Good, Bad & Ugly Faces of Campath

Alemtuzumab (Trade name Campath”) is a powerful monoclonal antibody that has been approved by the FDA for treating CLL patients across the board.  There is no doubt that Campath plays an important role in treating CLL patients. For those of you not quite familiar with this monoclonal or want a quick refresher, here is a thumb nail sketch.

Just as Rituxan targets the CD20 marker on B-cells, Campath targets CD52 marker. The big difference is that while CD20 marker is only dimly present on B-cells, CD52 is robustly expressed by all B-cells. Hence, the level of response to Campath is much better in almost all CLL patients. Single agent Campath packs a huge wallop as opposed to Rituxan (which works best in combination with other chemotherapy drugs).

Patients with 17p deletions can thank their lucky stars that Campath is available to this generation of patients. Campath seems to kill cells by a mechanism that is independent of the crucial TP53 gene, the one that resides at the p53 location of your 17th chromosome. Patients with 17p53 deletion are therefore missing the TP53 gene (so-called “suicide gene”). When it is present and working the way it is supposed to work, damaged cells (such as cancer cells damaged by chemotherapy) obediently commit suicide. Deletion of this important gene makes the CLL cells much more able to withstand the damage inflicted by chemotherapy and still not die. The really good news is that there are other pathways of cell kill that do not depend as heavily on the TP53 gene, and Campath is able to use these pathways.

All the above is the good news - now for the not so good and downright ugly aspects of Campath therapy. For starters, infusion related adverse effects (feeling crappy during and right after getting the first one or two infusions) are substantial for Campath. Everything is relative. Rituxan has its share of infusion related side effects, usually brought under control by slowing down the rate at which it is infused into the patient. But Campath infusions are reputed to be quite a bit harder to tolerate. So much so that Campath protocols call for dosage to start small and gradually increases to full strength in a couple of weeks.

Unlike CD20 (the target of Rituxan) which is expressed only on mature B-cells, the CD52 marker targeted by Campath is freely expressed by many different cell types. Among them are B-cells, T-cells and neutrophils. So, when Campath is infused into your body the drug targets all these cell lines and a few more besides. All of them are equally killed by Campath. Bummer! This monoclonal is hardly the tightly targeted and well focused “smart bomb” that one would want.

Now for the truly ugly part. Not only does Campath therapy kill precious T-cells in droves, it takes a long time for T-cell populations to recover. A seminal paper from Karolinska Institute demonstrated that even a year after completion of Campath therapy T-cell populations are a mere shadow of their former selves. It is not quite clear exactly why this is the case. Perhaps it has to do with the fact that Campath lingers in the body for several weeks / months and continues killing T-cells as they try to recover.

T-cells are our main defense against viral infections. Remember, it does not always require an external virus to invade us to get sick. Our bodies retain small trace amounts of many viruses that we have been exposed to over our life times. Good examples are chicken pox virus, Epstein-Barr virus, hepatitis. Reactivation of these dormant traces of viral infections of long ago can cause serious illness when T-cell defenses are down. Chicken pox virus reactivation can cause a painful attack of shingles. Reactivation of EBV can cause all kinds of problems, including possible Richter’s transformation. CMV (cytomegalovirus) reactivation can lead to dangerous bout of pneumonia. Given today’s concerns about a possible swine flu pandemic this fall, increased risk of infection by H1N1 is something to take into consideration before initiating Campath therapy.

Just as important as long standing T-cell deficits is the issue of deep and prolonged neutropenia (low neutrophil counts ) that invariably accompanies Campath therapy. Neutropenic patients are at much higher risk of all sorts of infections, not just viral infections. Many patients suffered life threatening infections in the early days. More recent Campath protocols have built in safeguards to protect patients against infections – more careful monitoring, preventative use of broad spectrum antibiotics and anti-viral drugs, growth factors such as Neupogen / Neulasta to increase neutrophil counts.

FDA has approved use of Campath in CLL with few restrictions, including its use as single agent frontline therapy (based on one of those low powered chlorambucil straw-man comparison studies). Frankly I have my reservations about using Campath as frontline therapy, except in the case of patients with proven 17p and 11q FISH defects – I think its use as frontline therapy for patients with good prognostics might be jumping the gun, using up this valuable bullet right up front when it might be prudent to save it for later rainy day.

Campath Therapy Protocols: Then & Now

We now have more than 10 years of experience using Campath in CLL. The classic schedule is intravenous (iv) infusion of the drug at a dose of 30mg / 3 times a week for 12 weeks. Infusion related side effects as well as life threatening infections seen in early trials have mandated more prudent protocols. This is particularly important when the patient is quite elderly or salvage patient that is severely immune compromised because of prior chemotherapy or aggressive disease.

