Cusatuzumab synergized with a hypomethylating agent in older patients with acute myeloid leukemia.

  • Major Finding: Cusatuzumab synergized with a hypomethylating agent in older patients with acute myeloid leukemia.

  • Concept: Hypomethylating agents increase expression of the cusatuzumab target CD70 on leukemia stem cells.

  • Impact: If validated, this treatment may provide an option for older patients with acute myeloid leukemia.


For patients with acute myeloid leukemia (AML) who are older or have significant medical comorbitities, hypomethylating agents (HMA) are the standard of care; however, these treatments generally do not produce robust, lasting responses. Riether and colleagues found that, in response to HMA treatment, leukemia stem cells (LSC)—which are often resistant to chemotherapy and may drive relapse—upregulate CD70, a TNF-family ligand, increasing CD70–CD27 signaling. In vitro and xenograft experiments showed that cusatuzumab, a monoclonal CD70 antibody that elicits antibody-dependent cell-mediated cytotoxicity, was able to eradicate LSCs. Given these promising preclinical results, a phase I/II trial was initiated to evaluate the use of cusatuzumab (first dosed as monotherapy, then combined with the HMA azacitidine) in 12 patients with previously untreated AML who had a median age of 75 years and were deemed not to be candidates for intensive chemotherapy. The overall response rate was 100%, with two thirds of patients (8/12) attaining complete responses, one sixth of patients (2/12) attaining complete remission with incomplete blood-count recovery, and one sixth of patients (2/12) attaining partial responses. Notably, four patients experienced minimal residual disease negativity. Median progression-free and median overall survival were not reached at the time of data cutoff. Adverse events were experienced by all 12 patients, most commonly hematologic toxicities; infusion reactions were also observed. However, the maximum tolerated dose was not reached, and no dose-limiting toxicities were discovered. Supporting the proposed mechanism that initially justified the use of cusatuzumab in this context, LSC levels were diminished following cusatuzumab treatment, and upregulation of genes involved in myeloid differentiation and apoptosis were observed. In summary, the results presented here—representing only the phase I dose-esclation portion of the trial—support further investigation of cusatuzumab and perhaps other treatments blocking the CD70–CD27 interaction in patients for whom intensive chemotherapy is not indicated.

Riether C, Pabst T, Höpner S, Bacher U, Hinterbrandner M, Banz Y, et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med 2020 Jun 29 [Epub ahead of print].

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