88 Chronic Myelogenous Leukemia and Related Disorders Flashcards
The translocation between chromosomes 9 and 22 in more than _______% of patients
90%
Leads to an overtly foreshortened long arm of one of the pair of chromosome 22 (ie, 22,22q−), referred to as the Philadelphia chromosome (Ph)
ABL1 gene on chromosome 9 and the BCR gene on chromosome 22
The breaks at chromosomes 9 and 22 were localized to
Band 34 on the long arm of chromosome 9 and band 11 on the long arm of chromosome 22
What are environmental leukemogens associated with CML
- Very high doses of ionizing radiation
- Radioactive iodine for thyroid cancer
- Smoking
- Chemotherapy administered for germ cell tumors
- Chemical leukemogens, such as benzene and alkylating agents, are not causative agents of CML
- CML does not generally arise as a secondary malignancy.
Three main BCRs have been characterized on chromosome 22:
major (M-bcr): p210p
minor (m-bcr): p190
micro (μ-bcr): p230
Majority of CML patients have a BCR-ABL1 fusion gene that encodes a fusion protein of
p210BCR-ABL1
e14a2 or e13a2
50% of the Ph-positive acute lymphoblastic leukemia cases and results in the production of a
BCR-ABL1 protein of 190 kDa (p190BCR-ABL)
e1a2
Breakpoints develop a CML blast crisis with monocytosis and an absence of splenomegaly and basophilia
CML patients with m-bcr breakpoints
Breakpoint associated with neutrophilic CML or thrombocytosis
p230
e19a2
Perivascular infiltrate of neutrophils in the dermis
Fever accompanied by painful maculonodular violaceous lesions on the trunk, arms, legs, and face
Acute febrile neutrophilic dermatosis
(Sweet syndrome)
Most common blood cell at time of diagnosis
Segmented forms
Features of CML in child hood and young adolescents
- Hyperleukocytosis
- Increased frequency of splenomegaly and greater spleen size
- Lower rates of disease response to TKIs
- Higher rates of transformation
Neutrophil alkaline phosphatase activity is___________ in more than 90% of patients with CML.
Low or absent
Designation when eosinophils are so prominent that they dominate the granulocytic cells
Ph-positive eosinophilic CML
An absolute increase in the___________ concentration is present in almost all patients, and this finding can be useful in preliminary consideration of the differential diagnosis
Basophil
The proportion of basophils usually is not greater than______ during the chronic phase
15%
May represent 30% to 80% of the total leukocyte count during chronic phase and lead to the designation of Ph-positive basophilic CML.
Flow cytometry using __________ provides very accurate assessment of the basophil frequency.
anti-CD203c
Granules of basophils in patients with CML, unlike normal basophils, contain mast cell α-tryptase.
TRUE or FALSE
The total absolute lymphocyte count is increased (mean: approximately 15 × 109/L) in patients with CML
TRUE
The total absolute lymphocyte count is increased (mean: approximately 15 × 109/L) in patients with CML
As a result of the balanced increase in T-helper and T-suppressor cells.
- B lymphocytes are not increased.
- T lymphocytes are increased in the spleen.
- NK cell activity is defective in CML patients as a result of decreased maturation of these cells in vivo.
TRUE or FALSE
The platelet count is elevated in all of patients at the time of diagnosis.
FALSE
The platelet count is elevated in approximately 50% of patients at the time of diagnosis and is normal in most of the rest.
Occasionally, the platelet count may be below normal (<150 × 109/L) at the time of diagnosis, but this finding usually signals an impending progression to the accelerated phase of the disease and may also occur with massive splenomegaly.
BMA features of CML
- Markedly hypercellular and hematopoietic tissue takes up 75% to 90% of the marrow volume
- Granulopoiesis is dominant, with a granulocytic-to-erythroid ratio between 10:1 and 30:1
- Erythropoiesis usually is decreased, and megakaryocytes are normal or increased
- Eosinophils and basophils may be increased
- Collagen type III (reticulin fibrosis), which takes the silver impregnation stain, is increased at the time of diagnosis in nearly half the patients, and is correlated with the proportion of megakaryocytes in the marrow.
