Chronic M yeloid Leukemia
description
Transcript of Chronic M yeloid Leukemia
Chronic Myeloid Leukemia
Amer Rassam, M.D.
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 phase
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 Objectives
Myeloproliferative Disorders
Chronic Myeloid Leukemia (CML) Polycythemia Vera (PCV) Essential Thrombocythemia (ET) Primary Myelofibrosis (PMF)
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 features
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 kinase
Uncontrolled production of mature and maturing granulocytes
Predominantly neutrophils, but also basophils and eosinophils
Triphasic or biphasic clinical course Chronic phase, accelerated phase, blast crisis
Introduction
Phases of CML (before Imatinib)
Chronic phase
Median duration5–6 years
Accelerated phase
Median duration6–9 months
Blast crisis
Median survival3–6 months
Advanced phases
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 known
Molecular Genetics 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.
Molecular Genetics 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:I. Uncontrolled proliferation of transformed cellsII. Discordant maturationIII. Escape from apoptosisIV. 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.
Molecular Genetics of CML
BCR
ABL
BCRABL
BCR{q11
Ph
9q+
22
9{q34 ABL
Ph chromosome and bcr-abl gene
bcr-abl
ablFUSION
PROTEINWITH
TYROSINEKINASE
ACTIVITY
22
bcr
Ph (or 22q-)
99 q+ 1
p210Bcr-Abl
p190Bcr-Abl2-11
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 structure
Philadelphia chromosome t(9;22)(q34;q11)
22q- = Philadelphia chromosome
Clinical Manifestations
Asymptomatic 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 > 600,000
Peripheral Blood Pathology
Leukocytosis (median of 100,000) Differentiation shows virtually all cells of neutrophilic
series Blasts < 2% Myelocytes 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 other
CML Peripheral Blood Smear
CML Peripheral Blood Smear
Bone Marrow Pathology
Granulocytic 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 absent
Pseudo-Gaucher cells
Pseudo-Gaucher cells
Sea Blue Histiocyctes
CML – Bone Marrow
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 intensive
BCR-ABL (FISH)
RT-PCR for BCR-ABL Qualitative 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 primersto form hydrogen bond with ends of target sequence
2
1
Extension: DNA polymerase adds nucleotides to the 3” end of each primer
3New nucleo-tides
Primers
Target sequence
Most CML patients are diagnosed in the chronic phase
Chronic phase Blastic phase
Differential Diagnosis
Leukemoid reaction Juvenile myelomonocytic leukemia (JMML) Chronic myelomonocytic leukemia (CMML) Atypical CML Chronic eosinophilic leukemia Chronic neutrophilic leukemia Other myeloproliferative neoplasms Other Ph chromosome positive malignancies
Accelerated Phase CML
10-19% 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 evolution
Blastic Phase CML
Blasts 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 face
Blast Phase CML – Bone Marrow
Blast Phase CML – Bone Marrow
Clinical Debate
What is the optimal frontline therapy for CML?
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)
Treatment Options
Potential 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.
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 TKIs
IRIS Study Design: Imatinib Mesylate Versus IFN- + ara-C
S
Imatinib Mesylate
IFN- + 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 2001
Hematologic Responses
96%
67%
0102030405060708090
100
0 3 6 9 12 15 18 21
% R
espo
ndin
g
Months Since Randomization
Imatinib mesylate
IFN- + ara-C
Cytogenic Responses
Imatinib mesylate
IFN- + ara-C
Months Since Randomization
% R
espo
ndin
g
83%
20%
0102030405060708090
100
0 3 6 9 12 15 18 21
Overall Survival on First-Line Imatinib (IRIS Study)
Resistance to Imatinib occurs predominantly during advanced phase CML
Advanced stage cancers are characterized by multiple genetic changes
Patients 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+ blastsPh-negative
Ph+ Imatinib mesylate-resistant blasts
Hem
atop
oiet
icdi
ffere
ntia
tion
Bone m
arrow to
peripheral blood
Initial Treatment
Imatinib (Gleevec) Dasatinib (Sprycel) Nilotinib (Tasigna)
Tyrosine kinase inhibitors are for first-line therapy in chronic phase CML
1. All 3 agents are considered to be (category 1) based on the NCCN guidelines and recommendations.
2. Second-generation TKIs (dasatinib or nilotinib) produce faster and deeper response than imatinib
Treatment of CML after failure of initial therapy
No 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 Nilotinib can result in QT prolongation
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 trials
Other Options
Interferon alfa plus cytarabineHydroxyureaBusulfan
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 TKI
Response Criteria
Hematologic response Cytogenic response Molecular response
Resistance to treatment
Primary resistance – patient fails to achieve a desired response to initial treatment
Secondary resistance – patient with an initial response to a TKI ultimately relapses
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 Nilotinib but sensitive to Dasatinib
F317L/V/I/C, V299L and T315A mutations Sensitive to Nilotinib but with intermediate sensitivity to
Imatinib and Dasatinib
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 tumors
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-kit
GLEEVEC (Imatinib)
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)
TASIGNA (Nilotinib)
Drug Interaction with TKIs
They 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 juice
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 effects
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 effect Black box: Arterial thrombosis; hepatic toxicity
Pregnancy and TKIs
All TKIs could be teratogenic during pregnancyWomen are advised not to become pregnant
while on TKIs (any TKI)Best effective contraception is the barrierWoman taking TKIs are advised to avoid to
breast-feeding
Prognosis
Improved 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.
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