General AML,   FLT3,  NPM1,  TP53

Innovative AML treatment with approved agents – Oral abstract session at ASH 2017

During the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, the AML Global Portal (AGP) was delighted to attend an entrancing oral presentation session which was titled “Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation Innovative AML Treatment with Approved Agents”. The session was jointly chaired by Francesco Buccisano, MD, from the University Tor Vergata and Tara L. Lin, MD, from the University of Kansas.

Several talks presented at this oral abstract session were focused on how chemotherapeutic and novel targeted agents can be advanced or modified for therapy in Acute Myeloid Leukemia (AML) and Acute Promyelocytic Leukemia (APL). Here we present the key highlights from abstracts presented at this session.

Abstract 146

Jianxiang Wang, MD, from the Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China gave a talk during this oral abstract session1.

Standard induction therapy consists of the use of a daily dose of 100–200 mg/m2 cytarabine. However, it is not very clear whether a higher dosage of cytarabine can improve outcomes of adult AML patients.

The speaker presented results from the phase III randomized controlled trial (ChiCTR-TRC-10001202) which aimed to evaluate whether higher dosage of cytarabine can improve the outcomes of adult AML patients. The primary endpoint of the study was Disease Free Survival (DFS).

Overall, 591 newly diagnosed de novo AML patients (median age = 36 years, range, 15–55) were randomly assigned to receive induction therapy consisting of either intermediate-dose cytarabine (100 mg/m2/d as a 12-hour IV infusion on Days 1–4 and 1,000 mg/mevery 12 hours as a 3-hour IV infusion on Days 5–7 [n =295]) or conventional-dose cytarabine (100 mg/m2/d as a 12-hour IV infusion for 7 Days [n = 296]) with homoharringtonine and daunorubicin. The median follow-up of survivors was 30.4 months.

Key findings:
  • Complete Remission (CR) in the Intermediate-dose and conventional-dose arms respectively; 86.8% (256/295) vs4% (229/296), P = 0.003
  • 30-day early mortality rate in the intermediate-dose and conventional-dose arms respectively; 2.4% vs 4%, P = 0.355
  • Median duration of thrombocytopenia in the intermediate-dose and conventional-dose arms respectively; 22 vs 20 days, P = 0.02
  • 3-year DFS in the intermediate-dose and conventional-dose arms respectively; 65.3% vs 0%, P = 0.0177
  • 3-year DFS in intermediate-risk group patients in the intermediate-dose and conventional-dose arms respectively; 69.7% vs1%, P = 0.004
  • In non-CBF AML CR patients whom are Minimal Residual Disease (MRD) negative, intermediate-dose cytarabine significantly improved survival compared to conventional dose; P = 0.035

Jianxiang Wang concluded his talk by highlighting that the results from this phase III study demonstrates that compared to conventional cytarabine, dose escalation of cytarabine in the induction regimen was well tolerated and prolonged the survival particularly in patients with intermediate-risk cytogenetics. Additionally, “induction regimen with dose escalation of cytarabine could produce deeper complete remission”.

Abstract 147

In patients with newly diagnosed APL, the prolonged use of All Trans Retionic Acid (ATRA) in combination with Arsenic Trioxide (ATO) has been shown to be effective. However, there is a paucity of studies on the efficacy of ATRA-ATO in relapsed APL patients.  

At this oral session, Laura Cicconi from the University Tor Vergata, Rome, presented results from a retrospective study which evaluated in a cohort of APL patients relapsing after ATRA plus chemotherapy, the efficacy of prolonged ATRA-ATO not followed by autologous or allogenic stem cell transplant (SCT).2

In total, 20 relapse APL patients (median age = 43.5 years, range, 18–80 years) who were treated with prolonged ATO-ATRA between 2005–2017 at two hematology units including the Policlinico Tor Vergata and the Policlinico Umberto I were retrospectively analyzed in this study.  Patients were administered ATRA-ATO induction and consolidation not followed by SCT.

  • Molecular Remission (CRm) after the 2nd ATO-ATRA cycle; 90% (18/20)
  • Molecular persistence of disease occurred in two patients which led to discontinuation of therapy
  • Two patients received allogenic and autologous HSCT respectively after the 3rd ATO-ATRA cycle

Eighteen patients were treated with a repeated ATRA-ATO cycle due to prolonged remission (n = 9), age or unfitness for intensive chemotherapy (n = 5), refusal of HSCT (n = 2) or lack of a suitable donor (n = 2). The median follow-up was 58 months.

