38

Beyond the classical Philadelphia

chromosome–negative
myeloproliferative neoplasms
Anand A. Patel and Brady Stein

Introduction 463
Myeloid/lymphoid neoplasms with KEY POINTS
eosinophilia and tyrosine kinase
gene fusions 467 • Several well-­characterized myeloproliferative neoplasms (MPNs) exist beyond
polycythemia vera, essential thrombocythemia, and myelofibrosis, but they are
Bibliography 470 quite rare.
• Chronic neutrophilic leukemia is typified by leukocytosis with neutrophilic
proliferation with a high percentage of cases having a mutation in CSF3R. ­There is
not a standard treatment approach but ruxolitinib can be considered in ­those with
a CSF3R mutation.
• Mastocytosis is a wide spectrum of disease phenotypes ranging from cutaneous
mastocytosis to systemic mastocytosis. ­There is a high rate of KIT mutations and
currently ­there are 2 FDA-­approved KIT inhibitors for this disease: midostaurin
and avapritinib.
• Myeloid/lymphoid neoplasms with eosinophilia oftentimes have a characteristic
tyrosine kinase gene fusion that greatly impacts clinical management.

Introduction
Beyond the classical Philadelphia chromosome–negative myeloproliferative neo-
plasms (MPNs) described in the previous chapter, ­there are several other MPN
subtypes that have been characterized based upon clinical and histopathologic fea-
tures. In this chapter, we focus on the diagnosis and management of chronic
neutrophilic leukemia (CNL), systemic mastocytosis (SM), and myeloid/lymphoid
neoplasms with eosinophilia. We also incorporate updated diagnostic criteria for
­these disease states from the World Health ­Organization (WHO) 5th edition and
the International Consensus Criteria (ICC).

Chronic neutrophilic leukemia

Introduction and diagnostic considerations
The WHO 5th edition defines chronic neutrophilic leukemia (CNL) as a
BCR::ABL1-­negative MPN with sustained leukocytosis ≥25 × 109/L, ≥80% seg-
mented neutrophils/bands, a hypercellular bone marrow with neutrophilic prolifer-
Conflict-­of-­interest disclosure: Anand ation, and hepatosplenomegaly. The ICC 2022 criteria allow for leukocytosis
A. Patel: research funding (to institution):
Pfizer, Kronos Bio, Sumitomo; honoraria:
≥13 × 109/L in the presence of an activating CSF3R mutation and also specify that
AbbVie, Bristol-Myers Squibb, Sobi. neutrophil precursors and monocytes should be ≤10% of the circulating leukocytes.
Brady Stein: nothing to disclose. A key differential diagnosis to consider is aty­pi­
cal chronic myeloid leukemia
Off-­label drug use: Ruxolitinib for (aCML), which is a myelodysplastic syndrome/myeloproliferative ­neoplasm overlap
CNL and aCML. disease; the WHO has renamed aCML as myelodysplastic/myeloproliferative

463
464 38. Beyond the classical Ph-negative myeloproliferative neoplasms

­ eoplasm with neutrophilia as a reflection of this. Key diag-

n Serum tryptase level
nostic criteria for both CNL and aCML are summarized in
Bone marrow, blood, or extracutaneous tissue sampling
­Table 38-1. Of note, ­there are conflicting data regarding
Molecular testing for activating KIT mutation
clinical outcomes in CNL vs aCML and ­whether prognostic
differences are primarily driven by molecular profile. Muta-
tions in colony-­stimulating ­factor 3 (CSF3R) are enriched
ICC/WHO
in both disease pro­cesses. criteria for SM met

