M yeloid Leukemia Amer Rassam MD Learning Objectives Myeloproliferative disorders MPDs Molecular genetics of chronic myeloid leukemia Clinical manifestations and diagnosis of chronic myeloid leukemia ID: 225672
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Slide1
Chronic Myeloid Leukemia
Amer Rassam, M.D.Slide2
Learning Objectives
Myeloproliferative disorders (MPDs)
Molecular
genetics of chronic myeloid
leukemia
Clinical manifestations and diagnosis of chronic myeloid leukemia
Overview of the treatment of chronic myeloid leukemia
Initial treatment of chronic myeloid leukemia in chronic phaseSlide3
Explain how to define and identify a relapse
Treatment of CML in chronic phase after failure of initial therapy
Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia
Treatment of CML in accelerated phase and blast crisis
Prognosis
Learning ObjectivesSlide4
Myeloproliferative Disorders
Chronic Myeloid Leukemia (CML) Polycythemia
V
era (PCV)
Essential
Thrombocythemia (ET) Primary Myelofibrosis (PMF)Slide5
Myeloproliferative Disorders
Clonal disorders of hematopoiesis that arise in hematopoietic stem or early progenitor cell.Characterized by the dysregulated production of particular lineage of mature myeloid cells with fairly normal maturation.
Exhibit a variable tendency to progress to acute leukemia
Share abnormalities of hemostasis and thrombosis
Overlap between the clinical featuresSlide6
Introduction
CML is a clonal myeloproliferative neoplasm
Dysregulated production and uncontrolled proliferation of mature and maturing granulocyte with fairly normal differentiation
Fusion of 2 genes: BCR (or chromosome 22) and ABL1 (on chromosome 9), resulting in BCR-ABL1 fusion gene
Final result: Abnormal chromosome 22 called Philadelphia (Ph) chromosome
Final product: BCR-ABL1 fusion protein, a dysregulated tyrosine kinaseSlide7
Uncontrolled production of mature and maturing granulocytesPredominantly neutrophils, but also basophils and eosinophils
Triphasic or biphasic clinical course
Chronic phase, accelerated phase, blast crisis
I
ntroductionSlide8
Phases of CML (before Imatinib)
Chronic phase
Median duration
5–6 years
Accelerated phase
Median duration
6–9 months
Blast crisis
Median survival
3–6 months
Advanced phasesSlide9
Epidemiology
Annual incidence: 1 to 2 cases per 100,000
15% – 20%
of all adult leukemias
Incidence increases significantly with age
Median age: ~
55
years
Prevalence increasing due to current therapy
Most patients present in CP, 85%
Majority of CML-related deaths due to progression to AP/BC
50% of CML patients are asymptomatic at diagnosis
Risk factors
Exposure to ionizing radiation, the only knownSlide10
Molecular G
enetics of CML
The Philadelphia chromosome was originally detected by workers in Philadelphia.
The first genetic abnormality to be associated with a human cancer.
The result of a balanced translocation between chromosomes 9 and 22.
Derivative chromosome 22 is significantly smaller
Ph chromosome is present in
hematopoietic cells
from patients with CML.
Therefore, the Ph chromosome is acquired and
NOT
inherited through the germline.Slide11
Molecular G
enetics of CML
The development of chronic phase CML appears to be a direct result of the BCR-ABL1 activity, which promotes its development by allowing:
Uncontrolled proliferation of transformed cells
Discordant maturation
Escape from apoptosis
Altered interaction with the cellular Matrix
The progression of CML from chronic phase to accelerated face or blast crisis is a complex, multistep process (may be related to GMP).