  • Fourteen patients were alive in prolonged CRm
  • 5-year DFS; 68.5%
  • 5-year Cumulative Incidence of Relapse (CIR); 22.6%
  • Progressive disease and relapse occurred in two and five patients respectively
  • Death occurred due to disease progression (n = 4) or unrelated causes (n = 1)

Laura Cicconi highlighted that although this study was retrospective, the findings suggest that prolonged ATRA-ATO without SCT might be an effective option for patients with relapsed APL after long first CR. She concluded by suggesting that a prospective study should be carried out in order to confirm the findings of this retrospective study.

Abstract 148

The next talk during this session was given by Maximilian Stahl, MD, from the Yale Cancer Center, New Haven, CT. He presented data from an international multi-center analysis, which aimed to evaluate if different schedules of Hypomethlyating Agents (HMAs) in combination with specific mutational profile can be used to predict response and survival in patients with Relapsed or Refractory (R/R) AML3.

Overall, 656 relapsed and refractory AML patients who were treated with HMAs between 2006–2016 in Europe and US were analyzed. Patients received HMA schedules consisting of either azacitidine in a 7-day schedule (77%), 5-day schedule AZA (18%), 7-day schedule with a weekend break (5-2-2 schedule [2%]) or decitabine in a 5-day (72%) or 10-day (20%) schedule.

FLT3, NPM1 and TP53 mutational profile status was available in 269, 228, and 64 patients respectively. Of these, 17%, 24 %, and 6% were found to have FLT3, NPM1 and TP53 mutation status respectively

Key findings:
  • Increased odds of achieving CR was associated with:
    • Presence of 5% Peripheral Blood (PB) blasts; Odds Ratio (OR) = 2.05, P = 0.0046
    • Duration of CR1 ≥ 6 months; OR = 1.76, P = 0.0108
    • 10-day schedule of DEC; OR = 2.23, P = 0.0215
  • Inferior OS was associated with:
    • Percentage of circulating blasts > 5%, HR 1.38, P = 0.0041
    • Blasts in the Bone Marrow (BM) > 20%, HR = 1.23, P = 0.004
    • Platelet count of ≤ 30 x109/L, HR = 1.24, P = 0.04
  • CR/CRi rate in patients who received DEC 10-day schedule and other HMA schedules; 28% vs7% respectively, P = 0.04
  • OS was not significantly different in patients who received 10-day DEC schedule and other HMA schedule; 8 vs6 months respectively, P = 0.13
  • Compared to non-mutated patients, patients with FLT3 (P = 0.9371), NPM1 or TP53 (P = 0.9042) mutations did not have a worse OS

In summary, the mutational status (FLT3, NPM1, and TP53) did not have an impact on response or OS of R/R AML patients treated with HMAs.

Maximillan Stahl concluded by highlighting that patients treated with 10-day schedule of DEC had a higher CR/CRi rate which is consistent with published data. He however, noted that this improved response rate did not translate into an improved OS in R/R AML patients.

Abstract 149

Anna B. Halpern, MD, from the University of Washington, Seattle, WA, gave the next talk in this session. She presented the final results from the phase I/II study (NCT02044796) of Granulocyte Colony Stimulating Factor (G-CSF), cladribine, cytarabine and dose –escalated mitoxantrone (G-CLAM) in adults with R/R AML4

This was a two-part study, the aim of the phase I portion was to determine the Maximum Tolerated Dose (MTD) of mitoxantrone as part of the G-CLAM regimen. In total, 26 R/R AML patients were treated in the dose escalating phase I part of this study. Patients were treated in a cohort of 6–12 patients and were assigned to one of four dose levels of mitoxantrone (12, 14, 16 or 18 mg/m2/d on Days 1–3).

Key findings:
  • Dose Limiting Toxicities including encephalopathy and cardiogenic shock occurred in two patients respectively at dose level 4 (18 mg/m2 mitoxantrone)
  • MTD = 16 mg/m2/day mitoxantrone

The phase II portion of the study aimed to evaluate the safety and efficacy of G-CLAM at the MTD of mitoxantrone. Forty R/R AML patients (median age = 63 years) received GCLAM at the MTD of mitoxantrone.