- Doubling of microvessel density and have more angiogenesis
Increased fibrosis also is correlated with larger spleen size, more severe anemia, and a higher proportion of marrow and blood blast cells.
The Ph chromosome is present in all blood cell lineages except in
B lymphocytes or in most T lymphocytes
TRUE OR FALSE
Interphase FISH is faster and more sensitive than cytogenetics in identifying the Ph chromosome.
TRUE
Interphase FISH is faster and more sensitive than cytogenetics in identifying the Ph chromosome.
The method of choice for monitoring patients for residual disease or reappearance of disease after marrow transplantation and for following response to TKIs
Quantitative RT-PCR
A complete cytogenetic response (CCyR) is equivalent to a negative FISH test and BCR-ABL1 transcripts ______
<1%
Patients with myeloproliferative neoplasms have an_________ serum level of vitamin B12–binding capacity, and the source of the protein is principally mature neutrophilic granulocytes
Increased
Spurious increase or decrease associated with CML
Pseudohyperkalemia
Spurious hypoxemia
Pseudohypoglycemia
In CML, LDH is (decreased/elevated) while cholesterol is (decreased/elevated)
In CML, LDH is elevated while cholesterol is decreased
TRUE OR FALSE
Elevated serum and urinary lysozyme levels are features of leukemia with greater monocytic components and are not features of CML.
TRUE
Elevated serum and urinary lysozyme levels are features of leukemia with greater monocytic components and are not features of CML
Characteristic of NEUTROPHILIC CHRONIC MYELOGENOUS LEUKEMIA
- Composed principally of mature neutrophils
- The white cell count is lower (30–50 × 109/L) at the time of diagnosis
- Do not have basophilia
- Have an unusual BCR-ABL1 fusion gene in that the breakpoint in the BCR gene is between exons 19 and 20–> larger fusion protein (230 kDa)
Characteristic of MINOR-BCR BREAKPOINT–POSITIVE CHRONIC MYELOGENOUS LEUKEMIA
- Result in a 190-kDa fusion protein
- Monocytes are more prominent
- White cell count is lower
- Basophilia and splenomegaly are less prominent
Observed in approximately 60% of patients with BCR rearrangement-positive ALL
Hyperleukocytosis may occur when white cell counts greater than ______
300 × 109/L
If signs of hyperleukocytosis are present,hydration, leukapheresis, and hydroxyurea can be used simultaneously
Management of hyperurecemia in CML
- Adequate hydration
- Allopurinol (Zyloprim) 300 mg/day orally
- Rasburicase (Elitek)
- Rasburicase is a recombinant urate oxidase that converts uric acid to allantoin.
- Reduces the uric acid pool very rapidly, does not result in the accumulation of xanthine or hypoxanthine, and does not require alkalinization of urine, thus facilitating phosphate excretion
Leukapheresis is useful in only 2 types of patients:
- The hyperleukocytic patient in whom rapid cytoreduction can reverse symptoms and signs of leukostasis (eg, stupor, hypoxia, tinnitus, papilledema, priapism) and
- The pregnant patient with CML who can be controlled by leukapheresis treatment without other therapy either during the early months of pregnancy when therapy poses a higher risk to the fetus or, in some cases, throughout the pregnancy
Dose of Hydroxyurea for cytoreduction
1–6 g/day orally
- Should be decreased as the total white cell count decreases and usually is given at 1–2 g/day when the total white cell count reaches 20 × 109/L
- The drug should be temporarily discontinued if the white cell count drops below 5 × 109/L.
Given in patients who still have significant thrombocythemia after a TKI is initiated
Anagrelide
Types of TKI
First generation
* Imatinib (Gleevec)
Second generation
* Nilotinib (Tasigna)
* Dasatinib (Sprycel)
Third generation
* Bosutinib (Bosulif)
* Ponatinib (Iclusig)
- Imatinib: first TKI developed
- An overall survival (OS) advantage of dasatinib, nilotinib, or bosutinib compared with imatinib has not been shown.
