Your blood and immune cells usually train like a decent gym class - build, recover, repeat - and then acute myeloid leukemia shows up like a maniac doing deadlifts in the fire exit while everyone else gets shoved off the equipment.
That is roughly the problem in acute myeloid leukemia, or AML: the bone marrow gets crowded by immature, fast-growing cells, and normal blood-making falls apart. People can end up exhausted, short of breath, bruising easily, bleeding, or getting infections because the marrow has basically turned into a hostile workplace with terrible management.[1]
The new paper by Kadia and colleagues asks a very practical question: for older adults, or for people not fit enough for full-intensity chemo, can we do better than the usual lower-intensity approach without launching them straight into the medical equivalent of being hit by a bus? Their answer looks pretty interesting.[2]
A smarter circuit, not a punishment workout
The regimen in this phase II study is a bit of a pharmacology group project, but the logic is clean. It used cladribine plus low-dose cytarabine plus venetoclax, alternating with azacitidine plus venetoclax, in 190 people with newly diagnosed AML. Median age was 68, and most had adverse-risk disease, which is not exactly the easy setting.[2]
Quick translation:
Venetoclaxblocks BCL-2, a protein leukemia cells use like a panic room to avoid cell death.[3]Azacitidinechanges gene regulation in leukemia cells and has become a backbone of lower-intensity AML therapy.[4]Cytarabineis an old-school chemotherapy staple.Cladribineadds another hit to leukemia cells, including cells that can be stubbornly hard to eradicate.[5]
Instead of one giant blast of intensive chemotherapy, this approach alternates lower-intensity combinations. Think less "boot camp run by an ex-marine with unresolved issues," more "carefully programmed interval training that still leaves the patient standing."
The part where the numbers raise an eyebrow
The headline results are hard to ignore. Overall, 84% of patients achieved complete remission or complete remission with incomplete count recovery, and 75% reached MRD-negative remission - meaning even highly sensitive testing could not find leftover disease. Early mortality was low: 1% at 4 weeks and 3% at 8 weeks. Median overall survival was 52 months, and 44% of responders went on to stem cell transplant.[2]
For older or medically unfit AML patients, those are not casual numbers.
This matters because venetoclax-based lower-intensity therapy already changed the standard of care years ago, especially for patients who are not candidates for classic intensive induction.[6] Reviews and meta-analyses over the past few years have consistently shown that venetoclax combinations beat the older "gentle" options that were, to be blunt, often gentle mainly toward the leukemia.[3,7,8]
What Kadia's group seems to be doing here is tuning that venetoclax era recipe. Their earlier 60-patient phase II study already looked strong, with a 93% CR/CRi rate and 84% MRD negativity among responders.[5] This newer, larger report suggests the signal did not evaporate when more patients showed up, which in oncology is always nice. Science has a long tradition of becoming less impressive the moment you invite extra people.
Why this is actually a big deal
Older adults with AML often face an ugly tradeoff. Intensive chemo can be too toxic. Lower-intensity therapy can be safer, but the disease is still aggressive and relapse is still very much a thing. Venetoclax helped shift that balance, yet resistance, prolonged low blood counts, and infection risk remain real problems.[3,8,9]
So this study is interesting for two reasons.
First, it suggests you may be able to get deep remissions with relatively low early death rates even in a high-risk population. That is the sort of result that changes clinic conversations from "How much treatment can this person survive?" to "How far can we realistically push for remission and maybe transplant?" Second, nearly half of responders made it to transplant, which means this regimen may work not just as disease control, but as a bridge to something more durable.[2]
If these outcomes hold up in broader settings, the real-world impact could be substantial. More people might reach remission without the full trauma of intensive induction. More patients might arrive at transplant in better shape. And some patients who once would have been treated with modest expectations might get a much longer runway.
That said, nobody should spike the football yet. This was a phase II study, not a head-to-head randomized trial against standard azacitidine-venetoclax. Single-center expertise matters. AML biology is wildly heterogeneous. And venetoclax resistance remains one of those recurring plot twists cancer biology keeps using because apparently the writers are out of ideas.[3,9]
Still, this is the kind of study that makes hematologists lean forward a little.
References
- Acute myeloid leukemia. Wikipedia. https://en.wikipedia.org/wiki/Acute_myeloid_leukemia
- Kadia TM, Bataller A, Bazinet A, et al. Cladribine With Low-Dose Cytarabine and Venetoclax Alternating With Azacitidine and Venetoclax for Newly Diagnosed Acute Myeloid Leukemia. Am J Hematol. 2025. doi:10.1002/ajh.70328
- Shimony S, Rozental A, Bewersdorf JP, et al. Investigational venetoclax combination therapy in acute myeloid leukemia - a systematic review and meta-analysis. Haematologica. 2022;107(12):2955-2960. doi:10.3324/haematol.2022.281453
- Ucciero A, Pagnoni F, Scotti L, et al. Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies. Cancers (Basel). 2023;15(18):4618. doi:10.3390/cancers15184618. PMCID: PMC10526951
- Kadia TM, Reville PK, Wang X, et al. Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. J Clin Oncol. 2022;40(33):3848-3857. doi:10.1200/JCO.21.02823
- Short NJ, Kantarjian H. Choosing between intensive and less intensive front-line treatment approaches for older patients with newly diagnosed acute myeloid leukaemia. Lancet Haematol. 2022;9(7):e535-e545. doi:10.1016/S2352-3026(22)00167-3
- Kantarjian H, Kadia T, DiNardo C, et al. Contemporary Management of Acute Myeloid Leukemia: A Review. JAMA Oncol. 2024;10(10):1417-1425. doi:10.1001/jamaoncol.2024.2662
- Nwosu GO, Ross DM, Powell JA, Pitson SM. Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia. Cell Death Dis. 2024;15:413. doi:10.1038/s41419-024-06810-7
- Chakravarthy S, Pulsoni A, Crispino JD, et al. Venetoclax resistance in acute myeloid leukaemia - Clinical and biological insights. Br J Haematol. 2024;204(4):1146-1158. doi:10.1111/bjh.19314
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.