Beat AML Master trial: can we use precision medicine to treat older patients with AML?

Acute myeloid leukemia (AML) is a heterogenous hematological malignancy, characterized by multiple genomic alterations, with limited therapeutic options for patients over the age of 60. Using a precision medicine approach, it may be possible to improve patient outcomes by matching each patient to the most effective targeted therapy for their specific subtype of AML.

The Beat AML Master trial is an umbrella study which contains 11 sub-studies covering the most prominent subtypes of AML. The study primarily aimed to assess whether molecular, immunophenotypic and/or biochemical studies could profile patients within seven calendar days, and subsequently assign them to molecularly defined, subtype-specific therapy based on the results. Another primary objective of the trial was to determine the clinical efficacy of novel treatment strategies in each sub study. The Beat AML trial was specifically conducted in an elderly patient population over the age of 60 years. Amy Burd, Leukemia and Lymphoma Society, White Plains, US, presented the results from the Beat AML Master trial during the 61^st American Society of Hematology (ASH) meeting in Orlando, US.

Study protocol and design

• Accelerated cytogenetic and mutational testing of a bone marrow sample was conducted within seven days of suspected diagnosis:
  • Local cytogenetics
  • Broad next generation sequencing (NGS) genomic analysis
  • Polymerase chain reaction (PCR)-based FLT3 assay
• Following this, marker-positive patients were assigned to a treatment arm using a targeted agent or combination of agents, specific for their subtype
• Marker-negative patients were assigned treatment with a broad-acting novel agent or combination meaning all patients in the study had the opportunity to receive a novel therapy
• Primary endpoints of the treatment were complete remission (CR) rate and CR with incomplete blood count recovery (CRi)
• Treatment was assigned based on molecular data, using a pre-determined algorithm that considered curability:
  • Presence of a dominant clone (with a variant allele frequency [VAF] of > 0.3)
  • If no dominant clone, a VAF of 0.2 was considered
  • If no dominant clone at VAF > 0.2, then assignment was done top to bottom of the algorithm, in the same order shown in Table 1 in the Treatment assignment (TA) section below
• TA considered the availability and efficacy of targeted therapeutics for that subset and the likelihood of cure with intensive chemotherapy

TA

• Treatment naïve patients with AML aged 60 years or older were enrolled between November 2016 and January 2019
  • Of 487 patients that consented, 395 patients were eligible for the study
  • Median patient age was 72 years (range: 60–92)
  • 38% of patients were aged 75 or older
  • Median white blood cell count was 4.85 x 10⁹ /L
• 94.7% of patients were assigned to different treatment based on diagnostic testing, within seven days, meeting the primary objective of the study
• Of the 395 eligible patients:
  • Patients who were assigned a treatment and consented to a BEAT AML sub-study: 224
  • Remaining patients (n= 171) received the following treatment:
    • Standard of care (SOC; induction therapy, 7+3, or hypomethylating agent): 103
      • 78 before TA, and 25 after
    • Alternative investigational agent on other clinical trial: 28
      • 5 before TA and 23 after
    • Palliative care: 38
      • Two had unknown treatment status and are grouped with palliative care
      • Patients receiving palliative care tended to be older (median: 77.5 years) and had a higher white blood cell count
    • Nine patients died before TA
  • Of the patient who were screened but deemed ineligible, this was predominantly due to an alternative diagnosis (77%) such as high-risk myelodysplastic syndrome
  • TA with targeted agents and combinations was conducted as per Table 1 with most common molecular groups being TP53-mutated (19.2%) and marker-negative (19.8%)

Table 1. Treatment assignments in the Beat AML study

Group

Prioritized schema

Treatment

-

N

%

-

Core binding factor (CBF)

9

2.3

Samalizumab + induction

NPM1 mutation / FLT3 wild type

46

11.7

Fit patients: entospletinib + induction

Unfit patients: entospletinib monotherapy

MLL rearrangements

11

2.8

Entospletinib

Entospletinib + azacitidine

IDH2 mutations

45

11.4

Enasidenib

Enasidenib + azacitidine

IDH1 mutations

23

5.8

Ivosidenib + azacitidine

TP53 mutations

76

19.2

Entospletinib + decitabine

Pevonedistat + azacitidine

Complex cytogenetics with no TP53 mutation

31

7.9

Entospletinib + decitabine

FLT3 mutations

27

6.8

Gilteritinib monotherapy

+/- decitabine

Hypermethylation

49

12.4

BI 836858 + azacitidine

Marker-negative

78

19.8

BI 836858 + azacitidine

Results

• Estimated mortality in all patients at 30 days: 14.1% (95% CI, 10.9–1)
  • BEAT AML: 3.7% (95% CI, 1.9–2)
  • Standard therapy: 20.4% (95% CI, 13–2)
  • Investigational drug: 0%
  • Palliative care: 72.6% (95% CI, 57.8–7)
• Overall survival (OS) was significantly longer in patients enrolled in a targeted therapy arm compared to standard therapy (p< 0.0001)
  • Median OS (Beat AML vs SOC): 12.8 vs 3.9 months
  • However, there was no difference in OS when compared to patients receiving an investigational therapy outside of the Beat AML study where median OS was not reached
  • Significant differences in survival between the groups occurs within the first 90 days of treatment

Conclusion

Dr Burd and co-investigators concluded that a rapid precision medicine approach was feasible in patients aged 60 years and older with treatment naïve AML and that delaying treatment for up to seven days was safe.

Patients receiving an assigned therapy based on molecular, immunophenotypic and/or biochemical information had an overall lower early death rate and superior OS compared to standard therapy, indicating an umbrella approach may improve short- and long-term clinical outcomes of patients with AML.

The results of this study have now been published in the journal Nature Medicine.²