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Table6.2 TKI dose schedules infrontline andlater- line therapies, toxicities, andsuggested dose reductions, clinically relevant TKI toxicities
andreduced dose schedules
Lower dose ranges if
TKI
Frontline
dose
schedule
Later line
dose
schedule Common side effects
Toxicities to
watch for
Prohibitive
toxicities
a
toxicities not
deemed worrisome/
irreversible
b
Imatinib 400 mg daily 400 mg daily Rash, fluid retention,
edema, weight gain,
musculoskeletal
aches, diarrhea, skin
depigmentation
Nilotinib 300 mg BID 400 mg BID Rash, headaches,
increased bilirubin,
impaired glycemic
control, dyslipidemia
Dasatinib 50–100 mg
daily
Bosutinibc400 mg daily 500 mg daily Gastrointestinal toxicity
Ponatinib – 45 mg daily Rash, hypertension Pancreatitis,
Abbreviations: TKI, tyrosine kinase inhibitor; BID, twice daily.
a
Clinical pancreatitis is a toxicity that can occur with all TKIs, though most common with nilotinib and ponatinib. Recurrent clinical pancreatitis
on the same TKI is prohibitive, requiring a change of TKI. See a more comprehensive list of prohibitive toxicities in the text.
b
Lowest dose range is a dynamic therapy decision that depends on the toxicity and grade, patient age, co- morbidities, and molecular
response at the time of the toxicity.
c
For bosutinib a dose escalation schedule may reduce the initial self- limited diarrhea, improve compliance, and reduce the discontinuation
rate: 100 mg/day ×one week, 200 mg/day × two to four weeks, 300 mg/day × two to four weeks, then decide on final dose of 400 mg/day or
500 mg/day depending on response and side effects.
100 mg daily Pleural effusion,
cytopenia
(diarrhea/colitis),
renal dysfunction,
liver dysfunction
Renal toxicity Neurotoxicity 100–300 mg/day
Renal toxicity,
pancreatitis,
Worsening
diabetes
Pulmonary
hypertension,
systemic
hypertension
Enterocolitis Enterocolitis 100–300 mg/day
liver
dysfunction
Arterio- occlusive
and vaso- occlusive
events
>1 episode of
pleural effusion,
pulmonary
hypertension
Arterio- occlusive
and vaso- occlusive
events; refractory
hypertension
200 mg/day- 200 mg
BID
20–50 mg/day
15 mg/day
The approved TKI dose schedules are a bit different in
later- line therapy (Table6.2). Nilotinib 400 mg orally BID
bosutinib 500 mg daily and ponatinib 45 mg daily are the
approved doses for the treatment of CML post failure of
frontline therapy. Recent studies suggest that dose- adjusted
ponatinib, starting at 45 mg daily in T315I- mutated CML
and perhaps at 30 mg daily in others, and reducing the
dose to 15 mg daily once the BCR::ABL1 transcripts [IS]
decrease to <1%, is safer and results in similar long- term
survival. Omacetaxine is given at the dose of 1.25 mg/m
twice daily subcutaneously for 14 days during induction,
and for 7days every 1–2months during maintenance. This
schedule may be too myelosuppressive, and five to seven
days during induction and two to five days every one to
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two months during maintenance may be less myelosuppressive and equally effective (alone or in combination
with a TKI).
As long- term experience is gained with the TKIs, drug
dose modifications can eliminate or reduce significant toxicities and allow continuation of therapy, either in frontline
or in later- line therapy. However, in later- line therapy, dose
reductions in patients in molecular response more likely may
result in molecular/clinical relapse, and such patients should
2
be monitored closely.
The FDA- approved indications of 5 TKIs are summarized,
with suggestions on dose reductions in case of mild- moderate
chronic side effects, or serious but reversible side effects in
Table6.2.
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Other therapies
Interferon alpha was developed as a CML therapy in the
1980s and became a standard of care in 1990–2000. It
improved survival but was toxic. A CCyR was obtained in
10–35% of patients and was associated with a 10- year survival rate of 78%, establishing the concept of achievement of
CCyR to improve survival. Of interest, 30% of patients in
CCyR had undetectable BCR::ABL1 transcripts, and most
had not relapsed after more than 10 years of follow- up, illustrating an uncommon but possible curative effect. Today,
interferon alpha is rarely used as a standard of care.
Hydroxyurea, a ribonucleotide reductase inhibitor, is a
well- tolerated oral agent that controls high CML white blood
cell counts rapidly. Rare side effects include nausea, rashes,
mouth ulcers, and hand or leg ulcers. The dose range is
1–10 g daily×1–5 days depending on the degree of leukocytosis. The dose is adjusted to keep the WBC count around
3–10 × 109 cells/L. Hydroxyurea can be used for initial
cytoreduction, or as part of a combination approach with
TKIs. It should not be used alone as a treatment in CML.
