Watch and wait is one of the most counter-intuitive and anxiety provoking time for CLL patients, so studying the question if early intervention might help seemed not only logical but sympathetic.
The truth is that doing such a trial is much more difficult than it seems.
Past trials that looked at early intervention with the best available treatments at the time, namely chemo-based therapies, failed to show any survival advantage of jumping in with treatment before it was needed.
But surely now with the combination of our better ability to predict who is likely to progress and with the newer highly effective and low toxicity therapies such as ibrutinib, circumstances have changed.
Turns out it is still much more complicated.
I interviewed Dr. Peter Hillman of Leeds who heads CLL and other blood cancer research in the United Kingdom on the CLL12 trial presented at European hematology Association (EHA) Annual Congress in Amsterdam, the Netherlands in 2019.
- 6% of all older individuals in the UK have millions of clonal CLL cells in their blood at levels below that needed to diagnose CLL. This is called monoclonal B cell lymphocytosis or MBL (for more on thisd, please see: https://cllsociety.org/2019/10/e-r-i-c-barcelona-2018-professor-john-seymour-on-mbl-or-monoclonal-b-cell-lymphocytosis-a-cll-chronic-lymphocytic-leukemia/. Most of these folks will never develop CLL.
- Many of the CLL patients with low absolute lymphocyte counts (ALC) (5,000 to 15,000) may represent the top end of MBL. Perhaps as many as ⅓ – ½ of these CLL patients may not progress.
- However, some patients are more likely to progress including those with unmutated IGVH.
- The CLL12 Trial looked at those patients more likely to progress and they were either given ibrutinib and or managed traditionally with no therapy or a placebo. Those at low risk to progress were not entered in the trial.
- One challenge is what is the best end of point of this study:
- Can’t use time to treatment as one group is already being treated.
- Can’t use overall survival (OS) data as that would likely take too long.
- The study used Event Free Survival (EFS) as the primary endpoint, defined as defined as time from randomization until occurrence of activedisease, new CLL treatment or death.
- The trial did prove Ibrutinib was superior for EFS (not reached vs. 47.8 months in the placebo arm), progression free survival (PFS) which was not reached for ibrutinib and was 14.8 months with placebo and in Time to Next Treatment (TTNT).
- Adverse events of “clinical interest” such as hypertension, atrial fibrillation and bleeding were more common in the ibrutinib arm.
This trial needs a careful and nuanced analysis. Clearly folks do better on ibrutinib in terms of EFS, PFS, and TTNT and that is not trivial. It comes at some cost. It was no surprise that those on ibrutinib had a greater risk of the predictable side effects, but still many would trade the side effects for a longer time without disease progression.
But OS is what we patients ultimately want and that data is a long way off. With such effective combination therapies available today, wouldn’t it make sense to just wait until we need treatment, and then intervene. Time and this trial will tell which is the best approach.
One important side benefit of this trial is that for the first time is was possible to compare ibrutinib to placebo in an ethical way. That allowed us to see how much of what happens in the way of adverse events was the direct result of the drug and how much was due to CLL and/or the age of the patient.
Finally, it is also a measure of just how fast the research is advancing in chronic lymphocytic leukemia. When this trial was designed and launched it was addressing an aching need for patients about doing better than watch and wait, and now with the prospect of fixed duration combinations there is the risk that this well designed and well-intentioned trial may be rendered moot.
To watch my interview with the thoughtful Prof. Hillmen, please click:
For the actual abstract and a cool video recording from the live presentation (I was there) of when this
important research was premiered at EHA 2019 see: IBRUTINIB VERSUS PLACEBO IN PATIENTS WITH ASYMPTOMATIC, TREATMENT-NAÏVE EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): PRIMARY ENDPOINT RESULTS OF THE PHASE 3 DOUBLE-BLIND RANDOMIZED CLL12 TRIAL