Management approaches
YES ≥20% immature MC in
At this time ­there is not a standard management approach MCL
bone marrow aspirate/biopsy?
for ­either of ­these diseases. Given the rarity of ­these diseases,
evaluation for appropriate clinical ­trials should be strongly NO
considered. Cytoreduction with agents such as hydroxyurea YES
can be utilized particularly in ­ those with constitutional SM-AMN Criteria met for AMN?
symptoms and/or splenomegaly in conjunction. Notably,
NO
Dao et al reported on a phase 1/2 study of the JAK inhibitor
ruxolitinib in 44 patients with CNL and aCML.The overall YES
ASM C findings?
response rate was 35% with a median survival of 23.1 months
in responders; the presence of a CSF3R mutation was NO
strongly correlated with response. Allogeneic hematopoietic
stem cell transplant (allo-­HCT) is the only curative modality YES NO
SSM ≥2 B findings? ISM
and should be considered in eligible patients.
Figure 38-1 ​Diagnostic algorithm for systemic mastocytosis
Abbreviations: AMN, associated myeloid neoplasm; ASM, aggressive
Systemic mastocytosis SM; ICC, International Consensus Classification; ISM, indolent SM;
Introduction and diagnostic considerations MC, mast cells; MCL, mast cell leukemia; SM, systemic mastocytosis;
SSM, smoldering SM; WHO, World Health ­Organization. Adapted
Mastocytosis encompasses a heterogeneous spectrum of
from Pardanani A, Am J Hematol. 2023;98(7):1097-1116 (© 2023
disorders characterized by mast cell proliferation and accu- Wiley Periodicals LLC), with permission; professionally redrawn
mulation. Clinical manifestations of mast cell disorders are from an illustration created using BioRender​.­com.
caused by uncontrolled proliferation of tissue mast cells and
the release of mast cell–­ derived mediators. A diagnostic
workup focused on mastocytosis should be strongly of SM are associated with somatic-­activating point muta-
­considered in patients with recurrent anaphylaxis, flushing, tions of KIT, with the most common point mutation being
­osteoporosis, or chronic gastrointestinal symptoms. While D816V. The point mutations result in ligand-­independent
cutaneous mastocytosis (CM) is usually a chronic, indolent activation of KIT, which promotes mast cell proliferation
disease, systemic mastocytosis (SM) can be ­either indolent and survival. Over 80% of indolent SM (ISM) and smolder-
or more aggressive and even life-­threatening. Cutaneous ing SM (SSM) cases have a KIT mutation, while the inci-
manifestations of mastocytosis typically include a reddish-­ dence is approximately 60% in aggressive SM. In addition,
brown maculopapular eruption (urticaria pigmentosa) or, mast cells contain secretory granule proteases, most com-
less often, a diffuse erythema, plaques, or nodules.The c­ lassic monly tryptase, which is increased in mast cell diseases. An
description of urticaria, following stroking of the skin, is increase in tryptase levels serves as a minor criterion for di-
called the Darier sign.Telangiectasia macularis eruptiva per- agnosis (­unless associated nonhematologic mast cell disease
stans, characterized by red-­brown macules with irregular [AHNMD] is pre­sent). Although the level itself cannot dis-
borders and a telangiectasia-­like appearance, is a less com- tinguish SM subgroups, marked increases are seen in more
mon cutaneous manifestation. The ICC and WHO diag- advanced/aggressive subtypes. Additionally, m ­ easurement
nostic criteria for SM are summarized in ­Tables 38-2 and serves as a practical means of assessing mast cell burden and
38-3. Within SM t­here are a number of subtypes that are monitoring response to therapy.
typified by the presence of B symptoms and burden of dis-
ease (­Table 38-4 and Figure 38-1). It is notable that KIT is Management approaches
the protein tyrosine kinase receptor for stem cell ­factor The treatment approach to mastocytosis differs greatly based
(SCF) and is expressed by mast cells. Also of note, most cases on the subtype of disease.Treatment of CM includes H1 and
Introduction465

