In this issue of Haematologica, Jaramillo and colleagues provide a report of results from a clinical trial.1 The trial was elegantly designed to answer an important question, namely, to determine if the addition of a potent and selective FLT3 inhibitor to salvage chemotherapy could improve the rates of response and successful bridging to transplant of patients with relapsed or refractory FLT3-ITD-mutated acute myeloid leukemia (AML).
FLT3-ITD-mutated AML is well known to have a generally poor outcome in the setting of treatment with conventional cytotoxic chemotherapy.2 The regulatory approval of the FLT3 inhibitor midostaurin has improved these outcomes for newly diagnosed patients to a degree,3 but relapse certainly still occurs. In the relapsed or refractory setting, FLT3-ITD mutations are one of the worst possible prognostic factors,4 and even the use of potent, selective FLT3 inhibitors such as quizartinib (Q) only modestly improves outcomes when used as monotherapy.5 Therefore, a logical approach is to combine potent, selective FLT3 inhibition with salvage chemotherapy. Randomized trials are required to demonstrate the degree of benefit of this approach, but such trials are difficult to accrue; no one wants to be randomized to the control arm. A 2:1 randomization scheme can sometimes overcome this barrier, but even these trials are still difficult to enroll to completion. Jaramillo and colleagues designed a study that had a reasonable chance of attracting participants by allowing all enrollees to receive the combination therapy (Q-HAM; quizartinib + cytarabine 3 g/m² twice daily at days 1-3, mitoxantrone 10 mg/m² at days 2 and 3) during the first cycle, with randomization to chemotherapy only (HAM) versus chemotherapy plus quizartinib (Q-HAM) reserved for those achieving remission. The response rate would be compared to historical controls using an established statistical method, and the follow-up treatment would still provide some crucial randomized data for this combination.
Gilteritinib, another selective, potent FLT3 inhibitor, received regulatory approval for the treatment of relapsed and/or refractory FLT3-mutated AML in the US, Europe, and Japan just as this Q-HAM versus HAM trial was getting started. Like the mouse in Robert Burns’ poem,6 the investigators planned their scheme well but for the approval of gilteritinib.7 With the availability of a simple, effective oral therapy for relapsed/refractory FLT3-mutated AML,8 patients and clinicians voted with their feet and accrual to the Q-HAM versus HAM trial ground to a halt.
Only 11 patients had been randomized when the study was stopped. Out of the 11 patients, 6 achieved a response, several made it to allogeneic hematopoietic cell transplant and there were a few long-term survivors. The tiny group of patients actually had a median survival of about a year (double the results of the QuANTUM-R trial5). These results, even though statistically weak, still provided a glimpse, almost like that of a pilot study, into this combination. We can never know when it might be appropriate to study a combination of quizartinib and this salvage regimen in the future, and so we should not be quick to discard any data, even if derived from so small a sample.
How many times have clinical investigators enrolled patients on studies only to find that they never see any follow up? If a trial is negative or does not accrue enough patients, there is apparently insufficient academic glory to induce the investigators to put together the data and publish, which is why Jaramillo and colleagues are to be lauded for sharing what they had. Their trial design was novel and could provide a spark of imagination for future trial designers.
The phenomenon of a new regulatory approval interfering with ongoing clinical studies is likely to be more and more common, as drug approvals in AML have increased seemingly exponentially.9 To paraphrase Burns, the best laid schemes of mice and leukemia researchers often fall apart. That does not mean the results should be plowed over and remain forever buried.
Footnotes
- Received October 24, 2025
- Accepted November 19, 2025
Correspondence
Disclosures
MJL reports a Laboratory Service Agreement with Astellas, and a Consultant/Advisory role and clinical trial funding from Astellas, Daiichi-Sankyo, Sumitomo, and Syndax.
References
- Jaramillo S, Krisam J, Cornet LL. Multicenter upfront randomized phase II trial of quizartinib and high-dose cytarabine plus mitoxantrone in relapsed/refractory acute myeloid leukemia with FMS-like tyrosine kinase 3-internal tandem duplication. Haematologica. 2026; 111(6):2109-2112. Google Scholar
- Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019; 33(2):299-312. Google Scholar
- Stone RM, Mandrekar SJ, Sanford BL. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017; 377(5):454-464. Google Scholar
- Chevallier P, Prebet T, Pigneux A. Influence of NPM1 and FLT3-ITD status on outcome in relapsed/refractory AML patients receiving salvage therapy including gemtuzumab ozogamicin. Leukemia. 2010; 24(2):467-469. Google Scholar
- Cortes JE, Khaled S, Martinelli G. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019; 20(7):984-997. Google Scholar
- Burns R. To a mouse, on Turning Her Up in Her Nest with the Plough, November.1785. Google Scholar
- Pulte ED, Norsworthy KJ, Wang Y. FDA Approval Summary: gilteritinib for relapsed or refractory acute myeloid leukemia with a FLT3 mutation. Clin Cancer Res. 2021; 27(13):3515-3521. Google Scholar
- Perl AE, Martinelli G, Cortes JE. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019; 381(18):1728-1740. Google Scholar
- Magee GH, Grunwald MR. Updates on therapy options in fit and unfit patients with newly diagnosed AML. Curr Treat Options Oncol. 2025; 26(9):829-840. Google Scholar
Figures & Tables
Article Information
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.