Clinical Lymphoma, Myeloma & Leukemia, Vol.21, Suppl.1 - September 2021

S28 healthy controls and a similar number of patients with FIP1L1- PDGFRA -negative hypereosinophilia found a similar frequency of the variant in the two cohorts with a median variant allele burden of 50.2% (range 4 7 .9–56.0%), consistent with KIT M541I being a benign germline polymorphism. 9 Still, the possibility cannot be ruled out that it is acquired as a somatic mutation in rare cases. Somatic insertion/deletion mutations (p.L583_A586delinsS) within exon 13 of the pseudokinase domain of JAK2 have also been described in patients with CEL, NOS and a concomitant diagnosis of polycythemia vera. 10 We have recently identified a JAK1 R629_ S632delinsSA mutation in a patient with chronic eosinophilia (submitted). The mutation is in close proximity to a heterozygous germline JAK1 A634D mutation described in a family with HES. Although initially characterized by NGS as a variant of unknown significance, functional interrogation found that the mutation leads to IL-3-independent growth of Ba/F3 cells and activation of the JAK-STAT pathway, which can be abrogated by the JAK1/JAK2 inhibitor ruxolitinib. When interpreting the results of NGS panels, it is important to consider whether variants are pathogenetically related to CEL, NOS or may alternatively represent clonal hematopoiesis of indeterminate potential (CHIP). Prognosis and Treatment The prognosis of WHO-defined CEL, NOS is dismal. In a cohort of 10 patients, the median survival was 22.2 months, and 5 of the 10 patients developed acute transformation after median of 20 months from diagnosis. 11 Three of 5 patients who did not develop AML died with active disease; one patient underwent an allogeneic hematopoietic stem cell transplantation and maintained a long-term remission, and the remaining patient was reported as achieving a complete remission on imatinib and hydroxyurea. In the Mayo Clinic series of 1 7 patients, 2 outcomes were similarly poor. At a median follow up of 13 months, nine patients died from infection, disease related organ failure, or leukemic transformation. The median overall survival was 16 months (range, 1–49 months) and 3 (1 7 .6%) patients progressed to acute myeloid leukemia. No consensus standard frontline treatment exists for CEL, NOS. Most agents have been co-opted from their use in idiopathic HES, and have included corticosteroids, hydroxyurea, [PEG]-interferon- alfa (PEG-IFN), and imatinib. In selected patients, these agents can elicit improvements in leukocytosis and hypereosinophilia, but responses tend not to be durable. PEG-IFN can elicit hematologic and cytogenetic responses, as well as reversion of end-organ damage, including in patients who are relapsed/refractory to corticosteroids and hydroxyurea. 12 In the absence of an established (or cryptic) tyrosine kinase target, hematologic improvement with imatinib may reflect non-specific myelosuppression, and responses tend to be short-lived. The role of the anti-CD52 antibody alemtuzumab remains undefined. Lack of response to the anti- IL5 antibody mepolizumab (currently approved for HES), and anti-IL5 receptor antibody benralizumab have been observed in CEL, NOS/myeloproliferative HES. 13,14 Given the poor prognosis of CEL, NOS, allogeneic hematopoietic stem cell transplantation should be considered early for suitable patients in whom a donor is available. 12 Conclusion CEL, NOS is a rare, genetically and clinically heterogeneous neoplasm with limited survival. NGS may be a useful diagnostic adjunct to identify oncogenic, druggable targets. A high priority is enrollment of CEL, NOS patients into clinical trials given the paucity of agents which can modify disease natural history. An unmet need remains the establishment of consensus response criteria to harmonize reporting of results from studies of novel agents. References 1. Bain BJ, Horny H-P, Hasserjian RP, Orazi A. Chronic eosinophilic leukaemia, NOS. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Theile J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, Sibert R, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 201 7 :54-59. 2. Morsia E, Reichard K, Pardanani A, Tefferi A, Gangat N. WHO defined chronic eosinophilic leukemia, not otherwise specified (CEL, NOS): A contemporary series from the Mayo Clinic. Am J Hematol 2020;95:E1 7 2-E1 7 4. 3. Ruan GJ, Smith CJ, Day C, et al. A population-based study of chronic eosinophilic leukemia-not otherwise specified in the United States. Am J Hematol 2020. 2020 Jun 13. doi: 10.1002/ajh.25906. 4. Wang SA, Hasserjian RP, Tam W, et al. Bone marrow morphology is a strong discriminator between chronic eosinophilic leukemia, not otherwise specified from reactive idiopathic hypereosinophilic syndrome. Haematologica. 201 7 ;102:1352-1360. 5. Wang SA, Tam W, Tsai AG, et al. Targeted next- generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Mod Pathol. 2016;29:854-864. 6. Cross NCP, Hoade Y, Tapper WJ, et al. Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia. 2019;33:415-425. 7 . Schwaab J, Umbach R, Metzgeroth G, et al. KIT D816V and JAK2 V61 7 F mutations are seen recurrently in hypereosinophilia of unknown significance. Am J Hematol. 2015;90: 77 4- 777 . 8. Iurlo A, Gianelli U, Beghini A, et al. Identification of kit(M541L) somatic mutation in chronic eosinophilic leukemia, not otherwise specified and its implication in low-dose imatinib response. Oncotarget. 2014;5:4665- 46 7 0. 9. Hoade Y, Metzgeroth G, Schwaab J, Reiter A, Cross NC. Routine Screening for KIT M541L Is Not Warranted in the Diagnostic Work-Up of Patients with Hypereosinophilia. Acta Haematologica. 2018;139: 7 1- 7 3. 10. Patel AB, Franzini A, Leroy E, et al. JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera. Blood. 2019;134:2388-2398.