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Easy Does It — Questioning the Gold Standard

Date: November 18, 2024

If you are a frequent reader of CLL Topics, it should come as no surprise to you that I am not a big fan of fludarabine as the slam-dunk “gold standard” for frontline treatment of all CLL patients. Is there a sure-fire first therapy option that is right for all CLL patients? That is indeed the million dollar question. This is a very important question, and by rights it should be a full article on our website. But I have guests coming, and it is my birthday toady, so I thought I would cut myself some slack.

Frontline Rituxan?

Not everyone has access to Rituxan (and even more especially the new-kid-on-the-block HuMax-CD20) as frontline therapy. Even more importantly, not everyone is likely to respond sufficiently to such “kinder and gentler” approach. For example, people with poor prognostic CLL or bulky disease or heavy tumor burden are not likely to respond very well to single agent Rituxan, even if they go for overkill on the dosage or frequency of infusions. New concepts such as the CD20 Shaving Reaction suggest that under these circumstances you are most likely just flushing all that expensive Rituxan down the toilet, literally. Very few CLL patients get long lasting remissions with Rituxan, without the need for periodic maintenance.

Is Fludarabine the Answer?

This purine analog has been pushed very heavily as the “gold standard” frontline therapy for CLL in the USA, not so much in Europe. M. D. Anderson has been in the lead in promoting fludarabine, where as Mayo Clinic and others have regarded Pentostatin (also a purine analog and not all that different from fludarabine, in my humble opinion: FCR versus PCR comparison ) as less immunosuppressive. Since we do not yet have oral fludarabine available in this country, both fludarabine and pentostatin require intravenous infusions in the doctor’s backroom. The dollar costs ratchet up with every minute you occupy that very expensive recliner chair, hooked up to the infusion pole. If you think the dollar cost is not an issue for you, since your insurance company or Medicare will pay for it, I suggest you read a very important entry on Dr. Hamblin’s blog: NICE Work.

OK, fludarabine costs a bit more (quite a bit more) than the really old-fashioned chlorambucil. And it is a lot more of a hassle to get the fludarabine infusion done, than get the prescription filled for chlorambucil pills, to be taken as directed in the comfort of your own home. This is particularly true for people who live in remote areas, or older patients who have to depend on some one else to drive them to the doctor’s office, or working stiffs that need to take time away from the office. But all that and the much higher cost would be a lot easier to swallow, if fludarabine as frontline helped patients live longer and healthier lives.

Below is a very important and authoritative review of all the clinical trials that have ever been done, anywhere in the world, comparing fludarabine with chlorambucil. The Cochrane Reviews are about as credible as it gets, the facts and nothing but the facts, no strings attached and no conflicts of interest. They also have unimpeachable statistical analysis, none of this slicing and dicing of the data until the results come out the way that suits pre-conceived opinions of the researchers, or drug company quarterly profits.

The results of this rigorous analysis confirm the suspicions of many physicians with decades of experience in treating CLL patients. Patients treated with fludarabine as single agent frontline therapy get sexier response statistics, even longer remissions. But what they do not get is longer lives, or even better quality of lives. I don’t know about you, but if it were my precious body on the line, what matter most to me are (1) Overall Survival (2) Quality of life.

Fludarabine remissions fail, invariably, as do chlorambucil remissions. There is no doubt that fludarabine is more toxic to T-cells, and therefore makes patients more vulnerable to viral infections, secondary cancers such as skin cancer, autoimmune disease, and even the dreaded Richter’s transformation. There is unequivocal evidence that patients relapsing after fludarabine therapy have far fewer choices, and roughly 50% of them have additional chromosomal aberrations, such as the aggressive 17p (p53) deletion. For these folks with newly acquired 17p deletions, Campath + HDMP, "sledge hammer" therapy may be among few good options left.

In simple terms, fludarabine does a heavy duty job on the CLL cells, but not without doing a heavy duty job on you as well. The deeper remission is at the cost of more infections, fewer choices when (not if) you relapse. That is perhaps why patients treated with fludarabine do not live longer, or live healthier lives, compared to those treated with plain old fashioned chlorambucil. Does this sound like Winning the Battle but Losing the War?

So, Is Chlorambucil the Proverbial Free Lunch?

