Keeping up with the times
A little while ago the FDA approved Campath as single agent in the frontline treatment of CLL. I thought this was a poor decision based on a tricked out clinical trial that pushed all the FDA hot buttons but failed to impress most CLL experts. Not that I am saying I am a CLL expert, but I do read this stuff till my eyes bug out. Here is the latest stuff about Campath in ASH2009. There is so much Campath news that I had to break it up into a couple of articles. Some of these are truly definitive clinical trials and I am sorry to say the news about Campath is not all that rosy.
Campath: what makes it tick
It must be acknowledged that Campath (scientific name “alemtuzumab”) is a very potent monoclonal antibody. Modern day patients are lucky to have this drug available to them, since it is one of very few drugs that works in poor prognosis patients with 17p deletions (FISH). The trick is to know when to use it, and when not to use it.
Before diving into the ASH information, here is a very short tutorial on how Campath works. Campath targets the CD52 marker on cells. Unlike CD20 (the marker targeted by Rituxan), CD52 is heavily expressed on B-cells. There are literally thousands of copies of CD52 per B-cell and that means the cells are festooned with many molecules of Campath when they are exposed to the drug. This in turn means cell kill is very efficient. Campath packs a lot more oomph when it comes to killing CLL cells and that is the good news.
Here is the problem in a nutshell. This monoclonal is not a very smart “bomb” because many different cell types express CD52, not just B-cells. Among the other cell lines that express CD52 are neutrophils, T-cells and macrophages. What that means is that when a patient is treated with Campath, the drug kills all of these cell types, not just B-cells. (For those of you guys who worry about such things, did you know human sperm cells also express CD52 marker and Campath therapy may not be all that smart if you are thinking about becoming a brand new daddy?)
Why is it important if neutrophils, T-cells and macrophages get killed? It is important because these are all cell lines that are the crucial frontline troops that protect us from infections of various sorts. Kill off all the defenders and patients are sitting ducks waiting for an opportunistic infection to take hold and grow out of control. Campath lingers in the body for a nice long time, trace amounts are measured for months in blood and tissue, which in turn means the breach in our defenses lasts for at least as long. Deep seated neutropenia, across the board T-cell deficits and resulting infections are measured for many months past end of Campath therapy.
Bottom line, while we are happy about the effectiveness of Campath (especially in 17p deleted tough cases), we must stay very vigilant about the risk of potential infections – including life threatening infections. It is hardly a consolation to roll back the CLL only to have the patient die of an opportunistic infection, if you get my drift.
If FCR is good, is FC + Campath even better?
Oncologists have a tendency to keep ratcheting up the potency of their drug combintions in an effort to get ever higher remission statistics. The longest string of drug combos I have come across had 10 different drugs in it. But hey, as long as there was “non-overlapping toxicity”, what is a couple of more drugs between friends?
FCR has been in the news a lot lately. There is little question it is now the gold standard of CLL therapy by which all other therapy options are judged. So, it is a logical question to ask: can we make chemoimmunotherapy even better by replacing the “R” (Rituxan) in FCR with Campath? After all, since Campath targets CD52 that is plentifully available on the surface of CLL cells, is that not a better target than the CD20 that Rituxan tags?
Below is the ASH2009 abstract of a very important Phase – III clinical trial that addressed the very question we posed above. These were previously untreated patients. Half of them were randomized to get conventional FCR. This was the control arm. The other half got FC + Campath, the experimental arm. The study was a collaboration at many different centers, so there is no room for biased results. This is a terrific study, it is about as credible as it gets. The French Cooperative group on CLL does some excellent work. This well conducted clinical trial is an example of their work.
