Chronic Myeloid Leukemia

Август 1, 2022

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Chronic Myeloid Leukemia

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2. DEFINITIONS Myeloproliferative Neoplasms (MPNs): are a group of clonal myeloid neoplasms in which a genetic alteration
3. HEMATOPOIETIC PROGENITORS AND MPNS Genetic Mutation
4. MORE DEFINITIONS The type of disorder is often based on the predominant cell line that is
6. CML DEFINITION A pluripotent stem cell disease characterized by anemia, extreme blood granulocytosis and granulocytic immaturity,
7. EPIDEMIOLOGY OF CML Approximately 5,050 cases in the U.S. in 2009 (11% of all leukemias) with
8. ETIOLOGY OF CML The risk of getting CML does not seem to be affected by smoking,
9. PROJECTION OF CML PREVALENCE UP TO 2050 Modified from R. Hehlmann Assumptions: Population: 500 Mill., mortality:
10. CML The first malignancy with identified cytogenetic abnormality, molecular mechanism and specific therapy 1960 – Nowell
11. CML – PATHOPHYSIOLOGY – THE PHILADELPHIA CHROMOSOME
12. CML – PATHOPHYSIOLOGY – THE PHILADELPHIA CHROMOSOME The gene that breaks off from chromosome 9 is
13. WHAT IS PHILADELPHIA CHROMOSOME POSITIVE CML? The combination of BCR and ABL leads to the formation
14. BCR-ABL AND CML
15. MULTIPLE BREAKPOINTS IN BCR-ABL
16. PATHOPHYSIOLOGIC RESULT OF THE EXPRESSION OF BCR-ABL Bcr-Abl expression alone is necessary and sufficient for the
17. CHRONIC MYELOID LEUKEMIA CLINICAL PRESENTATION ▪ Asymptomatic (~ 30%) ▪ Fatigue, weight loss, fever ▪ Abdominal
18. CML Chronic phase 85% at diagnosis, asymptomatic or mild constitutional complaints, anemia or symptomatic splenomegaly, duration
19. PHASES OF CML The progression of Ph+ CML that occurs when the condition is left untreated
20. CHRONIC MYELOID LEUKEMIA - DIAGNOSTIC CRITERIA FOR THE 3 PHASES OF THE DISEASE
21. CML – PERIPHERAL BLOOD AND BM FINDINGS Peripheral smear can only give a presumptive diagnosis of
22. DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA Karyotyping in CML 1) Allows for the diagnosis of CML
23. DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA Bcr- Ch 22 Abl – Ch 9 Bcr-Abl Fusion
24. FISH IN CML Red → Bcr probe Green → Abl Probe Yellow → fusion of Bcr
25. DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA Quantitative RT-PCR for Bcr-Abl in CML 1) Allows for the
26. DISEASE DIAGNOSIS AND MONITORING IN CML *Number of leukemic cells detectable per 100 cells. BM =
27. n = 2830 Year after diagnosis Survival probability Primary imatinib, 2002-2008 (CML IV) 5-year survival 93%
28. HISTORY OF CP-CML THERAPIES → Interferon – α +/- AraC → Hydrea, or radiation therapy or
29. IMATINIB (GLEEVEC, NOVARTIS) A SMALL MOLECULE TYROSINE KINASE INHIBITOR Leukemia Leukemia X
30. FRONTLINE THERAPY IN CHRONIC PHASE - CHRONIC MYELOID LEUKEMIA
31. 1010 >1012 106 108 Leukemia cells CCyR MMR/CMR Undetectable range CHR Goals of CML Therapy
32. TREATMENT MILESTONES FOR CML Amount of Dz 1X1012 1X1011 1X1010 1X10 8-9
33. IMATINIB HAS REVOLUTIONIZED THE TREATMENT OF CML – IRIS TRIAL1 1. Newly diagnosed CML patients were
34. MECHANISMS OF IMATINIB RESISTANCE Resistance Mechanisms 1) Bcr-Abl Kinase mutations ▪ > 50 known mutations within
35. Bcr-Abl imatinib imatinib dasatinib
37. IMATINIB POORLY CONTROL ADVANCED PHASE DISEASE
38. TREATMENT OPTIONS FOR RESISTANT DISEASE 1) Dose Escalation of imatinib 2) Second Generation TKIs 3) Bone
39. SECOND GENERATION TYROSINE KINASE INHIBITORS (TKIS) The FDA has approved 2 additional oral TKIs for the
40. BONE MARROW TRANSPLANTATION Allogeneic bone marrow transplantation remains the only known curative option in CML with
42. Скачать презентацию

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DEFINITIONS
Myeloproliferative Neoplasms (MPNs): are a group of clonal myeloid neoplasms

in which a genetic alteration occurs in a hematopoietic progenitor cell leading to its proliferation resulting in an increase in the peripheral blood white blood cells (WBCs), red blood cells (RBCs), platelets, or a combination of these cells.

