clonal hypereosinophilia clonal hypereosinophilia clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. this population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell. the clone of eosinophils bear a mutation in any one of several genes that code for proteins that regulate cell growth. the mutations cause these proteins to be continuously active and thereby to stimulate growth in an uncontrolled and continuous manner. the expanding population of eosinophils initially formed in the bone marrow may spread to the blood and then enter into and injure various tissues and organs. clinically, clonal eosinophilia resembles various types of chronic or acute leukemias, lymphomas, or myeloproliferative hematological malignancies. however, many of the clonal hypereosinophilias are distinguished from these other hematological malignancies by the genetic mutations which underlie their development and, more importantly, by their susceptibility to specific treatment regiments. that is, many types of these disorders are remarkably susceptible to relatively non-toxic drugs. background hematopoietic stem cells give rise to: 1) myeloid precursor cells that differentiate into red blood cells, mast cells, blood platelet-forming megakaryocytes, or myeloblasts, which latter cells subsequently differentiate into white blood cells viz., neutrophils, basophils, monocytes, and eosinophils; or 2) lymphoid precursor cells which differentiate into t lymphocytes, b lymphocytes, or natural killer cells. malignant transformation of these stem or precursor cells results in the development of various hematological malignancies. some of these transformations involve chromosomal translocations or interstitial deletions that create fusion genes. these fusion genes encode fusion proteins that continuously stimulate cell growth, proliferation, prolonged survival, and/or differentiation. such mutations occur in hematological stem cells and/or their daughter myeloid precursor and lymphoid precursor cells; commonly involve genes that encode tyrosine kinase proteins; and cause or contribute to the development of hematological malignancies. a classic example of such a disease is chronic myelogenous leukemia, a neoplasm commonly caused by a mutation that creates the bcr-abl1 fusion gene (see philadelphia chromosome). the disease is due to conversion of the tightly regulated tyrosine kinase of abl1 protein to being unregulated and continuously active in the bcr-abl1 fusion protein. this philadelphia chromosome positive form of chronic myelogenous leukemia used to be treated with chemotherapy but nonetheless was regarded as becoming lethal within 18-60 months of diagnosis. with the discovery of the uncontrolled tyrosine kinase activity of this disorder and the use of tyrosine kinase inhibitors. philadelphia chromosome positive chronic myelogenous leukemia is now successfully treated with maintenance tyrosine kinase inhibiting drugs to achieve its long-term suppression. some hematological malignancies exhibit increased numbers of circulating blood eosinophils, increased numbers of bone marrow eosinophils, and/or eosinophil infiltrations into otherwise normal tissues. these malignancies were at first diagnosed as eosinophilia, hypereosinophilia, acute eosinophilic leukemia, chronic eosinophilic leukemia, other myeloid leukemias, myeloproliferative neoplasm, myeloid sarcoma, lymphoid leukemia, or non-hodgkin lymphomas. based on their association with eosinophils, unique genetic mutations, and known or potential sensitivity to tyrosine kinase inhibitors or other specific drug therapies, they are now in the process of being classified together under the term clonal hypereosinophilia or clonal eosinophilia. historically, patients suffering the cited eosinophil-related syndromes were evaluated for causes of their eosinophilia such as those due to allergic disease, parasite or fungal infection, autoimmune disorders, and various well-known hematological malignancies (e.g. chronic myelogenous leukemia, systemic mastocytosis, etc.) (see causes of eosinophilia). absent these causes, patients were diagnosed in the world health organization's classification as having either 1) chronic eosinophilic leukemia, not otherwise specified, (cel-nos) if blood or bone marrow blast cells exceeded 2% or 5% of total nucleated cells, respectively, and other criteria were met or 2) idiopathic hypereosinophilic syndrome (hes) if there was evidence of eosinophil-induced tissue damage but no criteria indicating chronic eosinophilic leukemia. discovery of genetic mutations underlining these eosinophilia syndromes lead to their removal from cel-nos or hes categories and classification as myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of pdgfra, pdgfrb, fgfr1, and, tentatively, pcma-jak2. informally, these diseases are also