- Ponatinib (Iclusig) is not yet approved for initial therapy
TKI that can be given to CML BP
- Imatinib
- Dasatinib
- Bosutinib
TKI for Ph+ ALL
- Imatinib
- Dasatinib
- Ponatinib
TKI approved in children with CML
Imatinib
TKI for T315I+ cases
Ponatinib
Dosing of TKI
Imatinib
* CP 400 mg/day
* AP/BP/progression 600–800 mg/day
Nilotinib
* CP 300 mg BID
* AP/BP 400 mg BID
Dasatinib
* CP 100 mg/day
* AP/BP 140 mg/day
Bosutinib
* 500 mg/day
Ponatinib
* 45 mg/day
Toxicities of TKI
- Muscle cramps, arthralgia
- Elevated LFTs (usually appear in first month)
- Severe periorbital edema
- Hair depigmentation and hypopigmentation of the skin
- Rare cardiac toxicity reported
Imatinib
Toxicities of TKI
- Elevated lipase, hyperglycemia
- Peripheral vascular disease
- PT prolongation
Nilotinib
Toxicities of TKI
- Pleural effusions, ascites and pericardial effusion
- Pulmonary arterial hypertension
- QTc prolongation
- Bleeding from inhibition of platelet aggregation
Dasatinib
Toxicities of TKI
- GI (diarrhea)
Bosutinib
Toxicities of TKI
- High blood pressure
- Headache
- Arterial and venous thrombosis
- Ocular toxicity
- Cardiac failure
Ponatinib
TKI with significant interactions with antacids, H2 antagonists, proton pump inhibitors
Dasatinib
Bosutinib
decrease levels
Administration of TKI
With food:
Without food:
With or without food:
With food: Imatinib, Bosutnib
Without food: Nilotinib
With or without food: Dasatinib, Ponatinib
Black box warnings for TKI
Nilotinib:
Ponatinib:
Nilotinib: QT prolongation and sudden death
Ponatinib: Arterial thrombosis; hepatotoxicity
Approved pediatric dose of Imatinib in CP CML
340 mg/m2/day
TKI that has CSF penetration
Dasatinib
Most common side effect of imatinib in younger patients
Weight gain
Musculoskeletal pain also may be greater in pediatric populations.
TRUE OR FALSE
Reduction to subtherapeutic doses is recommended in case of myelosuppression
FALSE
Reduction to subtherapeutic doses is not recommended; it is better to interrupt therapy for a time.
- Patients with imatinib-induced chronic cytopenias have inferior responses.
- Myelosuppression is an independent adverse factor for achieving cytogenetic responses with imatinib
Mild transaminase elevations with Imatinib often respond to
Glucocorticoids
The severe periorbital edema occasionally observed is postulated to be a drug effect on the function of ______________expressed by dermal dendrocytes.
Platelet-derived growth factor receptor (PDGFR) and KIT
Hair depigmentation and hypopigmentation of the skin, probably related to the inhibition of the ____________by imatinib
KIT receptor tyrosine kinase
TRUE OR FALSE
Imatinib has been found to cause regression of marrow fibrosis.
TRUE
Imatinib has been found to cause regression of marrow fibrosis.
A 2G-TKI oral BCR-ABL1 inhibitor with dual inhibition of ABL1 and SRC
Dasatinib
Bosutinib
______________from the clonal expansion of NK/T cells has occurred during dasatinib treatment
Lymphocytosis
- The presence of lymphocytosis may be associated with a higher response rate and improved OS.
- Lymph node follicular hyperplasia has been noted in patients on dasatinib therapy
This is an indication to discontinue dasatinib.
