2. Chronic myeloid leukemia is a myeloproliferative neoplasm
characterized by the dysregulated production and uncontrolled
proliferation of mature and maturing granulocytes with fairly
normal differentiation
CML is associated with the fusion of two genes: BCR (on
chromosome 22) and ABL1 (on chromosome 9) resulting in
the BCR-ABL1 fusion gene.
3. This abnormal fusion typically results from a reciprocal
translocation between chromosomes 9 and 22,
t(9;22)(q34;q11), that gives rise to an abnormal chromosome
22 called the Philadelphia (Ph) chromosome.
The BCR-ABL1 fusion gene results in the formation of a
unique gene product, the BCR-ABL1 fusion protein
4. This protein product includes an enzymatic domain from the normal
ABL1 with tyrosine kinase catalytic activity,
But relative to ABL1, whose kinase activity is tightly regulated, the
kinase activity of BCR-ABL1 is elevated and constitutive due to
fusion with a portion of BCR.
It is this deregulated tyrosine kinase that is implicated in the
pathogenesis of CML
5.
6. The identification of the Ph chromosome in 1960 started a chain
of discoveries that culminated 40 years later in the development
of imatinib as the first ABL inhibitor used to treat CML
In 1845, two pathologists, John Hughes Bennett in Edinburgh and
Rudolf Virchow at the Charité Hospital in Berlin, independently
reported cases of massive leukocytosis, splenomegaly, and death
apparently due to septicemia
7. Virchow understood the uniqueness of these cases and coined
the term leukemia that means “white blood.
Following more than a hundred years of research after the first
clinical description of CML, Peter Nowell and David
Hungerford identified in 1960 the Ph chromosome as a
chromosomal alteration present in practically all patients with
CML
8. A total of 23 years later, the nature of the Ph chromosome was
identified as a balanced reciprocal t(9;22)(q34;q11)
translocation
In 1985, it was finally revealed that at the genetic level, this
chromosomal event fused the BCR gene (breakpoint cluster
region) located on chromosome 22 with the Abelson gene
(ABL) on chromosome 9 resulting in a hybrid BCRABL
transcript
9. The clinical hallmark of CML is the uncontrolled production
of mature and maturing granulocytes, predominantly
neutrophils, but also basophils and eosinophils.
In the absence of treatment, CML has a triphasic or biphasic
clinical course as it progresses from a chronic phase to an
accelerated phase and on to a terminal blast crisis.
Sometimes it goes from chronic phase directly to blast crisis,
particularly when the blast phase is lymphoid.
10. EPIDEMIOLOGY
CML accounts for approximately 15 to 20 percent of
leukemias in adults .
It has an annual incidence of 1 to 2 cases per 100,000,
with a slight male predominance
The median age at presentation is approximately 50 years
11. Exposure to ionizing radiation is the only known risk
factor
There is no known familial disposition to CML
A genome-wide association study of Korean and
European cohorts suggested that persons with genetic
variants at two chromosomal loci, 6q25.1 and 17p11.1,
may be more likely to develop CML
12. CLINICAL MANIFESTATIONS
CML has a triphasic or biphasic clinical course:
A chronic phase, which is present at the time of diagnosis in
approximately 85 percent of patients;
An accelerated phase, in which neutrophil differentiation becomes
progressively impaired and leukocyte counts are more difficult to control
with treatment; and
Blast crisis, a condition resembling acute leukemia in which myeloid or
lymphoid blasts proliferate in an uncontrolled manner
13.
14. Twenty to 50 percent of patients are asymptomatic
with the disease first being suspected from routine blood tests
Among symptomatic patients, systemic symptoms such as
fatigue (34 percent),
malaise (3 percent),
weight loss (20 percent),
excessive sweating (15 percent),
abdominal fullness (15 percent), and
bleeding episodes due to platelet dysfunction (21 percent) are
common
Priapism
Altered mrntal status/confusion
Dyspnea
15. Abdominal pain and discomfort may include
left upper quadrant pain (sometimes referred to the left shoulder)
Early satiety, due to the enlarged spleen
with or without perisplenitis and/or splenic infarction.
Tenderness over the lower sternum, due to an expanding
bone marrow, is sometimes seen.
16. Other frequent findings include
anemia (45 and 62 percent),
white blood cell count above 100,000/microL (52 and 72 percent),
and
platelet count above 600,000 to 700,000/microL (15 and 34 percent)
Involvement of extramedullary tissues such as the lymph
nodes, skin, and soft tissues is generally limited to
patients with blast crisis.
17. PATHOLOGIC FEATURES
Peripheral blood
The peripheral smear --> a leukocytosis with a median
white count of approximately 100,000/microL
The white blood cell differential typically shows virtually
all cells of the neutrophilic series, from myeloblasts to
mature neutrophils
18. Blasts typically account for less than 2 percent
The presence of a greater percent of myelocytes than the more
mature metamyelocytes ("leukemic hiatus" or "myelocyte
bulge") is one of the classic findings in CML
The cytochemical reaction called leukocyte (or neutrophil)
alkaline phosphatase (LAP, or NAP) when scored is low.
19. The low LAP score is useful in excluding a reactive leukocytosis or
"leukemoid reaction," typically due to infection, in which the score
is typically elevated or normal.
Low LAP activity was also classically used to exclude polycythemia
vera (PV) in the differential diagnosis of CML, in which LAP
activity is also often increased.
20. Absolute basophilia is a universal finding in the blood
smears
Absolute eosinophilia is seen in about 90 percent of cases
Absolute monocytosis (>1000/microL) is also seen,
the percentage of monocytes is typically low (<3 percent).
