Differentiation syndrome with lower‐intensity treatments for acute myeloid leukemia

Abstract

Differentiation Syndrome (DS) has been identified in a subset of patients undergoing treatment with novel classes of differentiating therapies for acute myeloid leukemia (AML) such as IDH and FLT3 inhibitors. While DS is a well‐known treatment‐related complication in acute promyelocytic leukemia (APL), efforts are still ongoing to standardize diagnostic and treatment parameters for DS in AML. Though the rates of incidence vary, many of the signs and symptoms of DS are common between APL and AML. So, DS can lead to fatal complications in AML, but prompt management is usually effective and rarely necessitates interruption or discontinuation of AML therapy.

A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia

“…Six participants died while on study treatment from causes deemed by the local investigator to be unrelated to study drug: 4 from sepsis/infection, 1 from intracranial hemorrhage, and 1 from pulmonary embolus, all reported as not related to study drug. Differentiation syndrome, which has been reported in association with FLT3 inhibitor therapy, 30 , 31 occurred in 4 participants: 2 in the 75-mg BID cohort (1 of whom had wild-type FLT3 ), 1 in the 100 mg QD cohort, and 1 in the 100 mg BID cohort.…”

Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia

“…Although enasidenib had a longer half-life and stronger inhibition of D2HG generation in the mouse model, there are concerns that the strong long-term inhibitory effect on the target may cause side effects . Enasidenib was reported to release the differentiation block and promote cell maturation, which then extravasate from circulation into tissues in large numbers, in about 10–20% of patients with AML treated as differentiation syndrom . Some data suggest that as AML cells undergo myeloid differentiation, those mature myeloid cells that are highly expressing the CXCR4, release cytotoxic granules, and extravasate into local tissues via CXCL12, leading to local injury and fibrosis .…”

“…21 Enasidenib was reported to release the differentiation block and promote cell maturation, which then extravasate from circulation into tissues in large numbers, in about 10−20% of patients with AML treated as differentiation syndrom. 35 Some data suggest that as AML cells undergo myeloid differentiation, those mature myeloid cells that are highly expressing the CXCR4, release cytotoxic granules, and extravasate into local tissues via CXCL12, leading to local injury and fibrosis. 36 On the other hand, recently the report suggested a role for D2HG as a regulator of local and systemic inflammatory responses in vivo.…”

Small Molecule Menin Inhibitors: Novel Therapeutic Agents Targeting Acute Myeloid Leukemia with KMT2A Rearrangement or NPM1 Mutation

“…Differentiation syndrome is a notable treatment-related adverse event shared by menin inhibitors in their phase 1 trials. It is caused by cytokine alterations associated with hematopoietic differentiation and can include fever, arthralgias, leukocytosis, pleural or pericardial effusions, and respiratory or renal failure in severe cases, as differentiation syndrome previously observed after IDH inhibitors, arsenic trioxide, or all- trans retinoic acid administration [ 57 , 58 ]. Detection of differentiation syndrome justifies the evidence of a successful reversal of the differentiation block caused by KMT2Ar through menin inhibition.…”