Pulmonary arterial hypertension
Resistance to dasatinib is often found with point mutations in ABL1 at residue
315 or 317
2nd gen TKI, selective, orally bioavailable, ATP-competitive inhibitor of BCR-ABL1 which is 20–50 times more potent than imatinib in vitro
Nilotinib
An allosteric BCR-ABL1 kinase inhibitor that is designed to inhibit BCR-ABL1 in a non-ATP competitive fashion;
Have activity in those patients with resistance to or intolerance of at least 2 prior TKIs
Asciminib (ABL001)
Can be combined with the standard TKIs
The goal of initial TKI therapy
- Achieve a CCyR within 12 months or no later than 18 months of therapy
- Prevent progression to the accelerated or blast phase
TKI of choice for intermediate- or high-risk disease as assessed by the Sokal and Hasford models
Nilotinib or Dasatinib
Achieve rapid, better responses— the “hit hard, hit early” approach
Consideration of 2G-TKI as initial therapy
- Rapidity and depth of CCR/MMR
- Decreased risk of transformation
- Younger patients
- High Sokal, Hasford, or EUTOS score
- Desire for pregnancy
Consideration of Imatinib as initial therapy
- Availability of long-term toxicity data
- Cost
- Fewer vascular events
Indications for change in treatment
a) failure to meet the benchmarks at 3, 6, or 12 months
(b) loss of response as defined as loss of a CHR or CCyR
(c) development of new cytogenetic abnormalities
(d) acquisition of a BCR-ABL1 mutation, or
(e) an increase in the BCR-ABL1/ABL1 ratio of 1-log or more on serial RT-PCR testing or into the range associated with reappearance of the Ph chromosome on G-banding
Because of the variability in PCR testing, those changes should be confirmed within 1 month.
Definition of Complete hematologic response (CHR)
- White cell count <10 × 109/L
- Platelet count <450 × 109/L
- No immature myeloid cells in the blood
- Disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly) lasting for at least 4 weeks
Cytogenetic response
Minor cytogenetic response (mCyR)
Partial cytogenetic response (pCyR)
Major cytogenetic response (MCyR)
Complete cytogenetic response (CCyR)
Minor cytogenetic response (mCyR): >35% of cell metaphases are Philadelphia (Ph) chromosome–positive by cytogenetic analysis of marrow cells
Partial cytogenetic response (pCyR): 1–35% of cell metaphases are Ph-positive by cytogenetic analysis of marrow cells
Major cytogenetic response (MCyR): < 35% of cell metaphases contain the Ph chromosome by cytogenetic analysis of marrow cells
Complete cytogenetic response (CCyR): No cells containing the Ph chromosome by cytogenetic analysis of marrow cells
Molecular response
Major molecular response (MMR)
Complete molecular response (CMR)
Early molecular response (EMR)
Deep molecular response (DMR)
Major molecular response (MMR): BCR-ABL1/ABL1 ratio <0.1% or a 3-log reduction in quantitative polymerase chain reaction (qPCR) signal from mean pretreatment baseline value
Complete molecular response (CMR): BCR-ABL1 mRNA levels undetectable by qPCR with assay sensitivity at least 4.5 logs below baseline (IS)
Early molecular response (EMR): BCR-ABL1 ≤10% at 3 or 6 months
Deep molecular response (DMR): Major molecular response (MMR) 4.5-log reduction or not detected
Cytogenetic reassessment, however, should be done if the molecular response is suboptimal.
Monitoring of Patients in Chronic Phase on TKI
At diagnosis, before starting therapy, obtain:
- Giemsa-banding cytogenetics
- BCR-ABL1 transcript numbers by qPCR using marrow cells
If marrow cannot be obtained, use FISH on a blood specimen to confirm the diagnosis.
Qualitative RT-PCR should also be obtained to look for minor transcripts as well.
Monitoring of Patients in Chronic Phase on TKI
At __________________ months after initiating therapy, measure qPCR for BCR-ABL1 transcripts
3, 6, 9, and 12 months
- If qPCR using the International Standard is not available, perform marrow cytogenetics
- If there is a rising level of BCR-ABL1 transcript or 1-log increase after MMR achieved, qPCR should be repeated in 1–3 months.
Monitoring of Patients in Chronic Phase on TKI
Once CCyR is obtained, monitor qPCR on blood cells every ______ months for _______ years and then every ________months, thereafter.
every 3 months for 3 years
3–6 months
If there is a rising level of BCR/ABL1 transcripts (1-log increase after MMR achieved), repeat qPCR in 1–2 months for confirmation.
Mutation analysis should be performed:
- With loss of chronic phase
- Loss of any previous level of response
- Inadequate initial response (BCR/ABL1 transcripts >10%) at 3 or 6 months or no CCyR at 12 or 18 months, and
- A 1-log increase in BCR/ABL after MMR once achieved
Definition of Suboptimal Therapeutic Responses
- No cytogenetic response at 3 months
- Less than a partial cytogenetic response (PCyR) at 6 months
- PCyR at 12 months
- Less than a MMR at 18 months
Labeled as a “warning” response in the Network guidelines
These response levels may trigger ABL mutation analysis or closer monitoring.