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HEMATOPOIETIC PROGENITORS AND MPNS
Genetic
Mutation

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MORE DEFINITIONS
The type of disorder is often based on the predominant

cell line that is affected, but because blood counts are often abnormal in more than one cell line, diagnoses based upon blood counts and morphology alone may be inaccurate.
Four Main MPNs: Additional MPNs:
1. Chronic Myelogenous Leukemia (CML) 1. Systemic Mastocytosis
2. Polycythemia Vera (PV) 2. Hypereosinophilic Syndrome
3. Essential Thrombocytosis (ET) 3. Chronic Myelomonocytic Leukemia
4. Primary Myelofibrosis (PMF) 4. Chronic Neutrophilic Leukemia
5. Chronic Eosinophilic Leukemia

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CML DEFINITION
A pluripotent stem cell disease characterized by anemia, extreme blood granulocytosis

and granulocytic immaturity, basophilia, often thrombocytosis and splenomegaly
The clonal hematopoietic cells contain a reciprocal translocations between chromosomes 9 and 22 in more than 95% of the patients, which leads to an overtly foreshortened long arm of chromosome 22 referred as the Philadelphia chromosome.
Natural history - Phasic disease: chronic, accelerated and blast crisis

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EPIDEMIOLOGY OF CML
Approximately 5,050 cases in the U.S. in 2009 (11%

of all leukemias) with an incidence that increases significantly with age (median age ~ 55)
Risk Factors include:
▪ prior high dose radiation exposure (WW II / Chernobyl / etc…)
▪ exposure to certain organic solvents (benzene)
▪ age
▪ gender (male > female)

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ETIOLOGY OF CML
The risk of getting CML does not seem to

be affected by smoking, diet, or infections
CML does not run in families since inherited mutations do not cause CML
Instead, DNA changes related to CML occur
during the patient’s life time

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PROJECTION OF CML PREVALENCE UP TO 2050
Modified from R. Hehlmann
Assumptions: Population:

500 Mill., mortality: 2% per year, Incidence increasing by about 0.01/100.000 per year

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CML
The first malignancy with identified cytogenetic abnormality, molecular mechanism and specific

therapy
1960 – Nowell and Hungerfold discover Ph chromosome
1973 – J. Rowley discovered that the translocation leads to fusion gene bcr/Abl
1983 – bcr/Abl encodes to unregulated tyrosine kinase
1996 – Tyrosine Kinase Inhibitor

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CML – PATHOPHYSIOLOGY – THE PHILADELPHIA CHROMOSOME

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CML – PATHOPHYSIOLOGY – THE PHILADELPHIA CHROMOSOME
The gene that breaks off

from chromosome 9 is called ABL (after Abelson the scientist who first identified the gene), while the gene that splits from chromosome 22 is called BCR, short for breakpoint cluster region

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WHAT IS PHILADELPHIA CHROMOSOME POSITIVE CML?
The combination of BCR and ABL

leads to the formation of an abnormal fusion gene responsible for the pathogenesis of CML
In the words of Brian Druker the BCR-ABL gene in CML acts “like the gas pedal in a car stuck in the ‘on’ position fuelling the excess growth of white blood cells”

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BCR-ABL AND CML

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MULTIPLE BREAKPOINTS IN BCR-ABL

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PATHOPHYSIOLOGIC RESULT OF THE EXPRESSION OF BCR-ABL
Bcr-Abl expression alone is necessary

and sufficient for the development of CML

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CHRONIC MYELOID LEUKEMIA CLINICAL PRESENTATION
▪ Asymptomatic (~ 30%)
▪ Fatigue, weight loss, fever
▪

Abdominal fullness, pain and/or early satiety due to splenomegaly (~ 50-90%)
▪ Easy bruising and purpura
▪ Leukostasis
▪ Pulmonary symptoms
▪ Neurologic symptoms

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CML
Chronic phase 85% at diagnosis, asymptomatic or mild constitutional complaints, anemia

or symptomatic splenomegaly, duration until progression 3-5 years without treatment
Accelerated phase
Blast crisis – life expectancy <1 year, no effective treatment

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PHASES OF CML
The progression of Ph+ CML that occurs when the
condition

is left untreated is described in three phases:
Chronic Phase CML
Accelerated CML
Blast Crisis CML

