General AML,   FLT3,  NPM1

ASH 2017 | MRD risk-adapted therapy in AML 

At the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, the AGP attended an oral session which focused on risk-adapted therapies in Acute Myeloid Leukemia (AML). The session was co-chaired by Jonathan H. Schatz, MD, from the University of Miami, Sylvester Comprehensive Cancer Center and Marlise R. Luskin, MD, from the Dana-Farber Cancer Institute.

During this captivating oral session, there were a range of talks discussing the inclusion of MRD directed treatment strategies for AML patients. This article is based on data presented at the live session, which may supersede information in the pre-published ASH Abstract.

Abstract 565

The first talk in this session was presented by Uwe Platzbecker, MD, from the University Hospital Carl Gustav Carus Dresden, Dresden, Germany.

The speaker began by highlighting that intensive chemotherapy can help patients with Myelodysplastic Syndrome (MDS) or AML to achieve Complete Remission (CR), but many of them relapse even after subsequent Allogeneic (allo) Hematopoietic Stem Cell Transplantation (HSCT). Platzbecker then reported results from the prospective phase II MRD guided RELAZA2 trial (NCT01462578) by the Study Alliance Leukemia (SAL) group. The aim of this study was to evaluate the role of azacitidine (AZA) as treatment of MRD in order to prevent relapse in patients with MDS or AML in CR after standard chemotherapy and allo-HSCT.

In an interview with the AGP, Uwe Platzbecker discussed the design of the prospective RELAZA2 study. In summary, MRD was detected by quantification of NPM1 mutation level, leukemia-specific fusion genes or sensitive Donor Chimerism (DC) analysis of CD34 on peripheral blood cells (in patients undergoing allo-HSCT). Patients in CR with measurable MRD above the threshold defining imminent relapse were administered six cycles of AZA (75mg/m2 subcutaneously, Days 1–7) followed by a MRD risk-adapted AZA-based therapy for up to 18 additional months. Overall, 53 patients with AML (n = 58) and MDS (n = 5) in CR after receiving either standard chemotherapy (n = 29) or allo-HSCT (n = 24) were treated in this study.

The primary endpoint of the study was Relapse Free Survival (RFS) at 6 months from start of MRD treatment. The secondary endpoints were Overall Survival (OS), RFS, safety and biomarkers.

Key findings:

  • After completion of initial six cycles of AZA
    • 58% (31/53) of patients achieved a response and were still in CR
      • Major response was observed in 19 patients (36%) with either a decline of MRD below a predefined threshold (increasing CD34+ DC to ≥80% or mutation level ≤ 1%)
      • Minor response was observed in 12 patients (23%) with MRD of CD34+ DC to < 80% or mutation level ≤ 1% but no relapse
    • 52% (22/53) of patients had no response and relapsed after a median of three AZA cycles
  • Cumulative Incidence of Relapse (CIR) was significantly higher in patients that were treated with chemotherapy than allo-HSCT, P = 0.037
  • Compared to MRDpos patients, RFS (P < 0.001) and OS (P = 0.057) were significantly longer in MRDneg patients
  • Adverse Events (AEs) occurred in patients including Grade 3–4 thrombocytopenia (n = 3) and neutropenia (n = 45), infections, (n = 4), neutropenic fever (n = 2) and pneumonia (n = 3)

The speaker, Uwe Platzbecker, summarized his talk by stating that “MRD-triggered treatment with AZA is an effective strategy for preventing or substantially delaying hematological relapse in a considerable proportion of patients with MDS or AML and at a high-risk of relapse”. He further added that the success of treatment seems to be context-dependent, thus underlining the potential immunomodulatory role of hypomethylating agents.

Uwe Platzbecker concluded his talk by highlighting that RELAZA2 study “supports the prognostic importance of MRD in AML and may serve as a platform for future studies combining hypomethylating agents with novel targeted therapies.”

Abstract 567

Ana Garrido, MD, from Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, gave the next talk. The speaker presented results from a prospective risk-adapted phase II AML12 trial of which evaluated the feasibility and preliminary efficacy of intensive chemotherapy followed or not by Autologous (auto) or allo-HSCT depending on genetics of AML and levels of MRD after consolidation.  

In total, 549 patients (median age = 55 years) with primary AML treated at fifteen academic hospitals from the Spanish CETLAM group between February 2012 and April 2017. Patients received induction chemotherapy consisting idarubicin (12 mg/m2 Days 1–3) and cytarabine (200 mg/m2, continuous infusion, Days 1–7). Four-hundred and twenty-six patients (78%) achieved a CR.  Of these 426 patients in CR, 408 patients received consolidation therapy consisting of high-dose cytarabine (3 g/m2 or 1.5 g/m2 if older than 60 years, Days 1, 3, 5).

Consolidation therapy was based on risk allocation according to Medical Research Council (MRC) cytogenetic classification and was available for 524 patients. Patients in the Favorable Risk (FR) category (CBF, NPM1mut/FLT3-ITDwild or ratio <0.5, CEBPA biallelic mutation) were administered three consolidation courses. Patients in the Intermediate Risk (IR) category (intermediate cytogenetics without favorable or unfavorable molecular features [FLT3-ITD, MLL]) were administered two cycles followed by either allo or auto- HSCT depending on MRD levels while patients in the Adverse Risk (AR) category were administered one consolidation course followed by allo-HSCT.   

Key findings:
  • Survival according to genetics:

Patients’ cytogenetics (n)

OS

EFS

Favourable (191)

78±6%

73±6%

Intermediate (146)

46±9%

36±8%

Adverse (212)

32±7%

20±7%

  • CIR according to MRD status

Patients’ cytogenetics

CIR in MRDpos pts (n)

CIR in MRDneg pts (n)

P value

Favourable

45±12% (18)

12±6% (134)

P < 0.001

Intermediate

32±11% (23)

32±7% (52)

N.S

Adverse

59±9% (35)

44±6% (75)

N.S

The speaker highlighted that in AML patients with FR genetics, high-dose cytarabine without allo-HSCT in first CR is a “very good option” for MRD negative patients. Additionally, CIR in MRD+ after the third consolidation was increased and thus assessment at this time point is recommended. However, in patients in the IR or AR category, risk allocation considering MRD after first consolidation was not predictive and incidence of relapse was similar in both MRD+ and MRD- patients.

Anna Garrido concluded by stating that “risk adapted therapy for primary AML based on genetics and MRD is feasible in a cooperative group setting”. Despite these promising results, relapse rates remain high for intermediate and adverse AML patients based on genetics and MRD. Further investigations are required.

References
  1. Platzbecker U. et al. Minimal-Residual Disease Guided Treatment with Azacitidine in MDS/AML Patients at Imminent Risk of Relapse: Results of the Prospective RELAZA2 Trial. Oral Abstract #565. 59th American Society of Hematology Annual Meeting. 2017 Dec 9-12; Atlanta, GA, USA.
  2. Sierra J. et al. Therapy for Acute Myeloid Leukemia (AML) Adjusted to Genetic Data and Minimal Residual Disease: Results of the AML12 Trial of the Spanish Cetlam Group in Adults up to the Age of 70 Years. Oral Abstract #567. 59th American Society of Hematology Annual Meeting. 2017 Dec 9-12; Atlanta, GA, USA.
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