General AML

ASH 2017 | Novel immune-based approaches for therapy in AML

At the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, on Monday 11th December 2017, there was an oral abstract session focused on the use of immune-based therapy in Acute Myeloid Leukemia (AML). This oral session was co-chaired by Monica L. Guzman, from Weill Cornell Medical College, and Courtney DiNardo, from The University Texas MD Anderson Cancer Center.

Abstract 811

The first talk during this session was given by Lihua Budde, MD, from the City of Hope, Duarte, CA.

CD123, the Interleukin 3 α-chain receptor (IL3Rα), is differentially and significantly overexpressed in a majority (93%) of patients with AML and MDS. Binding of Interleukin 3 (IL-3) to CD123 can induce hematopoietic progenitor cell differentiation, proliferation and also up-regulation of anti-apoptotic proteins. CD123 has been identified as a marker for Leukemic Stem Cells (LSCs), which are a small population of stem cells that have properties of differentiation, self-renewal and homeostatic control, and which contribute to the maintenance and propagation of AML. In AML, a LSC reservoir can lead to disease resistance, relapse and often death in patients.

Lihua Budde reported results from the first-in-human phase I dose-escalation study (NCT02159495) of CD123- Chimeric Antigen Receptor (CAR) T cell therapy in patients with CD123+ Relapsed or Refractory (R/R) AML and Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).  CD123 CAR T cells contains a CD123-specific single-chain variable fragment, in combination with a CD28 costimulatory domain and CD3-ζ signaling domain, targeting different epitopes on CD123. Pre-clinical studies have demonstrated that CD123 CAR T cells exhibit an antigen-specific activation, antigen-driven proliferation and are effective in killing autologous AML blasts.

The main objective of this phase I study was to evaluate the safety and activity of CD123CAR T cells in patients with R/R AML (Cohort 1, n = 6) and BPDCN (Cohort 2). Patients were administered a lymphodepleting regimen (fludarabine 25–30 mg/m2 daily for 3 Days and cyclophosphamide 300 mg/m2 daily for 3 Days) followed by a single dose of CD123 CAR T cells at two different dose levels (DL) including 50M (DL1, n = 2) or 200M (DL2, n = 4). Here we report on the results from the AML cohort (n = 6). Patients in the AML cohort had refractory AML following Allogenic-Hematopoietic Stem Cell Transplantation (allo-HSCT) and a median of six prior lines of therapy).1

  • Of the patients treated at DL1 (n = 2)
    • One patient achieved a morphologic leukemic free state that lasted two months
      • After second infusion at 3-months, there was a blast reduction from 77.9% to 0.9% after 35 Days
    • Of the patients treated at DL2 (n = 4)
      • One patient achieved Complete Response (CR) and was transfusion independent
        • Proceeded to allo-HSCT on Day 70 and was Minimal Residual Disease (MRD) negative CR at Day +161 post-transplant
      • One patient with CR prior to treatment remained in CR at Day 28 and proceeded to second allo-HSCT
      • Two patients had reductions in blast count but did not achieve remission
    • Adverse Events (AEs) which were manageable and reversible occurred including cytokine release syndrome (n = 5), adenoviral pneumonia (n = 1) and grade 3 rash due to drug hypersensitivity (n = 1)

The speaker noted that the findings of this first-in-human phase I trial of CD123 CAR T cell therapy have demonstrated the safety and feasibility of targeting CD123 in AML. Additionally, infusions of up to 200M CAR T cells are safe with no treatment related AEs observed and “promising anti-leukemic activity” was observed in patients with R/R AML.

Lihua Budde further concluded by adding that no myeloablative effects were observed in this trial which supports the evaluation of this immune-based therapeutic strategy in “both transplant eligible and ineligible patients”.

Abstract 813

Naval Daver, from The University Texas MD Anderson Cancer Center, also gave a talk during this session, presenting preliminary results from the phase Ib dose-escalation study (NCT02670044), which is evaluating the safety, tolerability and efficacy of novel combinations of venetoclax (VEN), a BCL-2 inhibitor, with cobimetinib (cobi), a MEK inhibitor, or idasanutlin (idasa), a MDM2 inhibitor, in patients ≥ 60 years old with R/R or secondary AML.2

As of 21st August 2017, a total of 54 patients were treated with either VEN plus cobi (Arm A, n = 30 [median age = 71.5 years]) or idasa (Arm B, n = 24 [median age = 73 years]). Arm A was split into four cohorts consisting of patients receiving cobi 40 mg plus 400 mg (n = 4), 600 mg (n = 7), 800 mg (n = 12 [on-going cohort]) of VEN and cobi 60 mg plus VEN 400 mg (n = 7). Patients on Arm A received oral VEN daily plus oral cobi on Days 1–21.

