Acute myeloid leukemia in SRP54‐mutated congenital neutropenia

Abstract

SRP54 mutations have recently been implicated in congenital neutropenia (CN) and the in‐frame deletion, p.Thr117del, is the most common pathogenic mutation reported. The largest study of SRP54‐mutated CN to‐date followed 23 patients for a median of 15 years. No patients developed a hematologic malignancy in that study. Given the known risk of leukemia in other CNs it is crucial to know whether patients with SRP54‐mutated CN have an increased risk of leukemia. We report the first case of leukemia in a patient with SRP54‐mutated CN. A 15‐year‐old male with SRP54‐mutated CN (p.Thr117del) was diagnosed with acute myeloid leukemia with myelodysplasia‐related changes on a screening bone marrow evaluation. Next generation sequencing of the leukemia cells identified CSF3R and RUNX1 mutations. These mutations commonly co‐exist in CN‐associated malignancies and suggest leukemogenesis in SRP54‐mutated CN may occur in a similar manner to other CNs. He was successfully treated with CPX‐351 followed by hematopoietic cell transplant (HCT) and remains in remission at a follow‐up time of 9 months. Although conclusions from this single report must be limited, this has potentially significant implications for both screening and treatment practices for these patients, including the role and timing of HCT.

Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance

“…The current literature lacks standard guidelines and expert consensus recommendations for managing SRP54 pathogenic variants. Two reports published in 2022 described the first known malignant transformations in patients with SRP54 ‐related SCN, one with B‐cell acute lymphoblastic leukemia (Calvo et al, 2022) and the other with AML (Sabulski et al, 2022). Interestingly, both patients also harbored RUNX1 and CSF3R cytogenetic abnormalities, possibly associated with leukemogenesis in SCN (Skokowa et al, 2014).…”

“…This leads to protein secretion defects that impair granulocyte differentiation, causing apoptosis and autophagy (Juaire et al, 2021). To date, there are two reports of malignant transformation in individuals with SRP54 pathogenic variants (Calvo et al, 2022; Sabulski et al, 2022). Here, we present a patient with SRP54 pathogenic variant and SCN, along with a literature review, and propose surveillance recommendations for MDS/AML and other associated complications.…”

Severe congenital neutropenia, SRP54 pathogenicity, and a Framework for Surveillance

“…Two reports published in 2022 described the first known malignant transformations in patients with SRP54 -related SCN, one with B-cell acute lymphoblastic leukemia (B-ALL) [25] and the other with AML. [24] Interestingly, both patients also harbored RUNX1 and CSF3R cytogenetic abnormalities, possibly associated with leukemogenesis in SCN. [30] A previously reported French cohort of 231 SCN patients demonstrated an increased risk for leukemic transformation with higher average/cumulative G-CSF dose.…”

“…However, despite high-dose G-CSF, nine patients (23%) required HSCT, seven due to refractory neutropenia and two for subsequent leukemia diagnosis. [24,25] Patients with SRP54 PV display notable clinical differences from classical SDS. Most patients with SRP54 and SCN were diagnosed earlier, with a median age of 4.2-6 months vs 1-1.3 years for SDS.…”

“…[23] To date, there are two reports of malignant transformation in individuals with SRP54 PV. [24,25] Here, we present a patient with aSRP54 PV and SCN, along with a literature review, and propose surveillance recommendations for MDS/AML and other associated complications.…”