Novel lysine‐specific histone demethylase 1 inhibitor in acute myeloid leukaemia transformed from essential thrombocythaemia

Abstract Background While progress continues in the understanding of molecular abnormalities in acute myeloid leukaemia (AML), with some specific targeted therapies now available, it remains commonly fatal in the elderly. Leukaemic evolution and transformation from myeloproliferative neoplasms (MPN) may be associated with increased numbers of mutations in the genes associated with myeloid neoplasm and the prognosis in such patients is invariably dismal. Targeting of intracellular enzymes associated with integral cellular function has advanced understanding and promises improvements in treatments. Case We report impressive prolonged response to therapy in a case of secondary AML, arising from essential thrombocythaemia (ET). The trial agent, the oral lysine‐specific histone demethylase 1 (LSD1) inhibitor Bomedemstat (IMG‐7289) was well tolerated. In addition to suppressing the malignant clone, these blasts showed differentiation to monocytes morphologically as well as by surface markers seen on flow cytometry. Bomedemstat has efficacy in the treatment of myelofibrosis and may have a special role in treatment of specific AML subtypes, including secondary leukaemias arising from MPN as seen. Conclusion We report a case of an older adult with secondary AML transformed from ET, with a remarkable response to LSD1 inhibition with Bomedemstat, with prolonged reduction in blasts demonstrating differentiation to monocytes.


| INTRODUCTION
While progress continues in the understanding of molecular abnormalities in acute myeloid leukaemia (AML), with some specific targeted therapies now available, it remains commonly fatal in the elderly. 1 Leukaemic evolution and transformation from myeloproliferative neoplasms (MPN) may be associated with increased numbers of mutations in the genes associated with myeloid neoplasm and the prognosis in such patients is invariably dismal. 1,2 Targeting of intracellular enzymes associated with integral cellular function has advanced understanding and promises improvements in treatments. We report impressive prolonged response to therapy in a case of secondary AML, arising from essential thrombocythaemia (ET). The trial agent, the oral lysine-specific histone demethylase 1 (LSD1) inhibitor Bomedemstat (IMG-7289) was well tolerated. In addition to suppressing the malignant clone, these blasts showed differentiation to monocytes morphologically as well as by surface markers seen on flow cytometry. Bomedemstat has efficacy in the treatment of myelofibrosis and may have a special role in treatment of specific AML subtypes, including secondary leukaemias arising from MPN as seen. We report a case of an older adult with secondary AML transformed from ET, with a remarkable response to LSD1 inhibition with Bomedemstat, with prolonged reduction in blasts demonstrating differentiation to monocytes.  inhibitors act by disrupting the interaction between LSD1 and the transcription factor GFI1B on chromatin. 5 Recently, LSD1 has been shown to be essential for glycosis and haeme synthesis, stabilising with GATA1, and shaping metabolic phenotypes in erythroid leukaemia cells. 6 A number of LSD1 inhibitors have been developed and are in clinical trials for patients with AML and MPNs. LSD1 inhibitors act by disrupting the interaction between LSD1 and the transcription factor GFI1B on chromatin. It has been demonstrated that LSD1 enzyme activity is not required for AML survival, and the main mechanism of action is through protein binding interactions. 7 Similarly, knockout of LSD1 in AML in murine models led to blast differentiation with monocytic features, increased ATRA sensitivity, and prolonged survival, associated with upregulation of GFI1B and IRF8 (monocytic transcription factor). 8 The LSD1 inhibitor Bomedemstat (IMG-7289) demonstrated sustained clinical activity and a favourable tolerability in advanced MF. 9 Similarly, the LSD1 inhibition have been associated with some encouraging outcomes in the treatment of AML. 10 Our case with secondary AML transformed from ET, had a prolonged response to LSD1 inhibition with Bomedemstat. The monocytoid changes seen morphologically were confirmed by flow cytometry, by gating and surface markers. Monocyte expansion following commencement of therapy was seen in this patient.

| CASE DESCRIPTION
LSD1-deficient animals show inhibition of granulopoiesis and stimulation of monocytopoiesis, 11 and knockout of LSD1 in AML murine models has led to blast differentiation with monocytic features. 8 These findings and this patient's response to treatment with an LSD1 inhibitor suggests that LSD1 plays an important role in lineage choice during granulocyte differentiation and maturation. 12 LSD1 inhibition leads to increased sensitivity of AML blasts to ATRA. 13 In this case, ATRA was used in combination with Bomedemstat for three months, however ceased due to side effects, so the impact of ATRA in this specific leukaemia is unclear. Treatment with an LSD1 inhibitor in combination with Ruxolitinib may also be of interest for future studies of patients with secondary AML transformed from JAK2 positive ET, as it has demonstrated synergy in murine models for MF. 14 The LSD1 inhibitor Bomedemstat has received fast-track designation for the treatment of myelofibrosis. 15

| CONCLUSION
Targeting of IDH1 with its integral cellular function has advanced understanding and possible treatments in haematological malignancies. This case demonstrates impressive prolonged response in secondary AML, arising from ET, to the LSD1 inhibitor Bomedemstat. In addition to its effective role in the treatment of myelofibrosis, 5 this illustrates the potential role for novel targeted therapies, alone or in combination in this group of neoplasms. This strategy may have a special role in treatment of specific AML subtypes, including secondary leukaemias arising from MPN.

ACKNOWLEDGEMENT
The authors acknowledge to Hugh Rienhoff, Imago Biosciences, California USA.
F I G U R E 3 Bone marrow aspirate at 6 months on Bomedemstat