Arm B was split into four cohorts consisting of patients receiving idasa 200mg plus 400 mg (n = 3), 600 mg (n = 8 [on-going cohort]) of VEN, idasa 400 mg plus VEN 400 mg (n = 9) and idasa 150 mg plus VEN 600 mg (n = 4). Patients on Arm B received oral VEN daily plus oral idasa on Days 1–5 in 28-day cycles.

Key findings:
  • Safety
    • Arm A
      • Most common grade ≥ 3 AEs include diarrhea (37%), febrile neutropenia (37%), pneumonia/ lung infection (33%) and sepsis/ septic shock (10%)
      • 30-day mortality rate: 6.7%
      • Dose Limiting Toxicity (DLT) of grade 3 diarrhea occurred in one patient in the VEN 600 mg plus cobi 40 mg cohort
      • DLT of grade 3 diarrhea (n = 1) and grade 3 decrease in ejection (n = 1) occurred in the VEN 400 mg plus cobi 60 mg cohort
      • VEN 400 mg plus cobi 60 mg was discontinued due high rates of grade ≥3 diarrhea (57%)
    • Arm B
      • Most common grade ≥ 3 AEs include diarrhea (8%), nausea (4%), febrile neutropenia (29%) pneumonia/ lung infection (25%) and sepsis/septic shock(38%)
      • 30-day mortality rate: 43% DLT of grade 3 generalized muscle weakness (n = 1) and grade 3 diarrhea (n = 1) occurred in the VEN 600 mg plus idasa 200 mg cohort
      • DLT of grade 3 acute coronary syndrome (n = 1) and elevated bilirubin (n = 1) occurred in the VEN 400 mg plus idasa 400 mg cohort
      • DLT of grade 4 prolonged neutropenia occurred in two patients in the VEN 600 mg plus idasa 150 mg cohort
    • Efficacy
      • Arm A
        • Anti-leukemic response: 20% (6/30)
          • CR/CRi/CRp: 17% (5/30)
          • Morphologic Leuekmic Free State (MLFS): 3% (1/30)
        • Arm B
          • Anti-leukemic response: 33% (8/24)
            • CR/CRi/CRp: 17% (4/24)
            • MLFS: 13% (3/24)
          • Anti-leukemic response for patients in the VEN 600 mg plus idasa 200 mg and VEN 600 mg plus idasa 150 mg cohorts were 38% (3/8) and 75% (3/4) respectively
        • High responses were observed in patients with IDH1/2 mutations at baseline in Arm B (63%) but not in Arm A (17%)
        • Low responses were observed in patients with TP53 mutations at baseline in Arm A (0%) and Arm  B (25%)

In summary, this is the first study evaluating novel-novel oral combinations with VEN in patients with AML.  The primary results demonstrate an “early clinical activity” in R/R AML patients and the ORR observed for VEN 600 mg plus 200 mg idasa is promising. The Maximum Tolerated Dose (MTD) was not determined in both arms and the speaker noted that the study is still ongoing.

Abstract 815

Farhad Ravandi, from the University Texas MD Anderson Cancer Center, presented results from a phase II study (NCT02464657) of nivolumab, a PD-1 inhibitor, in combination of cytarabine and idarubicin in newly diagnosed AML.3

In total, 35 patients (median age = 54 years) with newly diagnosed de novo (n = 26), therapy-related AML (n = 3), sAML (n = 4), and high-risk MDS (n = 2) were enrolled in this study. During induction, patients were administered one or two cycles of cytarabine (1.5 g/m2 over 24 hours, Days 1–4) and idarubicin (12 mg/m2,  Days 1–3) plus nivolumab (3 mg/kg on Day 24 ± 2 Days continued every two weeks for up to a year).  Consolidation therapy  for patients achieving a CR consisted of cytarabine (0.5 g/m2 by IV infusion over 24 hours daily x 3) and idarubicin (8 mg/m2 iv daily x 20 for up to five cycles. For mainetenance, patients were administered nivolumab (3 mg/kg every two weeks for total of up to 1 year).