21. Peripheral
smear
1- Blast cell (probably
basophilic normoblast)
2- Band cell
3- Band cells going to
be segmented
4- Dysplastic cell
5- Metamyelocyte
6- Basophil
7- Eosinophilic
myelocyte
8- Late
metamyelocyte
22. 1- Blast cell (probably
basophilic normoblast)
2- Band cell
3- Band cells going to
be segmented
4- Dysplastic cell
5- Metamyelocyte
6- Basophil
7- Eosinophilic
myelocyte
8- Late
metamyelocyte
23. Bone marrow biopsy
granulocytic hyperplasia with a maturation pattern that reflects
that seen in the peripheral smear
immature neutrophils in the paratrabecular cuff and
mature neutrophils are found in the intertrabecular areas.
24. Erythroid islands are reduced in number and size
Small megakaryocytes with hypolobulated nuclei (so-called
"dwarf megakaryocytes") are present
In general, peripheral blood and bone marrow blasts between
10 and 19 percent are diagnostic of accelerated phase disease
Blasts over 20 percent are diagnostic of blast crisis.
25. Reviewing a bone marrow smear by cytology allows
the differentiation between CP, AP, and BC
A pathology sample from a bone marrow biopsy can
provide additional information on the presence and
degree of fibrosis
sometimes present
reflects a secondary phenomenon, and
usually resolves after the initiation of an effective treatment
and control of the primary disease
26.
27. Genetics
The vast majority of patients (90 to 95 percent) demonstrate
the t(9;22)(q34;q11.2) reciprocal translocation that results in
the Ph chromosome.
Some of them have variant translocations such as complex
translocations involving other chromosome (eg, t(9;14;22)).
28. The rest have cryptic translocations of 9q34 and 22q11.2 that
cannot be identified by routine cytogenetics.
These are referred to as "Ph-negative" and require FISH
analysis to identify the BCR-ABL1 fusion gene, or RT-PCR to
identify the BCR-ABL1 fusion mRNA.
29. There are several distinct BCR-ABL1 fusion proteins
generated from the chromosomal translocation, depending
on the site of the breakpoint in the BCR gene on
chromosome 22
30. The most common abnormal BCR-ABL1 fusion transcript produced
is from a breakpoint in exon 13 or exon 14 (alternatively called exon
b2 or b3) in the BCR gene, fused to the ABL1 gene at exon a2.
These are referred to as e13a2, e14a2 or alternatively as b2a2 or
b3a2.
Result in a BCR-ABL1 protein with 210 kilodalton molecular mass
--> referred to as the p210 BCR-ABL1 protein.
31. Less commonly, an alternative e19a2 fusion transcript is found,
producing a larger fusion protein with 230 kilodalton weight (p230
BCR-ABL1).
This is seen in rare CML cases (<1 percent).
A smaller e1a2 fusion transcript --->produces the p190 BCR-ABL1
protein is also seen in a very small number of CML patients,
but is more frequently associated with Ph-positive acute
lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)
32. In addition, rare patients with fusion of BCR exon 1 or
exon b2 to ABL1 exon 3 (e1a3 and b2a3) and BCR exon 6
to ABL1 exon 2 (e6a2) have been described.
35. The definite diagnosis of CML is obtained by
demonstrating the presence of a BCR-ABL1 fusion.
This can be accomplished by conventional
cytogenetics analysis with the identification of the Ph
chromosome and/or by PCR based detection of the
BCR-ABL1 transcript
36. In rare cases of masked translocations or presence of
atypical transcripts, a fluorescent in situ
hybridization (FISH) technique can be employed to
identify the fusion.
Classical cytogenetics analysis for the detection of
the Ph chromosome requires the analysis of at least
20 bone marrow metaphases.
37. In most patients (80% to 90%), a typical t(9;22)(q34;q11)
translocation can be identified
In the remaining patients, variant translocations are present:
In these cases, either of the following
minimal exchange of genetic material between chromosomes 9 and 22
happens (so-called microscopical translocation or Ph-negative CML),
sufficient to produce the BCR-ABL1 hybrid gene but not to alter the
cytogenetics, or
more complex translocations which involve a third chromosome and
will finally produce the BCR-ABL1 hybrid gene are present.
39. Leukemoid reaction
high leukocyte count with neutrophilia and prominent left shift
usually in response to infection.
peripheral blood count can be as high as 50,000/microL
toxic granulation in the neutrophils
a high LAP score
lack of a "myelocyte bulge," and
most importantly, the presence of an obvious cause for the
neutrophilia
40. Juvenile myelomonocytic leukemia:
hepatosplenomegaly, lymphadenopathy, pallor, fever,
and skin rash
demonstrate clonal overproduction of maturing
myeloid cells,
usually with an excess of monocytic lineage cells that are hyper-
responsive to GM-CSF
organ infiltration with relatively normal-appearing
monocytes
41. In contrast to CML, the karyotype in JMML is normal or
sometimes shows monosomy 7,
Progression to acute leukemia is rare.
Many have mutations in genes that encode elements of the
GM-CSF signal transduction pathway,including:
PTPN11,
NRAS and
KRAS2,
CBL, and
NF1
42. Chronic myelomonocytic leukemia
Myelodysplastic /myeloproliferative neoplasm
The overproduction of maturing monocytic cells and
sometimes dysplastic neutrophils
accompanied by anemia and/or thrombocytopenia
demonstrates prominent dysplastic changes in at least two
of the three myeloid lineages
no evidence of BCR-ABL1, the Ph chromosome or their
products
43. "Atypical CML“
myelodysplastic/myeloproliferative neoplasm
characterized by features of dysplasia and of myeloid
proliferation at the same time.
high neutrophil counts but with thrombocytopenia and/or
anemia
bone marrow shows increased cellularity due to a granulocytic
proliferation without increased blasts.
no monocytosis
44. The distinguishing feature of "atypical CML" is the presence of
dysplasia in the neutrophils ± megakaryocytes and erythroid forms
Somatic point mutations of set-binding protein 1 (SETBP1) were
identified in 24 percent cases.
Activating point mutations in the colony stimulating factor 3
receptor (CSF3R) gene were identified in 8/18 patients with atypical
CML.
