a greatly decreased CD4:CD8 ratio- t cell count very low.
I remain vigilant about my health- always have been. However, I certainly to “catch” my share of viruses-infections take longer to attack ( fludarabine also contributes). I must admit that my “issues” have been post treatment. The FR and campath were much easier than dealing with a very faulty immune system.
That being said, I remain in a strong remission ( just had a BMB- no detectable disease).
Good luck to you all- hope this information helps.
I am in the eighth week of my THIRD full round of subQ campath. After relapsing from my 4/05 stem cell transplant 4/2005, Dana Farber recommended rituxan/campath, which I started in 4/07. I did approximately 20 weeks of campath (30mg every mon/wed/fri). The result was a good remission for one year. I repeated the above 20 week campath regimen starting 4/09… I received another good one year remission. Now, with some resistence on my part, I’m five weeks into the third rituxan/subQ campath regimen. I told my Hematologist/Oncologist I was afraid of walking this plank again. He feels my demonstrated tolerance justifies this approach, especially with such very CLL-packed marrow and extreme numbers. Through all this I have had a variety of infections, though not the dreaded CMV nor pneumonia.
If “campath consolidation” sets the stage for such down the road train wrecks, I wonder what a triple dose of full campath therapy does?
I love getting my one year remissions, but the rest of the picture is sure scary. At today’s rituxan/campath session I gave my doc your article Chaya. I’ll bet we have a lively discussion when I see him next Monday.
Thanks for always staying on top of the game for all of us. You are a treasure.
Bob Larkin
North Branford, CT
I want to make a couple of things clear.
First, this article is about Campath consolidation. In other words, this is NOT about all uses of Campath, in any form, under all circumstances. This is about following up prior induction therapy (using combination of chemoimmunotherapy such as FR) with Campath chaser – in an attempt to improve overall response. Campath continues to be valuable as it is one of very few precious drugs that are effective in treating patients with 17p defects. Unfortunately it is not able to deal with bulky lymph nodes.
It seems to me that the combination of prior fludarabine containing induction thereapy followed by Campath as consolidation is a double whammy of immune suppression. Both fludarabine and Campath kill T-cells. In addition, Campath also kills monocytes / macrophages. What is most worrisome to me is that the immune suppression is not only deep but that it lasts for so long. How does one protect against infection risk for months on end?
I find myself gritting my teeth when professional papers do the careful dance of double-speak. Calling deaths as “grade 5 toxicity” is an insult to every patient who participated in this trial.
Then there is the question that is at the back of my mind: is this trial unrepresentative in the high number of deaths? Was CALGB that sloppy in their trial design? They did use all the usual precautions and prophylactic medications in their trial. Did other trials not catch the mortality risk because they did not follow / report on long term mortality? 58 patients participated in the FR + Campath arm. Frankly, I doubt there will be much larger Campath consolidation studies in the future. Tell me, would you sign up for a Campath consolidation study given what you know now?
This much is clear. CALGB (which includes some of our best expert centers such as Ohio State, Long Island Jewish, Duke, U of Iowa, U of Chicago etc) will no longer use Campath consolidation for their patients. That is a pretty powerful statement, whether or not the article is published in Blood. By the way, the JCO article was also cited in the Lymphoma & Leukemia Society Newsletter a couple of months back. I doubt the drug company that markets Campath is happy about this development.
I participated in this study at University of Iowa. I am 3 years out from Campath and have just got back to normal blood levels. 1 case of shingles and 1 nasty case of rotovirus in those 3 years but am doing great now. Also got married and had a baby boy 4 months ago!! Life is GREAT!!
Chaya,
Thanks for an informative report; I believe that Campath consolidation must be an individual decision based on your best estimation of your own prognostic factors. I’m also unsure as to why this study was conducted administering Campath at three months post FR treament since a German study had already suggested three months was too early.
Initially diagnosed in April 2005, I completed FCR in December 2006 and was then diagnosed as nPR with all the aggresive markers. My MD Anderson physician suggested Campath consolidation, no earlier, than six months post FCR. My local hematologist was strongly opposed to Campath due to toxicity. After a lot of research and prayer I opted for the sub-Q treatment started in October 2007 and completed in December 2007.
My experience during and since has been a mixed bag but I’m still comparatively healthy with March 2010 blood and marrow tests indicating no CLL. SLL is in a lymph node in vicinity of aorta.
– During 9th week of 10 of Campath treatment red blood count dropped requiring several transfusions over the next few weeks.
– February 2008 diagnosed with non-alcoholic steato hepatitis. Liver tests returned to normal in a couple of weeks.
– September 2008 developed ITP or Evan’s Syndrome requiring platelet transfusions and treatment with prednisone.
– Calendar year 2009: Event free
– February 2010 developed fever and chills and other symptoms indicating possible Richter’s transformation. Subsequent testing indicated EBV(mono) and rheumatoid arthritis and SLL in one lymph node. Received rituxan treatment, once a week for four weeks. EBV and RA gone and activity in lymph noded is reduced.
Owen Martin
The Woodlands, TX
Could you please respond to “Manhattan’s” questions regarding the flu vaccinations. One minute we are told to get the shots, and the next minute we are told that they do nothing for us. Very confusing to say the least.
Thank you
Flu shots
It is true that CLL patients have less than desired response to flu shots. Early stage patients, those that have been recently diagnosed and have not been treated with chemotherapy may mount better responses than patients who have been around the block a few times.
Nevertheless, full blown influenza infection can be quite serious in CLL patients and something to be avoided if at all possible. (1) Try and get everyone around you vaccinated, this gives you much needed “herd immunity”. If everyone around you is protected and does not come down with the flu, you are protected as well. (2) Practice good personal hygiene and social distancing from people who are obviously at risk of being flu carriers (3) Get the flu shot, for what it is worth. Even a small percentage chance of getting some level of protection is worth it. It also gives you the moral high ground when you try to convince everyone else around you to get the shot themselves.
Bottom line, the flu shot is cheap and easy to get. It may not give CLL patients as much protection as it does “normal” people, but it is still worth getting. My two cents.
Thanks as always Chaya. Hope you’re feeling better.
Thanks Chaya. No doubt.I think also this is a very good advise.Also hope you are feeling better.
Jorge&Ana
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