Busulfan (1,4- dimethane- sulfonyl- oxybutane) is the first
alkylating agent to demonstrate activity in CML. It is associated with significant toxicities: severe, prolonged myelosuppression; myelofibrosis (“spent phase of CML”); and an
Addison’s- like syndrome. Today, busulfan is used primarily
as part of conditioning regimens for allogeneic SCT.
Other effective therapies that can be used in combination
with TKIs in patients with resistant CML- CP, and in whom
there are no better treatment choices (e.g. older patients and
no SCT option), include hypomethylating agents (decitabine
or azacitidine) and low- dose cytarabine. Decitabine has
shown good activity in CML- CP and CML- AP/BP as a single
agent. Omacetaxine, discussed above, can be used cautiously
in combination with TKIs in resistant CML, but at lower
dose schedules (two to three days/month).
Pregnancy and CML
If a pregnant woman is diagnosed with CML, she can be
managed with leukapheresis as indicated during the first
trimester of pregnancy, and with hydroxyurea therapy
subsequently until delivery, then with more definitive TKI
therapy. Some experts recommend interferon alpha therapy, but this may have adverse effects on the fetus. If a
woman with CML becomes pregnant while on TKI therapy,
the drug should be discontinued. Among 125infants born
to women with CML on imatinib (drug discontinued after
pregnancy documented), 12 had birth defects, including
3with a syndrome of ocular, renal, and skeletal abnormalities. On dasatinib therapy, the risk of fetal malformation
was higher, close to 10%. Children of women whose male
partners have CML and are on imatinib have all been
normal.
Allogeneic hematopoietic stem cell
transplantation
Allogeneic HCT is curative in CML but is associated with significant morbidities and with a one- year mortality of 5–30%
depending on several factors: patient age, source of cells,
degree of matching, CML phase, others. It is most effective in
CML- CP. Among patients in the first CML- CP who undergo
matched related sibling transplant, the 20- year survival rate is
40–50%. The International Bone Marrow Transplant Registry
(IBMTR) data of >6000 patients showed a five- year survival
rate of 60% in CML- CP/sibling donor SCT but a 20- year survival rate of 40–45%. About 10% of patients still die in years
5–20 from transplant- related complications rather than CML
relapse. Chronic morbidities post- SCT include graft- versushost disease (GVHD), second neoplasm, cataracts, infertility,
joint osteonecrosis, and GVHD- related organ damage (pulmonary, hepatic) and immune- mediated complications.
Disease- free survival (DFS) rates are 60–80% among patients
<40 years of age, and 30–40% in patients >50 years. DFS rates
are 30–50% in patients with CML- AP and 5–30% in patients
in CML- BP. Patients with clonal evolution as the only
CML- AP criterion have DFS rates of 60%. Patients receiving
SCT in second chronic phase have DFS rates of 40%.
Nonmyeloablative preparative regimens are safer in older
patients and have reduced transplant- associated complications and mortality. Haplo- identical and cord blood transplants are showing promising results.
The role and timing of allogeneic HCT in patients with
CML are changing based on the maturing experiences with
TKIs and HCT, as well as the cost of therapies and regional
considerations. Patients who present with or evolve into
CML- AP/BP should receive TKI combinations with chemotherapy to reduce CML burden and proceed to allogeneic
HCT. The exception may be de- novo CML- AP, which may
still respond well to long- term TKI therapy, particularly if a
CCyR is achieved early. Among patients whose CML manifests resistance to TKI therapy in CMLchoice depends on whether mutations are detected, and
whether there is clonal evolution. Patients with a T315I mutation should receive ponatinib and proceed to allogeneic SCT
if no optimal response is achieved or if early signs of resistance are observed. Patients with other mutations may be
treated with the most appropriate TKI (nilotinib, dasatinib,
bosutinib, or ponatinib) based on the mutation sensitivity.
(Table6.1). Patients with clonal evolution or with mutations
unresponsive to TKIs have short response durations; allogeneic HCT should be considered as definitive therapy, particularly in patients who do not achieve a cytogenetic response
after 6–12months of TKI therapy. Older patients (≥65–70
years) and patients who lack a donor may forgo the option of
curative allogeneic HCT in favor of years of good disease control in CML- CP with TKI- based therapies.
CP, the treatment
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Most relapses after HCT occur in the first three to five
years. Patients usually exhibit molecular relapse prior to
cytogenetic- hematologic relapse and typically respond to
TKI therapies (response rates 50–60% if molecular or cytogenetic relapse in CML- CP). Other options include donor lymphocyte infusions, interferon alpha, or second HCT. Donor
lymphocyte infusions may exacerbate GVHD (which can be
fatal) and cause severe myelosuppression (20%).