45. Chronic eosinophilic leukemia
overproduction of normal-appearing eosinophils in the bone
marrow
proliferation in the blood and infiltration into the organs
resulting in end-organ damage
Cytogenetics :
normal or exhibit clonal abnormalities including del(4q12),
rearrangement of 5q22, 12p12-133, or 8p11
46. underlying molecular pathogenesis:
overactivity of an imatinib-sensitive tyrosine kinase
47. Chronic neutrophilic leukemia
Mature granulocytic proliferation in the blood and marrow, and
Infiltration into the organs resulting in hepatosplenomegaly.
Nuclear hypersegmentation and an increased leukocyte alkaline
phosphatase (LAP) score
Point mutations in the CSF3R gene, which encodes the receptor for
CSF3 (previously called G-CSF)
48. CSF3R truncation mutations --> sensitive to the multikinase
inhibitor dasatinib,
membrane proximal mutations -->sensitive to the JAK
inhibitor ruxolitinib
49. KARYOTYPING
Karyotyping is the process of pairing and ordering all the
chromosomes of an organism, thus providing a genome-
wide snapshot of an individual's chromosomes.
Karyotypes can reveal changes in chromosome number
associated with aneuploid conditions, such as trisomies.
Analysis of karyotypes can also reveal more subtle
structural changes, such as chromosomal deletions,
duplications, translocations, or inversions
50. Visualizing Metaphase Chromosomes
A blood sample is taken and white blood cells grown in
special medium for three days under the influence of the
mitotic stimulant ( phytohemagglutinin " PHA " ) to enter
into mitosis by DNA replication
After 68-72 hours, a mitotic inhibitor ( Colchicine ) is added
to the culture to stop mitosis in the metaphase stage.
After treatment by hypotonic solution ( KCl ) to cause
swelling of the cells and allow dispersion of the
chromosomes within the cell membrane
51. Fixation is used as wash solution to lyse the remaining red cells
and remove some chromosomes protein.
After staining by Giemsa Stain, chromosomes can be
microscopically observed and evaluated for abnormalities
Observe the chromsomes under microscope by using 10, 40 and
100x and photograph it and cut each chromosome from the
photograph and arrange the chromosomes according to the size
and position of centomer
53. FISH
FISH allows the visualization of specific chromosome nucleic acid
sequences within a cellular preparation.
This method involves the annealing of a large single-stranded
fluorophore-labeled oligonucleotide probe to complementary DNA
target sequences within a tissue or cell preparation.
The hybridization of the probe at the specific DNA region within a
nucleus is visible by direct detection using fluorescence microscopy
54.
55. FISH can be used for quantitative assessment of gene
amplification or deletion and for qualitative evaluation of
gene rearrangements.
Oncologic FISH assays employ two probe types:
locus-specific probes, which are complimentary to the gene of interest,
centromeric probes, which hybridize to the alpha-satellite regions near
the centromere of a specific chromosome and help in the enumeration of
the number of copies of that chromosome.
56. For the quantitative assessment of gene amplification, a locus-
specific probe and a centromeric probe are labeled with two
different fluorophores
Signal generated by each of these probes is counted, and a ratio of
the targeted gene to the chromosome copy number is calculated
The amount of signal produced by the locus-specific probe is
proportional to the number of copies of the targeted gene in a cell.
This type of gene amplification assay can be used for detection of
HER2 gene amplification
57. For detection of deletion mutations and for loss of heterozygosity
(LOH) studies, dual-probe hybridization is usually performed using
locus-specific probes.
For instance, for detection of 1p/19q codeletion in
oligodendrogliomas, locus-specific probe sets for 1p36 and 19q13
and for 1q25 and 19p13 (control) are used.
The frequencies of signal patterns for each of these loci are
evaluated. A signal pattern with 1p and 19q signals that are less than
control signals is consistent with deletion of these loci
58.
59.
60. Dual-color, dual-fusion translocation assays employ two probes that
are located in two separate genes involved in a specific
rearrangement
Each gene probe is labeled in a different color.
Dual-color, dual-fusion translocation assays are very specific for
detecting a selected translocation
They can only be used for detecting translocations that involve
consistent partners, where both partners are know
61. In break-apart FISH assays, both dual-colored probes(red and
green) are designed on the opposite side of breakpoint region
in a single gene that represents the constant partner in the
translocation.
By this approach, rearranged alleles show two split
signals, whereas normal alleles show fusion signals
64. PCR
Polymerase chain reaction is a molecular technique for
the rapid amplification of targeted DNA sequences
This technique was developed in 1983 by Kary Mullis,
he was awarded Nobel prize in 1993 for his work in
PCR along with Michael Smith
65. The reaction includes :
The specimen template DNA
Forward and reverse primers (18 to 24
oligonucleotides long) that define the amplification
region,
Taq DNA polymerase, and
Each of the four nucleotides bases (dATP, dTTP,
dCTP, dGTP).
67. Taq polymerase does not recognize RNA as a starting material
PCR can be adapted to RNA testing by including a reverse-
transcription step to convert a RNA sequence into its cognate
cDNA sequence before the PCR reaction is performed
Multiplex PCR reactions can also be designed with multiple
primers for simultaneous amplification of multiple genomic
targets
68. Reverse-transcription PCR (RT-PCR) can also be
used for relative quantification of target RNA in
minimal residual disease testing, such as BCR-ABL1
transcripts in CML.
69. PCR is a highly sensitive and specific technique that can be
employed in different capacities for detection of :
point mutations, small deletions, insertions and duplications, as well as gene
rearrangements and clonality assessment.
Limits of detection can reach 0.1% mutant allele or lower, which is
important for detection of somatic mutations because tumor
specimens are usually composed of a mixture of tumor and normal
cells
Another advantage of PCR is its ability to amplify small amounts of
low-quality FFPE derived DNA
70. Real-time Polymerase Chain Reaction
In real-time PCR, the PCR is performed with a PCR reporter that is
usually a fluorescent double-stranded DNA binding dye or a
fluorescent reporter probe.
