Disease overview
The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end‐organ damage.
Diagnosis
...Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ‐hybridization, flow immunocytometry, and T‐cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder.
Risk stratification
Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi‐molecular classification scheme of disease subtypes which includes the major category “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1‐JAK2,” and the “MPN subtype, chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS). Lymphocyte‐variant hypereosinophilia is an aberrant T‐cell clone‐driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.
Risk‐adapted therapy
The goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (e.g., < 1500/mm3) without symptoms or signs of organ involvement, a watch and wait approach with close‐follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant hypereosinophilia and HES. Hydroxyurea and interferon‐alpha have demonstrated efficacy as initial treatment and steroid‐refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. The use of antibodies against interleukin‐5 (IL‐5) (mepolizumab), the IL‐5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils remains an active area of investigation.
Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of ...aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.
Disease overview
The eosinophilias encompass a broad range of non‐hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end‐organ damage.
Diagnosis
...Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L, and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ‐hybridization, flow immunophenotyping, and T‐cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm.
Risk stratification
Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi‐molecular classification scheme of disease subtypes. This includes the major category “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1‐JAK2”, and the MPN subtype, “chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS). Lymphocyte‐variant hypereosinophilia is an aberrant T‐cell clone‐driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.
Risk‐adapted therapy
The goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (eg, <1.5 × 109/L) without symptoms or signs of organ involvement, a watch and wait approach with close‐follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant hypereosinophilia and HES. Hydroxyurea and interferon‐alfa have demonstrated efficacy as initial treatment and in steroid‐refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. The use of antibodies against interleukin‐5 (IL‐5) (mepolizumab), the IL‐5 receptor (benralizumab), as well as other targets on eosinophils remains an active area of investigation.
Disease Overview
The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end‐organ damage.
Diagnosis
...Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, next generation sequencing gene assays, and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm.
Risk Stratification
Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi‐molecular classification scheme of disease subtypes. This includes the major category “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1‐JAK2”, and the myeloproliferative neoplasm subtype, “chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS). Lymphocyte‐variant HE is an aberrant T‐cell clone‐driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.
Risk‐adapted Therapy
The goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (eg, < 1.5 × 109/L) without symptoms or signs of organ involvement, a watch and wait approach with close follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant HE and HES. Hydroxyurea and interferon‐α have demonstrated efficacy as initial treatment and in steroid‐refractory cases of HES. Mepolizumab, an interleukin‐5 (IL‐5) antagonist monoclonal antibody, was recently approved by the US Food and Drug Administration for patients with idiopathic HES. The use of the IL‐5 receptor antibody benralizumab, as well as other targeted therapies such as JAK2 and FGFR1 inhibitors, is under active investigation.
Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating
D816V mutation that leads to the growth and accumulation of neoplastic mast cells. ...While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective
D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of
D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.
Mastocytosis is a rare disease characterized by KIT-driven expansion and accumulation of neoplastic mast cells in various tissues. Although mediator symptoms related to mast cell activation can ...impose a symptom burden in cutaneous disease and across the spectrum of systemic mastocytosis subtypes, the presence of an associated hematologic neoplasm and/or organ damage denotes advanced disease and the potential for increased morbidity and mortality. In addition to the revised 2016 World Health Organization classification of mastocytosis, a new diagnostic and treatment toolkit, tethered to enhanced molecular characterization and monitoring, is poised to transform the management of patients with advanced systemic mastocytosis (advSM). Although the efficacy of midostaurin and novel selective KIT D816V inhibitors, such as avapritinib (BLU-285), have validated KIT as a therapeutic target, the clinical and biologic heterogeneity of advSM requires that we reimagine the blueprint for tackling these diseases and use tools that move beyond KIT-centric approaches.
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