Acute Myeloid Leukemia 2025 – �from Diagnosis to Remission and Transplantation or Maintenance

Richard A Larson, MD

University of Chicago

Agenda

• The journey (courtesy of Dr. Laura Michaelis)
• Nomenclature and diagnosis
• Heterogeneity and targets
• Remission Induction – fit vs frail
• Time from diagnosis to treatment
• FLT3-mutant AML
• MENIN inhibitors
• Post-remission maintenance therapy

​

2

5-year Relative Survival: 30.5%

Newly Diagnosed Acute Myeloid Leukemia

CR Rates: 55%-85%

Primary Induction Failure: 20-25%

Relapse: 50% of patients under 60 years

The syndrome of AML and MDS

International Consensus Classification (ICC) of AML

^a Bone marrow or peripheral blood blast count of ≥10% required, except for AML with t(9;22)(q34.1;q11.2); BCR::ABL1.

^b Variant rearrangements involving RARA, KMT2A, or MECOM should be recorded accordingly.

^c AML with in-frame mutation in the bZIP domain of the CEBPA gene, either monoallelic or biallelic.

^d The presence of a pathogenic somatic TP53 mutation (at a variant allele fraction of at least 10%, with or without loss of the wild-type TP53 allele) defines the entity AML with mutated TP53.

^e Cytogenetic abnormalities sufficient for the diagnosis of AML with MDS-related cytogenetic abnormalities and the absence of other AML-defining disease categories.

o Complex karyotype: ≥3 unrelated chromosome abnormalities in the absence of other class-defining recurring genetic abnormalities.

o Unbalanced clonal abnormalities: del(5q)/t(5q)/add(5q); -7/del(7q); +8; del(12p)/t(12p)/(add(12p); i(17q), -17/add(17p) or del(17p); del(20q); and/or idic(X)(q13)

Döhner et al.

BLOOD 2022

Mutational Profiling in AML

Patel et al. NEJM 2012

2022 ELN risk categorization

Note:

• The ELN AML risk classification has been developed based on data from intensively treated patients and may need modifications for patients receiving less intensive therapies
• Initial risk assignment may change during the treatment course based on the results from MRD analyses

2022 ELN risk categorization

Note:

• The ELN AML risk classification has been developed based on data from intensively treated patients and may need modifications for patients receiving less intensive therapies
• Initial risk assignment may change during the treatment course based on the results from MRD analyses

Döhner et al.

BLOOD 2022

Remission Induction treatment of AML��a) Intensive��b) Less intensive

Definition of Complete Remission

• Neutrophils >1000/ul
• No peripheral AML blasts
• Platelets >100,000/ul
• RBC transfusion independent
• Bone marrow adequate cellularity
• Bone marrow blasts <5%
• (cytogenetically normal; disappearance of pretreatment chromosomal abnormalities or driver mutations)
• CRi = incomplete recovery of ANC or platelets
• MLFS (marrow leukemia-free status)
• Measureable residual disease (MRD) positive/negative

​

​

​

Conventional AML Treatment (pre-2020)

Eligible for intensive induction therapy

Ineligible for intensive induction therapy

Cytarabine (D1-7)

+

Anthracycline (D1-3)

New AML

Azacitidine* or decitabine*

Best supportive care

Favorable Risk: High-dose Cytarabine x 2-4 cycles

Intermediate Risk:

HiDAC or Allo-SCT

Adverse Risk:

Allo-SCT

* Hypomethylating agent

Impact of Time from Diagnosis to Treatment (TDT) on Outcomes of Adults with AML Treated with HMA and Venetoclax:

A US-Based, Multi-Center, Real-World, Retrospective Analysis from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)��

Samuel J. Yates,¹ Julian J Weiss,² Abigail Sneider,¹ Emily Geramita,³ Guru Subramanian Guru Murthy,⁴ Talha Badar,⁵ Annie Im,³ Chenyu Lin,² Wei Cheng,⁶ Eric S. Winer,⁷ Yasmin Abaza,⁸ Mark R. Litzow,⁵ Ehab L. Atallah,⁶ Alok Swaroop,⁸ Anand Ashwin Patel,¹ and Rory M. Shallis⁹

¹Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL; 2. Duke University Medical Center, Durham, NC; 3. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA; 4. Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 5. Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL; 6. Department of Biostatistics, Yale School of Public Health, New Haven, CT; 7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 8. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 9. Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT

Yates et al. Blood 2024; ASH abstract #447.

