Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

17 days ago

Review • Journal • IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD33 (CD33 Molecule) • IL3RA (Interleukin 3 Receptor Subunit Alpha)

Venclexta (venetoclax) • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • Tibsovo (ivosidenib) • Mylotarg (gemtuzumab ozogamicin) • Vyxeos (cytarabine/daunorubicin liposomal formulation) • Revuforj (revumenib) • Idhifa (enasidenib) • Inqovi (decitabine/cedazuridine) • Rezlidhia (olutasidenib) • Onureg (azacitidine oral) • Daurismo (glasdegib)

23d

A Study of Lenalidomide and CC-486 With Radiation Therapy in Patients With Plasmacytoma (clinicaltrials.gov)

P2, N=21, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

23 days ago

Trial completion date • Trial primary completion date • Combination therapy

lenalidomide • Onureg (azacitidine oral)

REMAIN1: Oral Azacitidine in Transplant-Eligible Patients With Acute Myeloid Leukemia (AML) Suffering From Health-Inequality (clinicaltrials.gov)

P4, N=12, Recruiting, Virginia Commonwealth University | Not yet recruiting --> Recruiting

1 month ago

Enrollment open

Onureg (azacitidine oral)

2ms

Results from a Clinical Study of the All-Oral Regimen of CC-486 (Oral Azacitidine) and Venetoclax for Newly Diagnosed and Relapsed and Refractory Acute Myeloid Leukemia (ASH 2024)

The MTD of CC-486 in combination with ven was previously reported as 300mg QD d1-14 in relapsed/refractory (R/R) AML (Amaya et al. High response rates have been seen in the newly diagnosed cohort with 7/7 (100%) of the patients achieving a CR/CRi, including 3/3 who harbor a TP53 mutation. Final results of the R/R cohort, as well as a larger sample size of the ND subjects, with genomic annotation, as well as translational studies exploring mechanistic differences and similarities with this all-oral regimen and conventional aza/ven, will be presented.

2 months ago

Clinical

TP53 (Tumor protein P53)

TP53 mutation

Venclexta (venetoclax) • Onureg (azacitidine oral)

2ms

A Post-Marketing Surveillance Study to Assess the Safety of Oral Azacitidine Maintenance Therapy in Korean Patients With Acute Myeloid Leukemia (clinicaltrials.gov)

P=N/A, N=154, Recruiting, Bristol-Myers Squibb | Trial completion date: May 2029 --> Jul 2027

2 months ago

Trial completion date

Onureg (azacitidine oral)

3ms

Oracle: Efficacy and Safety of Oral Azacitidine Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory AITL (clinicaltrials.gov)

P3, N=86, Active, not recruiting, The Lymphoma Academic Research Organisation | Trial completion date: Jun 2024 --> Dec 2024

3 months ago

Trial completion date

PD-1 (Programmed cell death 1) • BCL6 (B-cell CLL/lymphoma 6) • CXCL13 (Chemokine (C-X-C motif) ligand 13) • ICOS (Inducible T Cell Costimulator) • MME (Membrane Metalloendopeptidase)

PD-1 expression

gemcitabine • bendamustine • Istodax (romidepsin) • Onureg (azacitidine oral)

3ms

GS-US-546-5920: Study of Magrolimab Combinations in Participants With Myeloid Malignancies (clinicaltrials.gov)

P2, N=54, Completed, Gilead Sciences | Trial primary completion date: Oct 2023 --> Mar 2024

3 months ago

Trial primary completion date

Venclexta (venetoclax) • cytarabine • etoposide IV • mitoxantrone • magrolimab (ONO-7913) • Onureg (azacitidine oral)

3ms

An Efficacy and Safety Study of Oral Azacitidine (CC-486) as Maintenance Therapy in Chinese Participants With Acute Myeloid Leukemia in Complete Remission (clinicaltrials.gov)

P2, N=78, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

3 months ago

Enrollment closed

Onureg (azacitidine oral)

3ms

CC-486, Lenalidomide, and Obinutuzumab for the Treatment of Recurrent or Refractory CD20 Positive B-cell Lymphoma (clinicaltrials.gov)

P1, N=8, Active, not recruiting, Joseph Tuscano | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

3 months ago

Trial completion date • Trial primary completion date

CD20 (Membrane Spanning 4-Domains A1) • CD4 (CD4 Molecule)

lenalidomide • Gazyva (obinutuzumab) • Onureg (azacitidine oral)

3ms

A Study to Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Best Supportive Care as Maintenance Therapy in Japanese Participants With Acute Myeloid Leukemia (AML) in Complete Remission (clinicaltrials.gov)

P2, N=15, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

3 months ago

Enrollment closed

Onureg (azacitidine oral)