Let’s not get too sold on chlorambucil either. It is by no means without its own toxicity. However, these days the trend seems to be to administer smaller daily doses of chlorambucil, and often with regular breaks of one or more weeks, thereby giving the body a chance to recover from the side effects. It is generally thought to be less toxic to T-cells than fludarabine, and therefore less likely to leave the patient vulnerable to infections and the like. It is known to have some level of bone marrow toxicity, and therefore I am all in favor of the lower doses. Besides the lower T-cell toxicity, the big advantage of chlorambucil seems to be that patients have several more options for salvage after the remission fails. For example, it is generally accepted that fludarabine is likely to work in folks that have already been through chlorambucil, but not the other way around. Chlorambucil burns fewer therapy bridges, which is a very good thing.

Will chlorambucil work for all patients, and will the CLL be held at bay for the natural span of your life? Absolutely not! People with 17p deletions going in are not likely to respond to chlorambucil or fludarabine. That is why we urge patients to get their prognostic testing done prior to making therapy decisions. Why would you want to mess with chlorambucil or fludarabine, all that hassle and toxicity, if they are not even going to work for you?

Would fludarabine look better if it was combined with another chemotherapy drug? Comparisons of single agent fludarabine versus combination of F with cyclophosphamide have been done as well. You can read our review of this interesting comparison Comparing F+C versus F.

The Era of Monoclonals

There is little doubt that monoclonals such as Rituxan and Campath have changed the landscape. While single agent Rituxan has only limited efficacy in CLL (we sincerely hope HuMax-CD20 improves on this, and that this new monoclonal is soon available to all patients), there is ample evidence to show that Rituxan works wonders in synergizing with chemo drugs. Combination chemo-immunotherapy regimens are here to stay, until and unless we come up with new monoclonals that can do the job all by themselves. Not enough apples-to-apples comparisons have been done to say which of the various combinations is going to be the new “gold standard”.

My guess is that no single gold standard will emerge. CLL is not a uniform disease, and one shoe does not fit all of us, not even chemoimmunotherapy combos. The process of making therapy decisions is undeniably complex and frustrating, and the time you put into understanding the issues involved absolutely crucial. That is also the reason for the existence of CLL Topics. We try to make the science accessible to laypersons, so that you can make the decisions that are right for you.

Be well,

Chaya
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Abstract:

Cancer Treat Rev. 2024 Aug;32(5):377-89. Epub 2024 Jun 21.

Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis.

Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R.

On behalf of the Cochrane Haematologic Malignancies Group.

Innsbruck Medical University, Division of Hematology and Oncology, Anichstrasse 35, A-6020 Innsbruck, Austria.

BACKGROUND: Recent trials suggest improved response rates for purine analogues compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. Thus, a systematic Cochrane review may be able to further define the role of purine analogues in the first-line treatment of B-CLL.
METHODS: Randomized controlled trials comparing single-agent purine analogues with alkylator-based regimens were included. Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and trial registers were searched. We included full-text and abstract publications as well as unpublished data. Relative risks (RR) and hazard ratios (HR) were calculated under a fixed-effects model, clinical and statistical heterogeneity was examined with sensitivity analyses and meta-regression. If applicable, numbers needed to treat or harm (NNT, NNH) were also determined.
FINDINGS: Five trials with 1838 randomized patients were included. Importantly, four trials had a cross-over design. There was a trend for improved overall survival for patients receiving purine analogues as initial therapy but statistical significance was just not reached (HR 0.89 [95% CI 0.78-1.01]). The RR for achieving an overall (RR 1.22 [95% CI 1.13-1.31]; NNT 8 [95% CI 6-13]) and complete response (RR 1.94 [95% CI 1.65-2.28]; NNT 6 [5-8]) was significantly improved, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82]). Incidence of grade III/IV infections (RR 1.83 [95% CI 1.30-2.58]; NNH 20 [95% CI 12.5-50]) and haemolytic anaemia (RR 3.36 [95% CI 1.27-8.91]; NNH 21 [95% CI 6-185]) was significantly higher in patients receiving purine analogues.
INTERPRETATION: Despite significantly increased response rates and longer progression-free survival with purine analogues as first-line therapy, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine analogues augments the risk for grade III/IV infections and haemolytic anaemia.

PMID: 16793209 [PubMed – indexed for MEDLINE]
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