­Table 38-1 ​Diagnostic criteria for aty­pi­cal chronic myeloid leukemia and chronic neutrophilic leukemia
Aty­pi­cal chronic myeloid leukemia Chronic neutrophilic leukemia
Nomenclature ICC: Aty­pi­cal chronic myeloid leukemia ICC and WHO: Chronic neutrophilic leukemia
WHO: Myelodysplastic/myeloproliferative neoplasm
with neutrophilia
White blood ICC: ≥13 × 109/L with immaturea myeloid cells ICC: ≥13 × 109/L with segmented neutrophils +
cell (WBC) constituting ≥10% of WBC banded neutrophils ≥80% of WBCs. WBC should be
WHO: ≥13 × 109/L with neutrophilia, with ≥25 × 109/L in the absence of an activating CSF3R
immaturea myeloid cells ≥10% of WBC mutation
WHO: ≥25 × 109/L with segmented ­neutrophils +
banded neutrophils ≥80% of WBC. Immature
myeloid cells ≤10% of WBC
Cytopenia ICC: MDSb-­qualifying thresholds ICC: Not specified
WHO: Not mentioned WHO: Not specified
Peripheral blood and ICC and WHO: <20% ICC: 10%-19% blasts in peripheral blood or bone
bone marrow blasts marrow represent accelerated phase and ≥20% blasts
represents blast phase
WHO: <2% in blood and <5% in bone marrow
Dysplasia ICC: Dysgranulopoiesis; hyposegmented or ICC: Not specified
hypersegmented neutrophils, with or without WHO: No dysgranulopoiesis
abnormal chromatin clumping
WHO: Circulating immaturea myeloid cells
constituting ≥10% of WBC, with neutrophilic
dysplasia
Eosinophils ICC: <10% of WBC ICC: Not specified
WHO: Not mentioned WHO: Not specified
Monocytes ICC and WHO: <10% of WBC ICC: Not specified
WHO: <10% of WBC and absolute monocyte
counts <1 × 109/L
Bone marrow cellularity ICC and WHO: Hypercellular with granulocytic ICC and WHO: Hypercellular bone marrow with
and hematopoiesis hyperplasia and granulocytic dysplasia, with or neutrophil granulocytes increased in percentage and
without involvement of other lineages absolute number, showing normal maturation
Exclusionary criteria ICC: BCR::ABL1 or tyrosine kinase fusions ICC: Not meeting diagnostic criteria for
associated with myeloid/lymphoid neoplasms with BCR::ABL1-­positive CML, polycythemia vera,
eosinophilia; JAK2, MPL, and CALR mutations essential thrombocythemia, primary myelofibrosis, or
WHO: BCR::ABL1 or tyrosine kinase fusions myeloid/lymphoid neoplasms with eosinophilia and
associated with myeloid/lymphoid neoplasms with tyrosine kinase gene fusions
eosinophilia; JAK2, MPL, and CALR mutations; WHO: BCR::ABL1 or tyrosine kinase fusions
CSF3R mutations; MDS/MPN-­RS-­T with SF3B1 associated with myeloid/lymphoid neoplasms with
mutations eosinophilia; reactive neutrophilia; other WHO-­
defined MPN or MDS/MPN
Molecular datac and ICC: Desirable to document presence of ASXL1 ICC and WHO: CSF3R T618I or another activating
supportive clinical data and SETBP1 mutations CSF3R mutation OR per­sis­tent neutrophilia ≥3 mo,
WHO: Desirable to document presence of SETBP1 splenomegaly, and no identifiable cause of reactive
and/or ETNK1 mutations neutrophilia
Abbreviations: ICC, International Consensus Classification; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasm; RS, ring sideroblasts; T, thrombocytosis;
WBC, white blood cell count; WHO, World Health ­Organization.
Adapted from Patnaik MM, Tefferi A, Am J Hematol. 2023;98(4):681-689 (© 2023 Wiley Periodicals LLC) and Szuber N et al, Am J Hematol. 2024;99(7):1360-1387, with
permission.
a
Immature myeloid cells include promyelocytes, myelocytes, and metamyelocytes.
b
MDS-­defining cytopenias include Hb <13 g/dL in males and <12 g/dL in females, neutropenia with absolute neutrophil count <1.8 × 109/L, and thrombocytopenia with
platelet counts <150 × 109/L.
c
Supportive and desirable criteria.
466 38. Beyond the classical Ph-negative myeloproliferative neoplasms