TRUE OR FALSE
Cytogenetic clonal evolution is an independent poor prognostic factor for survival of patients in chronic and accelerated phases of CML
TRUE
Cytogenetic clonal evolution is an independent poor prognostic factor for survival of patients in chronic and accelerated phases of CML
Cytogenetic clonal evolution may not be an important impediment to achieving a MCyR or CCyR with imatinib
Some investigators have found that, with the possible exception of +8, +Ph, and i(17), additional chromosomal abnormalities at diagnosis are not associated with an inferior outcome to imatinib therapy.
The most unfavorable cytogenetic abnormalities
observed in more than 2000 patients with de novo CML
i16(q10), 3q26, and −7
Only 1 gene that was found to differentiate primary imatinib resistance.
Prostaglandin-endoperoxide synthase 1/cyclooxygenase1 (PTGS1/COX1)
Primary resistance to imatinib is defined as lack of CHR at 6 months or failure to achieve any level of cytogenetic response at 6 months, a MCyR at 12 months, or a CCyR at 18 months.
Ponatinib was active against ___________and against other BCR-ABL1 mutations resistant to dasatinib or nilotinib.
T315I
In addition to ponatinib, agents such as IFN-α and homoharringtonine (omacetaxine, Synribo) also have been proposed as therapy for those with the T315I mutation.
TRUE OR FALSE
Allogeneic hematopoietic stem cell transplantation is not recommended unless patients have inadequate response or intolerance to multiple TKIs or have the T315I mutation.
TRUE
Allogeneic hematopoietic stem cell transplantation is not recommended unless patients have inadequate response or intolerance to multiple TKIs or have the T315I mutation.
Dose escalation, combination therapy, and treatment interruption have been proposed as means to overcome drug resistance.
ABL1 Mutations
Treatment for:
V299L, T315A, F317L/V/I/C
Consider nilotinib (Tasigna) over dasatinib (Sprycel)
Bosutinib (Bosulif) and ponatinib may be effective
ABL1 Mutations
Treatment for:
F359V/C/I
Consider dasatinib rather than imatinib (Gleevec)
Bosutinib and ponatinib may be effective
A Cephalotaxus alkaloid that has activity against the T315I mutation
Omacetaxine
The most common side effects with this medication are cytopenias, which are usually managed with dose delays or reductions.
This agent also has activity in accelerated phase CML, but little in blast phase.
Formerly the most effective agent, is rarely used in the treatment of CML
Proposed as an immune stimulant to consolidate imatinib remissions because additive effects have been noted
Can be given to patients intolerant to a TKI
Interferon-α
It may be used occasionally in older patients who do not tolerate TKIs.
Busulfan
Utility of radiotherapy in CML
- Palliative splenic irradiation: accelerated or advanced chronic phase and are troubled with extreme splenomegaly with splenic pain, perisplenitis, and encroachment of the spleen on the gastrointestinal tract
- Extramedullary myeloid sarcomas
Splenectomy can be considered in selected patients:
- Patients with symptomatic thrombocytopenia unresponsive to therapy
- Mechanical discomfort
- Hypercatabolic symptoms
- Portal hypertension
Therapy of choice for pregnant patients
IFN
- TKIs should be discontinued immediately as data indicate safety of discontinuation of TKIs after prolonged DMRs.
- If conception is desired, attaining a MMR before the TKI therapy is discontinued and a 3-month washout period are recommended
*
TRUE OR FALSE
Hydroxyurea may be useful during the second and third trimester but should be avoided in the first trimester.
TRUE
Hydroxyurea may be useful during the second and third trimester but should be avoided in the first trimester.
