Campath Consolidation – Not What We Hoped For

campath15I 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.

Campath consolidation remission duration

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”.

campath consolidation 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?

Campath as front-line therapy

CLL and Infectious Complications

How T-cells work

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.

Impcolortrees