Among patients with myelofibrosis, LCL161, a mimetic of second mitochondrial activator of caspases (SMAC), may induce a response, according to research published in Blood Advances.

Myelofibrosis is a hematologic malignancy characterized by anemia, thrombocytopenia, and hepatosplenomegaly. High-risk patients with myelofibrosis have, furthermore, a significant risk of transformation to acute myeloid leukemia.

While JAK inhibitors have improved outcomes in this patient population, the median overall survival among those resistant to JAK inhibition therapy is as low as 13 months. Patients with myelofibrosis may, further, have severe anemia owing to both the underlying disease and JAK inhibitor treatment.

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The low survival rates among patients with JAK inhibitor–resistant disease, and among whom JAK inhibition is unlikely to be tolerated, indicates a need for novel therapies in this patient population. SMAC mimetics—otherwise known as antagonists of inhibitors of apoptosis—has shown promise in previous study among both patients with solid tumors and hematologic malignancies.

For this phase 2 study, researchers evaluated the safety and efficacy of orally administered LCL161 among patients with myelofibrosis. The study was conducted at a single center, and aimed to evaluate objective response rate (ORR) as defined by International Working Group-Myeloproliferative Neoplasms Research and Treatment (2013) criteria.

Overall, 50 patients were enrolled in this trial. The median patient age was 72 years (range, 56-85), 28 (56%) were male, 28 (56%) had received prior JAK inhibitor therapy, and 37 (74%) had received at least 2 prior therapies.

The objective response rate was 30% (15 patients); the median overall survival was 34 months (range, 2.2-60.11). A total of 43 (86%) patients discontinued therapy, for reasons including stable disease or no objective response (16 patients), progressive disease (11 patients), and comorbidities (4 patients).

A total of 6 patients (4 with a hemoglobin response and 2 who reached transfusion-independence) had a clinical improvement in anemia.

Grade 3 to 4 hematologic and non-hematologic adverse events included thrombocytopenia (6%), anemia (4%), syncope (4%), nausea/vomiting (2%), and skin eruption/pruritis (2%); all were considered related to treatment. Two deaths during the study period were recorded, neither of which were related to treatment.

“In conclusion, we report the first study of patients with [myelofibrosis] receiving weekly administration of a novel oral monotherapy, LCL161, a monovalent SMAC mimetic that showed both a safe profile and overall clinical efficacy in a large, high-risk, older study population,” the authors wrote.

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Pemmaraju N, Carter BZ, Bose P, et al. Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis. Blood Adv. 2021;5(16):3163-73. doi:10.1182/bloodadvances.2020003829