WHU 2022 - Acute Myeloid Leukemia

Topline Presentation Points 

Updates – Newly Diagnosed AML in older and/or unfit patients (0:25 – 6:10)

Real World Experience of CPX-351 as first-line treatment (Rautenberg et al. ASH 2021)
Builds 5-year study results of CPX-351 by Lancet, JCO 2020

Key Takeaways:

• Promising CR rate of 47% and majority go onto transplant
  • CR rates significant across subgroups regardless of mutation status
• Encouraging long term survival with 1 year CIR 23%

Limitations: Real world data and retrospective analysis

Comparing CPX-351 vs HMA+VEN (Grenet et al. ASH 2021)
Retrospective multicentre analysis of outcomes

Key Takeaways:

• Significant survival advantage for CPX-351 in TP53 Mut
  • Greater transplant rate which may underline observed OS advantage
• HMA+VEN has similar CR/CRi at 56.6% in this high-risk population

Limitations: Disparity in terms of age and high-risk cytogenetics which didn’t favour VEN+AZA arm

VEN+AZA vs intensive chemotherapy as induction (Zeidan et al. Blood 2021)
Retrospective analysis of an electronic database in the US

Key Takeaways:

• OS similar in both treatment groups, regardless of age group and censoring patients with ASCT
  • 48% OS VEN+AZA in older population with high risk is quite encouraging

Update – Practice changing in Fit (6:10 – 7:35)

Updated results QUAZAR AML-001 Trial – long term OS with oral AZA in first remission after intensive chemotherapy (Wei et al. ASH 2021)
Important update on practice changing study in fit patients

Key Takeaways:

• Compelling OS benefit of maintenance with survival benefit maintained
  • Long term survivors more likely:
    • Intermediate-risk cytogenetics and NPM1 Mut at initial diagnosis
    • MRD negative by MFX at screening (post-IC)
• Statistical improvement maintained across all subgroups

Update – Not fit for intensive chemo (7:35 – 10:56)

Phase I/II Study of AZA+VEN and Magrolimab (Daver et al. ASH 2021 or Blood 2021)
Aims of study: Dose finding, signs of activity, and safety in newly diagnosed older/unfit or high risk and rrAML

Key Takeaways:

• Preliminary data with encouraging signs:
  • Well tolerated
  • Complete Cytogenetic CR was achieved in 75% of evaluable patients
  • ORR in TP53 (86%) or wild type (100%)
  • Med TT ANC >500 28 days
  • Med TT Pit >50K 24 days

Limitations: Preliminary data with relatively small cohorts

TARGETABLE MUTATIONS (10:57- 18:57)

Phase 3 QuANTUM-First

Intensive ChemoRx +/- Quizartinib in newly diagnosed FLT3-ITD AML

• Patients randomized to 3+7 chemoRx +/- QUIZ or Placebo
• Post-chemoRx continue QUIZ for up to 3 years

Key Takeaways:

• Primary end point of OS
• Full data set at EHA 2022?

Phase 3 Gilteritinib+Aza vs Aza for newly diagnosed FLT3 Mut ineligible for intensive induction chemotherapy (Wang et al. ASH 2021)
An open label randomized study

Key Takeaways:

• Median time to first subsequent AML therapy was 8.2 mo for GIL+AZA and 4.5 mo for AZA
• CR rates similar for both arms, CRc significantly higher for GIL+AZA

Limitation: Higher proportion of patients in AZA received subsequent AML therapy

Phase 1b Evaluating the safety and efficacy of VEN+GILT in rrAML (Daver, ASH 2021)
Multicentre, open label where 59% of patients had received >1 prior FLT3 TKI

Key Takeaways:

• Encouraging data as VEN+GILT demonstrated deep reduction in FLT3 allelic burden with 74.5% patients achieving mCRc

AZA+VEN+GILT in FLT3 Mut (Short, Blood 2021)

Key Takeaways

• This triplet can be administered in upfront disease or rrAML
  • Frontline ORR 100%
  • Salvage ORR 69%

HMA+VEN with FLT3 inhibitor – “triplet” therapy in older/unfit patients with FLT3 Mut (Yilmaz, Blood 2021)

Key Takeaways:

• FLTi added to HMA+VEN appears to be safe and effective

Phase III AGILE Study – Ivosidenib+AZA vs Placebo+AZA in newly diagnosed with IDH1 Mut (Montesinos et al. Blood 2021)
Unfit patients ineligible for intensive induction chemotherapy

Key Takeaways:

• IVO+AZA significantly improved EFS and OS
• Favourable safety profile – well tolerated, modest toxicity
• Emerging combo in this patient population

Phase 1, First in human study of SNDX-5613 (Stein et al. ASH 2021)
Safety and efficacy of Menin Inhibition in patients with MLL-Rearranged and NPM1 mutant Acute Leukemia

• SNDX-5613 turns off leukemic transcription programs by binding and to Menin and displacing MLL complexes

Key Takeaways:

• SNDX-5613 patients are heavily pre-treated and have poor prognosis
• SNDX-5613 demonstrates promising anti-Leukemia activity in rrMLLr and mNPM1 leukemias

Phase 1b/2 Study of IMGN632 combination AZA+VEN (Daver et al. ASH 2021)
Treatment directed at patients with CD123-Positive AML

Key Takeaways:

• Antileukemic activity observed across all doses/schedules
• Manageable safety and efficacy

ALLOGENEIC TRANSPLANT (18:57 – 22:35)

ASCT remains a key modality in high-risk AML

Treatment and outcomes for Patients with TP53 Mut AML: Impact of ASCT on survival (Badar et al. Blood 2021)
Clinical outcomes analyzed on 315 patients with TP53 Mut over last decade

Key Takeaways:

• Allo-HCT as a time dependent covariate retained favourable prognostic significance in MVA

Allogeneic Hematopoietic Cell Transplant can overcome adverse prognosis of secondary-type mutation positive de novo AML (Song et al. Blood 2021)

Key Takeaways:

• Benefit of allogeneic transplant
• ASCT remains a key modality in high-risk AML