• Retrospective cohort study of adult patients ≥18 years
• with newly diagnosed AML
• treated with HMA + Venetoclax
• at 8 participating US academic centers with AML expertise.

​

• TDT: number of days between date of diagnosis and date of initiation of HMA + Venetoclax.

​

• Covariates:
• Disease Biology: ELN 2022 Risk, ELN 2024 Less-intensive Risk Score¹
• Patient Fitness: HCT-CI, ECOG PS
• Severity of presentation +/- cytoreduction

Methods: study design and key covariates

¹Dohner et al. Blood 2024 November.

Results: time from diagnosis to treatment�

• Longer TDT associated with improved OS in univariate (HR: 0.99, 95% CI: 0.98-0.99; p = 0.01) and multivariable analyses (HR: 0.98; 95% CI: 0.97-0.99; p=0.02).

​

• Longer TDT, IDH 1/2 mutations, AlloHCT in CR1 were the only factors associated with improved OS

​

• ECOG PS of 2 or 3-4, when compared to ECOG PS=0 (p=0.04 and 0.0002, respectively), therapy-related AML (p=0.004), secondary AML (0.009), were associated with worse OS.

​

• ELN 2024 Less-intensive risk, FLT3-ITD or TKD, RAS mutations, or NPM1 mutation status did not impact OS.

​

P=0.24

P=0.01

Median TDT: 9 days (IQR: 5-17)

Longer TDT is associated with improved OS (HR=0.98; p=0.02)

VIALE-A: Azacitidine + Venetoclax

• Multicenter, double-blind, placebo-controlled, randomized phase III trial for “unfit” patients

• Primary endpoints: OS, rate of CR + CRi
• Other endpoints: EFS, OS by molecular subtype, QoL, transfusion independence

Adults with previously untreated AML ineligible for standard cytarabine/anthracycline

due to age (≥ 75 yrs),

ECOG PS 2-3,

or comorbidities.

No hypomethylating agent for antecedent hematologic disorder. (N = 431)

Azacitidine 75 mg /m² SC or IV QD

for D1-7 + Venetoclax 400 mg PO QD

on 28-day cycles (n = 286)

Azacitidine 75 mg /m² SC or IV QD

for D1-7 + Placebo PO QD on 28-day cycles (n = 145)

Until progression, intolerance, or withdrawal

DiNardo. N Engl J Med. 2020;383:617.

VIALE-A: Azacitidine + Venetoclax

DiNardo. N Engl J Med. 2020; 383: 617.

Median time to response: 1.3 months. No differences in quality of life

Long-term follow-up of VIALE-A

Pratz et al. Long-Term Follow-up of the Phase 3 Viale-A Clinical Trial of Ven Plus Aza for Patients with Untreated AML Ineligible for Intensive Chemotherapy. ASH 2022

18

Randomized Clinical Trial for newly diagnosed patients pts with AML ineligible for intensive chemotherapy: Aza/ven vs aza/placebo

Median OS: 14.7 mos vs 9.6 mos

Pts with IDH2 mutation

Three prognostic risk signatures were derived to indicate higher,

intermediate, and lower benefit from treatment with Ven+Aza

Abbreviations: Aza, azacitidine; OS, overall survival; Ven, venetoclax; WT, wild-type

TP53^WT, No FLT3-ITD, K/NRAS^WT

TP53^WT and FLT3-ITD or K/NRAS mutated

TP53 mutated

Patients at Risk

Time (months)

Abbreviations: Aza, azacitidine; OS, overall survival; Ven, venetoclax; WT, wild-type

Dohner H et al. ASH 2022, abstract #602.

