Amongst match sufferers with acute myeloid leukemia, the mix of azacitidine plus Venclexta (venetoclax) was related to a considerably improved event-free survival (EFS) in contrast with intensive induction chemotherapy, research outcomes have proven.
Outcomes from the section 2 PARADIGM trial have been offered on the 2025 ASH Annual Assembly. Within the trial, sufferers receiving azacitidine/Venclexta had a 39% discount in threat of progressive illness, persistent illness prompting remedy change, relapse, hospice or loss of life in contrast with these receiving typical intensive induction chemotherapy. Sufferers additionally had improved high quality of life (QOL) with azacitidine/Venclexta.
Induction chemotherapy with cytarabine plus anthracycline has been the usual of care for many years however just isn’t tolerable in older or much less match sufferers and might nonetheless yield suboptimal long-term outcomes in fitter sufferers. The hypomethylating agent (HMA) azacitidine plus the BCL2 inhibitor Venclexta was established because the routine of alternative for sufferers who weren’t eligible for induction chemotherapy primarily based on the section 3 VIALE-A trial, however no potential randomized trials have proven a bonus with direct comparability.
Glossary
Occasion-Free Survival (EFS): The size of time after therapy throughout which a affected person has no main issues associated to the most cancers—such because the illness coming again, getting worse, or needing new therapy.
Mucositis: Soreness and irritation of the liner of the mouth or digestive tract. It will possibly trigger mouth sores, ache, and problem consuming, and is a typical aspect impact of some most cancers remedies.
Full Response (CR): When all indicators of most cancers disappear on checks after therapy. It doesn’t all the time imply the most cancers is cured, but it surely means medical doctors can’t detect it.
CR with Partial Hematologic Restoration (CRh): A kind of full response the place the most cancers is gone, however blood counts—particularly platelets and sure infection-fighting cells—have solely partially recovered.
CR with Incomplete Hematologic Restoration (CRi): A kind of full response the place the most cancers is gone, however some blood counts are nonetheless beneath regular. Sufferers should want monitoring and help whereas blood ranges enhance.
Hematopoietic Cell Transplant: A process that replaces broken or diseased blood-forming cells with wholesome ones. The cells could come from the affected person (autologous transplant) or from a donor (allogeneic transplant). This helps rebuild the blood and immune system after intensive therapy.
“Intensive induction chemotherapy comes with substantial burden and price,” mentioned Dr. Amir Fathi, program director of the Heart for Leukemia on the Massachusetts Normal Hospital Most cancers Heart, in a press briefing. “It’s related to vital morbidity, together with deep and extended marrow suppression, weeks’ lengthy hospitalizations, frequent infections and bleeding problems, mucositis, malnutrition, deleterious psychosocial results, and an elevated threat of cardiac harm and secondary malignancies.”
PARADIGM Trial Design
The open-label, multicenter, investigator-initiated PARADIGM medical trial randomly assigned 172 sufferers with beforehand untreated AML at 9 facilities in america to obtain induction chemotherapy or azacitidine/Venclexta. Sufferers have been excluded in the event that they have been beneath 60 years outdated and had NPM1 mutations, or if that they had core binding issue fusions or FLT3 mutations.
The median age was 64 years within the experimental arm and 65 years within the comparator arm, and 55% versus 60% have been male in these respective arms. Seventy-two p.c had adversarial threat with 15% having intermediate and 12% having favorable threat standing. The arms have been balanced for threat standing in addition to TP53, NPM1 and IDH1/IDH2 mutations.
The induction chemotherapy used was a 7+3 routine (cytarabine plus an anthracycline) in 54% with the remaining 46% receiving liposomal daunorubicin plus cytarabine (CPX351).
Efficacy Outcomes in PARADIGM
Outcomes have been reported as of July 25, 2025. The median variety of therapy cycles was 4 with azacitidine/Venclexta versus two with induction chemotherapy.
The general response fee was 88% with azacitidine/Venclexta versus 62% with the comparator. The speed of full response (CR), CR with partial hematologic restoration and CR with incomplete hematologic restoration was 81% versus 55%, respectively. Though these have been statistically vital, the CR charges weren’t considerably totally different (59% versus 50%). Each arms have been allowed to proceed to hematopoietic cell transplant (HCT); 52 sufferers (61%) acquired HCT after azacitidine/Venclexta versus 34 sufferers (40%) after induction chemotherapy. HCT had a big protecting impact for EFS, however after adjustment in univariate and multivariate fashions, azacitidine/Venclexta nonetheless confirmed protecting impact on EFS.
The median EFS was 14.6 months for azacitidine/Venclexta versus 6.2 months for induction chemotherapy, and the one-year fee of EFS was 53% versus 39%, respectively.
Fathi said that total survival enchancment was not statistically vital, however this was a troublesome finish level to interpret in contrast with EFS as a result of sufferers may benefit from receiving the trial regimens as subsequent remedy. “Even when we have been to do a bigger section 3 research, total survival, in my view goes to be fraught with problem due to this in depth crossover in each instructions, however primarily from intensive remedy to azacitidine/[Venclexta],” he mentioned.
Tolerability, QOL and Hospitalization
When it comes to unwanted effects, there have been related charges of grade 3 (extreme) or 4 (life-threatening) treatment-related unwanted effects, which have been primarily hematologic. Grade 3 or 4 lung infections have been reported in 12% within the experimental arm versus 15% within the comparator arm, and grade 3/4 sepsis occurred in 7% versus 11%, respectively. There was no 30- and 60-day mortality with azacitidine/Venclexta, whereas 30-day mortality was 3.5% and 60-day mortality was 4.7% with induction chemotherapy.
High quality of life was additionally assessed, with sufferers within the experimental arm reporting considerably higher QOL within the first two weeks. Symptom burden and melancholy signs have been additionally considerably improved.
Intensive care unit care throughout index hospitalization was not wanted in any sufferers receiving azacitidine/Venclexta in contrast with 9.8% with induction chemotherapy. Additionally they had fewer days of inpatient index hospitalization versus these receiving induction chemotherapy (15 versus 36) and fewer days hospitalized within the first six months (41 versus 58).
Fathi famous that these with favorable threat, similar to CEBPA-associated AML and people with targetable mutations, have been excluded to keep up equipoise and characterize the affected person inhabitants who would seemingly obtain HCT as consolidation. “This was actually a research geared toward sufferers who have been transplant eligible for consolidation, and in that affected person inhabitants, it met its main finish level,” he mentioned.
“We subsequently imagine these knowledge help the usage of azacitidine and [Venclexta] in functionally match sufferers eligible for transplant with intermediate or adversarial threat, FLT3 wild-type AML,” Fathi concluded.
Reference
1. “Outcomes from paradigm – a section 2 randomized multi-center research evaluating azacitidine and venetoclax to traditional induction chemotherapy for newly identified match adults with acute myeloid leukemia,” by Dr. Amir Fathi et al., Blood.
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