Therapy of CML- AP and CML- BP
All 6 TKIs and omacetaxine have shown efficacy in CML
AP/BP. The single- agent TKI activity is modest in CML- AP
and even lower in CML- BP. In CML- AP, TKIs are associated
with CCyR rates of 20–30% and four- year survival rates of
40–50% depending on the CML- AP definition and extent of
prior TKI therapies. The second- generation TKIs, either
alone or in combinations, produce better results than
imatinib. In CML- BP, all TKIs have shown fewer responses
that are less deep and of shorter duration, and combination
modalities should be pursued. These include acute myeloid
leukemia regimens (e.g. idarubicin+ cytarabine) plus TKI,
or azacitidine/decitabine and venetoclax plus TKI in
myeloid- undifferentiated CML- BP, and acute lymphoid leukemia regimens plus TKI (e.g. hyper- CVAD + dasatinib or
ponatinib; possible addition of blinatumomab) in lymphoid
CML- BP. Central nervous system (CNS) prophylaxis should
also be administered in lymphoid CML- BP since 30% of
patients may develop CNS disease. In all cases, patients
should be referred for allogeneic HCT as soon as possible.
Philadelphia chromosome-negative
CML
Some patients present with a morphologic picture of CML
without detectable Ph- positive by cytogenetic analysis. This
condition encompasses diverse entities. A third of patients
with typical CML morphology have the BCR::ABL1 molecular abnormality detected by FISH or PCR (PhBCR::ABL1- positive CML), and have similar clinical features, response to TKI therapy, and prognosis as patients
with Ph- positive CML.
Patients who have atypical CML morphologies (anemia,
thrombocytopenia, absent basophils or eosinophils, presence
of monocytosis) and who do not have the BCR::ABL1
molecular abnormality (Ph- negative, BCR::ABL1- negative)
are classified for practical purposes into: (i) chronic myelomonocytic leukemia (CMML), (ii) atypical CML, BCR::ABL1negative; (iii) myelodysplastic/myeloproliferative neoplasm,
unclassifiable (MDS- MPN- U); and (iv) myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and marked
thrombocytosis (MDS- MPD- RS- T).
negative,
Patients with CMML are diagnosed based on peripheral
monocytosis greater than 0.5
monocytes. The most frequent somatic mutations, typically
present in 40–50% of patients, include TET2 (typically biallelic or multi- hit), SRSF2 and ASXL1, with up to 30% of
patients having mutations in RAS pathway genes (BRAF,
CBL, KRAS, NF1, NRAS, PTPN11). Patients with CMML can
be treated with hypomethylating agents (azacitidine, decitabine), hydroxyurea, cytarabine or AML- type therapy, and
considered for allogeneic SCT, depending on the clinical
condition and prognosis.
Atypical CML (aCML), currently recognized by the WHO
as MDS/MPN with neutrophilia, is an MDS/MPN overlap
syndrome that does not meet WHO criteria for BCR::ABL1positive CML, primary myelofibrosis, polycythemia vera,
or essential thrombocythemia. It is typically characterized
by leukocytosis with granulocyte predominance and >10%
immature granulocytes in peripheral blood with no absolute
or relative basophilia (<2%) or monocytosis (<10%). The bone
marrow is characteristically hypercellular with dysplastic
granulocytic hyperplasia. Mutations in ASXL1 and SETBP1
are observed in more than 50% of patients. Although a fraction of patients has CSF3R mutations, the benefit of ruxolitinib
(JAK2inhibitor) in this setting is limited. Prognosis of patients
with aCML is poor, with median survival of 20–24months.
Hypomethylating agents represent the standard therapy, and
all eligible patients should be considered for allogeneic SCT.
Patients with chronic neutrophilic leukemia have significant neutrophilia without dysplasia. Ninety percent have
mutations of CSF3R, and 50% have mutations of SETBP1.
Patients with chronic neutrophilic leukemia and CSF3R
mutations may respond to ruxolitinib.
MDS/MPN- RS- T manifests as anemia with 15% or more
ringed sideroblasts in the erythroid precursors and thrombocytosis >/= 450 × 109 with bone marrow megakaryocytic
atypia and hyperplasia. Fifty to seventy percent have mutations of SF3B1, which is associated with better prognosis
(median survival 6.9 years versus 3.3 years with wildSF3B1. Overall prognosis is superior to that of MDS with
ringed sideroblasts, but inferior to that of essential thrombocytosis. The associated anemia may respond to erythropoietin (if EPO levels are low), luspatercept, or lenalidomide.
Lenalidomide can also help control thrombocytosis and
might reduce the need for cytoreduction with hydroxyurea.