Dohner et al. Blood 2024 Nov; 144:2169

​

​

ELN risk classification for patients receiving less-intensive therapies (ELN 2024 Less-Intensive)

Dohner et al. Blood 2024 Nov; 144:2169

Overview of median survival times by genetic marker (ELN)

Dohner et al. Blood 2024 Nov; 144:2169

Measureable residual disease (MRD)

_{Overall survival (OS) according to response status after course 1.}

​

_{(A) All patients.}

Freeman et al. Measurable residual disease at induction redefines partial response in AML and stratifies outcomes in patients at standard risk without NPM1 mutations. JCO  2018; 36: 1486

FLT3-mutant AML

Published NEJM. June 23, 2017

FDA Approval: “Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.”

​

EMA Approval: “Midostaurin is indicated in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by midostaurin single-agent maintenance therapy, for adult patients with newly diagnosed AML who are FLT3-mutation–positive.”

​

RATIFY trial (CALGB 10603)�

R

A

N

D

O

M

I

Z

E

​

DNR

ARA-C

MIDO

DNR

ARA-C

PLACEBO

HiDAC

MIDO

HiDAC

PLACEBO

MIDO

MAINTENANCE

12 months

PLACEBO

MAINTENANCE

12 months

Stratify*

FLT3

ITD

or

TKD

FLT3 WILD TYPE not eligible for enrollment

X 4

X 4

CR

CR

Study drug is given on Days 8-21 after each course

of chemotherapy, and Days 1-28 of each 28 day

Maintenance cycle.

PRE-REGISTER

FLT3 SCREEN

• Stratification: TKD; ITD with allelic ratio <0.7; ITD with allelic ratio >=0.7

Stone RM et al. NEJM. June 23, 2017

Kaplan Meier Curve: Overall Survival�(Primary ITT Analysis)

• 5 year survival rate: MIDO 51% vs PBO 43%
• Median follow-up time for survivors: 56.7 months (range: 0.1 - 79.2)
• 22% reduction in risk of death with Midostaurin + chemotherapy

NE: not estimable

* controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)

Stone RM et al. NEJM. June 23, 2017

Richard M Stone, MD¹, Jun Yin^2*, Sumithra J Mandrekar, PhD^3*, Axel Benner^4*, Maral Saadati^4*, Ilene Galinsky, MSN, ANP-C¹, Ben L. Sanford, MS^5*, Rebecca Teske^6*, Susan M. Geyer, PhD⁷, Thomas Prior, PhD^8*, Sergio Amadori, MD⁹, Frederick R. Appelbaum, MD¹⁰, Joseph Brandwein, MD¹¹, Konstanze Döhner, MD¹², Gerhard Ehninger, M.D.¹³, Arnold Ganser, MD¹⁴, Rebecca B. Klisovic, MD¹⁵, Jürgen Krauter^16*, Guido Marcucci, MD¹⁷, Bruno Medeiros, MD¹⁸, Dietger W. Niederwieser, MD¹⁹, Miguel A. Sanz, MD, PhD²⁰, Richard F Schlenk^21*, Hubert Serve, MD²², Jorge Sierra, MD²³, Martin S. Tallman, MD²⁴, Andrew H. Wei, MBBS, PhD²⁵, Theo J.M. de Witte, MD, PhD²⁶, Christian Thiede, MD²⁷, Hartmut Döhner, MD¹² and Richard A. Larson, MD^28��¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; ²HL Moffitt Cancer Center, Tampa, FL; ³Mayo Clinic, Alliance Statistics and Data Management Center, Rochester, MN; ⁴Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany; ⁵Duke Cancer Institute, Durham, NC; ⁶Mayo Clinic, Rochester, MN; ⁷Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN; ⁸Johnson and Johnson, princeton, NJ; ⁹Tor Vergata Polyclinic Hospital Rome, Rome, ITA; ¹⁰Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA; ¹¹Department of Medicine, University of Alberta, Edmonton, AB, Canada; ¹²Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany; ¹³Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, DEU; ¹⁴Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; ¹⁵University Hospitals Seidman Cancer Center, Cleveland, OH; ¹⁶Department of Hematology and Oncology, Städtisches Klinikum Braunschweig, Braunschweig, Germany; ¹⁷Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA; ¹⁸AbbVie, San Francisco; ¹⁹Universitaetsklinikum Leipzig Aor, Leipzig, Germany; ²⁰Hospital Universitario y Politécnico La Fe, Valencia, Spain; ²¹Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany; ²²Goethe-University Frankfurt, University Hospital, Department of Medicine II - Hematology and Oncology, Frankfurt am Main, Germany; ²³Hospital Santa Creu Sant Pau, Barcelona, ESP; ²⁴Memorial Sloan-Kettering Cancer Center, New York, NY,  ²⁵Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; ²⁶Department of Tumor Immunology, Radboud Institute of Molecular Life Sciences, Radboud university medical centre, Nijmegen, NLD; ²⁷University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany; ²⁸Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL

