https://orcid.org/0000-0001-6998-662X
Key points
In older patients with CMML, tagraxofusp monotherapy is tolerable without new safety signals, with modest clinical efficacy.
While CD123 targeting monotherapy had limited efficacy, some patients derived benefit, and combination therapies are being explored.
Abstract
Chronic myelomonocytic leukemia (CMML) is an aggressive hematological neoplasm characterized by an expansion of CD123+ monocytes and plasmacytoid dendritic cells (pDC). PDC bone marrow clusters in CMML have been associated with higher rates of acute myeloid leukemia transformation. We evaluated tagraxofusp, a CD123-targeted therapy, in a phase 1/2 trial in patients with CMML. There were no dose-limiting toxicities. At the recommended phase 2 dose of 12 μg/kg/day, 37 patients were treated: 15 treatment-naïve; 22 with relapsed/refractory disease (median number of prior therapies: 1, range 1-7). Common nonhematologic treatment-emergent adverse events included fatigue (49%), hypoalbuminemia (46%), nausea, hypokalemia, and decreased appetite (44% each). Capillary leak syndrome occurred in nine patients (23%; grade 3-4, 13%), while tumor lysis syndrome was seen in 13%. Hematologic grade 3-4 treatment-related AEs included thrombocytopenia (28%), anemia (13%), leukocytosis (15%), and neutropenia (13%). No complete or partial responses were observed. One patient each in the treatment-naïve and relapsed/refractory groups achieved complete cytogenetic remission with marrow response. Stable disease and clinical benefit were achieved by 40% and 27% of treatment-naïve patients and by 59% and 23% of relapsed/refractory patients, respectively. After a median follow-up of 43.7 months, overall survival was 11.2 months in treatment-naïve and 15.6 months in relapsed/refractory patients. Exploratory analysis showed stable CD123+ blast frequency, mutational variant allele frequencies, and monocyte subsets with treatment. Tagraxofusp demonstrated a manageable safety profile with limited clinical efficacy in CMML. ClinicalTrials.gov identifier: #NCT02268253.
Author notes
M.M.P. and H.A. are co-lead authors and contributed equally.
Data Sharing Statement: The data that support the results of this study may be requested for products and the relevant indications that have been authorized by the regulatory authorities in Europe/the United States (or, if not, 2 years have elapsed since the study completion). The Menarini Group will review requests individually to determine whether (1) the requests are legitimate and relevant and meet sound scientific research principles, (2) the requests are within the scope of the participants’ informed consent, and (3) the request is compliant with any applicable law and regulation and with any contractual relationship that Menarini Group and its affiliates and partners have in place with respect to the study and/or the relevant product. Prior to making data available, requestors will be required to agree in writing to certain obligations, including without limitation, compliance with applicable privacy and other laws and regulations. Proposals should be directed to medicalinformation@menarinistemline.com.