Key findings:
  • Overall Response Rate (ORR); 60%
    • CR = 28% (11/40)
    • CRi = 32% (13/40)
  • Treatment Mortality Rate (TRM) within 28 Days of therapy; 5%
  • Median OS; 11.5 months
  • Most common grade ≥ 3 AEs include rash and hypoxia
  • Compared to patients (n = 41) treated with G-CLAM with mitoxantrone at 10 mg/m2/day outside of this study, GCLAM with mitoxantrone at 16 mg/m2/day significantly improved OS; HR = 0.45, P = 0.01

In summary, GCLAM with mitoxantrone at 16 mg/m2/day was well tolerated with a low TRM rate in R/R AML patients. The speaker noted that the results from this phase I/II study demonstrates that the G-CLAM regimen at the MTD of mitoxantrone has a potent anti-leukemic activity in R/R AML.

Additionally, G-CLAM with mitoxantrone at 16 mg/m2/day appears to better survival compared to mitoxantrone at 10/mg/m2/day which has been used in previous trials and other salvage regimens.

Abstract 150

The final talk in this session was given by Anjali S. Advani, MD, from the Taussig Cancer Institute, Cleveland Clinic, OH5.

Early findings from the phase I dose-escalation study (NCT02070458) of mitoxantrone, etoposide, cytarabine (MEC) in combination with ixazomib, an oral proteasome inhibitor, in patients with R/R AML demonstrated that this combination was well tolerated with an MTD of ixazomib at 1.0 mg. Additionally, MEC in combination with ixazomib led to an ORR of 55% in R/R AML patients. The speaker presented the final results of this phase I study.

Overall, 30 patients (median age = 58 years) with R/R AML were enrolled and treated at the Cleveland Clinic and University Hospitals of Cleveland from October 2014 to January 2017. Patients were administered MEC: M (8 mg/m2), E (80 mg/m2), C (1000 mg/m2) intravenously on Days 1-6 in combination with ixazomib orally on Days 1, 4, 8, and 11. Ixazomib was administered at one of three dose levels including 1.0 mg 2.0 mg and 3.0 mg. Eighteen patients were treated at the MTD. One cycle of treatment was administered and response was assessed by Day 45.

Key findings:
  • ORR; 53%
  • Median OS; 4.9 months
  • Early Mortality Rate; 10%
  • Grade 3–5 non-hematologic toxicities occurred ≥ 15% of patients including infection (74%), febrile neutropenia (85%), hypotension (18%), hypoxia (19%), mucositis (15%), hypokalemia (33%) and Hypoalbuminemia (30%)

In order to identify the association of gene expression with response to MEC plus ixazomib, RNA sequencing was performed on samples from 17 and 11 patient pre-treatment and post-treatment samples.

  • Genes involved in erythoblast differentiation, inflammatory response, cytokine/ STAT signalling and hypoxia were differentially expressed in responders and non-responders
    • Two genes were significantly different between responders and resistant patients including IFI30 (may increase the levels of anti-oxidants and lead to a decreased ER stress) and RORα (tumor suppressor gene)
      • IFI30 was highly expressed in non-responders
      • RORα was down-regulated in non-responders

The speaker concluded by stating that the combination of MEC and ixazomib was well tolerated and effective in R/R AML patients. Moreover, the findings from the gene profiling of this study may be used to identify non-responders to this combination and aid further therapeutic targets.

Additional in vitro study investigating whether “RORα agonists may help sensitize resistance cells” to treatment are planned.

References
  1. Wei J. et al. The Intermediate Dose Verse Conventional Dose Cytarabine in Induction Therapy in Adult Acute Myeloid Leukemia: A Phase III Randomized Controlled Trial. Oral Abstract #146: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  2. Cicconi L. et al. Prolonged Arsenic Trioxide (ATO) and All-Trans Retinoic Acid (ATRA) Therapy for Relapsed Acute Promyelocytic Leukemia. Oral Abstract #147: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  3. Stahl M. et al. The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis. Oral Abstract #148: 59th  ASH Annual Meeting and Exposition, Atlanta, GA.
  4. Halpern A. B. et al. G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (GCLAM) in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Grade Myeloid Neoplasms: Final Results from a Phase 1/2 Trial. Oral Abstract #149: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  5. Advani A.S. et al. A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib (MLN9708) for Relapsed/ Refractory Acute Myeloid Leukemia (AML). Blood. 2016; 128: 4065.
  6. Advani A.S. et al. A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib (MLN9708) for Relapsed/ Refractory Acute Myeloid Leukemia (AML): Final Results. Oral Abstract #150: 59th ASH Annual Meeting and Exposition, Atlanta, GA.