General AML

Response to flotetuzumab, a bispecific CD123 × CD3 molecule, is seen in refractory patients with acute myeloid leukemia and may be dependent on the tumor microenvironment 

Relapse is the major cause of treatment failure in patients with acute myeloid leukemia (AML). Novel treatments, such as immunotherapies (monoclonal antibodies, bispecific molecules, immune checkpoint blockade, and CD123-CAR T cells) are under investigation. This article describes encouraging results with a bispecific antibody, flotetuzumab (FLZ), and underlying factors which support response to this therapy.

Immune landscape in AML predicts response to therapy1

The tumor microenvironment (TME) plays an important role in determining responsiveness to immunotherapy as well as resistance to chemotherapy and identifying biomarkers in the TME can be useful to predict response to immunotherapies.

At the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Sergio Rutella, Nottingham Trent University, Nottingham, UK, presented the gene-expression profile of bone marrow (BM) samples from patients with newly-diagnosed non-promyelocytic AML (n= 367). This multicohort study aimed to characterize the immune landscape of AML and to correlate this finding with chemotherapy responses, immunotherapy responses, and with clinical outcomes.1

Results
  • Three distinct gene expression profiles were identified in the discovery cohort (n= 290): IFNγ-dominant, adaptive, and myeloid
  • The relative intensity of gene expression was used to stratify BM samples into two subgroups:
    • immune-infiltrated (n= 136) high levels of IFNγ stimulated genes, antigen processing genes, and immune checkpoint genes
    • immune-depleted (n= 154)
  • An IFNγ high profile, representing the immune infiltrated subgroup, was predictive of therapeutic resistance to induction chemotherapy (‘7+3’)
  • These results were then validated in silico with publicly available data obtained from three studies (HOVON, Beat-AML, TCGA, n=1032) where the IFNγ high profile was significantly more predictive of therapeutic resistance to induction chemotherapy than the European LeukemiaNet (ELN) risk categories

Could the higher expression of IFNγ inducible genes identify AML patients who derive benefit from immunotherapy with FLZ?1

  • FLZ is a bispecific molecule targeting both CD3 (on T cells) and CD123 (a tumor associated antigen)
  • BM samples were collected prior to and during FLZ treatment from 30 patients with AML, treated at the recommended phase II dose of 500ng/kg/day in the CP-MGD006-01 clinical trial (NCT#02152956). Results of this study are presented below
  • An IFNγ high expression profile at baseline correlated with response to FLZ therapy
Conclusion

Using gene expression profiling to identify an immune infiltrating tumor microenvironment based on a high expression of IFNγ inducible genes profile can be used to identify patients who are:

  • less likely to respond to cytotoxic chemotherapy
    • more responsive to immunotherapies such as FLZ
Update of an ongoing phase I/II study with flotetuzumab in patients with refractory AML2

FLZ clinical activity and acceptable safety profile in primary refractory AML have been previously reported and an ongoing  phase I/II study in relapsed/refractory (R/R) AML patients is providing additional data on FLZ in R/R AML patients. At the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Geoffrey L. Uy, Washington University School of Medicine, Saint Louis, US, presented the results from this ongoing study.

Method
  • Fifty R/R AML patients received FLZ at the recommended phase II dose of 500ng/kg/day (total population)
  • FLZ was delivered at a lead-in dose escalation during Week 1 of treatment, followed by FLZ recommended phase II dose of 500ng/kg/day administered intravenously 7 days/week during Weeks 2–4 of Cycle 1, and a 4-day on/3-day off schedule for Cycle 2 and beyond
  • 30 patients had primary induction failure or early relapse AML (refractory population):
    • 24 patients were refractory to ≥ 2 induction attempts and six relapsed after remission of < 6 months
Results
  • The most common treatment related adverse events (AEs) are represented by infusion related reaction (IRR) and cytokine release syndrome (CRS), but the vast majority were Grade 1 and 2:
    • IRR/CRS:
      • 96%, of which 8% Grade 3 in the total population
      • 100%, of which 3.3% Grade 3 in refractory population
    • Key interventions, such as the early use of tocilizumab and sequential increment in steps of LID schedules, have mitigated CRS severity. CRS events median duration was one day for Grade 1 and two days for Grade 2
    • 28 patients were evaluable for response
      • CR: 17.9%
      • CR + CR with partial hematological recovery (CRh): 28.6%
      • CR + CRh + CR with incomplete hematological improvement (CRi): 32.1%
    • The response rate to FLZ was greater in patients with up to four lines of prior therapy:
      • Two prior lines of therapy, CR + CRh + Cri: 55.6% (5/9)
      • Three prior lines of therapy, CR + CRh + Cri: 25% (1/4)
      • Four prior lines of therapy, CR + CRh + Cri: 37.5% (3/8)
      • Five prior lines of therapy, CR + CRh + Cri: 0% (0/7)
Conclusion
  • FLZ was well tolerated, with a manageable safety profile
  • CRS severity was low and could be mitigated by delivering a lead-in dose and early tocilizumab usage
  • FLZ induces CR in this population of heavily pre-treated patients with poor response rates to previous therapies
  • Enrollment has been expanded to better define biomarkers associated to FLZ response
References
  1. Vadakekolathu J. et al. Immune Landscapes Predict Chemotherapy Resistance and Anti-Leukemic Activity of Flotetuzumab, an Investigational CD123×CD3 Bispecific Dart® Molecule, in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Oral Abstract #460. 2019 Dec 7. 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, US
  2. Uy G.L. et al. Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients. Oral Abstract 733. 2019 Dec 9. 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, US

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