3ms

NCI-2021-13436: CC-486 and Nivolumab for the Treatment of Hodgkin Lymphoma Refractory to PD-1 Therapy or Relapsed (clinicaltrials.gov)

P1, N=33, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting

3 months ago

Enrollment closed

PD-L1 (Programmed death ligand 1)

Opdivo (nivolumab) • Onureg (azacitidine oral)

4ms

Maintenance Therapy in Acute Myeloid Leukemia. (PubMed, Am J Clin Oncol)

Hypomethylating agents like azacitidine and decitabine have shown promise in improving relapse-free and overall survival, particularly in older patients with AML ineligible for transplantation. Combination regimens involving azacitidine and venetoclax have demonstrated encouraging outcomes post-hematopoietic stem cell transplantation. Targeted therapies, particularly FLT3 inhibitors like midostaurin and quizartinib, have shown significant benefits in improving survival outcomes, especially in FLT3-mutated AML cases. Gilteritinib and sorafenib also exhibit the potential to reduce relapse rates post-transplant. Isocitrate dehydrogenase inhibitors, including ivosidenib and enasidenib, present novel options for postchemotherapy and posttransplantation maintenance...The approval of oral azacitidine represents a significant advancement, emphasizing the need for further investigation into personalized maintenance approaches. In conclusion, the evolving landscape of maintenance therapy and integrating targeted therapies in AML offers promising avenues for improving patient outcomes.

4 months ago

Journal • IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • WT1 (WT1 Transcription Factor)

FLT3 mutation

Venclexta (venetoclax) • sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • decitabine • Tibsovo (ivosidenib) • Idhifa (enasidenib) • Onureg (azacitidine oral)

4ms

QUAZAR AML-001: Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia (AML) in Complete Remission (clinicaltrials.gov)

P3, N=472, Completed, Celgene | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jun 2024

4 months ago

Trial completion • Trial completion date

Onureg (azacitidine oral)

4ms

RELION: Characteristics and Outcomes of Acute Myeloid Leukemia (AML) Patients Treated With Oral-Azacitidine Maintenance Therapy in France (clinicaltrials.gov)

P=N/A, N=112, Active, not recruiting, Bristol-Myers Squibb

4 months ago

New trial

Onureg (azacitidine oral)

6ms

REMAIN1: Oral Azacitidine in Transplant-Eligible Patients With Acute Myeloid Leukemia (AML) Suffering From Health-Inequality (clinicaltrials.gov)

P4, N=12, Not yet recruiting, Virginia Commonwealth University | Trial completion date: Oct 2028 --> Jan 2029 | Initiation date: Jun 2024 --> Sep 2024 | Trial primary completion date: Oct 2026 --> Jan 2027

6 months ago

Trial completion date • Trial initiation date • Trial primary completion date

Onureg (azacitidine oral)

6ms

Efficacy and Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma (clinicaltrials.gov)

P3, N=93, Active, not recruiting, Celgene | N=22 --> 93 | Trial completion date: Feb 2024 --> Mar 2026

6 months ago

Enrollment change • Trial completion date

PD-1 (Programmed cell death 1) • BCL6 (B-cell CLL/lymphoma 6) • CXCL13 (Chemokine (C-X-C motif) ligand 13) • ICOS (Inducible T Cell Costimulator) • MME (Membrane Metalloendopeptidase)

gemcitabine • Istodax (romidepsin) • Onureg (azacitidine oral)

7ms

AMLM22/D4: The International AML Platform Consortium (IAPC) trial – Combining Oral Azacitidine and Dendritic Cell Vaccination Vididencel in maintenance (CADENCE) (ACTRN12624000738527)

P2, N=140, Not yet recruiting, Australian Leukaemia and Lymphoma Group (ALLG)

7 months ago

New P2 trial

NPM1 (Nucleophosmin 1)

Onureg (azacitidine oral) • vididencel (DCP-001)

7ms

A Study Comparing Treatment Preference Between Oral Decitabine/Cedazuridine and Azacitidine in Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia (clinicaltrials.gov)

P3, N=13, Active, not recruiting, Otsuka Australia Pharmaceutical Pty Ltd | Recruiting --> Active, not recruiting | N=42 --> 13 | Trial primary completion date: Apr 2025 --> Jan 2025

7 months ago

Enrollment closed • Enrollment change • Trial primary completion date

Inqovi (decitabine/cedazuridine) • Onureg (azacitidine oral)

7ms

Evaluating in Vivo AZA Incorporation in Mononuclear Cells Following Vidaza or CC486 (clinicaltrials.gov)

P2, N=40, Completed, Kirby Institute | Active, not recruiting --> Completed | N=60 --> 40

7 months ago

Trial completion • Enrollment change

Onureg (azacitidine oral)

7ms

Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study. (PubMed, Lancet Haematol)

Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial.

