Decisions, decisions…

I am one of those people who gets flustered when the checkout clerk at the supermarket asks me whether I want paper or plastic bags. That is nothing compared to making literally life or death therapy choices in controlling CLL. What makes it particularly difficult and frustrating is the lack of clear cut information on which to base sensible decisions and valid one-on-one comparisons between drugs .

The results of clinical trials are only as dependable as the agendas of the trial designers. In a perfect world human volunteers would not be subjected to clinical trials that are designed to prove a preconceived concept dear to the heart of the researcher involved. That is not the way science is supposed to work and scientists are supposed to rise above such pettiness.

Even more suspicious are the “straw man” comparison trials done by drug companies trying to make their drug candidate look as good as possible and satisfy arcane FDA requirements as quickly as possible. Witness the recent flurry of clinical trials testing modern day marvel drugs against a less than adequate dosing of chlorambucil. Treanda and alemtuzumab (Campath) are two drugs that won recent FDA approvals based on such questionable comparisons.

But once in a while a clinical trial report comes along that goes the extra distance in giving us credible, actionable information. Here is one such trial. It is not sexy, it will not win the authors any great brownie points, but it will help some of you make difficult therapy decisions. And for that I sincerely thank the authors. The abstract is below. Write to me if you want help in locating the full text PDF of the article.

Blood. 2009 Jul 15.

First line therapy with fludarabine compared to chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia.

Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhofer N, Rohrberg R, Soling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Dohner H, Emmerich B, Hallek M.

Department I of Internal Medicine, Centre of Integrated Oncology Koln Bonn, University of Cologne, Cologne, Germany.

While CLL is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicentre phase III trial for CLL patients older than 65 years comparing first line therapy with fludarabine to chlorambucil. 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight with increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% versus 51%; P = .003; 7% versus 0%; P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 versus 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P =.7). Moreover, fludarabine did not increase the overall survival time(46 in the fludarabine versus 64 months in the chlorambucil arm) (P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit when compared to chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.
PMID: 19605849

Background

These two drugs have been the mainstay of treating CLL, before the advent of monoclonal antibodies such as Rituxan, Campath etc.

Chlorambucil (trade name “Leukeran”) is the oldest drug in our armory.It is an alkylating agent (another well known alkylating agent is cyclophosphamide, the “C” in FCR). Chlorambucil is an orally administered small brown pill, available as 2mg tablets. All the physician has to do is write the prescription and the pharmacy fills it - no fuss, no muss. It is a very cheap drug since the patents on it have run out a long time ago. It is also generally accepted that chlorambucil is a lot less immunosuppressive than fludarabine.

Fludarabine (trade name “Fludara”) is a purine analog (similar to its sister drugs pentostatin and cladrabine) and in its heyday just a few short years ago it has been considered the “gold standard” frontline therapy for CLL. Until recently the only way fludarabine could be administered is as an intravenous infusion – a trip to the back room of your oncologist’s practice and a short stint in the fake leather reclining chair.However, unlike Rituxan infusions, getting fludarabine infusion is a relatively quick and low drama affair. More recently an oral form of fludarabine has been available in Europe and the USA.

Fludarabine earned its “gold standard” status because it packed a mush bigger wallop; a lot more people got “complete remission” (CR) from fludarabine frontline therapy, compared to good old chlorambucil. The overall response rate (percentage of patients who got any kind of a response) was also much higher with fludarabine. This much we knew already from prior clinical trials and historical information.

But it is important to remember a CR does not mean a cure. The CLL will return, sooner or later, even for people who got a CR. I think you will agree with me, from the patients’ perspective the million dollar questions are these:

  1. How long did the remissions last, when did it become necessary to start therapy again?
  2. Are there good choices for treating people who have relapsed after fludarabine induced remissions?
  3. Overall, did patients live longer overall, if they used fludarabine instead of chlorambucil as their front-line therapy?
  4. How did the quality of life compare after treatment?

Chlorambucil and fludarabine are still the two major drugs available for treatment in much of the world. This rigorous and well conducted trail from the prestigious German CLL Group gives us much needed information on which to base a choice between these two drugs.

Trial design

The researchers correctly point out that many of the clinical trials done in recent years use patient cohorts who are younger than 65 and this may not be representative of the general CLL population which tends to be older. This trial recruited patients who were between the ages of 65-80 years, whose disease met the standard guidelines for initiating therapy.