Earlier work has shown that subcutaneous administration of Campath at lower doses but for longer period may be both effective and easier to tolerate. The aim of the clinical trials we review below was to demonstrate safety and efficacy of less aggressive subcutaneous low dose Campath in refractory CLL patients, especially those with poor prognostic indicators such as 17p deletion, advanced age, fludarabine resistance etc.

Sub-q Campath: German study

Stilgenbauer, Dohner et al of the German CLL group are highly regarded CLL experts. They were the first group identify the value of FISH testing in defining prognostic risk groups. Their classification of FISH risk groups (17p, 11q deletions: high risk;  12 trisomy, “normal”: median risk13q deletion: low risk) several years ago stands unchallenged.

Below is the abstract of their very recent paper studying the effect of sub-q Campath in fludarabine refractory CLL patients, with detailed analysis of how different prognostic groups fared. If you want help in getting hold of the full text of their paper, send me a personal email.

J Clin Oncol. 2009 Aug 20;27(24):3994-4001.

Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group.

Stilgenbauer S, Zenz T, Winkler D, Bühler A, Schlenk RF, Groner S, Busch R, Hensel M, Dührsen U, Finke J, Dreger P, Jäger U, Lengfelder E, Hohloch K, Söling U, Schlag R, Kneba M, Hallek M, Döhner H; German Chronic Lymphocytic Leukemia Study Group.

Department of Internal Medicine III, University of Ulm, Ulm, Germany. stephan.stilgenbauer@uniklinik-ulm.de

PURPOSE: The phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome. PATIENTS AND METHODS: One hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter. RESULTS: The overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival (OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters (in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased beta2-microglobulin (beta2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, beta2-MG, and TK were independent prognostic factors for OS. CONCLUSION: Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.

PMID: 19597025

Notice this study used the usual Campath dosage and duration, 30 mg three times weekly for 12 weeks. There was the usual gradual dose escalation in the first week (3mg first time, 10mg the next time and 30mg the third time). Using present day guidelines, patients got antibiotic (cotrimoxazole) and antiviral (famciclovir) prophylaxis, as well as Neulasta (longer acting version of Neupogen, the neutrophil growth factor). The only difference is that Campath was given subcutaneously rather than as an infusion. Patients got the monoclonal as a jab in the arm (or elsewhere), and did not have to sit in the infusion chair with a needle stuck in their veins for any length of time. In this study and elsewhere in similar studies, patients are often able to give themselves the shot of Campath in the privacy and comfort of their own homes.

The patients were all heavily pre-treated prior to entering this trial and fludarabine refractory (defined as getting less than a CR or PR to a fludarabine containing regimen, or disease progression within 6 months after completing therapy). We know by now that this group of patients has poor prognosis and few good therapy options. Below is a summary table describing the patient cohort.

Adverse effects

I was disappointed to see no great decrease in toxicity or adverse effects. Grade 3-4 toxicity is pretty heavy stuff and the table shows significant percentage of the patients suffered this and high grade infections. The sub-q method was somewhat better tolerated than the infusion method immediately after drug administration, but down the road the risk of blood toxicity and infections was roughly the same.  Bummer!

Efficacy

So, did the sub-q method work at least as well as the more laborious infusion method of drug administration? Below is a comparison of the results in this study with historical results using the older infusion method. Not much of a difference, certainly not anything we can hang our hats on. I suppose the half full glass viewpoint is that sub-q administration did not reduce the efficacy.

 

Survival

As we mentioned above, this was a very heavily pre-treated group of patients with poor prognosis, majority of them fludarabine refractory.  Below is the overall survival for the group as a whole. Grim news, majority of the patients had relapsed within 6 months and less than half the patients survived past the 2 year mark. 

But there was one bit of good news I would like to share with you.  Was there a difference in survival rates depending on what the patients did when they relapsed after this Campath trial? You bet!! There is dramatically different overall survival times depending on whether the patients chose a stem cell transplant (blue line) or chose other salvage therapies (gold line), as shown in the diagram below.

Median survival was less than 10 months for patients who chose other salvage therapy options. As for the SCT group, more than half of them are still alive at the time of this analysis. I think you will agree, the SCT folks fared a lot better! The same point was made earlier in an M. D. Anderson study we reviewed, discussing salvage options for patients who have relapsed after FCR therapy. The consensus is now emerging across the board: for poor prognosis patients (refractory to fludarabine, and / or patients who have relapsed soon after FCR or Campath therapies) stem cell transplants are much more effective than any other salvage therapy option available today. Here is the bottom line quote from the authors:

“Although alemtuzumab is efficacious in inducing remissions in fludarabine refractory CLL, the disease will eventually relapseand progress. Currently, the only potentially curative therapy for fludarabine-refractory CLL is alloSCT.”