­Table 38-2 ​ICC diagnostic criteria for systemic mastocytosis and ­Table 38-3 ​WHO 5th edition systemic mastocytosis diagnostic
systemic mastocytosis with associated myeloid neoplasm criteria
SM diagnostic criteria Diagnosis of SM requires 1 major and 1 minor criterion
Major criterion OR 3 minor criteria
Multifocal dense infiltrates of tryptase-­and/or CD117 positive Major criterion
mast cells (≥15 mast cells in aggregates) detected in sections of Multifocal dense infiltrates of mast cells (≥15 mast cells in
bone marrow and/or other extracutaneous organ(s)a aggregates) in bone marrow biopsies and/or in sections of other
In the absence of the major criterion, at least 3 of the extracutaneous organ(s)
following 4 minor criteria must be pre­sent: Minor criteria
• In bone marrow biopsy or in section of other extracutane- ≥25% of all mast cells are aty­pi­cal cells (type I or type II) on
ous organs >25% of mast cells are spindle ­shaped or have an bone marrow smears or are spindle ­shaped in mast cell infiltrates
aty­pi­cal immature morphologyb detected in sections of bone marrow or other extracutaneous
• Mast cells in bone marrow, peripheral blood, or other organsa
extracutaneous organs express CD25, CD2, and/or CD30, KIT-­activating KIT point mutation(s) at codon 816 or in other
in addition to mast cell markers critical regions of KITb in bone marrow or another
• KIT D816V mutation or other activating KIT mutation ­extracutaneous organ
detected in bone marrow, peripheral blood, or other
Mast cells in bone marrow, blood, or another extracutaneous
extracutaneous organsa,c
organ express one or more of: CD2 and/or CD25 and/or CD30c
• Elevated serum tryptase level, per­sis­tent­ly >20 ng/mL. In
cases of SM-­AMN an elevated tryptase does not count as Baseline serum tryptase concentration >20 ng/mL (in the case of
a SM minor criterion an unrelated myeloid neoplasm, an elevated tryptase does not
count as a criterion)
SM-­AMN diagnostic criteria
Adapted from Valent P et al, HemaSphere. 2021;5(11):e646, with permission from
• Meets the diagnostic criteria for SM John Wiley & Sons; permission conveyed through Copyright Clearance Center, Inc.
• Meets the criteria for an associated myeloid neoplasm (eg, a
In tissue sections, an abnormal mast cell morphology counts in both a compact
CMML or other MDS/MPN, MDS, MPN, AML, or other infiltrate and a diffuse (or mixed diffuse + compact) mast cell infiltrate. However, the
myeloid neoplasm)d spindle-­shaped form does not count as an SM criterion when mast cells are lining
vascular cells, fat cells, nerve cells, or the endosteal-­lining cell layer. In the bone mar-
• The associated myeloid neoplasm should be fully classified row smear, an aty­pi­cal morphology of mast cells does not count as SM criterion when
according to established criteriae mast cells are located in or adjacent to bone marrow particles.
b
Abbreviations: AML, acute myeloid leukemia; AMN, associated myeloid neoplasm; Any type of KIT mutation counts as a minor SM criterion when published solid
CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome; MPN, evidence for its transforming be­hav­ior is available.
c
myeloproliferative neoplasm; SM, systemic mastocytosis. All 3 markers fulfill this minor SM criterion when expression in mast cells can be