Also, it appears to involve the constitutive expression of the BCR-ABL1 tyrosine kinase.Slide12
Molecular G
enetics of CML
BCR
ABL
BCR
ABL
BCR
{
q11
Ph
9q+
22
9
{
q34
ABLSlide13
Ph chromosome and bcr-abl gene
bcr-abl
abl
FUSION PROTEIN
WITH TYROSINE
KINASE ACTIVITY
22
bcr
Ph (or 22q-)
9
9 q+
1
p210Bcr-Abl
p190Bcr-Abl
2-11
2-11
Chromosome 9
c-
bcr
Chromosome 22
c-
abl
2-11
Exons
Introns
CML Breakpoints
ALL Breakpoints
t(9;22) translocation
bcr-abl
gene structureSlide14
Philadelphia chromosome t(9;22)(q34;q11)
22q- = Philadelphia chromosomeSlide15
Clinical ManifestationsAsymptomatic in 20-50% of patients
Fatigue 34%, weight loss 20%, excessive sweating 15%, abdominal fullness 15%, bleeding episodes 21% (platelet dysfunction).
Abdominal pain in the LUQ (enlarged spleen)
Tenderness over the lower sternum.
Acute gouty arthritis
Findings: Splenomegaly, anemia, WBC > 100,000, platelet count > 600,000Slide16
Peripheral Blood Pathology
Leukocytosis (median of 100,000)
Differentiation shows virtually all cells of neutrophilic series
Blasts < 2%
M
yelocytes more than metamyelocytes (a classic finding in CML)Neutrophils
cytochemistry
is abnormal – low LAP score
Basophilia in 90% of cases
Thrombocytosis. If low platelets – consider an otherSlide17Slide18
CML Peripheral Blood SmearSlide19
CML Peripheral Blood SmearSlide20
Bone Marrow PathologyGranulocytic maturation pattern same as in the peripheral blood
Increased reticulin fibrosis and vascularity
Erythroid islands are reduced in number and size
Dwarf megakaryocytes
Pseudo-Gaucher’s cells and Sea Blue histiocytes (markers of increased cell turnover)
Iron-laden macrophages are reduced or absentSlide21
Pseudo-Gaucher cells Slide22
Pseudo-Gaucher cells Slide23
Sea Blue HistiocyctesSlide24
CML – Bone MarrowSlide25
Diagnosis of CML
Typical findings in the blood and bone marrow
Requires the detection of the Ph chromosomal or its product, the BCR-ABL1 fusion mRNA and the BCR-ABL1 protein.
Conventional cytogenetic
analysis (karyotyping) – The first method
Florence
and in situ hybridization (FISH) analysis
RT-PCR
(
The BEST)
Southern blot techniques – rarely used
Western Blotting – low sensitivity and labor intensiveSlide26
BCR-ABL (FISH)Slide27
RT-PCR for BCR-ABLQualitative RT-PCR allow for the diagnosis of CML
Quantitative RT-PCR is used to quantify the amount of disease
Allows for the identification of cryptic BCR-ABL translocations
Does not require a bone marrow aspirate for optimal results
Cycle 1 yields 2 molecules
Cycle 2 yields 4 molecules
Cycle 3 yields
8 molecules;
2 molecules
(in white
boxes)
match target sequence
Denaturation: Heat briefly to separate DNA strands
Annealing: Cool
to allow primers
to form hydrogen bond with ends
of target sequence
2
1
Extension: DNA polymerase adds nucleotides to the 3” end of each primer
3
New nucleo-tides
Primers
Target sequenceSlide28
Most CML patients are diagnosed in the chronic phase
Chronic phase
Blastic phaseSlide29
Differential DiagnosisLeukemoid reaction
Juvenile myelomonocytic leukemia (JMML)
Chronic myelomonocytic leukemia (CMML)
Atypical CML
Chronic eosinophilic leukemia
Chronic neutrophilic leukemiaOther myeloproliferative neoplasms
Other Ph chromosome positive malignanciesSlide30
Accelerated Phase CML10-19% blasts in the peripheral blood or bone marrow
Peripheral blood basophils ≥20%
Platelets < 100,000/microL, unrelated to therapy
Platelets > 1,000,000/microL, unresponsive to therapy
Progressive splenomegaly and increasing WBC, unresponsive to therapy
Cytogenic evolutionSlide31
Blastic Phase CMLBlasts in the peripheral blood ≥20% or in the bone
marrow ≥30%
Large foci or clusters of blasts on the bone marrow biopsy
Presence of extramedullary blastic infiltrate (e.g., myeloid sarcoma, also known as granulocytic sarcoma or chloroma)
Blast crisis is generally refractory to treatment, occurs approximately 3-5 years after the diagnosis of CML and 18 months after the onset of accelerated faceSlide32
Blast Phase CML – Bone MarrowSlide33
Blast P
hase CML – Bone MarrowSlide34
Clinical Debate
What is the optimal frontline
therapy for CML?Slide35
Principles of CML treatment
Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis.