termed clonal hypereosinophilias. new genetic mutations associated with, and possibly contributing to the development of, eosinophilia have been discovered, deemed to be causes of clonal eosinophilia, and, in certain cases, recommended for inclusion in the category of myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of pdgfra, pdgfrb, fgfr1, and, tentatively, pcma-jak2. many of the genetic causes for clonal eosinophilia are rare but nonetheless merit attention because of their known or potential sensitivity to therapeutic interventions that differ dramatically form the often toxic chemotherapy used to treat more common hematological malignancies. genetics, clinical presentation, and treatment clonal hypereosinophilia derives from germline mutations in genes that are involved in the development and/or maturation of hematopoietic stem cells and/or their myeloid or lymphoid descendants. in general, these mutations cause the mutated genes to form protein products that, unlike their natural counterparts, are less susceptible to inhibition: the mutant proteins continuously stimulate precursor cells to grow and proliferate while failing to differentiate and therefore result in, or at least are associated with, malignancies which have features dominated by myeloid, lymphoid, or both types of hematological malignancies. in most but not all instances, the resulting malignancies are associated with increases in blood, bone marrow, and/or tissue eosinophil levels as well as one or more of the signs, symptoms, tissue injuries, and organ dysfunctions (e.g. eosinophilic myocarditis) associated with the hypereosinophilic syndrome. the world health organization in 2015 included in their classification of eosinophilia disorders the category "myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of pdgfra, pdgfrb, and fgfr1" genes. this was updated in 2016 to include a provisional entity, a specific translocation mutation of the jak2 gene that forms the pcm1-jak2 fusion gene. these mutation-associated eosinophilic neoplasms as well as some recently discovered mutations that give rise clonal hypereosinophilias are described in the following sections. pdgfra-associated eosinophilic neoplasms genetics pdgfra-associated eosinophilic neoplasms are the most common forms of clonal eosinophilia, accounting for some 40% to 50% of all cases. the pdgfra gene encodes the platelet-derived growth factor receptor a (pdgfra) which is a cell surface, rtk class iii receptor tyrosine kinase. pdgfra, through its tyrosine kinase activity, contributes to the growth, differentiation, and proliferation of cells. chromosome translocations between the pdgfra gene and either the fip1l1, kif5b, cdk5rap2, strn, etv6, foxp1, tnks2, bcr or jak2 gene create a fusion gene which codes for a chimeric protein consisting of the tyrosine kinase portion of pdgfra and a portion of these other genes. the fusion protein has uninhibited tyrosine kinase activity and thereby is continuously active in stimulating cell growth, prolonged survival (by in inhibiting cell death), and proliferation. clinical presentation and treatment patients with the cited pdgfra fusion genes are overwhelmingly male (30:1 male to female ratio). they may present with cutaneous and/or pulmonary allergic symptoms, mucosal ulcers, splenomegaly, current or history of thrombosis events, and the most serious complication, cardiac dysfunction, which occurs in 20% to 30% of patients. the serious complications of eosinophilic myocarditis causing heart failure and arrhythmia and the pathological formation of blood clots causing the occlusion of diverse blood vessels occur often in, and may be part of the presentation of, this clonal eosinophilia. patient laboratory findings are compatible with the findings seen in a) eosinophilia, hypereosinophilia, the hypereosinophilic syndrome, chronic eosinophilic leukemia, or acute eosinophilic leukemia; b) myeloproliferative neoplasm/myeloblastic leukemia associated with little or no eosinophilia; c) t-lymphoblastic leukemia/lymphoma associated with eosinophilia; d) myeloid sarcoma associated with eosinophilia (see fip1l1-pdgfra fusion genes); or e) combinations of these presentations. variations in the type of malignancy formed likely reflect the specific type(s) of hematopoietic precursor cells that bear the mutation. pdgfra fusion gene-induced diseases generally respond well to the first line treatment drug, tyrosine kinase inhibitor, imatinib. if no hematological response is observed within 4 weeks of imatinib, primary resistance should be considered. this resistance is linked to the occurrence of a s601p mutation in pdgfra. acquired resistance to imatinib have in most cases been in association with the t674i mutation of fip1l1-pdgfra. second generation tyrosine kinase inhibitors, e.g. bosutinib, sorafenib, and