Adapted from Arber DA et al, International Consensus Classification of Myeloid Neo- confirmed by either flow cytometry or immunohistochemistry or by both techniques.
plasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood.
2022;140(11):1200–1228, with permission from the American Society of Hematology.
a
In the absence of a KIT mutation, particularly in cases with eosinophilia, the pres-
inhibitors, cromolyn, and other mast cell stabilizers may be
ence of tyrosine kinase gene fusions associated with myeloid/lymphoid neoplasms
with eosinophilia (M/LN-­Eo) must be excluded. sufficient to alleviate symptoms. Patients with SM should
b
Round-­cell well-­differentiated morphology can occur in a small subset of cases. In
carry epinephrine in an injectable form available at all times
­these cases, the mast cells are often negative for CD25 and CD2 but positive for CD30.
c for treating anaphylaxis. Aspirin and nonsteroidal anti-­
To avoid false-­negative results, use of a high sensitivity PCR assay for detection of
inflammatory drugs have been helpful for some patients
KIT D816V mutation is recommended. If negative, exclusion of KIT mutation vari-
ants is strongly recommended in suspected SM.
d with flushing and syncope, but hypersensitivity to t­hese
A high degree of suspicion can be raised by the presence of monocytosis, eosino-
drugs is relatively common and must be excluded. Accord-
philia, splenomegaly, elevated LDH, high KIT D816V variant allele frequency, and
additional somatic mutations in genes associated with myeloid malignancies (particu-
ingly, a major goal in the management of mastocytosis is
larly if occurring in combination) as they could be signs of an AMN.
e the avoidance of known triggers. Avapritinib, a potent and
If eosinophilia is pre­sent, the presence of tyrosine kinase gene fusions associated
selective KIT inhibitor, is approved for ISM based on a ran-
with M/LN-eo should be excluded. Although usually mutually exclusive, rare cases
with both a KIT mutation and a gene fusion associated with M/LN-eo have been
domized trial demonstrating a mean decrease in total
reported. In ­these rare instances, the M/LN-eo would represent the SM-­associated
symptom score of 15.6 points compared to a mean decrease
AMN, but it is recommended to assign such cases only in instances in which both a
KIT mutation and an M/LN-eo gene fusion are pre­sent. of 9.2 points in patients treated with placebo.
Advanced SM includes systemic mastocytosis with an
H2 antihistamines, cromolyn, other mast cell stabilizers, topi- associated myeloid neoplasm (SM-­ASM), aggressive SM
cal or intralesional glucocorticoids, psoralen, and UV-­ A (ASM), and mast cell leukemia (MCL). For SM-­ASM,
phototherapy. Adults with chronic CM may require long-­ treatment approach needs to be individualized to the pa-
term continuous or intermittent symptomatic treatment. tient based on which disease component drives morbidity
For adult patients with ISM and SSM, treatment of and needs most immediate intervention. For ASM, while
mediator-­related symptoms with combinations of H1 and vari­ous cytoreductive approaches including cladribine can
H2 antihistamines, leukotriene antagonists, proton pump be considered, a number of tyrosine kinase inhibitors
Introduction467