Key findings:
  • Median follow-up: 8.4 months (range, 0.7–21.1 months)
  • Median number of nivolumab administered: 6 (range, 0–13)
    • CR/CRi/CRp: 76%
    • 8-week mortality rate: 9%
    • Median relapse free survival: 17.3 months
    • Median overall survival: 8 months
    • Median event free survival: 8.3 months
    • Median remission duration in patients treated with IA plus nivolumab compared to IA alone: NR vs 27.8 months, P = 0.247
    • Grade 3–4 immune mediated toxicities occurred in six patients including rash (n = 2), pancreatitis (n = 1), cholecystitis (n = 1) and colitis (n = 1)

    Multicolor flow cytometry was performed on baseline (prior to nivolumab administration) and treatment Bone Marrow and peripheral blood in order to assess the T cell repertoire and expression of co-stimulatory receptors or ligands on T-cell subsets and leukemic blasts respectively. Baseline BM was evaluated in both responders (n = 19) and non-responders (n = 5).

    • Responders had a higher frequency of CD3+ T-cell infiltrates compared to non-responders
    • Compared to responders, non-responders had a significantly higher percentage of CD4 T effector cell co-expressing PD1 and TIM3; P = 0.04
    • Compared to responders, non-responders had a higher percentage of CD4 T effector cell co-expressing PD1 and LAG3

    The speaker concluded by stating that the addition of nivolumab to cytarabine and idarubicin induction chemotherapy was “feasible and safe” in younger AML patients. He further added that CD4+ T effector cells display an “exhausted phenotype” in non-responders, which could potentially be reversed.

    Abstract 816

    The final talk in this captivating oral abstract session was delivered by Geoffrey L. Uy, from the Washington University School of Medicine, Saint Louis, MO.4

    Selinexor is a novel, Selective Inhibitor of Nuclear Export (SINE) compound, which inhibits Exportin 1 (XPO1), a karyopherin protein, that facilitate the nuclear export of Tumor Suppressor Proteins (TSPs). In AML patients, high levels of XPO1 is associated with poor outcomes. Preclinical studies of selinexor in combination with cytarabine have demonstrated that this regimen could prolong the survival of leukemic mice. Hence the rationale for this study.

    Geoffrey L. Uy, reported results from the phase I study (NCT02416908) which tested the safety and efficacy of selinexor in combination with chemotherapy in patients with R/R AML.

    Overall, 33 R/R AML patients with a median age of 56 years (range, 21–70 years) were administered selinexor (60 mg/d on Days 1, 4, 8 and 11) in combination with CLAG (cladribine [5 mg/m2 on Days 4–8], cytarabine [2000 mg/m2/d on Days 4–8) and granulocyte- colony stimulating factor (300 mcg SC/d on Days 3–8)]. The primary endpoint of the study was Complete Remission (CR) rate.

    Key Findings:
    • CR/CRi rate: 45% (15/33)
      • CR rate : 24% (8/33)
      • CRi rate: 21% (7/33)
    • Safety
      • Serious Adverse Events (AEs) occurred in 204 patients mostly due to sepsis (n = 7) and other infections (n = 4)
      • 60-day mortality rate; 6%
        • Two deaths occurred as result of lung infection and respiratory failure respectively
      • Eighteen patients of the first 30 treated underwent allo-HCT

    The speaker concluded by stating that selinexor in combination with CLAG was “highly active” in patients with R/R AML. The CR rates observed were “encouraging” and indicate that this regimen may serve as a bridge which allows a high percentage of patients to undergo allo-HCT. He also noted that accrual into this study is expected to end in January 2018.

References
  1. Budde L. et al. Remissions of Acute Myeloid Leukemia and Blastic Plasmacytoid Dendritic Cell Neoplasm Following Treatment with CD123-Specific CAR T Cells: A First-in-Human Clinical Trial. Oral Abstract #811: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  2. Daver N. et al. Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML. Oral Abstract #813: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  3. Ravandi F. et al. Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia. Oral Abstract #815: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  4. Uy G.L. et al. Selinexor in Combination with Cladribine, Cytarabine and G-CSF for Relapsed or Refractory AML Oral Abstract #816: 59th ASH Annual Meeting and Exposition, Atlanta, GA.