Clonal hypereosinophilia

Clonal Eosinophilia, also termed Primary Eosinophilia, is a malignant or pre-malignant expansion of a white blood cell type, the eosinophil, in bone marrow, blood, and/or tissues due to any one of numerous genetic mutations. Clinically, the disease resembles various types of chronic or acute leukemias, lymphomas, or myeloproliferative hematological malignancies. Clonal eosinophilia is distinguished from most other hematological malignancies by the genetic mutations which underlie its development and, more importantly, by its therapeutic treatment which in most cases differs markedly from the treatment recommended for these other malignancies.

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. Philadelphia chromosome positive chronic myelogenous leukemia I now successfully treated with maintenance tyrosine kinase inhibitors but before this at the time novel therapeutic approach was generally lethal within 18-60 months of diagnosis. 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 as 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 eosinophilias. 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 eosinophilia 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 differeniate 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. The World Health Organisation 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 entitiy, 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 eosinophilias are described in the following sections.

World Health Organization-identified clonal eosinophilias

PDGFRA-associated eosinophilic neoplasms

Main article: PDGFRA § Myeloid and lymphoid cells

Main article: FIP1L1 § FIP1L1-PDGFRA fusion genes

Genetics

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, 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 and proliferation.

Clinical presentation and treatment

As detailed in FIP1L1-PDGFRA fusion genes and other PDGFRA fusions, patients with the cited PDGFRA fusion genes present with: a) chronic eosinophilia or chronic eosinophilic leukemia; b) a form of 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. Their disease generally responds well or are anticipated to respond well to imatinib or other tyrosine kinase inhibitor.

PDGFRB-associated eosinophilic neoplasms

Main article: PDGFRB § PDGFRB-ETV6 translocations

Main article: PDGFRB § Other PDGFRB translocations

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

As detailed in PDGFRB-ETV6 translocations and Other PDGFRB translocations, patients with the cited PDGFRB fusion genes generally present with eosinophilia, 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.

FGFR1-associated eosinophilic neoplasms

Main article: FGFR1 § Hematological cancers

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 hematoglogical 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 in general do not respond to tyrosine kinase inhibitors, are aggressive and rapidly progressive, and require treatment with chemotherapy agents followed by bone marrow transplantion in order 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. The JAK2 protein associates with the cytoplasmic tails of various cytokine and growth factor receptors that reside on the cell surface and reagulate Haematopoiesis, i.e. the development and growth of blood cells. Examples of such receptors include the erythropoietin receptor, Thrombopoietin receptor, granulocyte colony-stimulating factor receptor, Granulocyte macrophage colony-stimulating factor receptor, Interleukin-3 receptor, Interleukin-5 receptor, Interleukin-6 receptor, and the receptor Thymic stromal lymphopoietin, which is a complex composed of the CRLF2 receptor combined with alpha chain of the IL-7 receptor. JAK2 protein's association with these receptors is responsible for a) correctly targeting and positioning these receptors at the cell surface and b) indirectly activating critical cell signaling pathways including in particular the STAT family of transcription factors which are involved in promoting the growth, proliferation, differentiation, and survival of the myeloid and lymphoid precursor cells that populate the bone marrow, other blood cell forming tissues, and the blood. The PCM1 gene codes for the PCM1 protein, i.e. pricentriolar material 1. also known as PCM1, is a protein which in humans is encoded by the PCM1 gene. The PCM1 protein exhibits a distinct cell cycle-dependent association with the centrosome complex] and microtubules; it is critical for the normal cell cycle and cell division (see PCM1).

Genetics

Acquired mutations in early hematopoietic stem cells involving the JAK2 gene, located on human chromosome 8 at position p22 (i.e. 8p22), and the PCM1 gene, located at 12p13, create the PCM1-JAK2 fusion gene. This fusion gene encodes the chimeric PCMI-JAK2 fusion protein which has continuously active JAK2-assoicated tyrosine kinase and therefore continulously phosphorylates tyrosine residues on the cytoplasmic tail of the cell surface receptor to which the it is attached. In consequence, the receptor remains continuously active in attracting docking proteins such as SOS1 and STAT proteins which drive cell growth, proliferation, and survival.

Clinical presentation and treatment

PCM1-JAK2 gene positive patients present with features of myeloid neoplasms, lymphoid neoplasms, or features of both types of neoplasms. Most commonly, the present with features of myeloid neoplasms with 50-70% of cases associated with eosinophilia and/or bone marrow fibrosis Their disease usually progresses rapidly from a chronic phase to an acute blast cell phase resembling chronic myelogenous leukemia's conversion form chronic to acute phases. Rarely, the acute phase of PCM1-JAK2 gene positive disease resembles a lymoblastic leukemia. PCM1-JAK2-induced hematological malignances are rare and relatively newly discovered. The disease is aggressive and therefore has been treated aggressively with chemotherapy followed by bone marrow transplantation. However, of 6 patients treated with a tyrosine kinase inhibitor, ruxolitinib, 5 experienced complete remissions and have survived for at least 30 months. One patient relapsed after 18 months ruxolitinib therapy and required Hematopoietic stem cell transplantation (HSCT). The efficacy of ruxolitinib therapy in this therapy requires a larger study; ultimately, the drug may find use as initial single therapy or as an adjuvant to reduce tumor load prior to combination with HCST.