­Table 38-4 ​WHO 5th Edition B-­findings and C-­findings in approved for advanced SM in June of 2021. Across all ad-
systemic mastocytosis vanced SM subtypes in the phase 1 and phase 2 single-­arm
B-­findings studies of avapritinib, the overall response rate was 57%. Ap-
High MC burden: Infiltration grade (MC) in BM ≥30% in proximately half of patients had received prior midostau-
histology (IHC) and/or serum tryptase ≥200 ng/mL and/or KIT rin. Responses occurred relatively quickly (median time to
D816V VAF ≥10% in BM or PB leukocytes response 2 months) and ­were quite durable (median dura-
Signs of myeloproliferation and/or myelodysplasiaa: Hypercellular tion of response 38 months, range 19 months to not
BM with loss of fat cells and prominent myelopoiesis ± left shift
and eosinophilia ± leukocytosis and eosinophilia and/or discrete
reached). In select cases imatinib can also be considered as
signs of myelodysplasia (<10% neutrophils, erythrocytes, and an option in patients that do not have a KIT D816V mu-
megakaryocytes) tation. A similar treatment paradigm is utilized for MCL;
Organomegaly: Palpable hepatomegaly without ascites or other however, historical series have reported poor outcomes in
signs of organ damage and/or palpable splenomegaly without MCL. In patients with relapsed/refractory SM, ­there is no
hypersplenism and without weight loss or/and lymphadenopathy
palpable or visceral LN-­enlargement found in ULS or CT (>2 cm)
clear standard of care, with consideration given to multi-­
agent chemotherapy regimens. In addition, allo-­ HCT
C-­findings
should be considered for appropriate patients.
Cytopenia/s: ANC <1 × 109/L, Hb <10 g/dL, PLT <100 × 109/L
(1 or more found)
Hepatopathy: Ascites and elevated liver enzymesb ± hepatomegaly Myeloid/lymphoid neoplasms with
or cirrhotic liver ± portal hypertension
eosinophilia and tyrosine kinase
Spleen: Palpable splenomegaly with hypersplenism ± weight
loss ± hypalbuminemia gene fusions
GI tract: Malabsorption with hypoalbuminemia ± weight loss
Bone: Large-­sized osteolysis (≥2 cm) with pathologic frac- Introduction
ture ± bone pain The WHO and ICC both recognize myeloid/lymphoid
Abbreviations: AHN, associated hematologic neoplasm; ANC, absolute neutrophil neoplasms with eosinophilia and tyrosine kinase gene fu-
count; BM, bone marrow; CT, computed tomography; GI, gastrointestinal; Hb, hemo- sions (MLN-­TK) as a specific disease subtype character-
globin; IHC, immunohistochemistry; LN, lymph node; MC, mast cells; MDS, myelo-
dysplastic syndrome; MPN, myeloproliferative neoplasm; PB, peripheral blood; PLT, ized by rearrangements of genes encoding specific
platelet count; SM, systemic mastocytosis; SSM, smoldering systemic mastocytosis; tyrosine kinases leading to fusion products that cause
ULS, ultrasound;VAF, variant allele frequency.
constitutive activation of the kinase domain and subse-
Adapted from Valent P et al, HemaSphere. 2021;5(11):e646, with permission from
John Wiley & Sons; permission conveyed through Copyright Clearance Center, Inc. quent aberrant cell proliferation and survival. Workup for
a
Signs of myeloproliferation and/or myelodysplasia must be discrete and stable an under­lying neoplastic driver of eosinophilia should be
(neither dis­appear nor pro­g ress) and must not reach diagnostic criteria of an MPN,
MDS, or MPN/MDS, in which case the diagnosis changes to SM-­AHN. The pres-
pursued when the absolute eosinophil count is >1.5 × 109/L
ence of a myeloid AHN excludes B-­findings and SSM by definition. and secondary ­ causes have been excluded; given the
b
Alkaline phosphatase levels are typically elevated in patients with advanced SM broad differential of c­ auses and propensity for end-­organ
and SM-­induced liver damage. In some of ­these patients, only elevated liver enzymes
but no (clinically relevant) ascites are found. damage, evaluation at a center with subspecialty expertise
is recommended. ­There are a number of ge­ne­tic abnor-
malities characterized, including PDGFRA rearrange-
(TKIs) now carry approval. Midostaurin is a multikinase in- ment, PDGFRB rearrangement, FGFR1 rearrangement,
hibitor that has displayed potent activity against both JAK2 rearrangement, FLT3 rearrangement, ETV6::ABL1
wild-­type and mutant KIT. On this basis, an open-­label fusion, and other fusions described in the lit­er­a­ture. We
study of midostaurin for patients with aggressive SM was focus upon PDGFRA rearrangement, PDGFRB rear-
conducted. The overall response rate was 60%, including a rangement, and FGFR1 rearrangement given the specific
major response rate of 45% and a partial response rate of therapeutic implications. Diagnostic and treatment con-
15%. The median overall survival was 44.4 months in re- siderations for ­these diseases and other eosinophilic disor-
sponders and 15.4 months for nonresponders (28.7 ders are summarized in Figure 38-­2.
months for all patients). The median change in mast cell
burden, ­measured by reduction in tryptase, was 57%. The Myeloid/lymphoid neoplasms with PDGFRA
most clinically relevant treatment-­emergent toxicities ­were or ­PDGFRB rearrangements
nausea, vomiting, diarrhea, and myelosuppression, especially PDGFRA-­ and PDGFRB-­related neoplasms are multisys-
in patients with preexisting cytopenias. Based on the results tem disorders associated with bone marrow and peripheral
of this study, midostaurin was granted regulatory approval blood eosinophilia. The most common presenting signs
for the treatment of advanced SM. Avapritinib was FDA-­ and symptoms are weakness, fatigue, cardiopulmonary
468 38. Beyond the classical Ph-negative myeloproliferative neoplasms