Some other findings of this study:

  • As expected, Campath was equally effective in patients independent of their FISH status. There was no additional penalty paid by patients with the dreaded 17p or 11q deletions.
  • Not even IgVH gene mutational status had any effect.
  • The only two prognostic indicators that had an impact were beta-2-microglobulin (B2M) and serum thymidine kinase levels.

Low-dose, sub-q Campath in refractory CLL patients

OK, as we have seen above, Campath works just as well (or not, depending on whether you are in an optimistic or pessimistic mood) whether it is given as an intravenous infusion or as a sub-cutaneous jab. The later method of getting the drug into your body may make it easier to take; cheaper too, since you don’t have to rent squatter’s rights for several hours in that fake-leather reclining chair in your oncologist’s back office. But given at the same dosage, sub-q Campath did not have any significant reduction in the hematological toxicity or risk of infections.

But remember the German study was done with the same drug dosages.  Which leads us to the next obvious question, what if patients got Campath sub-q, and at significantly lower dosages? Are we over-dosing patients with this potent monoclonal? The abstract below explores this concept. Write to me if you want to read the full text article.

Leukemia. 2009 Jul 30.

Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study.

Cortelezzi A, Pasquini MC, Gardellini A, Gianelli U, Bossi A, Reda G, Sarina B, Musto P, Barcellini W, Neri A, Deliliers GL.

[1] Department of Medical Sciences, University of Milan, Milan, Italy [2] Hematology 1-Bone Marrow Transplantation Unit, IRCCS Foundation ‘Policlinico Mangiagalli and Regina Elena’, Milan, Italy.

Alemtuzumab is active in chronic lymphocytic leukaemia (CLL) patients refractory to alkylators and fludarabine. The aim of this study was to determine the efficacy and safety of subcutaneous alemtuzumab at low dose (10 mg three times per week, for 18 weeks) to 49 patients with pre-treated CLL. The overall response rate was 53%, including 27% of complete responses; it was 42% in patients over 70 years, and 54% in the fludarabine-resistant patients. Forty-five percent of the patients with an unfavourable karyotype responded, including 60% of those with the 17p- aberration. After a median follow-up of 25 months, the median overall time to disease progression was 8 months (responders 12 months, non-responders 4 months). The median overall time to alternative treatment was 9 months (responders 17 months, non-responders 6 months) and median overall survival was 30 months. The treatment was well tolerated: grade IV neutropenia was observed in 17%, and cytomegalovirus (CMV) reactivation in 24% of the patients, with no CMV disease. We observed a total of 30 infections (50% during treatment and 50% during the 12-month follow-up), only one-third of which was severe. This study confirms that low-dose subcutaneous alemtuzumab is effective in poor prognosis CLL, and has a particularly favourable toxicity profile.Leukemia advance online publication, 30 July 2009; doi:10.1038/leu.2009.148.

PMID: 19641526

To cut to the chase, Campath was given at a dose of 10mg, three times per week, for 18 weeks. That is a total of 540mg for the whole enchilada, compared to conventional dosing of 30mg thrice weekly for 12 weeks (1,080mg in total).

It is hard to do a strictly apples to apples comparison between this Italian study and the German study we described earlier in this review, since the patient cohorts were not well matched. I get the sense this group was not quite as far gone as the German study group.

As a result, the overall response rate was higher, at 53%. CR rates were also higher, at 27%. It is interesting to note that while Campath did a good job of clearing out CLL cells in peripheral blood (78%), it was less effective in clearing out bone marrow (63%) and substantially less so in killing CLL cells in the lymph nodes or spleen (53%, 52% respectively). Not surprising results, we knew already that patients with bulky lymph nodes (or grossly enlarged spleen) do not respond so well to Campath therapy.

Bang for the buck, I suppose, in terms of safety and tolerability. This lower dose regimen had less blood toxicity, especially at the grade 3-4 level. Infections were slightly lower as well, but not dramatically so. All in all, if you take slightly better off patients and give them lower doses of sub-q Campath, you will get somewhat better responses and somewhat reduced toxicity profile. We will not have more definitive comparison unless someone does a two arm study with two different dose regimens in well matched patient cohorts.

First dose local reactions were mild to moderate, usually nothing more than redness and slight swelling at the site of the jab. This seems to be the biggest advantage of sub-q method of administration compared to conventional infusion method, the lack of massive adverse response during the very first infusion of the drug. Lower dose and sub-q Campath may be a good choice for elderly patients unable to withstand more robust dosage or risk of infusion related adverse effects. And we must also remember sub-q Campath can be self administered by majority of patients, bringing down cost and hassle factors.

While I hoped for improved efficacy or lower toxicity from these trials, I think you will agree getting at least on-par efficacy and no additional toxicity beats the proverbial kick in the head. As expected, Campath works even in 17p and 11q deleted patients. And once again it is confirmed the best salvage therapy after patients relapse is a stem cell transplant.  Intravenous or sub-q, patients should be protected by appropriate antibiotic and anti-viral agents.