The subset of JAK2- mutated disease (50% of MDS/MPNRS- T) may benefit from ruxolitinib. In patients who have
failed prior therapies, hypomethylating agents can be used,
although activity is modest.
Patients with MDS- MPD and cytogenetic translocations
involving 5q33 [t(5q33; other); PDGFR- beta rearrangement]
may respond to imatinib therapy.
Finally, a subset of patients with MDS/MPN overlap syndromes do not meet criteria for other entities such as
× 109/L and >10% peripheral
type
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96 Molecular Hematology
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aCML, CMML or CNL but might have morphologic features akin to CML. Genomic features of MDS/MPN suggest
that this heterogeneous group of disorders includes subsets
with similar mutation profiles to CMML, aCML, MDS/
MPN- RS- T and a subgroup of TP53 mutations. Overall,
prognosis is more favorable than that of aCML, and hypomethylating therapy can be considered. In the subset of
patients with JAK2mutations, therapy with ruxolitinib can
be particularly effective.
Summary
The BCR::ABL1 TKIs have significantly improved prognosis in CML. Today, TKI frontline therapy in CML- CP is
associated with an estimated 10- year survival rate of 85%.
With TKI therapy, good patient compliance, and optimal
monitoring, the relative survival in patients with CML is
similar to that of normal individuals. Frontline therapy
with imatinib and new- generation TKIs result in durable
disappearance of BCR::ABL1 transcripts, which may lend
itself to treatment discontinuation and TFR. Combinations
of TKIs with other active agents that target the downstream signaling events or that are directed against the
“dormant” CML stem cells may increase the proportion of
patients with durable complete molecular responses, and
the rate of TFR.
Further reading
with interferon alfa. Writing committee for the collaborative CML
prognostic factors project group. J. Natl. Cancer Inst. 90: 850–858.
Kantarjian, H.M., Dixon, D., Keating, M.J. etal. (1988). Characteristics
of accelerated disease in chronic myelogenous leukemia. Cancer 61:
1441–1446.
Sokal, J.E., Cox, E.B., Baccarani, M. etal. (1984). Prognostic discrimina-
tion in “good-
risk” chronic granulocytic leukemia. Blood 63: 789–799.
Interferon- α
Guilhot, F., Chastang, C., Michallet, M. etal. (1997). Interferon alfa- 2b
combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N. Engl. J. Med. 337: 223–229.
Kantarjian, H.M., Smith, T.L., O’Brien, S. etal. (1995). Prolonged sur-
vival in chronic myelogenous leukemia after cytogenetic response to
interferon- alpha therapy. Ann. Intern. Med. 122: 254–261.
Kantarjian, H.M., O’Brien, S., Cortes, J.E. et al. (2003). Complete
cytogenetic and molecular responses to interferonapy for chronic myelogenous leukemia are associated with excellent
long-
term prognosis. Cancer 97: 1033–1041.
alpha- based ther-
Allogeneic hematopoietic stem cell
transplantation
Barrett, J. and Ito, S. (2015). The role of stem cell transplantation for chronic
myelogenous leukemia in the 21st century. Blood 125: 3230–3235.
Hu, B., Lin, X., Lee, H.C. etal. (2020). Timing of allogeneic hematopoi-
etic cell transplantation (alloHCT) for chronic myeloid leukemia
(CML) patients. Leuk. Lymphoma 61: 2811–2820.
Ma, L., Han, X., Jiang, S. etal. (2020). Haploidentical stem cell trans-
plantation vs matched unrelated donor transplantation in adults with
hematologic malignancies: a systematic review and metaHematology 25: 356–365.
analysis.
Molecular biology of CML
Daley, G.Q., Van Etten, R.A., and Baltimore, D. (1990). Induction of
chronic myelogenous leukemia in mice by the P210bcr/abl gene of
the Philadelphia chromosome. Science 247: 824–830.
Deininger, M.W., Goldman, J.M., and Melo, J.V. (2000). The molecular
biology of chronic myeloid leukemia. Blood 96: 3343–3356.
Groffen, J., Stephenson, J.R., Heisterkamp, N. etal. (1984). Philadelphia
chromosomal breakpoints are clustered within a limited region, bcr,
on chromosome 22. Cell 36: 93–99.
Heisterkamp, N., Jenster, G., ten Hoeve, J. etal. (1990). Acute leukemia
in bcr/abl transgenic mice. Nature 344: 251–253.
Melo, J.V. (1996). The diversity of BCR- ABL fusion proteins and their
relationship to leukemia phenotype. Blood 88: 2375–2384.
Prognostic factors andmodels
Gratwohl, A., Hermans, J., Goldman, J.M. etal. (1998). Risk assessment
for patients with chronic myeloid leukemia before allogeneic blood
or marrow transplantation. Chronic leukemia working party of the
European group for blood and marrow transplantation. Lancet 352:
1087–1092.