Hydration
Chemotherapy (Busulfan
,
hydroxyurea)Control and prolonging the chronic phase (non-curative)Tyrosine kinase inhibitors
Alpha-interferon + chemotherapy
Chemotherapy (hydroxyurea)Slide36
Treatment OptionsPotential cure with allogeneic hematopoietic stem cell transplantation
Disease control without cure using tyrosine kinase inhibitors (TKIs)
Palliative therapy with cytotoxic agents
Treatment decisions for patients with CML are complex, due to the variety of available options, many of which are conflicting.Slide37
Factors influencing choice of therapy
Phase of CML
Availability of a donor for allogeneic stem cell transplant
Patient age
Presence of medical co-morbidities
Response to treatment with TKIsSlide38
IRIS Study Design: Imatinib Mesylate
Versus IFN-
+ ara-C
S
Imatinib Mesylate
IFN-
a
+ ara-C
R
Crossover
IF:
·
Loss of MCR or CHR
·
Increasing WBC count
·
Intolerance of treatment
·
Failure to achieve MCR
at
12 months*
·
Failure to achieve CHR at 12 months*
·
Request to discontinue IFN-
*
Progression
·
Increasing WBC count
·
Loss of MCR or CHR
·
Accelerated phase or blast crisis
·
Death
S
= screening.
R
= randomization.
1106 patients enrolled from June 2000 to January 2001Slide39
Hematologic Responses
96%
67%
0
10
20
30
40
50
60
70
80
90
100
0
3
6
9
12
15
18
21
% Responding
Months Since Randomization
Imatinib mesylate
IFN-
+ ara-CSlide40
Cytogenic Responses
Imatinib mesylate
IFN-
+ ara-C
Months Since Randomization
% Responding
83%
20%
0
10
20
30
40
50
60
70
80
90
100
0
3
6
9
12
15
18
21Slide41
Overall Survival on First-Line Imatinib (IRIS Study)Slide42
Resistance to Imatinib occurs predominantly during advanced phase CML
Advanced stage cancers are characterized by multiple genetic changesPatients in advanced phase often relapse with the development of chemotherapy resistance
Some patients in blast crisis CML respond to Imatinib but then tends to relapse
Chronic Phase
Blast Crisis
Relapse
Ph+
Ph+ blasts
Ph-negative
Ph+ Imatinib mesylate-
resistant blasts
Hematopoietic
differentiation
Bone marrow to
peripheral bloodSlide43
Initial Treatment Imatinib (Gleevec)
Dasatinib (Sprycel)
Nilotinib (Tasigna)
Tyrosine kinase inhibitors are for first-line therapy in chronic phase CML
All 3 agents are considered to be (category 1) based on the NCCN guidelines and recommendations.
Second-generation TKIs (dasatinib or nilotinib) produce faster and deeper response than imatinibSlide44
Treatment of CML after failure of initial therapyN
o randomized trials have directly compared the efficacy of second-generation TKIs in patients with chronic phase CML who experience failure of an initial TKIs
A trial of another TKI.