nilotinib, show little success in treating t674i fip1l-pdgfra mutations leaving allogeneic stem cell transplantation as the treatment of choice for patients suffering such mutations. third generation tyrosine kinase inhibitors with in vivo efficacy for inhibiting pdgfra kinase activity are in development. genetics the pdgfrb gene encodes the platelet-derived growth factor receptor b (pdgfrb) which, like pdgfra, is a cell surface, rtk class iii receptor tyrosine kinase. pdgfra, through its tyrosine kinase activity, contributes to the growth, differentiation, and proliferation of cells. chromosome translocations between the pdgfrb gene and either the cep85l, hip1, kank1, bcr, ccdc6, h4d10s170), gpiap1, etv6, erc1, git2, nin, trip11, ccdc88c tp53bp1, nde1, specc1, ndel1, myo18a, bin2, col1a1, dtd1 cpsf6, rabep1, mprip, sptbn1, wdr48, golgb1, diaph1, tnip1, or sart3 gene create a fusion gene which codes for a chimeric protein consisting of the tyrosine kinase portion of pdgfrb and a portion of the other cited genes. the fusion protein has uninhibited tyrosine kinase activity and thereby continuously stimulates cell growth and proliferation. clinical presentation and treatment patients with the cited pdgfrb fusion genes generally present with a combination of eosinophilia and monocytosis, increased bone marrow eosinophils, and/or eosinophil tissue infiltrations but otherwise a disease resembling chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, acute myelogenous leukemia, acute lymphoblastic leukemia, or t lymphoblastic lymphoma. these patients usually respond well to imatinib or other tyrosine kinase inhibitor therapy. genetics fgfr1 is the gene for the fibroblast growth factor receptor 1, a cell surface receptor that similar to pdgfra and pdgfrb, is tyrosine kinase receptor. in some rare hematological cancers, the fusion of the fgfr1 gene with certain other genes due to chromosomal translocations or interstitial deletions create fusion genes that encode chimeric fgfr1 fusion proteins that have continuously active fgfr1-derived tyrosine kinase activity and thereby continuously stimulate cell growth and proliferation. these mutations occur in the early stages of myeloid and/or lymphoid cell lines and are the cause of or contribute to the development and progression of certain types of leukemia, myelodysplastic syndromes, and lymphomas which are commonly associated with greatly increased numbers of circulating blood eosinophils (i.e. hypereosinophilia) and/or increased numbers of bone marrow eosinophils. these neoplasmas are sometimes termed, along with certain other myelodysplastic syndromes associated with eosinophilia as myeloid neoplasms with eosinophilia, clonal eosinophilia, or primary eosinophilia. they have also been termed 8p11 myeloproliferative syndromes based on the chromosomal location of the fgfr1 gene on human chromosome 8 at position p11 (i.e. 8p11). the fusion gene partners of fgfr1 causing these neoplasms include: myo18a, cpsf6, tpr, herv-k, fgfr1op2, zmym2, cutl1, sqstm1, ranbp2, lrrfip1, cntrl, fgfr1op, bcr, nup98, myst3, and cep110. clinical presentation and treatment as detailed in fgfr1 hematological cancers, patients with the cited fgfr1 fusion genes usually evidence hematological features of the myeloproliferative syndrome with moderate to greatly elevated levels of blood and bone marrow eosinophils. less commonly and dependent upon the exact gene to which fbgfr1 is fused, patients may present with hematological features of t-cell lymphomas which may have spread to non-lymphoid tissues; chronic myelogenous leukemias; or chronic myelomonocytic leukemia with involvement of tonsils. some of these patients may present with little or no eosinophilia features but because of the underlying genetic mutation and its therapeutic implications are still regarded having clonal eosinophilia. because the fgfr1 gene is located on human chromosome 8 at position p11, hematological diseases associated with the cited fgfr1 gene fusions are sometimes termed the 8p11 myeloproliferative syndrome. fgfr1 fusion gene-associated hematological diseases are aggressive, rapidly progressive, and, in general, do not respond to first generation tyrosine kinase inhibitors. two newer generation tyrosine kinase inhibitors, sorafenib and midostaurin, have had only transient and/or minimal effects in treating the disease. currently, treatment with chemotherapy agents followed by bone marrow transplantion has been used to improve survival. the tyrosine kinase inhibitor ponatinib has been used as mono-therapy and subsequently used in combination with intensive chemotherapy to treat the myelodysplasia caused by the fgfr1-bcr fusion gene. pcm1-jak2 -associated eosinophilic neoplasms the jak2 gene encodes a member of the janus kinase family of non-receptor tyrosine kinase, jak2.