Other clonal eosinophilias

Ongoing studies continue to find patients with eosinophilia, hypereosinophilia, or other myeloid/lymphoid neoplasms that are associated with eosinophilia and that express previously unappreciated mutations in genes coding for other tyrosine kinases in bone marrow-derived cells. These cases fit the definition of clonal eosinophilia. The World Health Organization currently includes these mutation-related diseases in the categories of 1) idiopathic hypereosinophila when blood and bone marrow show no increase in blast cells and there is no eosinophil-related organ damage or 2) CEL-NOS when increased numbers of blast cells occur in blood and/or bone marrow and/or eosinophil-related tissue damage is present. Further studies may allow these mutation-related diseases to be considered for inclusion in the myeloid and lymphoid neoplasms associated with eosinophilia category.

Other JAK2-related eosinophilias

Genetics

Gene fusions of JAK2 with ETV6 or BCR have been discovered in rare instances of eosinophilia-associated hematological diseases. The product of the ETV6 gene is a member of the ETS transcription factor family; it is required for hematopoiesis and maintenance of the developing vascular network, as determined in mouse Gene knockout. ETV6 is located on human chromosome 12 at position p13.2; chromosome translocation between it and JAK2 located on human chromosome 9 at position p24.1 form the fusion gene t(9;12)(p24;13) which encodes the ETV6-JAK2 fusion protein. Forced expression of this fusion protein in mice causes a fatal mixed myeloid and/or T-cell lymphoproliferative disorder. BCR encodes the breakpoint cluster region protein. This protein possess Serine/threonine-specific protein kinase activity and also has GPAase activating effects on RAC1 and CDC42 but its normal function is unclear. BCR is located on human chromosome 22 at position q11.23. Translocations between it and JAK2 create the t(9;22)(p24;q11) fusion gene which codes for the BCR-JAK2 fusion protein. Forced expression of BCR-JAK2 in mice induces a fatal myeloid neoplasm involving splenomegaly, megakaryocyte infiltration, and leukocytosis. It is assumed but not yet fully proven that the Malignant transformation effects of these two fusion proteins are due to the effects of a presumtively continuously active JAK2-associated tyrosine kinase.

Clinical presentation and treatment

The clinical presentation of patients suffering ETV6-JAK2 or BCR-JAK2 fusion gene-associated disease is similar to that occurring in PCM1-JAK2-associated eosinophilic neoplasm. Like the latter neoplasm, hematologic neoplasms cause by ETV5-JAK2 and BCR-JAK2 are aggressive and progress rapidly. Too few patients with the latter fusion proteins have been treated with tyrosine kinase inhibitors to define their efficacy. One patient with BCR-JAK-related disease obtained a complete remission with ruxolitinib therapy that lasted 24 months but then required Hematopoietic stem cell transplantation (HSCT); a second patient wit this mutation failed treatment with dasatinib and also required HSCT.

ABL1-related eosinophilias

Genetics

The ABL1 gene encodes a non-receptor tyrosine kinase termed Abelson murine leukemia viral oncogene homolog 1. Among its numerous effects on cellular function, the ABL1 kinase- regulates cell proliferation and survival pathways during development. It mediates at least in part the cell proliferating signaling stimulated by PDGF receptors as well as by antigen receptors on T cell and B cell lymphocytes. The ABL1 gene is located on human chromosome 9q34.12; translocations between it and the BCR gene on human chromosome 22q11.23 create the well-known t(9;22)(q34;q11) BCR-ABL1 fusion gene responsible for Philadelphia chromosome positive chronic myelogenous leukemia and chronic lymphocytic leukemia. While BCR-ABL1 fusion gene-induce leukemias are sometimes accompanied by eosinophilia, they are not regarded as clonal eosinophilias since other features of these leukemias dominate. However, translocations between ABL1 and the ETV6 gene, located on human chromosome p13.2 creates the t(9;13)(q34;p13) ETV6-ABL1 fusion gene. This fusion gene is regarded as continuously active in drive hematological cell proliferation leading to clonal eosinophilia.

Clinical presentation and treatment

Patients with ETV6-ABL1 fusion gene-positive disease present with various hematological disorders. Children present predominantly with hematological findings similar to acute lymphocytic leukemia and less commonly with findings of acute myelogenous leukemia or chronic variants of these two leukemias. Adults are more likely to present with findings similar to acute myelogenous leukemia or myeloproliferative neoplasms. In a study of 44 patients with this fusion gene, eosinophilia was found in all patients with myelogenous and myeloproliferative diseases but only 4 of 13 with acute lymphocytic leukemia presentations. The prognosis was very poor in adults with acute leukemia forms of the disease; ~80% of these patients suffered fatal disease progression or relapse. Five patients with the myeloproliferative form of the disease responded to the tyrosine kinase inhibitor imatinib or sequential treatment with imatinib followed by recurrence and treatment with a second generation tyrosine kinase inhibitor nilotinib; dasatinib is also a recommended second generation tyrosine kinase inhibitor for treating the disease. Follow-up of these patients is too short to determine the overall length of time to relapse and the efficacy of single or serial tyrosine kinase inhibitor treatments. Patients with the blast cell phase of this disease have very poor responses to tyrosine kinase inhibitors and a median survival of ~1 year. Thus, tyrosine kinase inhibitors, including second-generation inhibitors, in the treatment of ETV6-ABL1-positive hematological malignancies have shown varying responses; it is suggested that further investigations into the clinical efficacy of these drugs in ETV6-ABL-induced clonal eosinophilia is warranted.