10-year follow up of C10603/RATIFY: midostaurin vs placebo plus intensive chemotherapy for newly diagnosed FLT3-mutant

acute myeloid leukemia (AML) patients 18-59 years old

Stone RM et al. Blood 2024; abstract

Overall survival by treatment arm

Stratified log-rank

p=0.0488

Favors Midostaurin

Favors Placebo

Stone RM et al. Blood 2024; abstract

OS for those transplanted in CR1 vs not

OS censored at CR1 transplant by rx

OS for those transplanted

in CR1 by treatment arm

p=<0.0001*

p=0.2961*

p=0.0640*

*Stratified long-rank test

Yes

No

Mido

Placebo

Stone RM et al. Blood 2024; abstract

Stratified log-rank p=0.6788

Stratified log-rank p=0.0626

Disease-free survival with or without maintenance (10-year follow up)

Midostaurin

Midostaurin

Placebo

Placebo

DFS of patients who started maintenance

DFS of patients who completed maintenance

Stone RM et al. Blood 2024; abstract

10-year EFS and OS according to mutations by treatment arm

Patients whose FLT3-mutant AML harbored NPM1 mutations or ‘secondary AML’ mutations benefited from midostaurin

Favors Mido

Favors Placebo

Favors Mido

Favors Placebo

EFS -- Midostaurin vs Placebo

OS -- Midostaurin vs Placebo

Stone RM et al. Blood 2024; abstract

Other FLT3 inhibitors

QuANTUM-First: Phase 3 trial of quizartinib vs placebo �with frontline intensive chemotherapy for FLT3-ITD AML

• Newly diagnosed AML with FLT3-ITD (n=539)
• Ages 18-75
• After a median follow-up of 39 months, the median Overall Survival was 32 months for the quizartinib arm vs 15 months for the placebo arm.
• 22% reduction in risk of death compared to standard chemotherapy alone (HR=0.78; 2-sided P=0.03)
• No significant differences in CR rate or Event-free Survival.

Harry P Erba, et al, on behalf of the QuANTUM-First Study Group. Lancet 2023

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-ITD-positive acute myeloid leukaemia (QuANTUM-First): a randomized, double-blind, placebo-controlled, phase 3 trial� �

Harry P Erba et al, on behalf

of the QuANTUM-First Study Group.

