Multicenter Retrospective Analysis of Eosinophilic Myeloid Neoplasms

Background. Some patients who present with clinical features consistent with idiopathic hypereosinophilic syndrome (HES; absolute eosinophil count (AEC) ≥1.5 x 10⁹/L with related end organ damage) are ultimately diagnosed with a myeloid neoplasm. Although FIP1L1::PDGFRA is the most common molecular abnormality in this setting, many other fusion genes, point mutations and cytogenetic abnormalities have been implicated in driving primary (neoplastic) eosinophilia. Given the poor prognosis of these disorders in the absence of treatment and the availability of targeted therapies for many of the driver mutations, it is becoming increasingly important to rapidly identify the underlying genetic alteration. In this regard, the expense and variable sensitivity of molecular diagnostic tests remains problematic. Although clinical features have been reported to distinguish between PDGFRA-associated myeloid neoplasms and D816V KIT-positive systemic mastocytosis with hypereosinophilia, little is known about the clinical phenotypes of other subsets of patients. This multicenter retrospective study aimed to assemble a large cohort of patients with HES secondary to a myeloid neoplasm to explore the utility of clinical and laboratory features in predicting the underlying molecular abnormality.

Methods. Retrospective, de-identified data from 16 centers were collected via an online Research Electronic Data Capture repository. Patients and associated data were obtained from in-house research databases and/or electronic medical record searches at each site. Clinical and laboratory data were entered in accordance with local Institutional Review Boards. Inclusion criteria were peripheral blood hypereosinophilia (AEC >1.5 x 10⁹/L) on at least two occasions and one of the following: ≥1 confirmed genetic abnormality recurrently associated with primary myeloid neoplasms, other evidence of clonal eosinophilia, or increased blasts (≥2% in the blood or >5% but <20% in the marrow). Patients with acute myeloid leukemia were excluded.

Results. A total of 277 patients followed between 1990 and 2022 were included in the analysis. Median length of follow up was 31 months (range <1-356), and 217/277 (78%) were alive at last follow up. The most common genetic abnormality was FIP1L1::PDGFRA (n=131) followed by D816V KIT mutations (n=39) and alterations involving JAK2 (n=22) (Figure 1). Five patients had genetic abnormalities involving two distinct genes recurrently associated with eosinophilic myeloid neoplasms. The overall median age at diagnosis was 55 years (range 12-89) and 79% of the patients were male. When patients with abnormalities involving PDGFRA and PDGFRB were excluded from the analysis, the male predominance was significantly lower at 62% (p<0.001, Fisher’s exact test as compared to the data set as a whole). The overall pattern of organ system involvement was similar irrespective of the underlying genetic abnormality with a few notable exceptions. Cardiac involvement was most common in patients with FIP1L1::PDGFRA, abnormalities involving JAK2 or without pathologic alterations identified (reported in 22%, 32% and 30%, respectively); whereas skin and gastrointestinal involvement, lymphadenopathy and splenomegaly were most frequent in patients with KIT D816V. Laboratory abnormalities also differed between groups. Whereas anemia was the most common blood abnormality (reported in >50% of patients), erythrocytosis was noted primarily in patients with abnormalities involving JAK2. In contrast, circulating blasts were identified in 70% of patient with BCR::ABL1 and 29% of patients with chromosomal abnormalities or KIT D816V, but in <15% of patients in any of the other groups. Whereas peak AEC alone did not discriminate between the different patient groups, the AEC/tryptase ratio was increased in patients with PDGFRA-associated myeloid neoplasms, molecular abnormalities involving JAK2, or chromosomal abnormalities as compared to those with KIT mutations (Figure 2).

Conclusions. Despite the limitations of retrospective data analysis, the data from this large multicenter cohort of patients with HES due to a chronic myeloid neoplasm suggest that routine demographic, clinical and laboratory features vary depending on the underlying molecular abnormality. This approach could ultimately help guide empiric therapy when molecular studies are negative or unavailable.