Leukapheresis in the first trimester (or longer) also can be used to avoid fetal drug exposure early in pregnancy
Primary symptom of “TKI withdrawal syndrome”
Musculoskeletal pain
Stopping TKIs should not be considered without:
- (a) prior TKI therapy for several years
- (b) a stable MR4.0 for at least 2 years, and
- (c) the availability of BCR-ABL testing
Requirements for Consideration of Treatment- Free Remission (Tyrosine Kinase Inhibitor Stoppage)
- Should have typical b2a2 or b3a2 BCR-ABL1 transcripts, which can be quantified to <4.5-log reduction levels by qPCR using the International Standard
- Should be in chronic phase
- Duration of TKI > 3 years (some studies recommend 5 years)
- MR4.5 reached
- MR4 or MR4.5 maintained for >2 years
- Should have availability of accurate qPCR which should be obtained on a monthly basis at the beginning of discontinuation. This must have a sensitivity of detection of at least MR4.5 (≤0.0032% IS).
- The qPCR assay must have a rapid turnaround time (2 weeks or less)
- Monthly monitoring is recommended for the first year, then every 6 weeks for 1 year, and then every 3 months thereafter
- Should have capability to rapidly intervene if BCR/ABL level is rising; if MMR is lost, TKI should be resumed within 4 weeks of loss with close monitoring thereafter
Allogeneic transplation can be considered in:
- Refractory or intolerant to serial TKIs
- Those who progress to accelerated or blast crisis in the face of treatment with a series of TKIs
Prognostic scale based on age, spleen size, platelet count, and percent blasts
Sokal score
Prognostic scale based on basophils and spleen size
Predicted progression-free survival and duration of CCyR
European Treatment and Outcomes Study (EUTOS) score
Prognostic scale for patients undergoing allogeneic hematopoietic stem cell transplantation, in which performance status is added to 5 variables (age, spleen size, blood blast cell count, basophil and eosinophil count, and platelet count [Hasford score])
The European Bone Marrow Transplantation Consortium Risk Score
The most objective findings of possible accelerated/blast phase
- Blood blast percentage greater than 10
- Platelet count lower than 100 × 109/L
- Blood basophils higher than 20%
- New clonal cytogenetic abnormalities accompanying the Ph chromosome
TRUE OR FALSE
CML stem cells do not undergo apoptosis when exposed to TKIs.
TRUE
CML stem cells do not undergo apoptosis when exposed to TKIs.
Approximately 65% of patients have cytogenetic abnormalities in addition to the Ph chromosome.
The secondary changes most commonly seen are:
- Double Ph chromosome
- Trisomy 8
- Isochromosome 17p
Extramedullary blast crisis is the first manifestation of accelerated phase in approximately ____ % of patients with CML.
10%
Characteristics of CML lymphoid blast crisis:
- Intermediate accelerated phase
- Have less splenomegaly and basophilia
- Have a higher degree of marrow blast infiltration
- Remission rate and survival were somewhat longer
Recurrent changes in patients’ cells prior to, or during, the accelerated phase:
- trisomy 8 (33% of cases)
- additional 22q− (30% of cases)
- isochromosome 17 (20% of cases)
- trisomy 19 (12% of cases)
- loss of Y chromosome (8% of males)
- trisomy 21 (7% of cases)
- monosomy 7
These abnormalities were more common in myeloid blast crisis and were associated with shorter remission.
In cases where the blastic transformation is in extramedullary sites, such as lymph nodes or spleen, the additional cytogenetic abnormalities may be in the cells at those sites but not in cells in the blood or marrow.
Optimal treatment for accelerated/blast phase
Allogeneic stem cell transplantation
TRUE OR FALSE
Those who progress from chronic phase while on TKI will do better than those who are in accelerated phase at diagnosis
FALSE
Those who are in accelerated phase at diagnosis will do better than those who progress from chronic phase while on TKI.
Median survival
Myeloid blast crisis:
Lymphoid blast crisis:
Median survival
Myeloid blast crisis: 6 months
Lymphoid blast crisis: 12 months
Type of CML
Characterized by an accumulation of leukemic monocytes in the blood, and a predilection for transformation to AML
Chronic myelomonocytic leukemia
In CMML blood monocytosis greater than ____ × 109/L and relative proportion of monocytes of at least ___ % of blood leukocytes
Greater than 1 × 109/L
10%
> 40% of Chronic myelomonocytic leukemia has mutation in
SRSF2 gene
CMML is now divided into
CMML-0 (<5% blasts in marrow)
CMML-1 (5–9% blasts in marrow)
CMML-2 (10–19% blasts in marrow)
“dysplastic” variant of CMML: leukocyte count ≤13 × 109/L, but often presents with cytopenias
“proliferative” variant CMML: leukocyte count >13 × 109/L.