Lancet 2023

Overall Survival

Relapse-free Survival

Aza+Ven+Gilteritinib in FLT3-mutated AML

• Relapsed/refractory FLT3-mutated* AML or high-risk MDS or CMML

or

• Newly diagnosed FLT3-mutated* AML unfit for intensive chemotherapy

Azacitidine

75 mg/m² IV/SC on D1-7

​

Venetoclax^#

D1-28 (bone marrow on D14)^%

​

Gilteritinib

80-120 mg on D1-28

Azacitidine

75 mg/m² IV/SC on D1-5

​

Venetoclax

400mg on D1-7

​

Gilteritinib

80-120 mg on D1-28

Induction

Consolidation

(up to 24 cycles)

* FLT3-ITD or FLT3 D835 mutations allowed

• Primary endpoints: MTD of gilteritinib in combination (phase I), CR/CRi rate (phase II)
• Secondary endpoints: CR rate, MRD negativity rate, duration of response, OS, safety

^# Venetoclax ramp-up during cycle 1:

100mg on D1, 200mg on D2, 400mg on D3+

^% If <5% blasts or insufficient on C1D14, venetoclax held (both cohorts) and gilteritinib held (frontline only)

Short NJ et al. J Clin Oncol 2024; 42:1499

Short NJ et al. 2024 ASH abstract 220

Aza+Ven+Gilteritinib in FLT3-mutated AML: Responses

* PR in 1 patient with extramedullary-only disease (assessed by PET scan)

Short NJ et al. 2024 ASH abstract #220;

Short NJ et al. J Clin Oncol 2024 May; 42:1499

*Best MRD response by PCR was undetectable in 27/30 (90%).

Aza+Ven+Gilteritinib in FLT3-mutated AML:

RFS and OS in Frontline Cohort (n=30)

Median follow-up: 19.3 months (range, 2-32 months)

Short NJ et al. J Clin Oncol 2024 May; 42:1499

Short NJ et al. 2024 ASH abstract #220

Majority of relapses were driven by FLT3-wild type disease.

Gilteritinib results in higher remission and transplant rates than midostaurin but does not increase the post-induction MRD negative rate: Results from Precog 0905 study in newly diagnosed FLT3 mutant AML��

• 180 patients 18-70 years with FLT3-ITD or TKD receiving 7+3 (cytarabine + daunorubicin) followed by HiDAC consolidation
• Gilteritinib 120 mg daily vs midostaurin 50 mg BID; starting on Day 8 for 14 days.

​

​

38

Salina Luger et al. 2024 ASH abstract #221

AUGMENT-101 phase 2 study of Revumenib in all patients �with relapsed or refractory KMT2A acute leukemia

• The interaction of Menin with KMT2A fusion proteins is a driver of leukemogenesis. (~10% of acute leukemias)
• 116 patients (0.6 – 75 years): 95 AML, 21 ALL/MPAL; 51% had prior alloHCT.
• Revumenib 163 mg PO every 12 hours (95 mg/m2 if <40 kg) with a strong CYP3A4 inhibitor azole.
• 22/97 (23%) had CR+CRh; 61% became MRD negative
• Median duration of remission of 6.4 months (95% CI,1.9-NR)
• CRc (CR+CRh+CRi) rate was 42%
• Now approved for R/R KMT2A rearranged acute leukemia; pending approval for NPM1 mutant AML.

​

​

39

Ibrahim Aldoss et al. 2024 ASH abstract #211.

Post-remission Maintenance

Why has maintenance therapy not been �clinically beneficial in AML?

• Treatment fatigue; time in clinic
• Dropouts for adverse events
• Only parenteral drugs were available
• Relatively impotent anti-leukemia agents
• Myelosuppressive

Transfusions

Infections

Bleeding

• Conclusion: Maintenance therapy delays but does not eliminate relapses

41

QUASAR trial

CC-486 Maintenance for AML in CR1 (QUASAR trial)

43

Wei et al.

NEJM 2020;

383:2526-2537

• > 55 years;
• CR1;
• Within 3 months of CR;
• 0, 1, or 2 consolidations;
• Not eligible for transplantation

​

Adapted from

Fleischmann et

al. Cancer 2021;

13: 5722

Daver et al, Blood Cancer J, 2020

rlarson@uchicago.edu