Dasatinib preferred in patients with pancreatitis, elevated bilirubin or hyperglycemia
Dasatinib crosses the blood brain barrier and would therefore be preferred in patients with CNS involvement
Nilotinib might be chosen for patients with a history of pleural or pericardial effusion or disease
Dasatinib and
N
ilotinib can result in QT prolongationSlide45
Other Options
Bosutinib – toxicity is a limiting factor Ponatinib – toxicity is a limiting factor
Increase the dose of Imatinib
Omacetaxine mepesuccinate – SQ Injection
Approved by the FDA for patients resistant or intolerant to 2 or more TKIs
Hematopoietic cell transplant – the only cure
Clinical trialsSlide46
Other OptionsInterferon alfa plus cytarabine
Hydroxyurea
Busulfan
Patients who are ineligible for HCT but have either a contraindication to a second-generation TKI or have failed to respond to treatment with available TKISlide47
Response Criteria Hematologic response
Cytogenic response
Molecular responseSlide48
Resistance to treatment P
rimary resistance – patient fails to achieve a desired response to initial treatment
Secondary resistance – patient with an initial response to a TKI ultimately relapsesSlide49
Loss of ResponsePatients should be re-evaluated with a bone marrow biopsy with cytogenetics, and BCR-ABL kinase mutation analysis
T315I mutation
Resistant to all TKIs, except Ponatinib
Patient should be evaluated for SCT
Y253H, E255k/V and F359V/C/I mutations
Resistant to Imatinib and
N
ilotinib but sensitive to
D
asatinib
F317L/V/I/C, V299L and T315A mutations
Sensitive to
N
ilotinib but with intermediate sensitivity
t
o
Imatinib and DasatinibSlide50
Mechanisms of action TKIs
They block the initiation of bcr-abl pathway
Many TKIs also affect other signaling pathways
Dasatinib and Bosutinib inhibit both Bcr-Abl and Src kinases.
Nilotinib inhibits Bcr-Abl, c-kit and platelet derived growth factor receptor (PDGFR)
These differences in targeted pathways may be responsible for their varied clinical effects in tumorsSlide51
Mechanisms of Action, Imatinib
Competitively inhibits the inactive configuration of the Bcr-Abl protein tyrosine kinase
Blocking the ATP binding site and thereby preventing a conformational switch to the active form
Inhibits cellular proliferation and tumor formation
Produces 95% decrease in CML colony growth
Inhibits platelet-derived growth factor and c-kitSlide52
GLEEVEC (Imatinib)Slide53
GLEEVEC (Imatinib)
Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine kinase activity
BCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of cytokines
It protects hematopoietic cells from programmed cell death (apoptosis) Slide54
TASIGNA (Nilotinib)Slide55
Drug Interaction with TKIsThey are metabolized by the CYP3A4 system – can inhibit other cytochrome P450 pathways
Therefore, they compete with Coumadin
Low TKIs levels – St. John’s wort, rifampin, carbamazepine, phenobarbital and phenytoin
High TKIs levels – diltiazem, verapamil, itraconazole, ketoconazole, clarithromycin, erythromycin and grapefruit juiceSlide56
Side Effects of TKIs
Imatinib - Bone marrow suppression; fluid retention/edema; gastrointestinal effects; heart failure;
hepatotoxicity
Dasatinib
-
Bone marrow suppression; pleural/pericardial effusions; pulmonary arterial hypertension; QT prolongation; aspirin like effect
Bosutinib
-
Bone marrow suppression; fluid retention/edema; gastrointestinal effectsSlide57
Side Effects of TKIs
Nilotinib - Bone marrow suppression; atherosclerosis-related events; electrolyte imbalance;
hepatotoxicity
Black box: QT prolongation (screening required)
Ponatinib
- Bone marrow suppression; fluid retention/edema; gastrointestinal effects; heart failure; hypertension; pancreatitis; aspirin-like effectBlack box:
Arterial
thrombosis; hepatic toxicitySlide58
Pregnancy and TKIsAll TKIs could be teratogenic during pregnancy
Women are advised not to become pregnant while on TKIs (any TKI)
Best effective contraception is the
barrier
Woman taking TKIs are advised to avoid to breast-feedingSlide59
PrognosisImproved dramatically since the incorporation of tyrosine kinase inhibitors into the initial treatment
SEER database. 5138 patient’s, year 2000 and 2005
15-44 years – OS 72 versus 86%
45-64 years – OS 68 versus 76%
65-74 years – OS 38 versus 51%
75-84 years – OS 19 versus 36%
Stage of disease at the time of diagnosis is the strongest single predictor of outcome.Slide60
www.tallahasseecancer.comSlide61
www.tallahasseecancer.com