The intensity of the fluorescence produced at each amplification
cycle is monitored in real-time, and both quantification and
detection of targeted sequences is accomplished
The intensity of the fluorescent signal for a given DNA fragment
(wild type or mutant) is correlated with its quantity, based on the
PCR cycle in which the fluorescence rises above background ---------
----->crossing threshold (Ct)
71. The Ct value can be used for qualitative or quantitative
analysis
Qualitative assays use the Ct as a cutoff for determining
“presence” or “absence” of a given target in the reaction
For quantitative analysis, the Ct of standards with known
template concentration is used to generate a standard curve to
which Ct values of unknown samples are compared to.
72. The concentration of the unknown samples is then
extrapolated from values from the standard curve.
Samples with higher template concentration reaches the Ct at
earlier PCR cycles than one with low concentration of the
amplified target
Quantitative real-time PCR has high analytical sensitivity for
detection of low mutant allele burden.
For that reason, this method has been widely utilized for monitoring of
minimal residual disease.
73.
74. Reverse-Transcription Polymerase Chain Reaction
In RT-PCR, RNA is isolated and reverse transcribed into cDNA by
using a reverse transcriptase enzyme and either :
(1) random hexamer primers, which anneal randomly to RNA and
reverse transcribe all RNA in the cell.
(2) oligo dT primers, which anneal to the polyA tail of mRNA and
reverse transcribe only mRNA or
(3) gene-specific primers that reverse transcribe only the target of
interest.
PCR is subsequently performed on the cDNA with forward and
reverse primers specific to the gene(s) of interest as in a standard
PCR
75. Breakpoints frequently occur within the intron of each partner
gene and the precise intronic breakpoint locations may be
variable.
This variability complicates design of primers used in DNA-based PCR
assays.
RT-PCR tests are advantageous because mature mRNA has
intronic sequence spliced out, allowing for simplified
primer design within the affected exon of each partner gene
RT-PCR can also be used to quantitate the amount of
expression of a gene when utilized with real-time PCR for
detection.
76. One major application of RT-PCR in this setting
includes quantitative detection of BCR-ABL1 fusion
transcript for prognostication and minimal residual
disease testing in CML
77.
78. Baseline prognostic factors
Three prognostic systems, Sokal, Euro, and EUTOS,
arithmetically derived, but based on simple clinical and
hematologic data,-- to estimate the survival risk at baseline.
The Sokal score has been particularly popular and was used
in most TKI-trials .
These risk scores were designed to evaluate differences in
survival or response
79.
80. Since most patients now die from causes other than leukemia while
still in remission,
A fourth risk score has been developed to predict the probability
of dying from CML (leukemia-related death, LRD): the new EUTOS
Long Term Survival (ELTS) score.
The ELTS score, factors same as Sokal.
The Sokal score apportions more patients to the intermediate- and
high-risk groups than ELTS, particularly among older patients
81.
82. • Several additional risk factors : Fiber content in bone marrow biopsies
and high-risk ACA .
• These include +8, a second Ph-chromosome (+Ph), i(17q), +19, −7/7q-,
11q23, or 3q26.2 aberrations, and complex aberrant karyotypes.
• High risk ACA predict a poorer response to TKIs and a higher risk of
progression.
• In the last version of the recommendations, ACA were mentioned as a
“warning”.
• Currently, the panel recommends classifying ACA and treating patients
with high-risk ACA as high-risk patients
83. ACA
MAJOR
a second Ph+ chromosome
trisomy 8
isochromosome 17q
trisomy 19
MINOR
t(3:12)
t(4:6)
t(2:16)
t(1:21)
84.
85. Molecular response definitions:
Molecular response must be assessed according to the
International Scale (IS) as the ratio of BCR-ABL1 transcripts to ABL1
transcripts, or to other internationally accepted control transcripts
(e.g., beta glucuronidase, GUSB)
Must be expressed and reported as BCR-ABL1 % on a log scale,
where 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a
decrease of 2, 3, 4, 4.5, and 5 logs, respectively, below the
standardized baseline that was used in the IRIS study
86. BCRABL1 ≤ 1% is equivalent to complete cytogenetic remission,
CCyR.
BCR-ABL1 transcript level ≤0.1% is defined as major molecular
response (MMR) or MR3.
A BCR-ABL1 transcript level ≤0.01% or undetectable disease in
cDNA with >10,000 ABL1 transcripts is defined as MR4.
A BCR-ABL1 transcript level ≤0.0032% or by undetectable disease
in cDNA with >32,000 ABL1 transcripts in the same volume of
cDNA used to test for BCR-ABL1 is defined as MR4.5.
87. Standardization of BCR ABL1 Monitoring
Selection of Control Genes
One of the most important issues encountered with the
introduction of qRT-PCR was the choice of a control gene
(CG).
A suitable CG can be defined as a gene with a stable
expression, not affected by any experimental conditions, and
should not show any pseudogenes
In the early 2000s, the Europe Against Cancer (EAC) program
started the first collaborative study aimed at selecting and
validating a suitable CG to monitor BCR-ABL1 transcript by
qRT-PCR
88. Fourteen potential CGs were evaluated and, among these,
only three were selected for a deep analysis: Abelson (ABL1),
beta-2-microglobulin (B2M), and glucuronidase beta (GUSB).
The ABL1 gene was identified as the most reliable CG because
it was similarly expressed in normal and pathological samples
its correlation with BCR-ABL1 expression was the highest
observed compared to B2M and GUSB.
89. Nevertheless, a slight inaccuracy in measurement was
highlighted of BCR-ABL1/ABL1 ratio at a high level of fusion
transcripts, due to the co-amplification of ABL1 and BCR-ABL1
It was proposed to use a correction that considers the
distinction between ratio and proportion.
This correction can be applied to all the range of BCR-
ABL1/ABL1, but it results as significant only when this
percentage is over 10%.
