General AML

MRD monitoring before and after allo-HSCT predicts outcomes

The presence of measurable (minimal) residual disease (MRD) after induction chemotherapy is a strong and independent prognostic marker of increased risk of relapse and shorter survival in patients with acute myeloid leukemia (AML) and can be used to stratify risk and assess treatment response.1 In two of the latest studies, presented at the 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US, in December 2019, MRD was used to predict relapse after autologous hematopoietic stem cell transplantation (allo-HSCT). These studies are summarized below.

To learn more about the use of MRD monitoring in the management of AML, visit the AML Global Portal.

Risk-adapted post-remission treatment allocation: final results of the Spanish AML12 trial2

The final results of the AML12 trial of the Spanish Cetlam Group were presented by Jorge Sierra, Hospital Santa Creu Sant Pau, Barcelona, ES. This prospective study was designed to evaluate the feasibility and outcomes of prospective, risk-adapted treatment based on AML genetics at diagnosis and the presence of MRD after consolidation chemotherapy.

A total of 812 adults (Table 1) were enrolled at 15 Spanish academic hospitals. Induction chemotherapy, which was administered to all patients, consisted of idarubicin plus cytarabine. Consolidation treatment was high-dose cytarabine (HDAC), with the number of courses depending on genetic risk: two courses for those with European LeukemiaNet (ELN)-favorable genetics and one for those with ELN-intermediate or -adverse genetics. Any subsequent therapy was allocated based on genetic and MRD risk analysis as follows:

  • Favorable risk group: MRD negativity and core binding factor mutations, NPM1 mutation with normal FLT3 or low FLT-ITD (ratio < 0.5) or CEBPα  biallelic mutation to received one additional HDAC course
  • Intermediate risk group: MRD negativity and intermediate cytogenetics without favorable or unfavorable molecular characteristics to receive one additional course of HDAC and, depending on the center’s decision, autologous HSCT (auto-HSCT) or allo-HSCT
  • Adverse risk group: MRD positivity (with any risk group) or adverse cytogenetics, intermediate cytogenetics with high FLT-ITD ratio, and KMT2A rearrangements without MLLT3-KMT2A to receive a mandatory allo-HSCT within four months of remission

Table 1. Baseline patient characteristics

  N= 812 (%)
Median age, years (range) 55 (18–70)
Male 421 (52)
Median WBC x109/L (range) 9.6 (0–530)
Cytogenetics (MRC) n= 764 (%)
Favorable 81 (11)
Intermediate 516 (67)
Normal karyotype 378 (73)
Adverse 167 (22)
Mutations in intermediate MRC  
NPM1+/FLT3-ITD negative 137 (26)
NPM1+/FLT3-ITD LR 35 (7)
NPM1+/FLT3-ITD HR 55 (11)
NPM1-/FLT3-ITD positive 42 (8)
CEBPα mut. (biallelic) 12 (2)
Triple mut neg./lack of information 210 (41)/25 (5)

HR, high ratio; LR, low ratio; MRC, Medical Research Council; WBC, white blood cells

Results
  • 799 patients received induction chemotherapy
    • 617 (77%) patients achieved complete remission (CR): 403 (79%) were ≤ 60 years, 214 (74%) were > 60 years
  • 586 patients completed the consolidation phase; 563 were risk allocated based on genetics and MRD
    • Favorable risk group: 192 (34%) patients
      • 182 (95%) patients received further HDAC
    • Intermediate risk group: 103 (18%) patients
      • 78 (76%) patients received allo-HSCT, 10 (10%) patients received auto-HSCT, 13 (13%) patients received only HDAC
    • Adverse risk group: 268 (48%) patients
      • 201 (75%) patients received allo-HSCT, 8 (3%) patients received auto-HSCT, 39 (14%) patients received HDAC
    • Median follow-up: 30 months
    • Overall 5-year survival
      • All patients: 45%
      • Favorable risk group: 86%
      • Intermediate risk group: 34%
      • Adverse risk group: 44%
    • Overall 5-year event-free survival:
      • All patients: 35%
      • Favorable risk group: 78%
      • Intermediate risk group: 32%
      • Adverse risk group: 38%
    • Cumulative incidence of relapse (CIR) at 5 years according to MRD status after consolidation:
      • All CR patients: 52% (MRD-positive) vs 32% (MRD-negative) (p< 0.001)
      • Favorable genetics: 37% (MRD-positive) vs 22% (MRD-negative) (p= 0.004)
      • Intermediate genetics: 48% (MRD-positive) vs 40% (MRD-negative) (not significant)
      • Adverse genetics: 63% (MRD-positive) vs 43% (MRD-negative) (p= 0.003)
Conclusions

