Evolving Treatment Paradigms in AML: New Data and Clinical Trials That Could Change Clinical Practice

Published on February 17, 2020 in Treatment

Naval Daver, MD
Associate Professor
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas
Elizabeth Paczolt, MD, FACNM
Contributing Author

Introduction

The treatment of acute myeloid leukemia (AML) has advanced significantly over the past few years due to an improved understanding of the roles of molecular stratification, clonal heterogeneity, and clonal evolution in therapy and prognostication for patients with the disease. While clinicians have traditionally used factors such as age and performance status (PS) to guide therapy, new and very predictive molecular and chromosomal factors now provide critical information about patient prognosis and can also predict therapy pathways and guide intensity of therapy to improve patient management and overall outcomes.


Several new therapies are undergoing continual investigation for treatment of AML, including monotherapies and 2- and even 3-drug novel combinations. These are aimed a several patient populations, including those at high risk for defined by molecular abnormalities1 (Figure 1):

Figure 1
Figure_1

One new epigenetic agent undergoing study is guadecitabine, considered a more potent methylating agent than decitabine. The Astral-1 study was a phase 3 trial that assessed this agent vs treatment of choice (TC), namely decitabine, azacitidine, or low-dose ARA-C (LDAC). Approximately 800 treatment-naïve patients with AML who were ineligible for intensive induction therapy were enrolled to assess co-primary endpoints of complete response (CR) rate and overall survival (OS). While the study failed to achieve the primary endpoints of statistically significant guadecitabine superiority vs TC, treatment with this agent demonstrated a CR of 19.4% vs 17.4% with TC and median OS of 7.10 months in the guadecitabine arm vs 8.47 months for those who received TC. The survival analysis of patients treated for a minimum of 4 cycles showed a median survival of 15.6 months in the guadecitabine cohort compared with 13.0 months in the TC group.2

One issue in AML therapy that continues to be debated is the use of B-cell leukemia/lymphoma-2 (BCL2) antagonist venetoclax in combination with azacitidine or decitabine for treatment of relapsed/refractory (R/R) AML. Multiple studies have been performed to assess outcomes of off-label use in this setting, but they have demonstrated only modest efficacy with low response rates along with suboptimal survival rates (median survival ranging between 3.0‒6.0 months, with 6-month survivals of only approximately 24%).3,4 A potential explanation for this is that there may be multiple pathways for resistance to venetoclax-based therapies in R/R AML. Upregulation of other antiapoptotic proteins (MCL1, BCLxL) may be one such key pathway of resistance, because while BCL2 inhibition promotes apoptosis, at the same time the malignancy can develop an escape mechanism by upregulating alternate anti-apoptosis proteins for protection. MCL1 is a protein coding gene and MCL1 inhibitors, including S6345, AMG176, AZD5991, and VU661013 may delay or prevent resistance to BCL2i-based therapy. MDM2 inhibition can reactivate wild-type p53, and this inhibition promotes degradation of MCL1 through p53 activation. Potential agents in this category include idasanutlin, miladematan, and AMG232.5 As a proof of concept, one early trial assessed the combination of venetoclax and the MDM2 inhibitor idasanutlin in patients with R/R AML who were 60 years of age and older. This combination of oral agents provided encouraging results with up to 45% to 50% CR + complete remission with incomplete blood count recovery (CRi).6 Idasanutlin itself has the potential to be an important agent in AML therapy as phase 3 MIRROS data in R/R AML (intermediate-dose AraC +/- idasanutlin) are being eagerly anticipated. Earlier phase 1/2 results showed that in the relapsed AML population, a combination of intermediate dose ARA-C (IDAC) plus idasanutlin demonstrated 38%/40% CR/CR with incomplete platelet recovery (CRp).7 The MIRROS phase 3 study has now completed enrollment, and results are anticipated in the coming year.8

Preclinically, combining venetoclax with the fms-like tyrosine kinase 3 (FLT3) inhibitors such as sorafenib, gilteritinib, or quizartinib has demonstrated both potential synergy and greater lethality because the FLT3 and other transduction pathways (eg, RAS, PTPN11) are also major mechanisms or resistance to BCL2-inhibition. Data from the initial phase 1 venetoclax monotherapy in R/R AML study demonstrated that the presence of a FLT3-ITD was one of the key mechanisms of both primary and secondary resistance. The three patients with the FLT3-ITD mutation at baseline did not respond to venetoclax therapy, and some without the initial mutation who did respond presented with the FLT3-ITD at relapse, and four patients who had no FLT3 mutation at baseline and relapsed had a new FLT3 mutation detectable at relapse. Because of this, the next logical step may be combining venetoclax as either a doublet or even triplet with FLT3 inhibitors or FLT3-inhibitors + hypomethylating agents (HMAs), with such combinations ongoing and data expected in the near future.9 Another drug of interest is APR-246, which impacts the folding of TP53. Data assessing the combination of APR-246 and azacitidine in patients with TP53-mutant oligoblastic (<30% blasts AML and myelodysplastic syndrome (MDS) has actually shown response rates of 80%-95% in patients with AML.10

Immunotherapies have also attracted attention for potential AML therapy, with two major approaches being studied11:

  • Antibody drug conjugates (ADCs)
  • T-cell based therapies:
    • Bi-specific antibodies (CD3 x AML antigen)
    • Immune checkpoint-based approaches
    • CAR-T (CAR-NK) strategies