90. International Standardization of p210 qRT-
PCR Results
In the early 2000s, the International Randomized Study of
Interferon versus STI571 (IRIS study) was conducted to
test imatinib versus interferon-cytarabine.
During this trial, qRT-PCR, the gold standard for molecular
diagnosis, was performed in three reference laboratories:
Adelaide, London, and Seattle.
91. Due to the huge heterogeneity in the qRT-PCR steps
among the three reference laboratories, it was observed a
significant inter-laboratories difference in the
reproducibility of both the pathological and control
genes.
Thus, the main problem was the interpretation of the
differences between the obtained results.
92. To overpass this problem, in the IRIS study it was established that
each reference laboratory should create its own assortment of the
same 30 newly diagnosed untreated CML patients to extrapolate
median value.
This laboratory-specific median value was assumed as a
standardized baseline, corresponding to 100% BCR-ABL1/ABL1.
The 3-log reduction was defined as a reduction from the
laboratory-specific median value and not as a log reduction
calculated from the BCR-ABL1 level at the time of diagnosis for
every newly diagnosed patient.
93. In 2005, an international consensus meeting was held in
Bethesda, USA recommended the expression of BCR-
ABL1 measurements on an international scale (IS).
When the values of the BCR-ABL1 transcripts produced
anywhere worldwide are expressed on an IS, they could
be more likely comparable
94. Conversion Factor
The calculation of a laboratory-specific conversion factor (CF)
was intended to equalize these discrepancies.
In a big collaborative study, Adelaide was the reference
laboratory, and 39 satellite laboratories participated in this
project.
The Bland and Altman method was used to calculate a CF for
each lab,
comparing the dataset from the same samples generated by the
participant laboratories with that obtained by the reference laboratory
95. The standardization process is impossible to be
performed worldwide if only one laboratory is taken
as a reference.
As a solution, the European Treatment and Outcome
Study (EUTOS) group in 2009, dicussed the idea of a
reference national or regional laboratory
96. Development of Reference Panels and Commercial
Kits
In 2010, the World Health Organization (WHO) developed
the first International Genetic Reference Panel for the
quantification of BCR-ABL1mRNA
The creation of this reference panel is based on the
preparation and titration of dierent dilutions of freeze-dried
cell lines, such as HL-60, as BCR-ABL1 negative, and K562, as
BCR-ABL1 positive
97. More recently, Cross et
al. developed a
secondary reference
panel which was cell-
based and reproduced
the first WHO panel
with an additional level
of disease MR4.5
100. Treatment
Therapy for CML in the pre-imatinib era
Historically, the first treatment for CML was Fowler’s
solution, a 1% solution of arsenic trioxide, used for therapy of
CML back in 1865
Following the discovery of X-rays by Roentgen in 1895,
radiation therapy was incorporated into the armamentarium
of CML therapy in the first half of the 20th century,
used mainly to alleviate symptoms caused by splenomegaly
101. 1950s --> busulphan and hydroxyurea became the
main therapeutic options for several decades
While these drugs could effectively control the WBC,
they did not eradicate the leukemic clone or altered
disease progression
102.
103.
104.
105.
106. The arise of interferon-α (IFN-α) in the 1980s
the drug could induce hematologic and cytogenetic
remissions and improvements in survival, but it was poorly
tolerated due to frequent and serious side effects7
A complete cytogenetic remission (CCyR; 0% Ph+-
metaphases) was achieved in a small but significant
percentage of patients,
and it was recognized that patients who achieved CCyR had
longer survival than those who failed to meet this endpoint
107.
108.
109. First-line treatment
Currently, four TKIs have been approved for first-line
treatment by the FDA and EMA:
Imatinib, dasatinib, nilotinib, and bosutinib.
A fifth TKI, radotinib has been approved in South Korea
only.
Dasatinib, nilotinib, bosutinib, and radotinib have been
tested against imatinib in randomized trials.
They have never been tested against each other.
110. Treatment with hydroxyurea is no longer needed unless
the patient is symptomatic and/or diagnostic results take
longer than 3 to 5 days.
Allopurinol is usually prescribed (100 to 300 mg per day)
to control hyperuricemia until CHR is obtained.
The usual dosage is 400 mg per day for imatinib, 400 mg
per day for bosutinib, 100 mg per day for nilotinib, and
300 mg twice a day (fasting) for nilotinib
111. Leukapheresis
Hyperleukocytic patient in whom rapid cytoreduction can reverse
symptoms and signs of leukostasis (e.g., stupor, hypoxia, tinnitus,
papilledema, priapism)
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
112. Tumor lysis syndrome is usually not observed with TKI
therapy even in patients with a high tumor load; --->
therefore, no precaution is necessary other than a generous
fluid intake.
If the patient is symptomatic, symptoms will fade within 1 to 2
weeks.
CHR is reached in >80% of cases within 4 weeks
CCyR is obtained in 65% to 80% of patients within 12 months
113. CCyR represents a powerful predictor of long-term control of
the disease and survival
Reaching CyR indicates that the hemopoietic system is no
longer formed predominantly by leukemic cells but by normal
cells.
In cases where normal Ph-negative hemopoietic cells are
limited in number or slow to regrowth,
a transient period of aplasia can develop usually in the
second or third month of treatment, with anemia,
thrombocytopenia, and neutropenia
114. Once evidence of normal bone marrow regrowth (i.e., a
cytogenetic response) is obtained, the course of the disease is
usually favorable and the prognosis so good that a normal life
expectancy was demonstrated
The risk of relapse is present, especially in the initial 18
months of treatment and is mostly due to the :
presence aof CML clones with additional genetic alterations in either
BCR-ABL1 kinase domain or in other genes
115. IMATINIB
Imatinib represents the first TKI with ABL inhibitory activity that
successfully completed clinical development and was approved for
CML treatment in 2001
Imatinib is a very specific drug and inhibits platelet-derived growth
factor receptor (PDGFR), Kit, and ABL, with greater activity on
PDGFR
Binding to ABL is conformation dependent ---> binds only to a
closed (inactive) conformation of the enzyme
116. Common AEs are related to the inhibition of PDGFR and include
edemas (due to an alteration in small vessel permeability) with weight gain,
conjunctival irritation and lacrimation, scleral and mucosal hemorrhage, muscle
cramps, asthenia, and diarrhea
Skin rash ---> with nummular lesions in lower limbs, trunk, or
forearms
Skin hypopigmentation (due to KIT blockage) and fragility, liver
function test (LFT) alterations, anemia, thrombocytopenia, and
neutropenia.