Hasford, J., Pfirrmann, M., Hehlmann, R. etal. (1998). A new prognostic
score for survival of patients with chronic myeloid leukemia treated
Imatinib andother tyrosine kinase
inhibitors
Björkholm, M., Ohm, L., Eloranta, S. etal. (2011). Success story of tar-
geted therapy in chronic myeloid leukemia: a population- based
study of patients diagnosed in Sweden from 1973 to 2008. J. Clin.
Oncol. 29: 2514–2520.
Breccia M, Olimpieri PP, Celant S, etal. Management of chronic myeloid
leukaemia patients treated with ponatinib in a realspective analysis from the monitoring registries of the Italian Medicines
Agency (AIFA). Br. J. Haematol. 2022;198(6):965–973. https://doi.org/
10.1111/bjh.18359. Epub 2022Jul 29. PMID: 35904979.
Cortes, J., Apperley, J., Lomaia, E. etal. (2021). Ponatinib dose- ranging
study in chronic- phase chronic myeloid leukemia: a randomized,
open- label phase 2 clinical trial. Blood 138: 2042–2050.
Cortes, J.E., Saglio, G., Kantarjian, H.M. etal. (2016). Final 5- year study
results of DASISION. The dasatinib versus imatinib study in
treatment- naïve chronic myeloid leukemia patients trial. J. Clin.
Oncol. 34: 2333–2340.
Hehlmann, R., Lauseker, M., Saußele, S. et al. (2017). Assessment of
imatinib as first- line treatment of chronic myeloid leukemia: 10- year
survival results of the randomized CML study IV and impact of nonCML determinants. Leukemia 31: 2398–2406.
life setting: a retro-
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Chronic myelogenous leukemia 97
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Hochhaus, A., Larson, R.A., Guilhot, F. et al. (2017). Long- term out-
comes of imatinib treatment for chronic myeloid leukemia. N. Engl.
J. Med. 376: 917–927.
Hochhaus, A., Réa, D., Boquimpani, C. etal. (2023). Asciminib vs bosu-
tinib in chronicwith at least two tyrosine kinase inhibitors: longerASCEMBL. Leukemia 37: 617–626.
Kantarjian, H.M., Hughes, T.P., Larson, R.A. etal. (2021). Long-
outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10analysis. Leukemia 35: 440–453.
Mahon FX. Treatment-
Hematology Am. Soc. Hematol. Educ. Program 2017; 2017(1):102–109.
https://doi.org/10.1182/asheducationPMCID: PMC6142562.
phase chronic myeloid leukemia previously treated
term follow- up of
term
year
free remission in CML: who, how, and why?
2017.1.102. PMID: 29222243;
Naqvi, K., Jabbour, E., Skinner, J. etal. (2020). Long-
lower dose dasatinib (50
diagnosed chronic67–75.
mg daily) as frontline therapy in newly
phase chronic myeloid leukemia. Cancer 126:
term follow- up of
Mechanisms ofresistance totyrosine
kinase inhibitors
Shah, N.P., Nicoll, J.M., Nagar, B. et al. (2002). Multiple BCR- ABL
kinase domain mutations confer polyclonal resistance to the tyrosine
kinase inhibitor imatinib (STI571) in chronic phase and blast crisis
chronic myeloid leukemia. Cancer Cell 2: 117–125.
Shah, N.P., Skaggs, B.J., Branford, S. etal. (2007). Sequential ABL kinase
inhibitor therapy selects for compound drug- resistant BCR- ABL mutations with altered oncogenic potency. J. Clin. Investig. 117: 2562–2569.
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Chapter7
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Myeloproliferative neoplasms
Jessica Spiers1, Dina Mahdi1, Christopher Saunders2 and Donal P. McLornan
1
Department of Haematology, University College Hospitals London, London, UK
2
Serviço de Hematologia, Hospital Santo António dos Capuchos, Centro Hospitalar e Universitário Lisboa Central, Lisboa, Portugal
Introduction, 99
JAK–STAT pathways with a focus on JAK2, 99
The JAK2 V617F mutation in Philadelphia- negative MPNs, 101
JAK2 V617F: One mutation yet multiple phenotypes, 102
Other JAK2 mutations, 103
MPL mutations in ET and MF, 105
CALR mutations in ET and MF, 106
Introduction
“Philadelphia chromosome negative” Myeloproliferative
Neoplasms (MPN) are a heterogeneous group of clonal stem
cell disorders characterized by MPN stem cells that drive a
“self- reinforcing” marrow niche and myeloid cellular proliferation. The three most common are polycythemia vera (PV),
essential thrombocythemia (ET), and myelofibrosis (MF).
