General AML|FLT3

Intensive treatment of AML – Oral abstract session at the 22nd congress of the EHA

During the 22nd Congress of the European Hematology Association (EHA), Madrid, Spain, the AGP were delighted to attend an enthralling oral session, which was solely dedicated to intensive therapies for Acute Myeloid Leukemia (AML). There were a range of talks discussing the use of targeted agents in combination with intensive chemotherapy in induction therapy in AML patients.

The session was co-chaired by the co-chair of our European (EU) Steering Committee (SC), Professor Charles Craddock, CBE, from the Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK, and a member of the EU SC, Professor Jorge Sierra, M.D., from the Hospital de la Santa Creu I Sant Pau Autonomous, University of Barcelona, Spain.

Abstract S790

Dr. Ana Garrido, M.D.,  from the Hospital de la Santa Creu I Sant Pau Autonomous, University of Barcelona, Spain, gave a talk during this session.

The speaker discussed 10-year follow-up results of risk-adapted treated de novo AML patients who were enrolled between 2003–2012 in the CETLAM-03 trial. In this study, patients were administered an intensive induction therapy course comprising of idarubicin, Intermediate-Dose cytarabine (IDC), etoposide, VP-16, and priming with Granulocyte-Colony Stimulating Factor (G-CSF) followed by mitoxantrone and IDC as consolidation therapy.

In total, 868 AML patients (median age = 53 years) were enrolled in this study. Post-consolidation therapy was based on risk allocation according to Medical Research Council (MRC) cytogenetic classification and was available for 802 patients; favorable (patients with favorable cytogenetics [n =99]) received either Autologous Stem Cell Transplantation (AuSCT) if Leukocyte Index (LI) was >20 or High Dose Cytarabine (HDAC) if LI <20, intermediate (patients in Complete Remission [CR], normal karyotype and absence of Fms Like Tyrosine Kinase 3–Internal Tandem Duplication [FLT3-ITD], [n = 581]) received AuSCT and adverse risk patients (patients not included in the either the favorable or intermediate risk group or with Minimal Residual Disease [MRD], [n = 122]) received either AuSCT or Allogenic Stem Cell Transplantation (ASCT).

The key results of the study were:
  • CR rate in all patients was 77%
  • 10-year Overall Survival (OS) in patients with favorable, intermediate, and adverse risk were 79±6%, 64±6%, and 41±3%, respectively; P < 0.001
  • 10-year Event Free Survival (EFS) in patients with favorable, intermediate, and adverse risk were 70±6%, 51±5%, and 33±3%, respectively; P < 0.001
  • 10-year Cumulative Incidence of Relapse (CIR) in patients with favorable, intermediate, and adverse risk were 22±1%, 47±2%, and 52±16%, respectively; P < 0.001

  • There were no differences in OS, EFS, and CIR in intermediate risk patients receiving either HDAC or AuSCT
  • In the adverse risk group, patients who underwent ASCT had a longer EFS and reduced CIR compared to patients who underwent AuSCT

The speaker concluded by stating that in patients with favorable MRC risk, “the adverse impact of high LI observed in our previous protocol was abrogated” with AuSCT. Additionally, ASCT reduced the risk of relapse inn advance risk patients.  

Abstract S791

The next talk was given by the co-chair of this session, Professor Charles Craddock, discussing results from the UK Trials Acceleration Programme RAvVA randomized phase II study (NCT01617226), which compared monotherapy with the Hypomethylating Agent (HMA) azacitidine (AZA) with AZA plus vorinostat (Histone Deacetylase [HDAC] inhibitor) combination therapy in AML patients as well as patients with high risk Myelodysplastic Syndrome (MDS).

Leukemic Stem Cells (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. However, the impact of AZA based therapy on LSC frequencies have not been elucidated yet. Hence, the study aimed to assess the impact of AZA based therapy on the LSC numbers as well as identify molecular predictors of outcomes of patients who were treated in the RAvVA trial.

In total, 259 patients with AML (n = 217) and MDS (n = 42) were randomized to receive either AZA monotherapy (n = 129) or AZA/VOR (n = 130). Next Generation Sequencing (NGS) and immunophenotypic quantification were used to identify genes and LSCs in patient samples.