Chronic

Accelerated

Blast

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CHRONIC MYELOID LEUKEMIA - DIAGNOSTIC CRITERIA FOR THE 3 PHASES OF

THE DISEASE

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CML – PERIPHERAL BLOOD AND BM FINDINGS
Peripheral smear can only give

a presumptive
diagnosis of CML [you need to confirm the t(9;22)]:
1) leukocytosis with a ‘left shift’
2) normocytic anemia
3) thrombocytosis in 50% of pts
4) absolute eosinophilia with a normal % of Eos.
5) absolute and relative increase in basophils
6) LAP score is low (not frequently employed)

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DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA
Karyotyping in CML
1) Allows for

the diagnosis of CML
2) Requires a bone marrow aspirate for optimal metaphases
3) Allows for evaluation of clonal evolution as well as additional chromosomal abnormalities - Isochromosome 17; Double Philadelphia chromosome; Trisomia 8; Trisomia 19; Loss of Y chromosome
4) Occasional cryptic and complex karyotypes can result in the missed identification of the t(9;22)

Demonstrating the presence of the t(9;22) or its gene product is
absolutely essential in diagnosing a patient with CML

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DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA
Bcr- Ch 22
Abl – Ch 9
Bcr-Abl

Fusion

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FISH IN CML
Red → Bcr probe
Green → Abl Probe
Yellow → fusion

of Bcr and Abl

Bcr- Ch 22

Abl – Ch 9

Bcr-Abl Fusion

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DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA
Quantitative RT-PCR
for Bcr-Abl in CML
1)

Allows for the diagnosis of CML
2) Does not require a bone marrow aspirate for optimal results
3) Can quantify the amount of disease
4) Allows for the identification of cryptic
translocations involving Bcr-Abl
5) Many primers sets only detect the p190 and/or the p210 translocation and may miss the p230 or alternative translocations

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DISEASE DIAGNOSIS AND MONITORING IN CML
*Number of leukemic cells detectable per

100 cells.
BM = bone marrow; FISH = fluorescence in situ hybridization; PB = peripheral blood; MRD = minimal residual disease; RT-PCR = reverse transcriptase polymerase chain reaction.

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n = 2830
Year after diagnosis
Survival probability
Primary imatinib, 2002-2008 (CML IV) 5-year

survival 93%

IFN or SCT, 1997-2008 (CML IIIA) 5-year survival 71%

IFN or SCT, 1995-2008 (CML III) 5-year survival 63%

IFN, 1986-2003 5-year survival 53%

Hydroxyurea, 1983-1994

Busulfan, 1983-1994 5-year survival 38%

(CML I, II)

Courtesy of the German CML Study Group

Survival 1983-2008

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HISTORY OF CP-CML THERAPIES
→ Interferon – α +/- AraC
→

Hydrea, or radiation therapy
or Busulphan

→ intensive chemotherapy

→ early Interferon – α trials

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IMATINIB (GLEEVEC, NOVARTIS) A SMALL MOLECULE TYROSINE KINASE INHIBITOR
Leukemia
Leukemia
X

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FRONTLINE THERAPY IN CHRONIC PHASE - CHRONIC MYELOID LEUKEMIA

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1010
>1012
106
108
Leukemia cells
CCyR
MMR/CMR
Undetectable range
CHR
Goals of CML Therapy

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TREATMENT MILESTONES FOR CML
Amount of Dz
1X1012
1X1011
1X1010
1X10 8-9

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IMATINIB HAS REVOLUTIONIZED THE TREATMENT OF CML – IRIS TRIAL1
1. Newly

diagnosed CML patients were randomized to receive either Imatinib 400 mg daily or Interferon-α at approximately 5X106 U/day
as well as Ara-C 20 mg/m2 d1-10 q 8 days. Graph shows outcomes of 553 pts randomized to Imatinib.

96%

98%

85%

69%

92%

87%

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MECHANISMS OF IMATINIB RESISTANCE
Resistance Mechanisms
1) Bcr-Abl Kinase mutations
▪ > 50

known mutations within Abl sequence which inhibits Imatinib from binding
▪ mutations identified in 30-80% of individuals with resistant disease
2) Bcr-Abl duplication
duplication of the Bcr-Abl sequence has been identified in cell lines with Im resistance
3) Pgp over-expression
export pump of many chemotherapeuticsleading to lower intracellular Im concentration
4) hOct-1 under-expression
import pump for Im which may lead to lower intracellular levels of IM
5) Src-Family kinase (SFK) expression
activation may circumnavigate the Bcr-Abl
‘addiction’ of the transformed cell

Primary resistance
▪failure to achieve preset hematologic and/or
cytogenetic milestones
▪IRIS data indicates a rate of ~ 15%
by failing to a achieve a PCyR at 12 months
and 24% by failing to achieve a CCyr
by 18 months of therapy.
▪rates higher in accelerated and blast phase
disease
Secondary resistance
▪loss of a previously achieved hematologic
or cytogenetic milestone
▪rates may be 10-15% on Imatinib, but
become rarer as time on therapy progresses
▪rates higher in accelerated and blast phase
disease