Patients with monocytosis and eosinophilia should be evaluated for
t(5;12)(q31or32;p13) translocation which encodes for ETV6(TEL)-PDGFβ fusion oncogene
Most prevalent cytogenetic findings in CMML
Trisomy 8 and, to a lesser extent, monosomy 7 and −Y
A CMML-specific prognostic scoring system has been proposed, and one model by the Groupe Francais des Myelodysplasies uses these variables:
- Age older than 65 years
- White blood cell (WBC) greater than 15 × 109/L
- Platelets less than 100 × 199/L
- ASXL1 mutation status
Type of CML
Blood eosinophil count >1.5 × 109/L
Cardiac and neurologic manifestations common
A proportion of cases have PDGFRα mutations and are responsive to imatinib mesylate
Chronic eosinophilic leukemia
Common translocations in CEL
Translocations involving chromosome 5, t(1;5), t(2;5), t(5;12), t(6;11), 8p11, and trisomy 8
CEL with elevation of serum tryptase level (>11.5 ng/mL) has been used to distinguish a subset of patients who are:
- (a) are male
- (b) have marrows that are intensely hypercellular with a higher proportion of immature eosinophils and with dysmorphic mast cells with a CD117−CD25+CD2− genotype and phenotype (distinguishing these cells from classic mastocytosis, which are CD117+CD25+CD2+)
- (c) have dramatically higher serum vitamin B12 and immunoglobulin E levels
- (d) are more prone to restrictive pulmonary disease and endomyocardial fibrosis
- (e) have the FIP1L1–PDGFRα fusion gene
- (f) are responsive to imatinib
Treatment of CEL:
FIP1L1–PDGFRα:
Without a TKI-sensitive translocation:
FGFR1:
PCM1-JAK2:
FIP1L1–PDGFRα: Imatinib at a dose of 100–400 mg/day
Without a TKI-sensitive translocation: Glucocorticoids, hydroxyurea, or IFN-α
FGFR1: Pemigatinib (Pemazyre)
PCM1-JAK2: Ruxolitinib
Unlike the case in CML, patients with CEL with significant side effects when taking imatinib, 400 mg/day, have a reasonable probability of having a good response at lower doses.
Antibodies to IL-5: mepolizumab and benralizumab
Type of CML
It occurs most often in infants and children younger than 4 years and is similar in some respects to adult CMML
The WHO classifies it as a myeloproliferative/ myelodysplastic overlap syndrome
More than half of the patients have eczematoid or maculopapular skin lesions and xanthomatous lesions, and multiple café-au-lait spots (neurofibromatosis type 1) may occur.
Juvenile myelomonocytic leukemia
A syndrome (dysmorphic facies, short stature, heart disease, mental retardation, cryptorchidism, webbed neck, chest deformities, and bleeding diathesis) may coexist with juvenile myelomonocytic leukemia
Noonan syndrome
A “watch-and-wait” strategy should be employed in those with germline CBL mutations, certain NRAS mutations, and in Noonan syndrome patients as spontaneous resolution has been reported.
Type of CML
Associated with a mutation in:
* Colony-stimulating factor 3 receptor gene (CSF3R) - 30%
* Combination of mutated CSF3R and a SET binding protein gene (SETBP1) - 60% or
* JAK2V617F - 10%
Chronic neutrophilic leukemia
TRUE OR FALSE
The leukocyte alkaline phosphatase level usually is markedly elevated in CNL and markedly decreased in CML.
TRUE
The leukocyte alkaline phosphatase level usually is markedly elevated in CNL and markedly decreased in CML.
Most common chromosomal abnormalities in CNL
Deletions of chromosome 20q and trisomy 21 or 9
Type of CML
Defined by neutrophilic leukocytosis and dysgranulopoiesis
Alternatively called myelodysplastic-myeloproliferative syndrome unclassifiable (MDS/MPN U)
Atypical chronic myelogenous leukemia
