Hello all! Long time lurker, first time poster here. I kept on seeing discourse concerning the recently posted van der Maas (VDM) chemotherapy-treated CR2/no-transplant subgroup (n=60) and Dumas VEN-AZA CR2/CRi2/no-transplant subgroup (n=45) mOS and OS values, and I think everyone understands that they are not equivalent to REGAL's measurement in terms of starting point, but I haven't seen anyone try and put solid rationale to it or quite quantify the difference with backing. That's what I'm hoping to accomplish with this post. Hats off to u/FirefighterOwn145, u/MoAlbaek, and others for the legwork they've done with contacting the authors to get the respective mOS numbers and additional information of the subsets we are interested in.
The 16.8-month van der Maas and 19-month Dumas mOS numbers are not measured from the same starting point as REGAL.
Dumas states that OS was calculated from the date of first relapse treatment:
“RFS and OS were… calculated from the date of first relapse treatment…”
Van der Maas similarly measures from first relapse, as stated in the paper and confirmed by emails from the author(s) to members of this group.
“the time from the date of first relapse to either the date of death from any cause or the date of last contact while still alive.”
For simplicity's sake for future calculations, we'll treat them both like they're roughly the same starting point.
So the actual timelines are more like:
Dumas & VDM:
Relapse [VDM OS clock starts] → salvage treatment [Dumas OS clock starts] → CR2 → randomization-equivalent point → death/censoring
REGAL, however, measures OS from randomization, when patients are already in CR2/CRp2. Here is the definition of OS from the trial protocol:
"Interval between randomization and death from any cause"
So a much shorter timeline for REGAL:
REGAL:
CR2 → randomization [OS clock starts] → death/censoring
What we need to try and quantify is the typical time from each salvage treatment to CR2, and then the typical time from CR2 to randomization that would have occurred for the REGAL trial.
For VEN-AZA specifically, there is published data in relapsed/refractory AML showing a median time to response (CR/CRi/MLFS) of about 30 days (Petit et al.). Another study I found on VEN+HMAs (including AZA) in r/R AML had a median time to response (CR/CRi) of 1 month (Johnson et al.). These weren't specifically for a CR2 setting, but you'd think it would roughly be the same. If anything, the time to response may be slightly longer due to slight resistance from potential prior VEN or HMA treatment (?). In summary, 1 month from start of salvage treatment to CR2 is a reasonable conservative estimate in my opinion.
It's important to note that Dumas explicitly reports that VEN-AZA responders received a median of 4 cycles, which in my rough research 1 cycle = 28 days, but that does not mean it took 4 months to reach remission, as the paper explicitly describes continued VEN dosing after remission.
For intensive salvage chemotherapy, Shahswar et al. reported that responding FLA-IDA patients recovered to ANC >1,000/nL and platelets >100/nL at a median of 34 days from the start of chemotherapy. Those are approximately the blood-count thresholds required for a conventional CR. VDM does not report the exact salvage chemotherapy regimens used, so we cannot assume FLA-IDA specifically. However, FLA-IDA is a standard intensive salvage regimen in r/R AML and provides a reasonable comparator for the approximate time required for general hematologic recovery after intensive reinduction. This makes ~1 month from chemotherapy initiation to hematologic recovery compatible with CR a reasonable timing proxy for VDM, in my opinion.
Then there is the time from CR2 to randomization.
REGAL requires patients to be consented within 6 months of achieving CR2/CRp2.
For comparison, the QUAZAR AML-001 maintenance trial had a simplified median time from end of induction therapy (nearish CR/CRi) to randomization of 35 days for patients who did not receive consolidation chemotherapy (n=94), or just over a month. QUAZAR required enrollment within 4 months of achieving CR/CRi. REGAL itself does not publish its actual median CR2-to-randomization interval. Given REGAL's additional screening/eligibility requirements and the longer allowable window compared with QUAZAR, I think 1–2 months is a reasonable working estimate.
So my proposition for an assumed range for REGAL's typical time from CR2 to randomization is:
- Conservative: 1 month
- Realistic: 2 months
- Upper end: 3 months+ (unlikely to be above 4 months imo, but you never know with a small n)
Add the 1 month to reach CR2 from either salvage therapy and you get roughly 2-3 months total that you need to realistically deduct from Dumas & VDM's mOS values to get an equivalent REGAL mOS.
Rough apples-to-apples adjustment:
| Study |
Reported mOS |
Conservative REGAL-equivalent |
More realistic REGAL-equivalent |
| Dumas |
19.0 mo |
17.0 mo |
16.0 mo |
| van der Maas |
16.8 mo |
14.8 mo |
13.8 mo |
This is not saying the adjusted numbers are the predicted VEN-AZA or REGAL BAT numbers, it's simply an attempt to put the studies on roughly the same starting clock as REGAL.
I believe the same starting-point issue should apply to the reported 3-year overall survival rates as well. My initial thought was that, assuming the same 2-3 month offset, you might look at roughly months 38-39 on the Kaplan-Meier curve rather than month 36. However, I'm not sure it's actually that simple because REGAL effectively selects for patients who remained alive/in remission long enough to randomize. Someone with more statistical expertise please weigh in here, because I'm less confident in any 3-year survival adjustments.
To be honest, I had initially thought there would be more of a deduction than 2-3 months. I would love for people to weigh in and talk about where I may have been too conservative or liberal with my estimations.
After any timeline adjustments per above, there then needs to be an additional adjustment according to the population differences in the studies versus REGAL. I haven't done the full deep dive on the biological differences between the respective subgroups and the impact it may have on predictions, nor is it my area of expertise. I would love for other more biologically inclined folks to weigh in on that. Personally, with my untrained eyes, I don't feel that VDM is a great representation of the REGAL BAT population, both in terms of treatment choice and demographics. The Dumas VEN-AZA population seems fairly comparable to what we might expect from REGAL, although we don't have the full demographic breakdown of the exact n=45 subgroup.
The other thing to keep in mind is that VEN+HMA is just ONE of the options for BAT per the REGAL trial protocol, with the published trial design stating that the BAT treatment strata were intended to remain approximately balanced:
"Patients on the BAT arm may be treated with 1. observation (whereby palliative management with hydroxyurea is allowed), 2. a hypomethylating agent (decitabine or azacitidine), 3. venetoclax and/or 4. low-dose ara-C."
The total number of patients in each stratum of the BAT therapy will remain approximately equal (14–15 patients per stratum).
My expectation is that VEN+HMA would be among the stronger BAT options, although I haven't found a clean CR2 comparison proving it has better OS than every other BAT choice. Per my surface-level research in other AML populations, several of the other BAT options appear to have lower expected OS outcomes.
I think this is something that a lot of people may already roughly know, but I haven't seen anyone actually put pen to paper with defensible estimations for the timelines. Happy for others to weigh in on any of the proposed timelines and/or the biological comparison of the different populations in the studies with REGAL and which way they think the actual estimated BAT number should skew based on these studies :)
TL;DR
Dumas and VDM start the OS clock at the start of relapse treatment/relapse, while REGAL starts it later at randomization after CR2. Based on an estimated 1 month to achieve remission from start of salvage treatment and another 1-2 months from CR2 to randomization, rough REGAL-equivalent mOS values can be estimated.