7 months ago

Clinical • P3 data • Clinical Trial,Phase III • Journal • PD(L)-1 Biomarker • IO biomarker

PD-1 (Programmed cell death 1) • BCL6 (B-cell CLL/lymphoma 6) • CXCL13 (Chemokine (C-X-C motif) ligand 13) • ICOS (Inducible T Cell Costimulator) • MME (Membrane Metalloendopeptidase)

gemcitabine • bendamustine • Istodax (romidepsin) • Onureg (azacitidine oral)

8ms

A Dose-Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Follicular Lymphoma (clinicaltrials.gov)

P1/2, N=2, Terminated, University of Chicago | Completed --> Terminated; funding

8 months ago

Trial termination

Venclexta (venetoclax) • Gazyva (obinutuzumab) • Onureg (azacitidine oral)

8ms

AMADEUS: Randomised Study of Oral Azacitidine vs Placebo Maintenance in AML or MDS Patients After Allo-SCT (clinicaltrials.gov)

P3, N=326, Active, not recruiting, University of Birmingham | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2024 --> Apr 2025

8 months ago

Enrollment closed • Trial primary completion date

HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)

Onureg (azacitidine oral)

8ms

ASTREON: A Study to Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Participants With International Prognostic Scoring System Revised (IPSS-R) Low- or Intermediate-risk Myelodysplastic Syndrome (MDS) (clinicaltrials.gov)

P2/3, N=230, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

8 months ago

Enrollment closed

Onureg (azacitidine oral)

8ms

FLO_CC-486-: Pilot Study of CC 486 (Oral Azacitidine) Plus BSC as Maintenance After sc Azacitidine in Elderly HR-IPSS-R MDS Patients (clinicaltrials.gov)

P2, N=11, Active, not recruiting, University of Florence | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2023 --> Aug 2024

8 months ago

Enrollment closed • Trial completion date • Trial primary completion date

Onureg (azacitidine oral)

8ms

Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC. (clinicaltrials.gov)

P2, N=143, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=101 --> 143

8 months ago

Enrollment change • Metastases

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase)

EGFR mutation • EGFR exon 19 deletion • ALK positive • ALK rearrangement • EGFR wild-type • ALK wild-type • ALK translocation

Opdivo (nivolumab) • Jingzhuda (entinostat) • Onureg (azacitidine oral)

8ms

A Post-Marketing Surveillance Study to Assess the Safety of Oral Azacitidine Maintenance Therapy in Korean Patients With Acute Myeloid Leukemia (clinicaltrials.gov)

P=N/A, N=154, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting | Trial completion date: Sep 2029 --> May 2029 | Trial primary completion date: Jan 2028 --> Aug 2027

8 months ago

Enrollment open • Trial completion date • Trial primary completion date

Onureg (azacitidine oral)

8ms

Oral Azacitidine Combined With Venetoclax in Previously Untreated Higher-risk Myelodysplastic Syndromes (clinicaltrials.gov)

P1/2, N=36, Recruiting, Groupe Francophone des Myelodysplasies | Not yet recruiting --> Recruiting

8 months ago

Enrollment open • Combination therapy

Venclexta (venetoclax) • Onureg (azacitidine oral)

8ms

Testing CC-486 (Oral Azacitidine) Plus the Standard Drug Therapy in Patients 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma (clinicaltrials.gov)

P2/3, N=422, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2025 --> Mar 2026

8 months ago

Trial completion date • Trial primary completion date

BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • CD4 (CD4 Molecule)

BCL6 rearrangement • BCL2 rearrangement

Rituxan (rituximab) • doxorubicin hydrochloride • cyclophosphamide • vincristine • Onureg (azacitidine oral) • Mabtas (rituximab biosimilar)

8ms

REMAIN1: Oral Azacitidine in Transplant-Eligible Patients With Acute Myeloid Leukemia (AML) Suffering From Health-Inequality (clinicaltrials.gov)

P4, N=12, Not yet recruiting, Virginia Commonwealth University

8 months ago

New P4 trial

Onureg (azacitidine oral)

9ms

ORAZ-351: Oral Azacitidine Maintenance Post-CPX 351 (clinicaltrials.gov)

P=N/A, N=100, Recruiting, Centre Hospitalier Universitaire de Nice

9 months ago

New trial

Vyxeos (cytarabine/daunorubicin liposomal formulation) • Onureg (azacitidine oral)

9ms

Duvelisib in Combination With BMS-986345 in Lymphoid Malignancy (clinicaltrials.gov)