The phenotype is markedly heterogeneous, with frequent
mimicry/overlap, and can range from largely asymptomatic
states through to patients with significant symptom burdens,
augmented risks of both thrombosis and hemorrhagic phenomena, progressive splenomegaly, and an inherent risk of
transformation to acute myeloid leukemia (AML). Phenotypic
recognition of some interrelated similarities by Dameshek in
1951led to the first attempt at classification across this spectrum. Discovery of the acquired JAK2 V617F mutation in
2005 by several groups, followed by description of thrombopoietin (TPO) receptor (MPL) and calreticulin (CALR)
mutations, rapidly transformed not only diagnostic algorithms for these disorders but also led to many novel drugs
entering the MPN clinical therapeutic arena (Tables 7.1
and 7.2). All are characterized by upregulated JAK–STAT
activity. The JAK2 V617F mutation is present in approximately 95–98% of those with PV and in around 50–60% of
patients with ET and MF, respectively. CALR mutations are
present in around 20–25% of patients with ET and MF,
whereas MPL mutations are identified in 1–4% of patients
with ET and 5–10% of those with MF. Normally, the driver
mutations are mutually exclusive, but rare cases of dual mutations have been described. Below we will discuss in detail current knowledge of the three driver mutations JAK2, CALR,
Other somatic mutations in ET, MF, and PV, 106
Chronic neutrophilic leukemia, 108
Integration of molecular information into diagnostic algorithms and
prognostication, 109
Conclusions, 110
Further reading, 110
and MPL in MPN paralleled with a review of our increasing
knowledge of how non- driver mutations can modulate both
disease phenotype/behavior and prognostication.
JAK–STAT pathways with a
focusonJAK2
JAKs are a family of non- receptor tyrosine kinases consisting
of JAK1, JAK2, JAK3, and TYK2. JAK2 consists of 7Janus
homology (JH) domains and is pivotal to signal transduction
of single- chain receptors such as erythropoietin (EPO), TPO,
and growth hormone receptors and additionally for members
of the Interleukin (IL)- 3 receptor family such as granulocytemacrophage colony- stimulating factor (GM- CSF). In brief,
the N- terminal FERM domain consists of half of JH4, JH5,
JH6, and JH7, and the Src- homology 2 (SH2) domain the
other half of JH4 and JH3. Both the FERM and SH2 domains
mediate cytokine receptor binding. JH1 is at the carboxyl
terminus and functions as the kinase domain. JH2 is the
so- called “pseudokinase” domain, which regulates kinase
domain activity via basal autoinhibition– this is “released”
upon binding to cytokine receptors. Following engagement of
cytokine receptors such as TPOR or EPOR via the relevant
ligand, subsequent receptor dimerization occurs, JAK2 is
activated and transphosphorylation of tyrosine residues on
the tail of the cytokine receptor in the cytoplasm occurs,
which triggers recruitment of pivotal mediators of downstream pathways including signal transducers and activators
of transcription (STATs). The CSTATs is phosphorylated by JAK2 – phosphorylated STAT
homodimers/heterodimers translocate to the nucleus, where
terminal tyrosine kinase of
1
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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Table7.1 The 2022World Health Organization (WHO) diagnostic criteriaa for polycythemia vera, essential thrombocythemia, and primary
myelofibrosis
Polycythemia vera
Major
1. Hb >165 g/L (men), >160 g/L (women) or Hematocrit >0.49 (men), >0.48 (women)
2. BM biopsy features: hypercellularity; trilineage hyperplasia (panmyelosis); pleomorphic, mature megakaryocytes
3. JAK2V617F or JAK2 exon 12mutation
Minor
Subnormal serum erythropoietin level
Essential thrombocythemia
Major
1. Platelet count ≥450 × 109/L
2. BM biopsy features: predominantly megakaryocytic hyperplasia; large, mature megakaryocytes with hyperlobulated nuclei
3. Not meeting criteria for another myeloid neoplasm (e.g. CML, PV, PMF, MDS)
4. JACK2, CALR, or MPL mutation
Minor
Another clonal marker; or absence of reactive thrombocytosis
Primary myelofibrosis (overt)
Major
1. Megakaryocytic hyperplasia and atypia; reticulin and/or collagen fibrosis
2. Not meeting criteria for another myeloid neoplasm (e.g. CML, ET, PV, MDS)
3. JAK2, CALR, or MPL mutation; in the absence of these mutations, another clonal marker (e.g. ASXL1, EZH2, TET2,
IDH1/2mutation) or absence of reactive myelofibrosis
Minor
1. Unexplained anemia
2. Leukocytosis ≥11 × 109/L
3. Splenomegaly (palpable)
4. Increased serum LDH
5. Leukoerythroblastic blood film
b
c
d
BM, bone marrow; CML, chronic myeloid leukemia; Hb, hemoglobin; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome.