The key results of the study were:
  • 1-year OS in patients treated with AZA and AZA/VOR; 43% vs 41%, P = 0.68

  • Reduced OS was significantly associated with mutations in CDKN2A (P < 0.001), IDH1 (P = 0.001), and TP53 (P < 0.001)

  • Quantification of Lymphoid-Primed Multipotential Progenitors (LMPP)-like LSC population during AZA based therapy showed no significant impact on LSC numbers in non-responders and partial responders
  • In CR patients, LSC numbers were reduced but not eradicated

Professor Charles Craddock spoke to the AGP about the findings of this study. The addition of vorinostat to AZA resulted in “no increase in response rate or survival in either de novo or relapsed disease” when compared to AZA monotherapy, which he said was “disappointing”. Furthermore, “molecular predictors of response and survival” were identified, most “importantly CDKN2A”, and “mutations in this gene were associated with poor response and survival”. Additionally, evaluation of the LSC population showed that, even in patients in CR, the LSC population was not eradicated with AZA therapy. He further added that the RAvVA study identified a “molecular footprint that predicts response and also identifies a potential mechanism of action of AZA” and suggested that new combination partners for AZA are required for therapy in AML patients.

Abstract S792

The next talk was presented by Associate Professor Betul Oran, M.D., from The University of Texas MD Anderson Cancer Center (MDACC), Houston, US.  

The speaker presented results from a retrospective study, which aimed to assess the outcomes of FLT3-ITD mutated AML patients who received sorafenib (tyrosine kinase inhibitor) maintenance after ASCT between January 2010 and October 2016 at the MDACC. The primary endpoints of the study were Progression Free Survival (PFS) and OS at 24 months.

In total, 214 FLT3-ITD positive AML patients who underwent ASCT during this period were identified. Thirteen patients were administered sorafenib maintenance and twenty-six patients were used as control and did not receive sorafenib maintenance.

The key results of the study were:
  • 24-month PFS post-ASCT in patients who received sorafenib maintenance and control; 82% vs 45%, HR = 0.3, P = 0.1

  • 24-month OS post-ASCT in patients who received sorafenib maintenance and control; 100% vs 60%, P = 0.035

  • Three patients on sorafenib maintenance relapsed post-ASCT
  • Eleven patients in the control group had disease progression post-ASCT

The speaker concluded her talk by stating that sorafenib maintenance was tolerable and can “produce long term durable remissions” after ASCT in FLT3-ITD mutated AML”. She further added that the findings of this study should be assessed further in a prospective clinical study. 

Abstract S793

The final talk of this session was presented by Dr. Moshe Y. Levy from Baylor University Medical Center, Dallas, TX, US.

Vadastuximab talirine (33A) is a CD33-directed antibody drug conjugate that has demonstrated an enhanced cytotoxic effect through upregulated CD33 expression. 

The speaker presented results from a phase Ib dose-escalation study (NCT02326584), which evaluated the safety  and anti-leukemic activity of escalating doses of 33A in combination with 7+3 induction therapy in newly diagnosed AML patients.

In the dose escalation phase, patients were divided into two cohorts; split-dose cohort and single dose cohort. In the split-dose cohort, 42 patients (median age = 45.5 years) received a split dose of 33A in combination with 7 + 3 induction therapy on days 1 and 4. In the single dose cohort, 25 patients (median age = 58 years) received a single dose of 33A on day 1. Responses and MRD were evaluated on days 15 and 28.  

They key results of the study were:
  • CR, Complete Remission with Insufficient Recovery Counts (CRi), and Morphologic Leukemia-Free Status (mLFS) were 60%, 17%, and 12%, respectively, in patients in the split dose cohort
  • CR, CRI, and mLFS were 50%, 18%, and 13%, respectively, in patients in the single dose cohort
  • Non-hematologic Treatment Emergent Adverse Events (TEAEs) of any grade occurring in ≥25% of patients were nausea (62%), as well as diarrhea and constipation (38% each)
  • The CR + CRi (CRc) rate in all patients (n = 70) was 73%
  • 79% of evaluable patients with blast clearance achieved MRD negativity
  • 30-day and 50-day mortality rates in all patients were 1% and 7%, respectively

33A was safely combined with 7+3 with acceptable count recovery in AML patients, the speaker concluded. He further added that a “high remission rate with the 1st induction cycle was observed, of which majority were MRD negative”.

References
  1. Garrido A. et al. Final results of the CETLAM LAM-2003 trial for the treatment of primary AML up to the age of 70. Abstract S790. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  2. Craddock C. et al. Molecular predictors of response to azacitidine therapy: the results of the UK trials acceleration programme RAVVA study. Abstract S791. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  3. Ahmed S. et al. Sorafenib maintenance in FLT3-ITD mutated acute myeloid leukemia after allogenic stem cell transplantation. Abstract S792. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  4. Levy M. Y. et al. A phase Ib study of the combination of vadastuximab talirine and 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Abstract S793. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.