General AML

ASH 2017 | Two ALFA studies reporting on frontline therapy in younger and older patients with AML: Clofarabine-based consolidation in AML (ALFA-0702); and RIC-SCT in elderly AML patients (ALFA-1200) 

On Sunday 10th December 2017, during the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, the AML Global Portal (AGP) was delighted to attend a captivating oral presentation session entitled “Acute Myeloid Leukemia: Clinical Studies: Advances in Frontline Therapy: Induction, Consolidation, and Maintenance”.  The session was co-chaired by Daniel A. Pollyea, MD, from the University of Colorado Denver and B. Douglas Smith, MD, from John Hopkins University.

Two abstracts  from clinical studies in Acute Myeloid Leukemia (AML) by the Acute Leukemia French Association (ALFA) group were presented at this session. Here we discuss the key highlights of the data presented.

Abstract 465

In February 2017, the AGP reported the phase II randomized  ALFA-0702 study (NCT00932412) which compared the efficacy and safety of  Intermediate Dose cytarabine (IDAC) in combination with clofarabine (CLARA) versus High Dose cytarabine (HDAC) as post-remission chemotherapy in young patients with intermediate or unfavorable risk AML in First Complete Remission (CR1) and no identified donor for allogenic Stem Cell Transplantation (SCT). The results of the study demonstrated that CLARA could prolong the Relapse Free Survival (RFS) of young AML patients in CR1 which was mainly attributable to the reduction of relapse in this group of patients.1

The effects of CLARA regimen according to patient subsets defined by Single Nucleotide Polymorphism (SNP)-array analysis was further evaluated in this phase III ALFA 0702 study. Laurène Fenwarth, MD, from the CHU Lille, Lille, France presented results from this analysis.2 SNP-array is a high resolution approach that can detect including Copy Number Alterations (CNA) and Copy-Neutral Losses of Heterozygosity (CN-LOH).  

In this ALFA-0702 study, 221 AML patients (median age = 48 years) in CR1 were randomly assigned to receive either 3 consolidation cycles of HDAC (n = 114) or CLARA (n = 107). SNP-array analysis was successfully analyzed in Bone Marrow (BM) or Peripheral Blood (PB) samples from 187 patients at diagnosis in the CLARA (n = 92) and HDAC (n = 95) arms.

Key findings:
  • Median number of genomic SNP-Array abnormalities reached 2 per patient (range, 0–46) and did not significantly differ in both arms
  • Most common SNP-array abnormalities were CNAs
    • Loss = 54%
    • Gain = 38%
    • CN-LOH = 8%
  • Complex Karyotype (CK) with at least three chromosomal abnormalities was observed in 37 patients in the CLARA (n = 11) and HDAC arms (n = 16)
    • Median RFS in patients with CK in the CLARA and HDAC arm: 22 vs 8 months, P = 0.027
  • Micro-complex karyotype defined by four or more SNP-array abnormalities was observed in 56 patients in the CLARA (n = 27) and HDAC (n = 29) arms
    • Median RFS in patients with micro-complex karyotype in the CLARA and HDAC arm: 22 vs 10 months, P < 0.0001
  • 4-year RFS in patients with micro-complex karyotype (n = 27) and non-micro-complex (n = 65) karyotype respectively in the CLARA arm: 44% vs 47%
  • 4-year RFS in patients with micro-complex karyotype (n = 29) and non-micro-complex (n = 66) karyotype respectively in the HDAC arm: 14% vs 47%

The speaker highlighted that the findings of their study suggest that CLARA benefits both patients with complex karyotypes in conventional cytogenetics and micro-complex karyotypes defined by four or more SNP-Array abnormalities, which enabled the identification of a new subset of AML patients that could potentially benefit from clofarabine-based consolidation regimen.

Laurène Fenwarth, MD, concluded by stressing the value of SNP-array, an approach that detects cryptic lesions and brings an opportunity to better characterize molecular profile of AML. The speaker added that SNP-array appears to be a relevant approach that could help improve AML management and refine adverse patient subgroups that could potentially benefit from new alternative consolidation regimens.

Abstract 466

The second study from the ALFA group was presented by Thorsten Braun from the Hospital Avicenne, University Paris 13, Bobigny, France. This talk was focused on the results from the prospective ALFA-1200 study (NCT01966497), which aimed to assess the benefit of Reduced Intensity Conditioning Stem Cell Transplantation (RIC-SCT) in older patients with AML.3

The benefit of RIC-SCT in older patients is difficult to assess prospectively in this group of patients due to lower SCT numbers and strong selection biases. Hence the rationale for this study.  

In total, 509 AML patients (≥ 60 years) with a median age of 68 years were enrolled into the ALFA-1200 trial between 2012–2016. Patients were risk stratified according to the European LeukemiaNet (ELN) stratification into favorable- (n = 76), intermediate- (347) and adverse- (n = 86) risk groups. Overall, 214 AML patients aged 60–70 years with intermediate- (n = 176) or adverse- (n = 38) risk in First Complete Remission (CR1) were eligible for SCT after treatment with chemotherapy. Of these, 90 patients in the ELN intermediate- (n = 75) and adverse- (n = 15) risk group were transplanted in CR1.

Key findings in patients (n = 90) transplanted in CR1:
  • Median post-transplant follow-up: 18 months
  • 2-years transplant related mortality: 20.4%
  • 2-years cumulative incidence of relapse: 22.7%
  • 2-years Overall Survival (OS): 65.1%
  • Post-SCT survival was not influenced by age, secondary AML diagnosis, ELN-risk, type of stem source or type of conditioning regimen
  • Patients in the adverse ELN-risk subset had an OS benefit associated with SCT; HR = 0.20, P = 0.006
  • Patients in the intermediate ELN-risk subset did not have an OS benefit associated with SCT; HR = 1.08, P = 0.76

The speaker highlighted that the study is limited by low patient numbers and short follow-up but summarized by stating that RIC-SCT in first remission “is the best post-remission option for alder patients with adverse-risk AML”. However, the benefit of RIC-SCT is questionable in older patients with intermediate ELN-risk AML.

The speaker concluded by suggesting that a longer follow-up and continued accrual should allow for a better assessment of long-term cure rates associated with RIC-SCT and intensive chemotherapy respectively.

References
  1. Thomas X. et al. Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission. J Clin Oncol. 2017 Feb 21. DOI: 1200/JCO.2016.70.4551. [Epub ahead of print].
  2. Fenwarth L. et al. Clofarabine-Based Consolidation Improves Relapse-Free Survival of Patients with Acute Myeloid Leukemia with Complex or Micro-Complex Karyotype: Results from the Randomized ALFA-0702 Study. Oral Abstract #465: ASH 59th Annual Meeting and Exposition, Atlanta, GA.
  3. Gardin C. et al. Clofarabine-Based Consolidation Improves Relapse-Free Survival of Patients with Acute Myeloid Leukemia with Complex or Micro-Complex Karyotype: Results from the Randomized ALFA-0702 Study. Oral Abstract #466: ASH 59th Annual Meeting and Exposition, Atlanta, GA.