General AML|FLT3

MRD directed treatment in AML - Oral abstract session at the 22nd Congress of the EHA

During the 22nd Congress of the European Hematology Association (EHA) Congress, Madrid, Spain, the AGP attended an enthralling oral session focused on therapies targeting Minimal Residual Disease (MRD) in Acute Myeloid Leukemia (AML). The session was co-chaired by the chair of our European Steering Committee, Professor Gert Ossenkoppele, VU University Medical Center, Amsterdam, the Netherlands, and Professor Adriano Venditti, M.D. from the University Tor Vergata, Rome, Italy.

During the captivating oral session, there were a range of talks discussing the importance of the inclusion of MRD detection in risk-adapted treatment strategies for patients with AML.

Abstract S110

The first talk was presented by Associate Professor Jessica Altman from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, United States. The speaker presented an exploratory analysis of a subpopulation of patients treated in the phase I/II CHRYSALIS study (NCT02014558) of gilteritinib, a potent, oral Fms Like Tyrosine Kinase 3 (FLT3)/AXL inhibitor, in FLT3 positive mutated Relapsed or Refractory (R/R) AML patients. The analysis specifically focused on the molecular response of FLT3-ITDmut+ patients to gilteritinib. The results of this study were reported here.

Jessica K. Altman concluded her talk by highlighting that their study is the first to demonstrate a “molecular response to a FLT3 inhibitor in AML”.  Additionally, molecular response to gilteritinib correlated with an improved clinical response. She further added that molecular response may predict durable clinical benefit from gilteritinib therapy.

The AGP interviewed Associate Professor Jessica Altman on the findings of this study, during the past 2017 ASCO Annual Meeting. She highlighted that patients who had a molecular response to gilteritinib had better Overall Survival (OS) compared to patients that did not have a molecular response.

Abstract S111

The co-chair of this oral session, Professor Adriano Venditti, gave the second talk, which discussed results from the phase II AML1310 study (NCT01452646).

The talk began by the speaker explaining the design of the study, which was tailored for AML patients based on the evaluation of MRD. MRD was measured at diagnosis and patients were risk stratified accordingly into three groups including favorable risk (NPM1+ FLT3-ITD- or CBF+ without c-kit mutation), high-risk (adverse karyotype or FLT3-ITD+), and intermediate risk (intermediate karyotype or FLT3-TKD+ or c-kit mutated CBF positive) before induction therapy and post-consolidation therapy.

followed by either Autologous Stem Cell Transplantation (AuSCT) or Allogenic Stem Cell Transplantation (ASCT) based on genetics of AML and MRD level after consolidation therapy in previously untreated de novo AML patients. The primary endpoint of this study is treatment strategy in terms of OS at 24 months.

In total, 515 newly diagnosed patients (median age = 49 years) were enrolled between January 2012–June 2015 from fifty-six institutions in the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) group. Five-hundred patients were administered induction therapy as well as subsequent post-consolidation chemotherapy. Post-consolidation chemotherapy was based on risk allocation and was completed by 342 patients including; low-risk patients (n = 115) received AuSCT (n =78), high-risk patients (n = 122) received ASCT (n = 78), and intermediate risk patients (n = 105) received either AuSCT (n = 20) or ASCT (n = 32) depending on the level of MRD detected after consolidation therapy. The median follow-up length of the study was 27.8 months.

The key results of the study were:
  • 2-year OS in favorable, high, intermediate MRD+, and intermediate MRD- risk patients was 74.8%, 42.5%, 78.6%, and 69.8%, respectively; P < 0.0001
  • 2-year Disease Free Survival (DFS) in favorable, high, intermediate MRD+, and intermediate MRD- risk patients was 63.8%, 44.8%, 61.4%, and 66.6%, respectively; P = 0.019

Professor Andriano Venditti concluded his talk by highlighting that a risk-stratified, MRD-directed therapy is “feasible in a multicenter, cooperative setting”. Furthermore, he suggested that AuSCT “might still have a role in the post remission treatment of patients with AML”.

Abstract S112

The next abstract discussed in this session was presented by Jurjen Versluis from the Erasmus Medical Center Cancer Institute, Rotterdam, Netherlands.

MRD assessment in patients can improve AML risk classification and may improve risk-adapted treatment strategies. In AML, MRD assessment after induction therapy has been shown to predict for relapse and overall outcome irrespective of the type of Post-Remission Therapy (PRT) used. Furthermore, PRT with ASCT may lead to a strong reduction of relapse (graft-versus-leukemia effect) in AML patients.

The main aim of the study by Jurgen Versluis was to investigate whether, and to what extent, ASCT quantitatively reduces relapse as compared to conventional PRT in upfront treated patients with MRD positive or MRD negative AML in first hematological Complete Remission (CR1). He discussed pooled results obtained from three prospective, consecutive HOVON-SAKK AML trials between 2006–2014 with newly diagnosed AML patients (n = 1,511). The endpoints of the study were relapse, OS, Relapse Free Survival (RFS), and Non-Relapse Mortality (NRM) at 4-years.

Overall, 547 patients in CR1 who received PRT of chemotherapy (n = 160), AuSCT (n = 105), and ASCT (n = 292) who were MRD positive (n = 418) and MRD positive (N = 129) were evaluated in this study.