a
WHO criteria: 5th edition, beta version ahead of print.
b
Diagnosis of polycythemia vera (PV) requires either all three major criteria, or the first two major criteria and the minor criterion.
c
Diagnosis of essential thrombocythemia (ET) requires all four major criteria or the first three major criteria and the minor criterion.
d
Diagnosis of overt primary myelofibrosis (PMF) requires all three major criteria and at least one minor criterion. Separate criteria exist for the
diagnosis of pre- fibrotic primary myelofibrosis, the principal difference being the absence of reticulin fibrosis >grade 1.
they function as transcription regulators following binding of
STAT dimers or oligomers to specific gene enhancer
sequences. Although this pathway seems somewhat simple,
multiple, complex “cross- talk” exists with other key signaling
pathways such as the Ras/Raf/MAPK/ERK and PI3K- Akt
pathways. JAK2 signaling can also modify BCL- XL, NF- E2,
and TPO- R expression. In addition, phosphorylated STATs
can be influenced by multiple other pathways and have nonnuclear roles, and non- phosphorylated STATs also possess
key functional properties.
Elegant murine studies have revealed the key importance
of JAK2in the function and maintenance of hematopoietic
stem cells (HSC). JAK2– “knockout” in mice leads to death
within two weeks due to disruption of definitive hematopoiesis. JAK2 deficiency has been shown to associate with
HSC functional impairment, lack of regenerative capacity,
and increased apoptosis.
Several inhibitory pathways of the JAK–STAT pathway
exist. Suppressors of cytokine signaling (SOCS) proteins
contain kinase inhibitory regions, can be recruited by the
ubiquitin ligase (E3) and both SOCS1 and SOCS3 inhibit
JAK2 activity and can mediate JAK2 degradation. There
hasbeen a particular focus on SOCS3 as it was shown that
this protein is able to directly inhibit JAK2kinase activity.
Phosphatases like SHP1 and SHP2 are protein tyrosine phosphatases that inhibit the JAK–STAT pathway. In addition,
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Myeloproliferative neoplasms 101
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Table7.2 British Committee forStandards inHaematology (BSCH) andBritish Society forHaematology (BSH) diagnostic criteria for
polycythemia vera, essential thrombocythemia, andprimary myelofibrosis
Polycythemia vera
A1 Hematocrit >0.52 (men), >0.48 (women), or increased red cell mass (>25% above predicted value)
A2 Mutation in JAK2
Essential thrombocythemia
A1 Sustained platelet count ≥450 × 109/L
A2 Presence of an acquired pathogenetic mutation (e.g. in JAK2, CALR, or MPL genes)
A3 No other myeloid malignancy, especially JAK2- positive PV, PMF, CML, or MDS
A4 No reactive cause for thrombocytosis and normal iron stores
A5 Bone marrow aspirate and trephine biopsy showing increased megakaryocytes with a spectrum of morphology, predominantly large
with hyperlobated nuclei and abundant cytoplasm. Reticulin generally not increased
Primary myelofibrosis
A1 Bone marrow reticulin fibrosis grade 3 or higher (on 0–4 scale)
A2 Pathogenetic mutation (e.g. in JAK2 or MPL) or absence of both BCR- ABL1 and reactive causes of bone marrow fibrosis
B1 Palpable splenomegaly
B2 Unexplained anemia
B3 Leukoerythroblastosis
B4 Teardrop red cells
B5 Constitutional symptoms (drenching night sweats, weight loss >10% over six months, unexplained fever, or diffuse bone pains)
B6 Histological evidence of extramedullary hematopoiesis
a
b
c
a
Diagnosis of polycythemia vera (PV) requires both criteria to be present. Separate criteria exist for the diagnosis of JAK2- negative PV.
b
Diagnosis of essential thrombocythemia requires A1–A3, or A1 + A3–A5.
c
Diagnosis of primary myelofibrosis (PMF) requires A1 + A2 and any two of the B criteria.
CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome.
Source: Adapted from McMullin, M.F., Harrison, C.N., Ali, S. etal. (2018). A guideline for the diagnosis and management of polycythemia
vera. A British Society for Haematology Guideline. Br. J. Haematol. 184:176–91; Harrison, C.N., Butt, N., Campbell, P., etal. (2014).
Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythemia. Br. J. Haematol.
167:421–3; Reilly, J.T., McMullin, M.F., Beer, P., etal. (2012). Guideline for the diagnosis and management of myelofibrosis. Br. J. Haematol.
158:453–71.
STAT- specific inhibitors – Protein inhibitor of activated
STAT (PIAS) proteins– have been shown to negatively regulate the JAK/STAT pathway– in part through ubiquitination
of STAT3/5 and subsequent proteasomal degradation.
