Introduction:

• Chronic eosinophilic leukaemia is a MPN in which there is autonomous clonal proliferation of eosinophilic precursors resulting in persistently increased numbers of eosinophils in blood (>1500/cmm), bone marrow and peripheral tissues.
• Patients with BCR-ABL translocations are excluded.
• Difference between CEL-NOS and hypereosinophilic syndrome is- CEL-NOS is a clonal disorder, i.e. cytogenetic abnormality is present or they have raised blast count (>2% in PB and >5% in BM).
• Definition of Idiopathic HES: It is unexplained elevation of peripheral blood eosinophils (>1500/cmm) for more than 6 months associated with end organ damage (Proliferation in this case is not clonal)
• Definition of Idiopathic hypereosiniphilia: It is same as above, but there is no end organ damage.

Epidemiology:

• M: F – 1: 1
• PDGFRA rearrangements: M: F- 17:1
• Usually seen at around 40 years

Etiology:

• Cryptic deletion at 4q12 leads to formation of FIP1L1-PDGFRA fusion gene. (Some of them can present with AML/T-ALL)
• t (1:4) and t (4:10) can also lead to this fusion gene formation.
• PDGFRB mutations occur due to translocations involving chromosome 5. Some of them can present with CMML with eosinophilia.
• FGFR1 abnormalities- They may present with AML/ALL/Mixed lineage acute leukaemia with eosinophilia. Gene is located on chromosome 8p11.

Pathogenesis:

• Tissue damage is due to release of mediators like – Eosinophil cationic protein and major basic protein

Clinical Features:

• 10% are asymptomatic
• Constitutional symptoms- Fever, fatigue, cough
• Muscle pain, arthritis, arthralgia, Raynaud's phenomenon
• Pruritus, papule / plaques, angioedema, mucosal ulcers, vesciculo-bullous lesions
• Diarrhoea, ascites, gastritis, colitis, pancreatitis, cholangitis, hepatitis, Budd chiary syndrome
• Restrictive cardiomyopathy due to endomyocardial fibrosis
• Pericarditis, myocarditis, intramural thrombus formation, scarring of mitral / tricuspid values leading to regurgitation
• Peripheral neuropathy, mononeuritis multiplex, paraparesis, cerebellar dysfunction, epilepsy, dementia, cerebrovascular accident, eosinophilic meningitis
• CNS dysfunction – Paraparesis, encephalopathy, dementia
• Pulmonary infiltrates, fibrosis, pleural effusion and pulmonary embolism
• Others- Microthrombi, vasculitis, retinal arteritis, digital necrosis

Investigations:

• Hemogram
  • WBC count- > 30 x 10⁹ /L
  • Marked eosinophilia – 30 – 70%
  • Mainly mature eosinophils with only few eosinophilic myelocytes or promyelocytes
  • Eosinophils show sparse granulation with clear areas of cytoplasm, cytoplasmic vacuolization, nuclear hypersegmentation /  hyposegmentation
  • Associated neutrophilia and blasts > 2% prompt the diagnosis of CEL
• Bone marrow
  • Hypercellular due to eosinophilic proliferation
  • Orderly maturation of eosinophils seen
  • Charcot – Leyden crystals often present
  • Erythropoiesis – Normal
  • Megakaryopoiesis – Normal
  • Marrow should be carefully searched for any process which might explain eosinophilia as a secondary reaction – vasculitis, lymphoma, ALL, granulomatous reaction etc
• Cytochemistry 
  • Cyanide resistant myeloperoxidase positive
  • Naphthol – ASD – chloroacetate esterase – positive (Normally absent in eosinophils)
• Immunophenotyping: No specific immunophenotypic abnormalities
• Cytogenetics
  • Chromosome 5 band 31-35 contains several genes relevant to eosinopoiesis- such as IL5, IL3, GM-CSF, PDGFR beta
  • t (1:5), t (2:5), t (5:12), t (6:11)
  • Other abnormalities include- +8,   i(17q)
  • t (5:12) – chronic myelomonocytic leukaemia with eosinophilia
  • t (8:13) -(p11; q22) & other 8p11 translocations- Related to FGFR1 gene
  • 8p11 syndrome includes – eosinophilic leukemia, AML, precursor T lymphoblastic leukaemia / lymphoma, Precursor B lymphoblastic leukaemia
  • Microdeletion on chromosome 4 leads to fusion of FIP1L1 & PDGFR alfa genes. This results in generation of constitutively active tyrosine kinase. FIP1L1-PDGFRA fusion tyrosine kinase is seen in 50% of HES.
• Serum cobalamin, uric acid and muramidase- Increased
• LAP score- Normal
• Annual echocardiography- To assess cardiac damage

Criteria for Diagnosis CEL-NOS:

• Persistent eosinophilia (>1500/cmm) with immature form
• <20% blasts in PS/BM
• Infiltration of tissues by eosinophils
• Brief clinical course measured in months associated with anaemia and thrombocytopenia
• Absence of t (8:21), inv (16), PDGFR, FGFR mutations and BCR-ABL translocations 
• Evidence of clonality- cytogenetic abnormality or raised blast count (>2% in PB and >5% in BM).

