Durable Disease Control with MEK Inhibition in a Patient with NRAS-mutated Atypical Chronic Myeloid Leukemia

Abstract

Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare hematologic neoplasms characterized by leukocytosis and a hypercellular bone marrow. Although recurrent mutations in the colony-stimulating factor 3 receptor (CSF3R) are frequently observed in patients with (CNL), the mutational landscape in (aCML) is less well-defined. In this report, we describe an 81-year-old male who was diagnosed with aCML. He presented with leukocytosis and anemia but no significant clinical symptoms. Standard laboratory studies revealed the absence of the Philadelphia chromosome. Massively parallel sequencing demonstrated no mutations in CSF3R, but the presence of a heterozygous NRAS-G12D variant (47% allele frequency). The patient was started on treatment with trametinib, an MEK1/2 inhibitor with Food and Drug Administration approval for malignant melanoma. Therapy with trametinib resulted in exceptional improvements in his blood counts and continued disease control with 14 months of follow-up. This case highlights the need for clinical trials evaluating the safety and efficacy of MEK1/2 as a therapeutic target for the treatment of patients with NRAS-mutated aCML/CNL.

An acquired NRAS mutation contributes to neutrophilic progression in a patient with primary myelofibrosis

“…It is acknowledged that not all genetic or epigenetic events resulting in this neutrophilic progression may be resolved by such a targeted approach, however, the utility of exon sequencing in defining clonal evolution and hierarchy underlying transformational events in PMF (Ferrer‐Marín et al , ) can aid in the identification of personalised therapeutic targets. Pharmacological inhibitors of MEK have shown considerable efficacy in BRAF ‐mutated metastatic melanoma, with case reports demonstrating significant clinical responses of these agents, such as trametinib, in NRAS ‐mutated haematological malignancies, including aCML with a similar neutrophilic hyperleucocytosis (Khanna et al , ). In context of the emerging array of treatments for MPN (Vannucchi & Harrison, ) such cases support the rationale for considering clinical trials of MEK inhibitors in the treatment of NRAS ‐mutated MPN.…”

How I treat atypical chronic myeloid leukemia

“…58,59 Treatment with trametinib 2 mg daily produced a durable near-complete hematologic response, with the WBC count decreasing from 256 3 10 9 /L to the 10 3 10 9 to 15 3 10 9 /L range and the platelet count improving from 66 3 10 9 /L to 168 3 10 9 /L. 57 Pharmacologic reactivation of the tumor suppressor PP2A, which is functionally suppressed because of SETPB1 mutations, is a promising therapeutic approach to pursue with drugs such as fingolimod (FTY720). 60,61 Spliceosome modulators are a novel class of therapeutics entering clinical trials for myeloid neoplasms and may have a role in aCML patients with mutations in SRSF2 or other genes that comprise the spliceosome machinery.…”

“…A recent example comes from investigators from Oregon Health and Sciences University who identified an NRAS G12D mutation at 47% mutant allele frequency in an aCML patient. 57 The mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor tramenitinib, approved for malignant melanoma, also exhibits activity in RAS-driven leukemias in vitro and in vivo. 58,59 Treatment with trametinib 2 mg daily produced a durable near-complete hematologic response, with the WBC count decreasing from 256 3 10 9 /L to the 10 3 10 9 to 15 3 10 9 /L range and the platelet count improving from 66 3 10 9 /L to 168 3 10 9 /L.…”

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

“…The identification of NRAS mutations in a portion of CNL patients has led to speculation that MEK inhibitor therapy with drugs such as trametinib, may provide clinical benefits in certain CNL subsets . As we gain further insight into the genomics of CNL, molecularly‐driven targeted therapy will likely emerge as the definitive treatment approach.…”