Based on these results, the investigators concluded that MRD was a good marker to predict relapse after consolidation chemotherapy and that allo-HSCT was feasible in a large proportion of patients in intermediate or adverse risk groups based on genetics and/or MRD positivity. However, they also believe that allo-HSCT during the first CR could be avoided in more than one-third of patients (those with favorable genetics at diagnosis and no MRD), since 5-year survival rates were high after chemotherapy only.

MRD monitoring predicts relapse after allo-HSCT3

Monitoring MRD after allo-HSCT is highly predictive of relapse and overall survival in AML, according to the results of a study presented by Felicitas Thol, Hannover Medical School, Hannover, DE. Building on previous work, which demonstrated that MRD status before allo-HSCT was predictive of relapse and non-relapse mortality (NRM),4 Thol and coworkers set out to answer the question of whether next-generation sequencing (NGS) from peripheral blood can be used to quantify MRD in AML patients who had undergone allo-HSCT. Samples (primarily peripheral blood) from 138 patients were taken at Day 90 (n= 133) and Day 180 (n= 125) post-transplant, and MRD was assessed by NGS, implementing read families of 42 different genes in order to overcome detection errors.

Results
  • Median follow-up time: 5.5 years
  • 393 samples were from peripheral blood, 17 from bone marrow
  • Detection threshold, as assessed by different methods, was between 0.012% and 0.071%
  • Combined MRD positivity on Day 90 and/or Day 120 was observed in 28 (20.2%) patients
  • No significant differences in clinical risk categories (such as cytogenetic risk and age) or transplant-associated characteristics were observed between the groups of MRD-positive and -negative patients
  • The 5-year CIR was 58% for MRD-positive patients and 27% for MRD-negative patients (p< 0.001)
  • A significant between-group difference in overall survival (OS) was also observed (p= 0.001)
  • In a multivariate analysis for CIR, MRD status remained significant (hazard ratio = 2.88; 95% confidence interval, 1.41–5.92; p= 0.004)
  • MRD at Day 90 and 180 after allo-HSCT was prognostic for CIR, NRM, and OS
  • An extended marker set (2–4 markers per patient) was more discriminative for OS and CIR differences compared to a limited marker set (1–2 markers per patient)
  • However, markers targeting mutations in DNMT3A, TET2 and ASXL1 (DTA markers) were not predictive for OS and CIR after allo-HSCT
Conclusions

NGS-based MRD monitoring of peripheral blood after allo-HSCT is feasible and predicts future relapse and survival in AML. It should be performed at Day 90 post-transplant with an extended marker set of non-DTA markers in order to help guide post-transplant care in AML patients.

References
  1. Ravandi F. et al., Evaluating measurable residual disease in acute myeloid leukemia. Blood Adv. 2018 Jun 12; 2(11):1356–1366. DOI: 10.1182/bloodadvances.2018016378
  2. Sierra J. et al., Final results of the AML12 trial of the Spanish Cetlam Group in adults with acute myeloid leukemia (AML) up to the age of 70 years: risk adapted post-remission allocation based on genetic data and minimal residual disease; 2019. Oral Abstract #289: 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US
  3. Thol F. et al., Post transplantation measurable residual disease (MRD) monitoring using next-generation sequencing is highly predictive for relapse after allogeneic stem cell transplantation; 2019. Oral Abstract #184: 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US
  4. Thol F. et al., Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML. Blood. 2018 Oct 18; 132(16):1703–1713. DOI: 10.1182/blood-2018-02-829911
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