538 Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine (F), Cyclophosphamide (C) and MabCampath (Cam) (FCCam) in Previously Untreated Patients (pts) with Advanced B-Chronic Lymphocytic Leukemia (B-CLL) : Experience On Safety and Efficacy within a Randomised Multicenter Phase III Trial of the french Cooperative Group On CLL and WM (FCGCLL/MW) and the “Groupe Ouest-Est d’Etudes Des Leucémies Aigües Et Autres Maladies Du sang” (GOELAMS) : CLL2007FMP (for fit medically patients)
Stephane Lepretre1*, Therese Aurran2*, Beatrice Mahe3*, Bruno Cazin4*, Olivier Tournihlac5*, Hervé Maisonneuve6*, Olivier Casasnovas7*, Alain Delmer8*, Veronique Leblond9*, Bruno Royer10*, Brigitte Corront11*, Sylvie Chevret12*, Roselyne Delepine13*, Sandrine Vaudaux1*, Eric Van Den Neste14*, marie-Christine Béné15*, Florence Cymbalista16 and Pierre Feugier15*
Introduction : Recent data suggest that FCR immunochemotherapy improves response rates and Progression-Free Survival (PFS) of previously untreated CLL pts. The monoclonal antibody alemtuzumab, a humanized anti-CD52 antibody (Campath), has shown activity alone and in combination in CLL pts. In order to validate the place of Campath in combination with the synergic association FC, the FCGCLL/MW and the GOELAMS conducted a multicenter French and Belgian phase III trial, CLL2007FMP, to evaluate the efficacy and toxicity of FCCam versus FCR in previously untreated patients with advanced CLL. PFS was the primary-end-point of this trial.
Methods and Patients : A cohort of 178 fit medically pts (cumulative illness rating scale (CIRS) score of up to 6), less than 65 years old, without 17p deletion, were enrolled between November 2007 and January 2009. Pts were randomly assigned to receive 6 oral courses of FC (F 40mg/m2 d1-3 and C 250 mg/m2 d1–3; q 28 days) in combination with either R (N=83; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or Cam (N=82; 30 mg s/cut d1-3; q 28 days). Patients were stratified according to IgVH mutational status and 11q deletion. Anti-infective prophylaxis included trimethoprim-sulfamethoxazole and valaciclovir during immunochemotherapy and until the CD4-positive lymphocyte count reached 0,2 109/l. In the FCCAm arm, CMV monitoring was monthly performed by either PCR or antigenemia. The use of GSCF was recommended. The trial’s recruitment was stopped in January 2009 after 165 pts had been randomized (83 and 82 respectively in the FCR and FCCam arms) because of an excess of mortality in the FCCam arm, while 13 patients were enrolled but not randomized because of this decision.
Results : We reported here a preliminary analysis including baseline characteristics and response rates in the first 100 included pts but safety analysis of the whole cohort ; among the first 100 pts, 81% were Binet B, 19 % Binet C ; median age was 56.8 years (range 52.8 to 60.6). Percentages of pts with 11q deletion, unmutated IgVH status, and elevated β2m, were 18.5%, 48.4%, and 77.6%, respectively. A number of 76.5% (FCR arm) and 71.4% (FCCam arm) of pts received 6 cycles. Reasons for discontinuation were mainly related to persistent grade 3-4 neutropenia. Safety analysis data were available for 165 pts. Number of patients reported with Common Toxicity Criteria (CTC) grade 3-4 adverse events were observed in 87.8% (FCCam arm) versus 90.2% (FCR arm) (p = 0.76). Grade 3-4 neutropenia was the most frequently reported adverse event (79.6% with FCCam and 74.6% with FCR arm). Interestingly, percentage of observed grade 4 neutropenia was stable during FCR treatment (17.6% for cycle 1 and 17.9% for cycle 6) but increased during FCCam treatment (28.4% for cycle 1 and 45.5% for cycle 6). A total of 63 Serious Adverse events (SAE) were declared (19 with 18 pts in FCR arm, and 44 with 35 pts in FCCam arm) consisting mostly of the cases in febrile neutropenia (13 with FCR arm, 27 with FCCam arm); 7 patients died, all in the FCCam arm : 3 of B diffuse large B-cell lymphoma (one of them EBV positive), 1 of mucormycosis, 1 of septic shock due to P.aeruginosae and 2 of heart failure during neutropenia. The Overall Response Rate ( ORR) in the first 100 patients was 96% in the FCR arm compared to 85% in the FCCam arm (p=0.086). The Complete Response rate was 78% (FCR arm) versus 58% (FCCam arm) (p=0.072). PFS and OS are not yet evaluable.
Conclusion: the FCCam regimen for the treatment of advanced CLL appeared to be associated with an unfavourable safety profile representing a significant limitation of its use in this indication. Other combinations with Alemtuzumab may be studied.