126. Dasatinib
Dasatinib is an oral, second generation TKI that is 350
times more potent than imatinib in vitro.
It also inhibits the Src family of kinases, which may be
important in blunting critical cell signaling pathways.
Blocks BCR ABL in both active and inactive
configuration
127. Dasatinib, at nanomolar concentrations, inhibits the
following kinases:
BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2,
and PDGFRβ.
Dasatinib is less specific than imatinib -->inhibits
>30 tyrosine-kinases
In contrast to imatinib, its binding to ABL is not
dependent on the conformation of the enzyme
128. The plasma half-life of dasatinib is short (3 to 4 hours)
compared to other TKIs but the drug has a slow off-rate from
the ABL pocket
prolongs its effects and renders the once-per-day administration
schedule feasible.
Dasatinib was approved for second-line treatment of CML in
2006 and for first-line treatmentof CML in 2010
129. The Src inhibitory effect of dasatinib is considered to be the cause of
lymphocytosis that develops in up to 73% of patients
The most important AE of dasatinib is the development of pleural
and pericardialeffusions, which show no plateau with time and can
develop after several years
can develop in 30% to 40% of patients and requires treatment
interruption and supportive therapy with steroids and diuretics
138. U.S. Food and Drug Administration (FDA) has
approved SPRYCEL (dasatinib) 100 mg once daily for the
treatment of adult patients with newly diagnosed
Philadelphia chromosome-positive (Ph+) chronic
myeloid leukemia (CML) in chronic phase in october
2010
139.
140.
141. NILOTINIB
Selectively binds with high affinity to ATP-binding
site of BCR-ABL kinase inhibiting cell proliferation
in cell lines and in primary Ph+ CML leukemia cells
Active against imatinib-resistant mutant forms of
Bcr-Abl
Inhibits PDGFR and c-Kit kinase
142. Does not cause the usual imatinib-dependent AEs, such as edemas
and muscle cramps, although it has higher rates of cutaneous
toxicity
Hyperbilirubinemia with/withoutLFT elevations.
Acute pancreatitis
“Metabolic syndrome ” characterized by
hyperglycemia, increased cholesterol and triglyceride levels, and progression of
atherosclerotic lesions
Peripheral occlusive arterial disease develops preferentially in lower
limbs
143.
144.
145.
146.
147.
148. Granted accelerated approval for the treatment of
newly diagnosed adult patients with Philadelphia
chromosome positive chronic myeloid
leukemia (Ph+ CML) in chronic phase in 2010
149. Bosutinib
Bosutinib, a dual Src/Abl kinase inhibitor, has shown
potent activity against chronic myeloid leukemia (CML).
Inhibits Bcr-Abl kinase that promotes CML
Also inhibits SRc-family kinases including Src, Lyn, and
Hck
Bosutinib inhibits at least 20 tyrosine-kinases
150. Does not block either PDGFR or KIT
The most frequent AE caused by bosutinib is diarrhea, which
is probably due to an effect on paceregulating cells in the gut,
has an early onset after few days, and usually resolves spontaneously
within 1 to 2 weeks
Grade 3 or 4 LFT elevations --> 24% of patients
Skin rash -->20% of patients and presents itself as
“folliculitis-like” lesions
Articular pain-->ankles, cervical spine, and knees
151. The management of bosutinib toxicities include
fluid and electrolyte replacement
loperamide for diarrhea (especially in older patients),
use of both topical and systemic steroids for skin lesions, and
articular pain.
LFT elevations can also benefit from steroid treatment.
152.
153.
154.
155.
156.
157.
158.
159.
160. Based on findings from the phase III BFORE trial,
the FDA has approved bosutinib (Bosulif) as a first-
line treatment for patients with Philadelphia
chromosome-positive (Ph+) chronic myeloid
leukemia (CML) in December 2017
161. Ponatinib is an approved potent oral tyrosine kinase
inhibitor (TKI) active against native and mutated forms
of BCR-ABL, including T315I.
The Phase II PACE study demonstrated that ponatinib is
highly active in patients with heavily pretreated
Philadelphia chromosome‒positive leukemia (NEJM
2013;369:1783).
162. The Phase III EPIC trial was established to
assess the activity and tolerability of ponatinib
versus imatinib in patients with newly
diagnosed CP-CML.
However, on October 18, 2013, the trial was terminated
due to arterial thrombotic events in the ponatinib clinical
program and due to patient safety considerations.
Study objective: To report the efficacy and
safety of ponatinib in the EPIC trial up to the
point of termination.
163.
164.
165.
166.
167.
168.
169. Despite early termination of the EPIC trial, preliminary analyses
of data suggest improved efficacy with ponatinib compared to
imatinib:
– <10% BCR-ABL at 3 months: 94% (ponatinib) vs 68%
(imatinib). This endpoint correlates with overall survival
– With ponatinib response rates were higher and responses were
deeper and more rapid than with imatinib
More adverse events were reported in the ponatinib arm:
– Higher incidence of Grade 3 or 4 and serious adverse events
– More patients experienced vascular occlusive events
170.
171. SELECTING A FRONTLINE THERAPY
Patient’s age and comorbidities and TKI toxicity
profile
Disease characteristics
173. AGE
Patients younger than 50 years are expected to live 30 more
years
Therefore, inducing a durable CMR may potentially lead to
therapy discontinuation
Second generation TKIs induce a significantly higher rate of
CMR compared with imatinib
The issue of durable CMR and potential therapy
discontinuation plays a less important role in elderly
patients
174. Disease characteristics:
Second generation TKI as frontline therapy based
upon the Sokal or Hasford or ELTS scores was
proven more beneficial in patients with intermediate
or high risk disease
175.