IMGN632 is a novel ADC that targets CD123 with a higher binding affinity. This agent administers a cytotoxic IGN payload (DGN549) with DNA-alkylating activity creating single-strand DNA breaks. This is combined with a stable peptide linker that confers circulatory stability, providing a controlled intracellular payload release.12,13 Data in bone marrow-evaluable patients with AML surrounding the best decreased from baseline in bone marrow blasts showed a CR/CRi at all dose levels of 27%.13 One bispecific antibody undergoing investigation in patients with R/R AML unlikely to benefit from cytotoxic chemotherapy is flotetuzumab (CD3 x CD123). Phase 1 data have demonstrated an overall response rate (ORR) of approximately 25.9% in patients treated with this agent, with a CR/CRi rate of 18.5%.14 Flotetuzumab is in phase 1b expansion specifically in primary refractory AML where it has shown an encouraging efficacy signal. Nivolumab is another immunotherapy being studied, predominantly in the combination setting, with data showing some improvements in response in AML with HMA + PD1 inhibitors vs the use of HMAs alone. The ORR in R/R AML was 33% with the combination of nivolumab and azacitidine.15 Toxicities with immune therapy must also be taken into consideration, closely monitored for and rapidly treated. Immune toxicities occur in 20% to 25% of AML patients undergoing HMA + immunotherapies. These toxicities can be easily overlooked, often mimicking infections. Nearly all toxicities are reversible if steroid therapy is initiated within 24 hours, and steroids may be initiated to cover a possible immune related adverse event (AE) while continuing concurrent antibiotic therapy if the patient is receiving treatment with immune checkpoint inhibitors.16,17

Finally, a macrophage checkpoint antibody is undergoing investigation and showing encouraging safety and efficacy in higher-risk MDS and AML therapy. CD47 is essentially a “do not eat me” signal on cancer cells that allows these malignant cells to evade phagocytosis and destruction by macrophages. Increased CD47 expression portends worse outcomes for patients with AML. Hu5F9-G4 (5F9) is an agent that targets CD47 on tumor cells. The CD47 antibody unleashes macrophages in combination with HMAs and has been studied in a clinical trial, with early data demonstrating a 65% CR/CRi response rates in frontline AML treated with azacitidine in combination with 5F9. Importantly, the response rate was high at about 75% CR/CRi in frontline AML with a TP53 mutation. The azacitidine with CD47 therapy has generally been well tolerated18

References

  1. Graphic courtesy of Naval Daver, MD.
  2. Fenaux P, Gobbi M, Kropt PL, et al. Results of ASTRAL-1, a phase 3 randomized trial of guadecitabine vs treatment choice (TC) in treatment-naïve acute myeloid leukemia not eligible for intensive chemotherapy. Oral abstract #S879. 2019 Jun 15. European Hematology Association (EHA) 24th Annual Meeting, Amsterdam, NL.
  3. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401-407.
  4. Maiti A, Dinardo CD, Cortes JE, et al. Interim Analysis of Phase II Study of Venetoclax with 10-day Decitabine (DEC10- VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Blood. 2018;132: Abstract 286.
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  6. Daver N, Garcia-Manero G, Basu S, et al. Safety, Efficacy, Pharmacokinetic (PK) and Biomarker Analyses of BCL2 Inhibitor Venetoclax (Ven) Plus MDM2 Inhibitor Idasanutlin (idasa) in Patients (pts) with Relapsed or Refractory (R/R) AML: A Phase Ib, Non-Randomized, Open-Label Study. ASH 2018. Abstract 767.
  7. Martinelli G, Pappayannidis C, Yee K, et al. Phase 1b results of idasanutlin + cytarabine (ARA-C) in acute myeloid leukemia (AML) patients (PTS). Available at: https://library.ehaweb.org/eha/2016/21st/135260/cristina.pappayannidis.phase.1b.results.of.idasanutlin.2B.cytarabine.28ara-c29.in.html.
  8. ClinicalTrials.gov. A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) (MIRROS). Available at: https://clinicaltrials.gov/ct2/show/NCT02545283.
  9. Chyla B, Daver N, Doyle K, et al. Genetic Biomarkers Of Sensitivity and Resistance to Venetoclax Monotherapy in Patients With Relapsed Acute Myeloid Leukemia. Am J Hematol. 2018;93(8):E202-E205.
  10. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML). Blood. 2019;134 (Supplement_1): 676.
  11. Assi R, Kantarjarian H, Ravandi F, Daver N. Immune therapies in acute myeloid leukemia: A focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol. 2018;25(2):136-145.
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  13. Daver N, Erba HP, Papadantonakis N, et al. A phase I, first-in-human study evaluating the safety and preliminary antileukemia activity of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia and other CD123-positive hematologic malignancies. 2018 Dec 1; Oral Abstract #27: 60th ASH Annual Meeting and Exposition, San Diego, CA.
  14. Uy GL, Rettig MP, Vey N, et al. Phase 1 cohort expansion of flotetuzumab, a CD123×CD3 bispecific Dart® protein in patients with relapsed/refractory acute myeloid leukemia (AML). 2018 Dec 3; Oral Abstract #764: 60th ASH Annual Meeting and Exposition, San Diego, CA.
  15. Daver N, Garcia-Manero G, Basu S, et al. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Cancer Discov. 2019;9(3):370-383.
  16. Daver N, Kontoyiannis D. Checkpoint inhibitors and aspergillosis in AML: The double hit hypothesis. Lancet Oncol. 2017;18(12):1571-1573.
  17. Sang K, Shannon V, Shedshadri A, et al. Th1/17 Cells Are Expanded in Bronchial Alveolar Lavage (BAL) Fluid from Leukemia Patients with Checkpoint Inhibitor-Induced Pneumonitis. Blood. 2017;130 (supplement 1): 3588.
  18. Sallman DA, Donnellon WB, Asch AS, et al. The first-in-class anti-CD47 antibody Hu5F9-G4 is active and well tolerated alone or with azacitidine in AML and MDS patients: Initial phase 1b results. J Clin Oncol. 2019;37(15_suppl):7009-7009.

Last modified: February 11, 2020