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Bcr-Abl
imatinib
imatinib
dasatinib

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IMATINIB POORLY CONTROL ADVANCED PHASE DISEASE

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TREATMENT OPTIONS FOR RESISTANT DISEASE
1) Dose Escalation of imatinib
2) Second Generation

TKIs
3) Bone Marrow Transplant
4) Clinical Trial Participation

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SECOND GENERATION TYROSINE KINASE INHIBITORS (TKIS)
The FDA has approved 2 additional

oral TKIs for the treatment of
imatinib relapsed/refractory or imatinib intolerant CML

dasatinib (Sprycel – BMS)
▪ oral multi-kinase inhibitor
▪ ~ 325 times more potent than IM
▪ active against the ‘open’ and ‘closed
confirmation of Bcr-Abl
▪ active against many of the identified
kinase domain (KD) mutations
▪ active against the SFKs
▪ may not be a substrat for Pgp or
hOct-1

nilotinib (Tasigna – Novartis)
▪ oral multi-kinase inhibitor
▪ ~ 30 times more potent than IM
▪ active against only the closed
confirmation of Bcr-Abl
▪ active against many of the KD
mutations
▪ not active against the SKFs
▪ may not be a substrat for
hOct-1

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BONE MARROW TRANSPLANTATION
Allogeneic bone marrow transplantation remains the only known curative

option in CML with Graft vs. Leukemia effect, in molecular relapse can achieve remission by Donor Lymphocyte Infusion
Associated with an increased morbidity and mortality (TRM -10%-30%)
Therefore, not typically applied for upfront therapy for CML
▪ considered only in cases of matched-related donor for extremely young pts (pediatrics)
However, often considered in those with relapsed/refractory disease to TKI based therapies
▪ efficacy of the transplant dependent upon the phase of the disease at the time of the
transplant: CP>AP>BP

Chronic Myeloid Leukemia

Содержание

DEFINITIONS Myeloproliferative Neoplasms (MPNs): are a group of clonal myeloid neoplasms

HEMATOPOIETIC PROGENITORS AND MPNSGeneticMutation

MORE DEFINITIONSThe type of disorder is often based on the predominant

CML DEFINITIONA pluripotent stem cell disease characterized by anemia, extreme blood granulocytosis

EPIDEMIOLOGY OF CMLApproximately 5,050 cases in the U.S. in 2009 (11%

ETIOLOGY OF CMLThe risk of getting CML does not seem to

PROJECTION OF CML PREVALENCE UP TO 2050Modified from R. HehlmannAssumptions: Population:

CMLThe first malignancy with identified cytogenetic abnormality, molecular mechanism and specific

CML – PATHOPHYSIOLOGY – THE PHILADELPHIA CHROMOSOME

CML – PATHOPHYSIOLOGY – THE PHILADELPHIA CHROMOSOMEThe gene that breaks off

WHAT IS PHILADELPHIA CHROMOSOME POSITIVE CML?The combination of BCR and ABL

BCR-ABL AND CML

MULTIPLE BREAKPOINTS IN BCR-ABL

PATHOPHYSIOLOGIC RESULT OF THE EXPRESSION OF BCR-ABLBcr-Abl expression alone is necessary

CHRONIC MYELOID LEUKEMIA CLINICAL PRESENTATION▪ Asymptomatic (~ 30%)▪ Fatigue, weight loss, fever▪

CMLChronic phase 85% at diagnosis, asymptomatic or mild constitutional complaints, anemia

PHASES OF CMLThe progression of Ph+ CML that occurs when thecondition

CHRONIC MYELOID LEUKEMIA - DIAGNOSTIC CRITERIA FOR THE 3 PHASES OF

CML – PERIPHERAL BLOOD AND BM FINDINGSPeripheral smear can only give

DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIA Karyotyping in CML1) Allows for

DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIABcr- Ch 22Abl – Ch 9Bcr-Abl

FISH IN CMLRed → Bcr probeGreen → Abl ProbeYellow → fusion

DIAGNOSTIC CONSIDERATIONS IN CHRONIC MYELOID LEUKEMIAQuantitative RT-PCR for Bcr-Abl in CML1)

DISEASE DIAGNOSIS AND MONITORING IN CML*Number of leukemic cells detectable per

n = 2830 Year after diagnosisSurvival probabilityPrimary imatinib, 2002-2008 (CML IV) 5-year

HISTORY OF CP-CML THERAPIES → Interferon – α +/- AraC →

IMATINIB (GLEEVEC, NOVARTIS) A SMALL MOLECULE TYROSINE KINASE INHIBITORLeukemia Leukemia X