JAK2 V617F- derived hemopoiesis have been extensively
described by many groups. Transplantation studies using bone
marrow cells retrovirally transduced to express JAK2 V617F
frequently expressed a PV phenotype with increased erythropoiesis, extramedullary hematopoiesis and splenomegaly and,
dependent on mouse model, could subsequently develop an
The JAK2 V617F mutation in
Philadelphia- negative MPNs
MF phenotype. “Knock- In” (KI) models have been generated
using the Cre- Lox method utilizing site- specific recombinase
technology. This frequently leads to JAK2 V617F expression
The JAK2 V617F mutation was reported by four separate
groups in 2005; it arises from a point mutation in exon 14,
leading to a switch from valine to phenylalanine and a subsequent conformational change in the JH2pseudokinase domain
(Figure7.1). Due to the removal of auto- inhibition following
this switch, constitutive tyrosine kinase phosphorylation
ensues with upregulation of JAK–STAT pathway activity. Cell
line work has highlighted how following transfection of the
IL- 3- dependent cell line BaF3 to express mutated JAK2 protein, cells demonstrated hypersensitivity to IL- 3 and portrayed
augmented phosphorylation of both JAK2 and STAT5 and
increased survival and proliferation. Murine models to model
in a predominance of cells rather than mimicking early- phase
disease in for example ET/PV. Subsequent refinement of the
models to evaluate JAK2 V617F expression in various cell
compartments such as stem progenitors and more “real- life”
pathophysiological levels of JAK2 V617F expression has fol-
lowed. It is also pivotal to note that the presence of the JAK2
V617F mutation can mediate additional non- hematopoietic
effects. Tie2FF1 murine model work utilizing transgenic
expression of human JAK2 V617F in both hemopoietic and
vascular endothelial cells (ECs) highlighted an ET phenotype
at a young age with the emergence of MF as the mice aged.
Mice displayed splenomegaly, thrombosis and of note
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102 Molecular Hematology
(A)
ERK/MAPK
ERK/MAPK
P
P
P
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Kinase Pseudokinase
(B)
JAK2
JAK2
EPOR
No signal
FERM SH2
JAK2
EPOR
P
P
P
617
ValPhe
EPO
P
JAK2
P
EPOR
JAK/STAT
PI3K/AKT
JH2 JH1
JAK2
P
EPOR
P
P
P
JAK2
JAK2
V617F
V617F
EPOR
JAK/STAT
PI3K/AKT
P
EPOR
P
P
P
Figure7.1 The JAK2V617F mutation. (A) JAK2 protein showing the valine to phenylalanine substitution at codon 617. (B) Role of JAK2in
cytokine signaling. The cytokine receptor EPOR binds JAK2 as a homodimer (left). On ligand binding, a conformational change within EPOR brings
the two JAK2molecules into close proximity, initiating a cascade of phosphorylation events and activation of downstream pathways (middle).
TheJAK2 V617F molecule is constitutively active, leading to erythropoietin (EPO)- independent activation of signaling pathways (right).
cardiovascular dysfunction over time and work has suggested
that, of interest, the JAK2 V617F mutated ECs can play a
pivotal yet differential role in both hematological and
cardiovascular disease manifestations in MPN.
of the disease phenotypes, multiple other factors have been
considered in determining the resultant phenotype. With
regard to allelic burden, using transgenic mice to express
varying mutant levels, low levels of JAK2 V617F led to an
ET- like phenotype with a predominant thrombocytosis,
whereas higher levels led to a more PV- like state. JAK2
JAK2 V617F: One mutation yet
multiple phenotypes
V617F clones in PV are frequently homozygous in contrast
to ET, where they are predominantly heterozygous. In PV
patients, JAK2 V617F mutation burden associates with
As described above, JAK2 V617F is present in 95–98% of
PV, and around 50–60% of cases of ET and MF, respectively.
JAK2 mutations have also been described in a range of
other disorders such as Chronic neutrophilic leukemia
(CNL), chronic myelomonocytic leukemia (CMML), MDS/
MPN with ring sideroblasts and thrombocytosis (MDS/
MPN- RS- T) and MDS/MPN- Not otherwise specified
(NOS). Clinically, the presence or absence of JAK2 V617F
is determined either via quantitative PCR (Figure7.2) or
using MPN- specific gene panels. Given the heterogeneity
higher hemoglobin and leukocyte counts. Iron levels have
also been shown to modify phenotype. It is well observed
that many PV patients are iron deficient, whereas the
majority of ET patients have normal iron stores. MPN JAK2
V617F murine model studies evaluating the effect of iron
on the clinical picture highlighted how iron availability
alteration predominantly affected the lineage bias of
premegakaryocyte- erythrocyte progenitors. Other muta-
tions can also modulate phenotypic characteristics and dis-
ease trajectory as will be discussed below.
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