176.
177. Monitoring, response to treatment, and
milestones
Blood cell counts and differential cell counts are required every 2
weeks until a complete hematologic response is achieved or, more
frequently, in the event of hematologic toxicity.
QPCR on blood cells, expressed as BCR-ABL1 % according to the IS, -
at least every 3 months even after an MMR is achieved and
confirmed, because close monitoring of molecular response is required
to assess eligibility for treatment discontinuation.
Cytogenetics, by CBA of marrow cell metaphases, may be useful when
performed, but alone is not sufficiently sensitive to monitor response
178. However, cytogenetics should be done in patients with :
Atypical translocations,
rare or atypical BCR-ABL1 transcripts that cannot be measured by
qPCR,
treatment failure/resistance to exclude ACA, and
with progression to AP or BP.
FISH monitoring may be needed in patients with atypical
transcripts
179. The monitoring milestones of BCR-ABL1 transcript levels by the
IS at 3, 6, and 12 months determine:
whether the current treatment should be continued (optimal
response),
changed (failure/resistance), or
carefully considered for continuation or change, depending on
patients´ characteristics, comorbidities and tolerance (warning).
180. The same definitions are recommended for second-line
treatment.
Achieving an MMR (BCR-ABL1 ≤ 0.1%) predicts a CML-
specific survival close to 100% as disease progression is
uncommon once this level of cytoreduction has been achieved
182. Indications for repeating bone marrow
When changing TKI(due to inadequate response)
Loss of response
to assess for cytogenetic clonal evolution.
In unusual situations like unexpected
myelosuppression
To exclude transformation or
Development of myelodysplastic syndrome or other marrow
conditions)
193. Imatinib mesylate (Gleevec) received accelerated
approval on May 10, 2001 for the treatment of
patients with chronic myeloid leukemia (CML) in
chronic phase after failure of IFN-α therapy,
accelerated phase, and blast crisis.
196. Dasatinib was approved in june 2006 for adults with
chronic, accelerated, or myeloid or lymphoid blast
phase Ph+ CML with resistance or intolerance to prior
therapy including imatinib
199. • 65% of responders had an MCyR lasting at least 18 months
• 43% of responders had an MCyR lasting at least 54 months
Median duration of MCyR was not reached at the
time of analysis
200. • 64% of responders had an MCyR lasting at least 9
months
• 36% of responders had an MCyR lasting at least 42
months
Median duration of MCyR was not reached at the
time of analysis1
201.
202.
203. BOSULIF was first approved in the U.S. in
September 2012 for the treatment of adult patients
with chronic, accelerated or blast phase Ph+ CML
with resistance, or intolerance, to prior therapy
206. Nilotinib
A single open label multicenter study was conducted to evaluate
the efficacy and safety of Tasigna (400 mg twice daily) in patients
with imatinib-resistant or -intolerant CML with separate cohorts
for chronic and accelerated phase disease
The definition of imatinib resistance included failure to achieve a
complete hematologic response (by 3 months),
cytogenetic response (by 6 months) or
major cytogenetic response (by 12 months) or
progression of disease after a previous cytogenetic or hematologic response
207.
208.
209.
210. On October 29, 2007, the U.S. FDA granted accelerated approval
to nilotinib (Tasigna) for use in the treatment of CP and AP
Philadelphia chromosome positive CML in adult patients
resistant to or intolerant of prior therapy that included imatinib
211. Eligibility (n = 449)
• CML-CP, CML-AP, CML-BP
or Ph+ ALL
• BCR-ABL T315I
mutation or resistant or
intolerant (R/I) to
dasatinib or nilotinib
Primary endpoints
• Major cytogenetic response (MCyR) at any time within 12 months for
CML-CP
• Major hematologic response (MaHR) at any time within 6 months for
advanced CML or Ph+ ALL
Ponatinib
45 mg orally once daily
PACE: Phase II Trial Design
CML-CP = chronic-phase CML; CML-AP = accelerated-phase CML; CML-BP =
blast-phase CML
212. Responses at Any Time
CML-CP CML-AP
CML-
BP Ph+ ALL
MCyR CCyR MMR MaHR* MaHR MaHR
R/I to dasatinib
or nilotinib
56% 48% 31% 62% 32% 50%
T315I mutation 72% 70% 58% 61% 29% 36%
Total† 60% 54% 38% 61% 31% 41%
* 14 patients with CML-AP with baseline MaHR and 1 patient with CML-AP with no
baseline MaHR assessment were counted as nonresponders
† Total comprises all eligible patients who received ponatinib. It excludes 5 patients
(3 CML-CP, 2 CML-AP) who were not cohort assigned (postimatinib, non-T315I) but
received treatment; all 5 achieved MCyR.