This was a good sized study using 178 patients. While they clearly needed treatment for their CLL, they were relatively young and fit patients. None had the dreaded 17p deletion since the researchers were looking to see if FC + Campath was viable for the general run of the mill CLL patient, not the special 17p deleted cases where Campath has special advantage.
The trial design was a prudent one. Patients got antibiotic (trimethoprim-sulfamethoxazole) and antiviral (valacyclovir) prophylaxis for the duration of therapy, and this was continued until T-cell counts had a chance to recover. GCSF (granulocyte colony stimulating factor, brand name Neupogen) was recommended to help neutrophil counts recover quicker. The patients getting Campath were carefully monitored for reactivation of CMV (cytomegalovirus) since we now know this is a common opportunistic infection in Campath treated patients.
Trials like this one cost a lot of time, money and effort, one reason why so few of them get done. So, you can imagine it is a big deal when one of these trials stops recruiting patients prematurely – because too many patients were dying in the Campath arm! That was quite a bombshell. Now for the deadly details.
The level of toxicity was quite high in both arms of the study. Not a big surprise, we know these chemoimmunotherapy regimens are no walk in the park. But I must confess the level of toxicity came as a bit of a shock to me. Of the seven patients who died on the FC + Campath arm (there were no deaths on the FCR arm), three died because their CLL became much more aggressive lymphoma. One of these lymphoma conversions was triggered by uncontrolled Epstein-Barr viral reactivation. Two died of infections. Two died due to heart attacks during high grade neutropenia. Wow.
Things like toxicity, neutropenia etc are graded on a scale of 1-4. Grade 1 is no big deal. Grade 2 is a bit more serious, but nothing to get too excited about. Grades 3-4, now we are talking big time problems that no one can pooh-pooh. As you can see, the level of high grade toxicity and neutropenia was roughly the same in both groups. The authors point out that the most serious Grade 4 neutropenia was stable in the FCR group but increased over time as patients went through additional cycles of FC+Campath. This too is to be expected, given the well understood and direct risk of neutropenia due to Campath exposure.
The million dollar details that caused premature shut down of the trial are highlighted in red. Serious Adverse Effects as well as the number of patients who were involved in such adverse effects are very important measures of the safety of therapy regimens. There were more than twice as many SAE in the FC+Campath arm and just about twice as many patients had serious adverse effects, compared to the FCR arm. This is a big deal, especially in view of the fact that the researchers tried their best to protect the patients with ongoing antibacterial and antiviral prophylaxis, as well as Neupogen shots.
Seven patients died in this study, all of them in the FC+Campath arm. There is no way of sugar-coating this one stark fact. Once again it points out the courage and sacrifice made by the patients who volunteered for this clinical trial. Half of them, the ones that got randomized to the FC+Campath arm, took on the additional risk of this untested combination. Seven of them paid with their lives so that you and other patients like you can make smarter choices down the road. How do we say “THANK YOU” to these brave souls and their families? This is high priced information indeed, purchased at the expense of 7 lives that would not have ended so abruptly but for FC+Campath.
How about the rewards side of the equation? After all, it is all about weighing the risks and rewards in this harsh game we play. Did FC + Campath group get higher overall remissions? Were there more complete responses (CRs) in this experimental group compared to the FCR control group? The answer to both questions is NO. The overall response rate was lower in the FC + Campath arm and there were significantly lower percentage of people who got a CR. All pain and no gain. I am amazed these crucial clinical trial results have not seen much broader publicity in the lay press or on patient chat rooms. Hello!? Anyone out there paying attention besides little old me?
If you are as yet untreated CLL patient that fits the profile of the patients in this clinical trial and your oncologist suggests FC+Campath as the frontline therapy, be sure to bring the results of this important trial to his / her attention. If he still insists FC+Campath is your best choice, find yourself another doctor. Stay smart guys. What you don’t know is dangerous. What your oncologist does not know can be downright lethal.
How about other roles for Campath? How about Campath consolidation after FR? How about FC+Camopath for relapsed or high risk patients? Last but not least, how about use of Campath in the preconditioning therapy prior to a stem cell transplant? I will be discussing each of these possible roles for Campath in the next couple of weeks.