The trail used 193 “elderly” previously untreated CLL patients age 65 or older (hey, watch out who you call elderly! Dontcha know 65 is the new 55?) They were randomized into two groups to get either fludarabine or chlorambucil. Fludarabine was given intravenously for 5 consecutive days. This was repeated every 28 days for a total of 6 courses. Chlorambucil was started at 0.4mg/kg of body weight and gradually increased to 0.8mg/kg every day for fifteen days on and fifteen days off, for a total of 12 months. Neither group got any routine antibiotic or anti-viral medications, nor did they get growth factors such as Neupogen or Procrit etc. In other words, both arms are your standard issue no nonsense chemotherapy regimen minus all the fancy bells and whistles.

Patient Profile

Below is a table that summarizes the description of the patient cohort.Details are important when making these comparisons and I am happy to report the two groups seem very well balanced, making it a true apples-to-apples comparison.

Toxicity

CTC grade 3 and 4 myelotoxicity was significantly more frequent in the fludarabine arm than in the chlorambucil arm. But surprisingly, severe infections or infections in general (32% in the chlorambucil arm versus 26% in the fludarabine arm) was not all that different. Three of these severe infections in the fludarabine arm were lethal pneumonias, compared to one lethal infection (septic shock) in the chlorambucil arm.

Conventional wisdom is that fludarabine is contraindicated for patients at risk of autoimmune disease. But in this study the rate of severe AIHA was not statistically different between both arms.

Eight patients developed a secondary cancer and 6 patients developed the dreaded Richter’s transformation during fludarabine therapy. In the chlorambucil arm there were 5 secondary cancers and 2 Richter’s transformations.

All in all, I must confess I am a little surprised there was not more difference between the two drugs in terms of their toxicity. It seems the reputation for being “kinder and gentler” is a little exaggerated in favor of chlorambucil.

Quality of life is not merely measured by these dry blood test statistics. This is one of the few studies that bothered to ask patients how they felt. A detailed quality of life survey was administered to patients before start of therapy and 6, 12 and 24 months later. There was significant improvement in general health and fatigue immediately after treatment but this good news went away (dramatically so) at the 24 month mark as more than half the patients had relapsed by then.

Bang for the buck

Now we come to the meat of the paper, description of how the two groups responded to therapy. Few surprises here, fludarabine showed its mettle in getting far more overall responses and complete responses than chlorambucil across all risk groups.

Patients with 17p53 deletions fared poorly on both drugs. None of the 5 such patients in the chlorambucil arm got any kind of response, let alone CRs. There was a lone patient on the fludarabine arm (out of 5 such patients) that got a response but it was not a CR.

How did the remissions play out over time?

They say a picture is worth a thousand words and the picture below shows how the patients fared long term.

These kinds of graphs are depressing reading but it is important that you learn how to understand them.On the horizontal (x-axis) are months. The vertical (y-axis) has the fraction of patients still in remission. The graph shows there is very little difference between the two drugs! Eighteen months out, roughly half the patients have relapsed.

OK, so much for long lasting remissions. How about overall survival? Did fludarabine do much better on that front? Did patients live longer because they happened to be randomized to the fludarabine arm of the trial?

As you can see, for the first 24 months are so there is almost no difference between the curves for fludarabine (lower curve) and chlorambucil (higher curve). The curves diverge a bit in the middle period but by 72 months they are both roughly the same, with slightly less than 45% of the patients surviving. Please bear in mind these are significantly older patients with more comorbidities than one would expect in a younger group. Your mileage may vary.

Putting it all together..

Here are some quotes from the authors themselves:

  1. This trial is the largest randomized study in an elderly CLL patient cohort.
  2. The median age of 70 years is approximately five years older than in most previous clinical trials and represents a different patient population in CLL.
  3. Without a question the fludarabine arm got much higher overall response rate and higher percentage of complete responses (CRs).
  4. But the better overall response rate and complete remission rate with fludarabine did not translate into a longer progression-free survival.
  5. This result is likely to have some impact on the general practice of CLL therapy.

No kidding! The modern “gold standard” is not all that much better than the old standby when it comes to long term survival or lasting remissions. But good old chlorambucil is not all that much gentler and kinder either. Take your pick.

As I said in my opening paragraphs, this is not a sexy study or one that will generate a lot of chatter in the research community. But it is solid work like this that is important to us chickens as we make life and death therapy decisions. All of us face very individual choices depending on medical, financial and family situations. One choice does not fit all, and the only right decision for you is the one that you make, that feels right to you and your family. All I can do is provide credible information on which you can hope to make sensible decisions.

But I think it is good to know that if you are not exactly a spring chicken and have more than your share of other health problems, you need not feel underprivileged if you have to “make-do” with taking a few little brown pills of chlorambucil to control your CLL, rather than getting the new-fangled fludarabine. Not a bad thing to know as you make tough choices.