P1, N=14, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=30 --> 14 | Trial completion date: Oct 2025 --> Mar 2025 | Trial primary completion date: Oct 2025 --> Mar 2024

9 months ago

Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy

ALK (Anaplastic lymphoma kinase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8) • TNFRSF8 (TNF Receptor Superfamily Member 8) • BCL6 (B-cell CLL/lymphoma 6)

BCL6 rearrangement • BCL2 rearrangement

Copiktra (duvelisib) • Onureg (azacitidine oral)

9ms

Study of Magrolimab Combinations in Participants With Myeloid Malignancies (clinicaltrials.gov)

P2, N=54, Completed, Gilead Sciences | Active, not recruiting --> Completed

9 months ago

Trial completion

Venclexta (venetoclax) • cytarabine • etoposide IV • mitoxantrone • magrolimab (ONO-7913) • Onureg (azacitidine oral)

10ms

P3, N=42, Recruiting, Otsuka Australia Pharmaceutical Pty Ltd | Not yet recruiting --> Recruiting | Phase classification: P3b --> P3

10 months ago

Enrollment open • Phase classification

Inqovi (decitabine/cedazuridine) • Onureg (azacitidine oral)

10ms

Oracle: Efficacy and Safety of Oral Azacitidine Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory AITL (clinicaltrials.gov)

P3, N=86, Active, not recruiting, The Lymphoma Academic Research Organisation | Trial completion date: Feb 2024 --> Jun 2024

10 months ago

Trial completion date

PD-1 (Programmed cell death 1) • BCL6 (B-cell CLL/lymphoma 6) • CXCL13 (Chemokine (C-X-C motif) ligand 13) • ICOS (Inducible T Cell Costimulator) • MME (Membrane Metalloendopeptidase)

PD-1 expression

gemcitabine • bendamustine • Istodax (romidepsin) • Onureg (azacitidine oral)

10ms

A Study of Lenalidomide and CC-486 With Radiation Therapy in Patients With Plasmacytoma (clinicaltrials.gov)

P2, N=21, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

10 months ago

Enrollment closed • Combination therapy

lenalidomide • Onureg (azacitidine oral)

10ms

Safety and Efficacy Study of CC-486 in Subjects With Myelodysplastic Syndromes (clinicaltrials.gov)

P2, N=65, Completed, Celgene | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Sep 2023

10 months ago

Trial completion • Trial completion date • Combination therapy

Imfinzi (durvalumab) • decitabine • Onureg (azacitidine oral)

10ms

Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies (clinicaltrials.gov)

P1, N=20, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=30 --> 20

10 months ago

Enrollment closed • Enrollment change

TNFRSF8 positive

lenalidomide • Istodax (romidepsin) • Onureg (azacitidine oral)

11ms

IMPACT OF CO-MUTATIONS ON THE TRANSPLANT OUTCOMES IN AML PATIENTS WITH DNMT3A MUTATION (EBMT 2024)

Notably, none of the patients received oral azacitidine as maintenance therapy... The results indicated that NPM1-/FLT3-ITD- and NPM1+/FLT3-ITD- subgroups in DNMT3A mutated AML benefit from allo-HSCT in CR1. Larger cohorts are warranted to validate these findings.

11 months ago

Clinical

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1)

FLT3-ITD mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation

TruSight Myeloid Sequencing Panel

Onureg (azacitidine oral)

11ms

IMPACT OF CO-MUTATIONS ON THE TRANSPLANT OUTCOMES IN AML PATIENTS WITH DNMT3A MUTATION (EBMT 2024)

11 months ago

Clinical

FLT3-ITD mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation

TruSight Myeloid Sequencing Panel

Onureg (azacitidine oral)

11ms

OMNIVERSE: A Study to Assess Safety and Tolerability of CC-486 (ONUREG®, Oral Azacitidine) in Combination Therapy in Participants With Acute Myeloid Leukemia (AML) (clinicaltrials.gov)

11 months ago

Trial completion • Phase classification • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy

Venclexta (venetoclax) • Onureg (azacitidine oral)

11ms

OGILAR: Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects ≥18 Years of Age With Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia (clinicaltrials.gov)

P2, N=33, Recruiting, French Innovative Leukemia Organisation | Not yet recruiting --> Recruiting

11 months ago

Enrollment open

FLT3 (Fms-related tyrosine kinase 3)

FLT3 mutation • FLT3 D835 • FLT3 I836

Xospata (gilteritinib) • Onureg (azacitidine oral)

11ms

Oral Azacitidine Plus Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B Cell Lymphoma (clinicaltrials.gov)

P1, N=9, Completed, Medical University of South Carolina | Active, not recruiting --> Completed

11 months ago

Trial completion

carboplatin • Onureg (azacitidine oral)