Page 17 - Haematologica - Vol. 105 n. 6 - June 2020

Editorials
study using data from the patients’ samples. The activity of APY0201 was highest in patient-derived samples with hyperdiploidy (trisomies with one or more odd-numbered chromosomes) and lowest in patients’ samples with a t(11;14) translocation. In addition, ex-vivo samples with high TFEB levels were sensitive to APY0201. High TFEB levels have been associated with increased autophagic flux suggesting that autophagic flux may be directly related to PIKfyve inhibition. These preliminary results may suggest patient populations that could be enriched for in a future clinical trial.
In conclusion, Bonolo de Campos et al. provide exciting data to support the ongoing investigation of therapeutical- ly manipulating targets specific to plasma cell function, particularly protein handling in myeloma.2 Although the finer details of the actual mechanisms may differ some- what between multiple myeloma and non-Hodgkin lym- phoma, data from this study and those performed in non- Hodgkin lymphoma provide compelling evidence for the role of PIKfyve inhibition in inducing cell death, with changes seen in the autophagy and lysosomal pathways. Notably, this study demonstrates the importance of the inherent genetic differences in myeloma biology and the potential role of PIKfyve inhibitors in targeting a distinct group of genetically defined myeloma to continue this era of personalized medicine.
References
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GayF,EngelhardtM,TerposE,etal.Fromtransplanttonovelcellular therapies in multiple myeloma: European Myeloma Network guide- lines and future perspectives. Haematologica. 2018;103(2):197-211. AronsonLI,DaviesFE.DangER:proteinovERload.Targetingprotein degradation to treat myeloma. Haematologica. 2012;97(8):1119- 1130.
Bonolo De Campos C, Zhu YX, Sepetov N, et al. Identification of PIKfyve kinase as a target in multiple myeloma. Haematologica. 2020;105(6):1641-1649.
Hoang B, Benavides A, Shi Y, Frost P, Lichtenstein A. Effect of autophagy on multiple myeloma cell viability. Mol Cancer Ther. 2009;8(7):1974-1984.
Aronson LI, Davenport EL, Mirabella F, Morgan GJ, Davies FE. Understanding the interplay between the proteasome pathway and autophagy in response to dual PI3K/mTOR inhibition in myeloma cells is essential for their effective clinical application. Leukemia. 2013;27(12):2397-2403.
Hessvik NP, Øverbye A, Brech A, et al. PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell Mol Life Sci. 2016;73(24):4717-4737.
Gayle S, Landrette S, Beeharry N, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non- Hodgkin lymphoma. Blood. 2017;129(13):1768-1778.
Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401-2409.
Pawlyn C, Davies FE. Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood. 2019 14;133(7):660-675.
Qiang YW, Ye S, Chen Y, et al. MAF protein mediates innate resist- ance to proteasome inhibition therapy in multiple myeloma. Blood. 2016;128(25):2919-2930.
core-binding factor acute myeloid
The increasing complexity of the management of leukemia
Mark R. Litzow
Division of Hematology and Transplant Center, Mayo Clinic Rochester, Rochester, MN, USA E-mail: MARK R. LITZOW - litzow.mark@mayo.edu
doi:10.3324/haematol.2020.249110
The core binding factor (CBF) acute myeloid leukemias characterized by the t(8;21) and inv(16)(p13q22)/t(16;16)(p13;q22) cytogenetic abnormalities have long been known to prognostically represent more favorable subcategories of acute myeloid leukemia (AML). These translocations are characterized by the presence of the RUNX1-RUNX1T1 (AML1-ETO) and CBFB-MYH11 fusion transcripts, respectively. In fact, the t(8;21) was the first cytogenetic abnormality identi- fied in AML in 1973.1 These CBF-AML subtypes have continued to remain in the favorable risk category in mul- tiple classification systems up to the current time based on their high rate of achievement of complete remission with induction chemotherapy and their relatively low relapse rate.2 Clinical trials over the years have demon- strated that these two CBF-AML subtypes are particularly responsive to high doses of cytarabine utilized in consol- idation regimens. Addition of the immunoconjugate drug, gemtuzumab ozogamicin, to induction chemother- apy further reduces the risk of relapse and improves over- all survival in patients with CBF-AML.3 The favorable results of chemotherapy in patients with CBF-AML have led to the widely accepted practice not to perform allo-
geneic blood or marrow transplant (alloBMT) in these patients who achieve first remission. This is in contrast to patients with AML with intermediate risk or unfavorable risk features where allogeneic blood or marrow trans- plant in first remission is a widely accepted practice.
However, the two subtypes of CBF-AML are not the same in all respects. Studies going back 15 years or more have pointed out the difference between these two sub- types.4 Use of next-generation sequencing (NGS) and identification of additional gene mutations in patients with AML have begun to further define differences between the two. One of the first mutational abnormali- ties found in subsets of patients with CBF-AML were c- KIT mutations. The c-KIT mutation has been suggested to be associated with a poorer prognosis in CBF-AML patients but, here again, this mutation seems to have less of a prognostic impact in patients with inv(16) compared to those with t(8;21).5 NGS studies, which are now widely utilized to assess prognosis in many subtypes of AML, have been applied to patients with CBF-AML. Multiple mutations in addition to c-KIT have been identified, including genes activating tyrosine kinase signaling, such as N/KRAS and FLT3. Mutations in genes that regulate
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