GIMEMA AML1310 trial of risk-adapted, MRD-guided therapy for young patients with newly diagnosed AML

Regardless of the advancements made in understanding the genetic and molecular landscapes of acute myeloid leukemia (AML) in young patients, bespoke treatment approaches are yet to be adopted. Based on the NCCN 2009 guidelines,2 AML risk stratification depends on genetic/cytogenetic abnormalities of AML cells and groups patients into “favorable-risk" (FR), “intermediate-risk” (IR) or “poor-risk” (PR) categories. This will then determine the treatment pathway of whether they will receive allogeneic stem cell transplantation (allo-SCT). Currently, treatment of IR patients is less defined and often post-induction treatment with allo-SCT is adopted. Nevertheless, this approach does not appropriately take into account the heterogeneity in this group regarding the risk of disease relapse. Despite high complete remission (CR) rates in these patients, overall survival (OS) remains low due to the high rate of relapse incidence.3

Adriano Venditti et al., from the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Foundation investigated in a multicenter prospective clinical trial (NCT01452646) the benefit of risk-adapted, MRD-based therapy in young adults with AML. This study consisted of the integration of pre-treatment cytogenetics/genetics with post-treatment MRD assessment (detected using multiparametric flow cytometry [MFC]) to stratify patients to receive post-consolidation autologous stem cell transplantation (auto-SCT) or allo-SCT.1

Study design1
  • Diagnostic work-up: Patients were evaluated up-front by bone marrow (BM) aspirate for morphology, cytogenetics, molecular genetics. A baseline MFC assessment from BM served to identify baseline leukemia-associated immunophenotypes (LAIPs), using a high-sensitivity 8-color MFC assay
  • Risk group assessment and treatment according to the international working group (NCCN 2009, version 1)2:
  • After induction and consolidation:
    • Patients in the FR group received auto-SCT
    • Patients in the PR group were allocated to allo-SCT
    • Patients in the IR groups were treated according to MRD status: MRD negative patients received auto-SCT, while MRD positive patients were scheduled for allo-SCT
    • IR patients who could not be assessed for MRD based on the presence of LAIP (NCCN-IR no LAIP) were considered for auto-SCT
  • Treatment:
    • Induction therapy consisted of daily intravenous (IV) daunorubicin 50mg/m2 on days 1, 3, and 5; daily IV etoposide 50mg/m2 on days 1–5; and daily continuous infusion of IV cytarabine 100mg/m2 on days 1–10
    • Consolidation therapy. Patients who achieved CR or complete remission with incomplete hematological recovery (CRi), after one or two induction cycles, received one course of consolidation that consisted of daily IV daunorubicin 50mg/m2 on days 4, 5, and 6, as well as IV cytarabine 500mg/m2 every 12 hours on days 1–6
  • Primary endpoint was overall survival (OS) at 24 months from treatment initiation
  • Secondary endpoints were CR/CRi following induction, disease-free survival (DFS), the cumulative incidence of relapse (CIR) from CR
Results1
  • N= 500 patients enrolled (Table 1), with the median follow-up of 28.8 months
  • Patient distribution within the risk categories:
    • 28% (n= 138) in the NCCN-FR category
    • 25% (n= 127) in the NCCN-IR category
    • 38% (n= 188) in the NCCN-PR category
    • 9% (n= 47) in the NCCN-IR no LAIP
  • After one to two cycles of induction 72% of patients achieved a CR (p< 0.001):
    • 88% in the NCCN-FR category
    • 65% in the NCCN-IR category
    • 69% in the and NCCN-PR category
  • Eighty-four patients (17%) had refractory AML and salvage therapy was given to 63 of them; from those 23 achieved CR (37%)
  • In the IR group, 27% (47/174) of patients could not be assessed for MRD by MFC and 12 of these patients received an auto-SCT while two patients received an allo-SCT. 127 patients were followed for MRD and of these, 35 were NCCN-IR-Neg, while 43 were NCCN-IR-Pos. 20 patients received auto-SCT and 41 had an allo-SCT
  • 2-year OS (Table 2):
    • 74% in the NCCN-FR category
    • 58% in the NCCN-IR category
    • 42% in the NCCN-PR category
    • 50% in the NCCN-IR no LAIP
    • 70% in the IR MRD positive group receiving allo-SCT
    • 79% in the MRD negative group receiving auto-SCT
Table 1. Patient characteristic and treatment allocation1
  Overall 
500 
Median age (range)  49 (18–60.9) 
Sex, n (%)   
 Male  260 (52) 
 Female  240 (48) 
Cytogenetics: FR, n (%)  47 (11) 
Cytogenetics: IR, n (%)  315 (73) 
Cytogenetics: PR, n (%)  67 (16) 
NCCN-FR, n (%)  138 (28) 
·       Received auto-SCT after consolidation, n 78
·       Received high dose of cytarabine, n 18
·       Received allo-SCT after salvage, n 1
NCCN-IR, n (%)  127 (25) 
·       Received auto-SCT after consolidation, n 20
·       Received high dose of cytarabine, n 1
·       Received allo-SCT after consolidation, n 32
·       Received allo-SCT-graft after salvage, n 9
NCCN-IR-no LAIP, n (%)  47 (9) 
·       Received auto-SCT after consolidation, n 12
·       Received allo-SCT after consolidation, n 1
·       Received allo-SCt after salvage, n 1
NCCN-PR, n (%)  188 (38) 
·       Received auto-SCT after consolidation, n 1
·       Received allo-SCT after consolidation, n 78
·       Received allo-SCT after salvage, n 9
LAIP; leukemia-associated immunophenotypes (LAIPs), FR; favorable-risk group, PR; poor-risk group, IR; intermediate-risk group
 