Prognosis:

• 5-year survival- 80%
• Poor prognostic markers:
  • Marked splenomegaly
  • High blast count in blood/ bone marrow
  • Cytogenetic abnormalities
  • Dysplastic changes in other myeloid lineages
  • Lack of response to steroids
  • Markedly elevated eosinophil count
  • Normal IgE levels
  • Male sex

Pretreatment Work-up: 

• History
• Examination:    Spleen:
• BMA and Bx
• Haemoglobin
• TLC, DLC, AEC
• Platelet count
• Peripheral smear: For monocytosis, dysplasiaor circulating blasts
• LFT: Bili- T/D       SGPT:       SGOT: Albumin:     Globulin:
• Creatinine
• Uric acid
• S. IgE levels
• Vitamin B12 level
• S. Tryptase level
• LDH
• HIV
• Cytogenetics
• FISH/ PCR- BCR-ABL1
• JAK 2
• CAL-R
• MPL
• FISH for PDGFRA
• FISH for PDGFRB
• FISH for FGFR1
• Inv (16)
• t (16:16)
• Cardiac Troponin, proBNPECHO and ECG- For end organ damage
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment:

• If patient has rearrangement of PDGFRA- Imatinib- Start with 100mg OD, then titrate the dose up to 400mg-OD, depending on AEC.
• In case of FIP1L1- PDGFRA rearrangement- even if patient has manifestation of acute leukaemia- Imatinib has to be given. As these patients can enter into remission with Imatinib alone.
• If patient has PDGFRB gene rearrangement- Standard dose Imatinib
• In both above cases if there is development of resistance (Ex. T674I mutation)- Sorafinib can be used.
• ETV6-FLT3- Consider sunitinib or sorafenib
• FGFR1 rearrangement: Pemigatinib/ midostaurin/ Ponatinib- Followed by HSCT (If fit)
• Eosinophilia with JAK 2 mutation- Ruxolitinib/ Fedratinib (Doses adopted to platelet count). HSCT should be considered irrespective of response to Ruxolitinib.
• For all other patients (CEL-NOS): A trial of Imatinib can be given. If there is no response, steroids (Prednisolone- 1mg/Kg) can be used. If this also fails, other options include hydroxyurea, IFN-alpha, Vincristine, Etoposide and Cladribine.

Related disorders:

• Myeloid/ Lymphoid neoplasm with eosinophilia and FIP1L1::PDGFRA Rearrangement
  • Can present with
    • Chronic eosinophilic leukemia
    • MPN in blast crisis
    • AML with eosinophilia
    • T- ALL
    • Myeloid sarcoma
  • Male predominance
  • Associated with
    • Elevated vitamin B12 levels
    • Elevated S. Tryptase
    • Splenomegaly
  • BMA: Hypercellular with increased eosinophilic precursors. Dense clusters of mast cells are present
• Myeloid/Lymphoid Neoplasms with Eosinophilia and PDGFRB Rearrangement:
  • Can present with
    • CMML
    • Atypical CML
    • MDS/MPN
    • JMML
  • Male predominance
• Myeloid/Lymphoid Neoplasms with Eosinophilia and FGFR1 Rearrangement:
  • Can present with
    • MPN with eosnophilia
    • AML
    • B-ALL
    • T-ALL
    • Mixed phenotype acute leukemia
• Myeloid/Lymphoid Neoplasms with Eosinophilia and JAK2 Rearrangement
  • Can present with
    • MPN with eosinophilia
    • MDS/MPN with eosinophilia
    • ALL
    • AML
  • Male predominance
  • Aggressive clinical course
• Myeloid/Lymphoid Neoplasms with Eosinophilia and FLT3 or ABL1 Rearrangement
  • Presents with
    • CEL
    • T- Lymphoblastic lymphoma
    • ALL
  • Aggressive clinical course

Figures:

Figure 2.7.1- Chronic eosinophilic leukemia- Peripheral smear