Five-year results for the iFCG regimen: first-line treatment of CLL patients with mutated IGHV and without del(17p)/TP53 mutation

[bennevisplace]

Published 4 months ago, journals.lww.com/hemasphere... is an update of the Phase 2 study S149, initiated in 2017 and previously reported here in "Novel Combos Are Shaking Up the CLL Landscape but FCR still has its place" healthunlocked.com/cllsuppo...

The update reports outcomes with a median follow-up of 56.8 months. The PFS and OS are, as depicted, very high, even allowing for favourable age profile (25-71, median 60) and CLL genetics (100 % IGHV mutated, 69% del 13q). The PFS and OS curves reflect one patient death (from heart failure).

Summary/Conclusion: The iFCG regimen, using only 3 cycles of chemotherapy (as opposed to 6 cycles of chemoimmunotherapy) achieves a very high rate of U-MRD in previously-untreated pts with CLL with IGHV-M CLL. No pt had disease progression with a median follow-up of close to 5 years. The 5-year PFS is 97.7%; this is favorable compared to 5-year PFS of ≈65% with FCR (CLL10), ≈70% with ibrutinib (A041202 trial), and 81% with ibrutinib (RESONATE-2) for IGHV-M CLL. Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity by NGS during therapy.

I have no doubt that these results are easily good enough to justify a phase 3 study enrolling many more patients. Will it happen? I guess it depends on whether potential sponsors see something to be gained, or lost. A phase 3 study would certainly burn a heap of cash. A "good" result could widen the market, or more likely could see a flagship product nibbling away at its own market share ("Stop taking Ibrutinib after a year??? after our lawyers worked their butts off to get the patents stretched out into the 2030s?"). Anyway, who wants to be associated with old-hat chemo drugs? Well, maybe some CLL patients do.

[johnliston]

What about adverse Events?

john

[bennevisplace in reply to johnliston]

This paper appears to have been made to accompany an oral presentation and as such is brief and to the point. It states:

The sole event noted on both the PFS and OS curve is a pt death from heart failure.

One pt developed therapy-related MDS; this pt is being monitored for 38+ months without any therapy for MDS with normal blood counts.

Another summary of the same study at the same stage obroncology.com/article/tar... says a bit more:

Toxicities observed in the study were among those commonly associated with ibrutinib, including atrial fibrillation and joint pain, as well as with chemoimmunotherapy, such as low blood counts and myelosuppression.

[may04cll]

What has become of the data from the IFCR trial ?

[bennevisplace in reply to may04cll]

The study sponsor retains the primary data, and researchers have access.

[LeoPa]

,,wow , how long do 3 cycles take?

[bennevisplace in reply to LeoPa]

🔎👴

[bennevisplace in reply to LeoPa]

I'm guessing 3 x 28 days of iFCG, because 6 x 28 days is a full course of FCR.

[LeoPa in reply to bennevisplace]

That would be perfect if so. Quite affordable compared to the price of current treatments.

[bennevisplace]

Prize for the person who figures out why the 5 year PFS = 97.7 % and the 5 year OS = 97.8 %

[LeoPa in reply to bennevisplace]

0.1% progressed but survived.

[bennevisplace in reply to LeoPa]

45 patients, 0.1% would be 0.045 of a patient progressing, which is about right.

The text says no patient had disease progression, i.e. 0.000 of a patient, so I can't award you the prize Leo, sorry.

[LeoPa in reply to bennevisplace]

That's the patient that halfway progressed and they rounded him down to zero 😁

[bennevisplace in reply to LeoPa]

Nice try Leo, consolation prize for persistence 🥥

[bennevisplace in reply to LeoPa]

See below

[bennevisplace in reply to bennevisplace]

Here's my answer to my own question. Open to comments from learned colleagues.

I maintain that both the PFS and OS figures should be 97.8 %. I have two explanations for the 97.7 % figure having arisen, and I wonder that such an obvious error could perpetuate into a paper authored by i.a. some celebrated names.

Back to basics. What are we talking about with PFS and OS?

Progression-free means that at the time of assessment the patient's disease has not returned; the important point being that the measure is binary: either the patient has progressed or the patient is progression-free, for the purposes of the study there is no halfway house.

Percentage Progression-free Survival (% PFS) is the percentage of patients starting the study (45 in this case) who were progression-free (44/45 = 97.7778 %) at the time of assessment (5 years, give or take a few months).

Percentage Overall Survival (% OS) is the percentage of patients starting the study (45) who were still alive (44/45 = 97.7778 %) at the time of assessment (5 years, give or take a few months).

The text of the paper explains that one patient died, and both the PFS and OS plots reflect this at ~10 months. The text also states that no patient progressed, which ties in with the fact that after 10 months the PFS plot remains horizontal.

So where did the figure PFS = 97.7 % come from?

Anyone, after all, can see that the % PFS and % OS in this case must be the same 44/45 = 0.97recurring = 97.8 % to the nearest 0.1 %.

First explanation Someone used a calculator with the display set to 3 or more decimal places, got an answer of 97.777(7...) for PFS and wrote down 97.7. They then left the study for unknown reasons. Someone else, possibly using a different calculator, nailed the figure 97.8 for OS.

Second explanation The study employed a statistician to do lots of analysis, including the simple task of drawing the PFS and OS plots and generating the 5-year % PFS and % OS figures. A typical software package would incorporate a Kaplan-Meier module en.wikipedia.org/wiki/Kapla... A useful estimator, which can account for missing data etc, but maybe it can also introduce small errors like this one - only noticeable because it's such a simple case.

The second explanation seems the more probable, but I prefer the first.

[LeoPa in reply to bennevisplace]

You really like your math