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Chronic Eosinophilic Leukemia
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
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
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
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