The key results of this study were:
  • 4-year OS in patients with or without MRD prior to PRT; 50±5% vs 65±2%, P = 0.002
  • NRM was not significantly different between MRD positive and MRD negative patients
  • 4-year RFS in MRD positive and MRD negative patients prior to PRT; 38±4% vs 58±3%, P < 0.001
  • 4-year Cumulative Incidence of Relapse (CIR) in MRD positive and MRD negative patients; 54±4% vs 32±2%, P < 0.001

  • Compared to chemotherapy or AuSCT, ASCT significantly reduced the incidence of relapse (HR = 0.36, P < 0.001) and also in MRD negative (HR = 0.38, P < 0.001) and MRD positive (HR = 0.53, P < 0.001) patients

Jurgen Versulius concluded his talk by highlighting that “the graft-versus-leukemia effect of alloHSCT is equally present in MRD positive and MRD negative patients”. Thus, “a personalized application of alloHSCT should take MRD response” as well as “the counterbalancing risk of NRM into account”.

Abstract S113

The next talk during this captivating oral session was given by Wendelien Zeijlemaker from the VU University Medical Center, Amsterdam, Netherlands. The speaker presented results from the prospective randomized phase III HOVON/SAKK H102 study. In this study, patients were profiled into four risk groups including good, intermediate, poor, and very poor.

The speaker suggested that further improvements are required to improve AML risk stratification such as the use of MRD and Leukemic Stem Cell (LSC) frequency. LSCs are a small population of stem cells that have properties including differentiation, self-renewal, and homeostatic control, and they contribute to the maintenance and propagation of AML. In AML, LSCs can contribute to disease resistance and lead to relapse.

In this study, data of from the HOVON/SAKK H102 trial were used to prospectively define, using flow cytometry, the leukemic CD34+CD38- stem cell and MRD frequencies to investigate the impact on patient outcomes.

In total, 242 AML patients in morphologic Complete Remission (CR) were included in this study. Patients were divided into four cohorts based on MRD positivity and LSC positivity; MRDneg + LSCneg (group 1, n = 136), MRDpos + LSCneg (group 2, n = 28), MRDneg + LSCpos (group 3, n = 58), MRDpos + LSCpos (group 4, n = 20).

The key results of the study were:
  • 3-year CIR in patients that were in groups 1,2, 3, and 4 were 35%, 43%, 53%, and 100% respectively, HR = 5.89, P < 0.001
  • 3-year OS in patients that were in groups 1, 2, 3, and 4 were 66%, 68%, 53%, and 100%, respectively, HR = 3.62
  • MRDpos + LSCpos patients have a significantly worse CIR (HR = 5.89) and OS (HR = 3.62) compared to patients that were MRDneg + LSCneg

Wendelien Zeijlemaker concluded the talk by highlighting that CD34+CD38 LSC frequency has an important additional value in MRD assessment. Most importantly, CD34+CD38 LSC frequency aids in the identification of very poor-risk patients in all different currently used risk categories. The speaker further suggested that both MRD and LSC could be integrated in future AML risk classification to better inform post-remission therapy.

Abstract S114

The final talk in this oral session was given by Dr Sylvie Freeman from the Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, U.K.

Induction therapy with cytarabine and anthracycline based regimens is guided by morphological response of patients after the first cycle. The impact of flow cytometric MRD assessment post-cycle 1 on the outcomes within AML risk subgroups including NPM1 Wild type standard risk is not very clear.

During this talk, the speaker presented results from their study which aimed to quantify the effect of MRD positivity for response after each cycle of induction therapy in younger AML patients.

Flow cytometric MRD (MFC-MRD) was monitored in AML patients treated in the UK NCRI AML17 trial (55675535) after each course of induction therapy. Following their first cycle of induction therapy, patients were allocated a risk group by a validated score (comprising of cytogenetics, White Blood Count [WBC], age, secondary disease, blast response to cycle 1, and mutation status). Poor risk patients received intensified therapy in cycle 2 with a view of proceeding to Stem Cell Transplantation (SCT).

In total, 1,555 patients (median age = 51 years) had MFC-MRD results after induction. Response data was available for 1,400 patients. After cycle 1, 70% achieved morphological CR, 14% had Resistant Disease (RD), and 16% were in Partial Remission (PR). Of the patients in CR (n = 984), 40% were MRD positive and 31% were MRD negative.

The key results of the study were:
  • 5-year OS in all patients that were MRD negative, MRD positive, PR, and RD; 63% vs 44% vs 37% vs 25%, P < 0.00001
  • 5-year OS in standard risk patients that were MRD negative, MRD positive, PR, RD; 67% vs 49% vs 46% vs 28%, P < 0.00001
  • 5-year OS for in MRD negative and MRD positive standard risk patients with NPM1wt in cycle 2; 32% vs 64%, P = 0.002
  • The effect of MFC-MRD status on relapse and OS was greater at cycle 2 compared to cycle 1

Dr Sylvie Freeman concluded her talk by highlighting that “MFC-MRD in CR post cycle 1 has similar outcomes to partial remission in younger patients with AML, particularly in patients with good and standard risk disease”. Additionally, “assessment of MFC-MRD post cycle 2 appears to provide additional discrimination to cycle 1”. She further concluded by suggesting that “MFC-MRD in courses 1-2 may be useful in further stratifying standard risk patients”.

References
  1. Altman J. et al. Deep molecular response to gilteritinib to improves survival in FLT3 mutation-positive relapsed/refractory acute myeloid leukemia. Abstract S110. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  2. Venditti A. et al. Risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia: results of the AML1310 trial of the GIMEMA group. Abstract S111. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  3. Versluis J. et al. Graft versus leukemia effect of allogenic stem cell transplantation and minimal residual disease in patients with AML in first complete remission. Abstract S112. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  4. Zeijlemaker W. et al. Leukemic stem cell frequency combined with MRD is an important biomarker to predict relapse in acute myeloid leukemia. Results from a prospective H102 study. Abstract S113. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  5. Freeman S. et al. Definition of partial response in younger AML patients after first induction course may be extended by inclusion of immunophenotypic detection of measurable residual disease. Abstract S114. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.