Cardiac, pulmonary, neurological, and dermatological involvement

Splenomegaly
Clinical and Lymphadenopathy (FGFR1)
laboratory Sustained eosinophilia (>1.5 × 109/L)
features Anemia, thrombocytopenia
Bone marrow fibrosis

PDGFRA/PDGFRB and FGFR1-rearranged

Subtypes HES CEL-NOS
neoplasms or with PCM1-JAK2

Persistent, primary PDGFRA PDGFRB FGFR1 PCM1-JAK2 Eosinophils ≥10% of WBC

eosinophilia with May have features Blasts <20% in
end-organ damage; in common with peripheral blood and
Additional no increased CMML, JMML,
diagnostic bone marrow, and not
blood/bone marrow MDS/MPN-U, meeting other diagnostic
features blasts; no clonal atypical CML criteria for AML
disease or aberrant
T-cell population No disease-defining
tyrosine kinase gene fusions
Not meeting criteria for
other myeloid malignancies
Bone marrow with
megakaryocyte dysplasia
associated with eosinophilic
infiltrate or increased blasts
(≥5% in bone marrow and/or
≥2% in peripheral blood)
Demonstration of a
clonal aberration

Steroids Imatinib (initiate Clinical trial or JAK2 inhibitor HU, IFNα, corticosteroids
First-line steroids if elevated induction (ruxolitinib) (if organ damage
treatment cardiac troponin) chemotherapy followed by is present), empiric
options and/or cardiac followed by allogeneic allogeneic trial of imatinib,
dysfunction transplantation; transplantation allogeneic transplantation
pemigatinib is an
option for R/R disease

Figure 38-2 ​Workup and treatment considerations for eosinophilic disorders. Abbreviations: CEL-­NOS, chronic eosinophilic
leukemia, not other­wise specified; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; HES, hypereosinophilic
syndrome; HU, hydroxyurea; IFNα, interferon α; JMML, juvenile myelomonocytic leukemia; MDS/MPN-­U, myelodysplastic syndrome/
myeloproliferative neoplasm-­unclassified; R/R = relapsed/refractory.

symptoms, myalgias, rash, and fever. Splenomegaly is a can be pre­sent. Immunophenotyping is typical for activated
common finding, with a minority of patients also pre- eosinophils with expression of CD23, CD25, and CD69.
senting with hepatomegaly. Organ damage occurs b­ ecause The gold standard for the diagnosis of ­ these neoplasms
of release of cytokines or direct organ infiltration by eo- is demonstration of the fusion gene. As mentioned, most
sinophils and possibly mast cells. The most serious compli- cases of CEL-­NOS pre­sent with normal karyotype; thus,
cation of PDGFRA-­ and PDGFRB-­related neoplasms is FISH and reverse transcription-­polymerase chain reaction
cardiac in nature, including endomyo­car­dial fibrosis with ­(RT-­PCR) are preferred methods of testing. FISH testing
ensuing restrictive cardiomyopathy. relies on the probe for the CHIC2 gene, which is deleted
The most prominent diagnostic feature of cases of uniformly in patients with the FIP1L1-­PDGFRA fusion
PDGFRA-­related neoplasms is the presence of peripheral gene. RT-­PCR can be used in cases with a high clinical
blood mature eosinophilia. An elevated serum tryptase is suspicion and negative FISH testing results. RT-­PCR is
usually also pre­sent. Bone marrow biopsy results demon- also used for monitoring of disease response and for
strate marked hypercellularity with increased mature and minimal residual disease testing.
precursor eosinophils. It is impor­tant to note that FIPL1-­ Patients with PDGFRB-­related neoplasms tend to pre­
PDGRFA rearrangements are not exclusively associated sent with anemia and thrombocytopenia, along with leuko-
with an MPN phenotype ­because ­these rearrangements are cytosis neutrophilia or monocytosis. Features characteristic
also associated with ­presentations of acute leukemia. ­Fibrosis of chronic myelomonocytic leukemia (CMML), including
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions469