Table 2. Survival data
Category Two-year OS, % (95% CI) Two-year DFS, % (95% CI)
FR 74 (67–82) 61 (52–71)
IR 58 (50–68)  61 (52–73)
IR-no LAIP 50 (37–67) 48 (33–70) 
PR 42 (36–50)  45 (37–55)
Whole series 56 (52–61) 54 (49–60)
Risk-adapted, MRD-driven post-consolidation treatment*    
NCCN-IR patients, MRD-negative who received auto-SCT 79 (66–94) 61 (47–80)
NCCN-IR patients, MRD-positive who received allo-SCT 70 (57–86) 67 (53–83)
*IR patients received auto-SCT or allo-SCT depending on the post-consolidation levels of MRD, LAIP; leukemia-associated immunophenotypes (LAIPs)
 
Conclusion1

In conclusion, the authors recognized that this study has intrinsic limitations due to scientific progression over time, such as better understanding of basic biology, new AML classification and increased MRD monitoring, which makes the historical control not wholly comparable. However, this is the first study that attempts to apply a prospective program of risk-adapted, MRD-driven treatment in patients with NCCN-IR AML, that integrates genetics and post-consolidation MRD status.

Patients that were in the NCCN-IR group demonstrated that allo-SCT can be avoided if patients are tested MRD-negative after induction therapy. In contrast, if patients are MRD-positive, allo-SCT improved OS and prolonged DFS to comparable levels as those of patients in the NCCN-FR group. Patients in the IR group, who could not be monitored for LAIP had an inferior 2-year OS of 50% when compared to the other risk groups. This suggests that, in this group, a number of patients could have benefited from an allo-SCT. Further studies that integrate baseline factors and monitor MRD are needed, as it could potentially be a promising tool to refine and customize outcome prediction in patients with AML.

References
  1. Venditti et al., GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia. Blood. 2019 Sept 19;DOI: 10.1182/blood.2018886960
  2. Acute Myeloid Leukemia. Version 1.2009, NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. [Accessed 2019 Dec 02]
  3. Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol. 2018;93(10):1267-1291. DOI: 10.1002/ajh.25214
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