DANIEL A. POLLYEA, MD MS

PROFESSOR OF MEDICINE

INTERIM CHIEF, DIVISION OF HEMATOLOGY

UNIVERSITY OF COLORADO SCHOOL OF MEDICINE

Treatment Options for Newly Diagnosed AML Patients

22^nd Annual Indy Hematology Review

March 8, 2025

Artwork: Phi Regions by Clark Richert

Denver Art Museum

Descriptive Case

• 35 year-old female with history of appendicitis s/p appendectomy
• Diagnosed with CD33+ AML with inv16 and mutation in WT1
• Performance status = 0

• Recommendation
• 7+3 with gemtuzumab to CR1
• Consolidate with gemtuzumab-based regimen
• Monitor without transplant in CR1

• Rationale
• Intensive chemotherapy is toxic and risky
• But this patient can theoretically tolerate it, and it offers potential for cure without a transplant

Basis for Intensive Chemotherapy with GO for CBF AML

Hills et al, Lancet Oncology 2014

Justification for Adding GO to Non CBF Favorable Risk AML?

No difference in OS

Reduced incidence in relapse

Dohner et al, Lancet Haematology 2023

New! Quizartinib in First Line FLT3+ AML

• Give midostaurin for FLT3 TKD
• OK to also use for FLT3 ITD if preferred or available based on Stone et al, NEJM 2017

Erba et al, Lancet 2023

CPX-351 in Older Patients With Newly Diagnosed AML: Updated OS (5-Yr Follow Up)

Lancet et al. Lancet Haematol 2021

Median Survival, Mo (95% CI) �9.33 (6.37-11.86)�5.95 (4.99-7.75)

CPX-351�7 + 3

HR: 0.70 (0.55-0.91)

My Preference is Venetoclax + Azacitidine

4-Gene Signature (mPRS)

Dohner…Pollyea, Blood 2024

Intensive Chemotherapy Vs Venetoclax/Decitabine

Event-Free Survival

Overall Survival

Lu et al, ASH 2024

Descriptive Case

• 83 year old woman with history of stroke, hepatitis C, hypertension and recent pneumonia
• Diagnosed with AML with a normal karyotype and IDH1 R132C mutation
• Performance status = 3

• Recommendation
• Dealer’s choice!
• Ven/aza or ivosidenib/aza

• Rationale
• Both better than aza alone
• No head to head comparison

VIALE-A: Long-Term (43 Months) Overall Survival

Pratz et al, AJH 2024

VIALE-A Responses

Median Time to First CR/CRi

1.3 months (range, 0.6–19.7) for venetoclax-azacitidine vs. 2.8 months (range, 0.8–26.8) for placebo-azacitidine

DiNardo et al, NEJM 2022

Venetoclax + AZA Efficacy in Patients With IDH Mutations

IDH1/2 Mutations

mOS: 24.5 mo vs. 6.2 mo

IDH1 Mutations

mOS: 15.2 mo vs. 2.2 mo

Pollyea et al, Clin Cancer Research 2022

AGILE trial: Study Design

Key Eligibility Criteria

• ≥ 18 yrs
• Previously untreated IDH1-mutated AML
• No previous IDH1 inhibitor or HMA for MDS
• ECOG PS 0-2
• Ineligible for intensive chemotherapy

​

Stratified by:

• Geographic Region
• De-novo status

Placebo PO QD +

AZA 75mg/m² SC or IV x 7 days in

28-day cycles

(N=74)

Ivosidenib 500mg PO QD +

AZA 75mg/m² SC or IV x 7 days in

28-day cycles

(N=72)

R

(1:1)

Primary Endpoint:

• EFS

​

Secondary Endpoints:

• CR
• CR + CRh
• Objective Response
• OS
• Safety
• Health-related quality of life

All the patients were to be treated for a minimum of 6 cycles unless a relapse, disease progression, unacceptable toxic effects, or death occurred.

Montesinos et al, NEJM 2022

Ivo/Aza Responses

Median time to CR

4.3 mos (range, 1.7 - 9.2) with ivosidenib + AZA vs. 3.8 mos (range, 1.9 - 8.5) with

placebo + AZA

Montesinos et al, NEJM 2022

AGILE trial: OS (Long-Term Follow Up)

mOS

29.3 mo (IVO + AZA) vs 7.9 mo (PBO + AZA)

HR 0.42 [0.27, 0.65]; p<0.0001)

Montesinos et al, NEJM 2022

IDH2 and FLT3 Inhibitors Can’t Beat Aza in Newly Diagnosed Unfit Patients

Enasidenib

Gilteritinib

DiNardo et al, Lancet Oncology 2021

Wang et al, Blood 2022

Alpenglow

Maroon Bells

Western Colorado