a monocytic leukocytosis with associated eosinophilia, are peripheral blood cell counts and disappearance of eosino-
often seen. Confirmation of diagnosis for PDGFRB-­related philia in 11; furthermore, 10 patients had complete resolu-
neoplasms requires demonstration of MPN with prominent tion of cytoge­ ne­
tic abnormalities and decrease in or
eosinophilia and occasional neutrophilia, monocytosis and disappearance of fusion transcripts ­measured by RT-­PCR.
the presence of the ETV6-­ PDGFRB fusion gene, or an al- A retrospective report of an expanded cohort of 26 patients
ternative PDGFRB gene rearrangement. The classic t(5;12) with a median follow-up of 10.2 years (imatinib duration,
(q31-­q33;p13) can be easily detected by conventional meta- 6.6 years) reported a 90% 10-­year survival, a 96% response
phase analy­sis, so FISH or RT-­PCR is usually used for the rate, and that no patient with complete cytoge­ne­tic (N = 13)
confirmation of diagnosis and determination of the fusion or molecular (N = 8) response lost their response.
gene. The bone marrow is hypercellular with increased fi-
brosis, and mast cells can be increased in number. Myeloid/lymphoid neoplasms
The mainstay of therapy for patients with PDGFRA-­ with FGFR1 rearrangement
and PDGFRB-­related neoplasms is the use of imatinib. This uncommon and heterogeneous group of neoplasms
One of the earliest pivotal reports identifying FIPL1-­ arises from pluripotent hematopoietic stem cells and is as-
PDGRA as a therapeutic target of imatinib was reported sociated with rearrangements in the FGFR1 gene and
by Cools et al in 2003. Following this report, investigators ­eosinophilia. Formerly known as 8p11 myeloproliferative
from the National Institute of Health (NIH) reported on syndrome or 8p11 stem cell syndrome, FGFR1-­related
improved hematological ­parameters, including reversal of neoplasms can pre­sent as classic MPNs, precursor B-­or
bone marrow fibrosis, along with molecular remissions in ­T-­cell lymphoblastic leukemia, or AML. FGFR1-­related
5 of 6 patients. Subsequently, several single-­and multi-­ neoplasms have been reported across a wide age range
institution studies have looked at the efficacy of low to (3 to 84 years), and the median age of diagnosis is
conventional doses of imatinib for the treatment of 32 years. Females constitute approximately 40% of the
PDGFRA-­related neoplasms. ­These studies report remark- cases. It is impor­tant to note that eosinophilia is not al-
ably similar results, in which patients with PDGFRA gene ways pre­sent despite the name of the diagnostic category.
rearrangements have rapid, deep, and durable responses to Clinical manifestations include fever, weight loss, and
low to conventional doses of imatinib (100 to 400 mg/d). night sweats. Lymphadenopathy is common in patients
In ­those with known eosinophilic heart disease, s­ teroids are with lymphomatous ­presentation. Hypercatabolism and
recommended concurrently with imatinib during the first splenomegaly are common features of AML and MPN pa-
1 to 2 weeks of therapy given prior reports of cardiogenic tients. The most common chromosomal translocation as-
shock. sociated with FGFR1-­ related neoplasms is t(8;13)
Interestingly, in a retrospective report of 44 patients by (p11;q12), which results in expression of the ZNF198-­
the French Eosinophil Network, complete hematologic FGFR1 fusion TK. Fifteen fusion gene partners have been
and molecular remission was obtained in 44 of 44 and 43 described in FGFR1 rearranged neoplasms, including
of 44, respectively. Among 11 patients in whom imatinib CEP110, FGFR1OP1, FGFR1OP2, TRIM 24, MYO18A,
was discontinued, 5 remained in remission (range, 9 to 88 HERVK, and BCR.
months). However, this strategy requires confirmation in a The prognosis for patients with FGFR1-­related neo-
prospective setting, and indefinite therapy is recommended. plasms is very poor, with evolution to AML typically oc-
Compared with BCR-­ABL1-­positive CML, kinase domain curring within 1 to 2 years. The clinical aggressiveness and
mutations that confer ­resistance to imatinib therapy, includ- diminished awareness about the features of this entity, and
ing T674I and D842V, are rare in FIP1L1-­PDGRFA the lack of approved therapies, make the treatment of ­these
rearrangement-­positive disease. Other tyrosine kinase in- patients very challenging. Early intensive chemotherapy
hibitors have been used in this setting with only modest followed by allogeneic stem cell transplant (SCT) remains
and transient benefit. the only potential curative therapy for patients with
In 2002, Apperley et al reported 4 patients with FGFR1-­related neoplasms.­There are currently no standard
PDGFRB-­related neoplasms treated with imatinib 400 mg frontline therapeutic approaches. The FGFR1 inhibitor
daily. Normalization of blood accounts occurred within pemigatinib was approved for relapsed/refractory myeloid/
4 weeks, the t(5;12) translocation was undetectable by 12 to lymphoid neoplasms (MLNs) with FGFR1 rearrange-
36 weeks, and transcript levels decreased in ­those with the ment based upon the results of the FIGHT-203 study.
ETV6-­PDGFRB fusion. A report on 12 patients with Of the 33 patients treated in the study with MLN and
PDGFRB-­related neoplasms who received imatinib ther- evaluable for cytoge­ne­tic response, 76% achieved a com-
apy for a median of 47 months revealed normalization of plete cytoge­ne­tic response.
470 38. Beyond the classical Ph-negative myeloproliferative neoplasms

Gotlib J, Kluin-­Nelemans HC, George TI, et al. Efficacy and safety

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