CCyR = complete cytogenetic response; MMR = major molecular response
213. Response Characteristics and Survival: CML-CP
Median time to response
MCyR 2.8 months
CCyR 2.9 months
MMR 5.5 months
Clinical outcomes
MCyR at 2 years (n = 149) 89%
PFS (n = 267)
Median PFS
PFS at 2 years
29 months
67%
OS (n = 267)
Median OS
OS at 2 years
Not yet reached
86%
214. Response Characteristics and Survival: CML-AP, CML-BP
and Ph+ ALL
CML-AP
Median time to response
MaHR 0.7 months
Clinical outcomes
MaHR at 2 years 21%
PFS (n = 83)
Median PFS
PFS at 2 years
15 months
37%
OS (n = 83)
Median OS
OS at 2 years
Not yet reached
72%
OS
CML-BP (n = 62)
Median OS
OS at 2 years
7 months
18%
Ph+ ALL (n = 32)
Median OS
OS at 2 years
8 months
21%
215. Hypertension
379/449 (84%) patients had elevated BP at baseline (≥140/90, 47%)
301/449 (67%) patients experienced any increase in BP* on study
AEs of hypertension were reported in 109/449 (24%) patients (serious AEs in
8/449 [2%])
* Any shift to higher grade (NCI CTCAE v.4.0), based on single BP measurements
Baseline BP (mm Hg),
NCI CTCAE
Increase in BP on study
(single measurement)*
Grade 1 Grade 2 Grade 3
Normal (<120/<80), N = 70 36% 30% 23%
Grade 1 (120-139)/(80-89),
N = 167
— 53% 34%
Grade 2 (140-159)/(90-99),
N = 157
— — 60%
Grade 3 (≥160/≥100), N = 55 — — —
216. * Combined incidence of cardiovascular, cerebrovascular, peripheral vascular, venous thromboembolism events;
† EMA press release Nov 22, 2013; ‡ FDA drug safety communication, Oct 31, 2013
USPI = US package insert; SAE = AE reported as serious by the investigator, per standard criteria
N = 449
N (%)
Data as of 23 July 2012 (USPI) 03 Sep 2013
Median follow-up (exposure)
12 months
(340 patient years)
24 months
(578 patient years)
Category SAE AE SAE AE
Cardiovascular 21 (5) 29 (6) 28 (6) 41 (9)
Cerebrovascular 8 (2) 13 (3) 18 (4) 25 (6)
Peripheral vascular 7 (2) 17 (4) 16 (4) 28 (6)
Total arterial thrombosis 34 (8) 51 (11) 53 (12) 77 (17)
Venous thromboembolism 10 (2) 15 (3) 13 (3) 23 (5)
Vascular occlusion*
Method 1† 41 (9) 62 (14) 62 (14) 91 (20)
Method 2‡ 47 (10) 81 (18) 67 (15) 109 (24)
Incidence of vascular occlusive events over
time
217. This study confirmed substantial clinical activity in patients with
heavily pretreated Ph+ leukemias.
Early, deep and durable responses were observed:
89% maintained MCyR for at least 2 years in CML-CP.
Arterial thrombotic events occurred --> higher dose intensity,
older age and presence of other risk factors at baseline were
associated with a higher likelihood of events.
Overall survival was not reduced for patients experiencing arterial
thrombotic events.
Ponatinib is an important treatment for patients in whom the need
and potential benefit outweigh the risks.
222. The agent received an accelerated approval in October
2012 for adult patients with chronic-phase or
accelerated-phase chronic myeloid leukemia (CML) with
resistance or intolerance to two or more tyrosine kinase
inhibitors.
223. ASCIMINIB
Asciminib is an allosteric inhibitor that binds a myristoyl
site of the BCR-ABL1 protein, locking BCR-ABL1 into an
inactive conformation through a mechanism distinct
from those for all other ABL kinase inhibitors.
Asciminib targets both native and mutated BCR-ABL1,
including the gatekeeper T315I mutant.
224.
225.
226.
227.
228.
229.
230. Among patients with CML-CP previously treated with ≥ 2 TKIs and
failure of or intolerance to last TKI, asciminib significantly
improved MMR rate at Wk 24 vs bosutinib
25.5% vs 13.2%, respectively; adjusted treatment difference:
12.2% (95% CI: 2.19-22.3); P = .029
5 arterial occlusive events in asciminib arm vs 1 in bosutinib arm
Numerically lower rates of AEs leading to d/c, dose
adjustment, or requirement for additional therapy with
asciminib vs bosutinib
It was concluded that BCR-ABL1 still is the key CML driver in ≥
third-line therapy population, ASCEMBL data support use of
asciminib as novel option for these patients based on favorable
benefit–risk profile.
231. Treatment duration and discontinuation
An attempt at treatment discontinuation can be
considered, if sustained DMR of sufficiently long
duration has been achieved
234. STIM1 Trial: Update of Stop Imatinib Study
in Chronic Myeloid Leukemia (CML)
Single-arm, multicenter study of stopping imatinib (IM), with median
follow-up of 65 months
N = 100 patients with CML receiving IM for >3 years with deep
molecular response (DMR = 4.5 log reduction) ≥2 years
Relapse-free survival at 6 months (M6): 43%; at M24: 38%
Etienne G et al. Proc ASH 2015;Abstract 345.
80%
15%
5%
0%
0%
20%
40%
60%
80%
100%
Months 1-3 Months 4-7 Months 18-22 Month >22
Molecular
relapse
(n = 49) (n = 9) (n = 3) (n = 0)
235. STIM1: Conclusions
Molecular relapse (MR) occurs mostly within the first 6
months of stopping IM:
Sokal score is associated with risk of MR (p = 0.0149)
If no relapse by M6, chance of relapse at M24 is 10%
Treatment resumption at MR resulted in another DMR
in 55/57 patients with median follow-up of 67 months:
No CML progression
39/57 remain free of MR
IM can be safely discontinued if DMR duration ≥2 years.
241. Study Methods
Eligibility (8 countries): n = 200
Adult patients with CML in chronic phase (CP) on TKI treatment
Achievement of confirmed deep molecular response (MR4, BCR-ABL
<0.01%) for ≥1 y and
Undergoing TKI therapy for ≥3 y
No patient with CP-CML after progression on TKI therapy
MR4 confirmation was performed in 6 standardized laboratories.
Primary endpoint: Duration of molecular response (defined by
continuous major molecular response) after discontinuation of a TKI.
A planned interim analysis was performed after 200 patients with eligible
molecular results at month 6 were available to test the null hypothesis
that relapse-free survival at 6 months is ≤40%.
242. Disease Recurrence and
Determination of Prognostic
Significance of Molecular Response
Patients with disease recurrence (loss of MMR) n/N (%)
With treatment for <8 years 43/92 (47%)
With treatment for >8 years 23/87 (26%)
p-value 0.005
Patients with MR4* n/N (%)
With MR4 at <5 years but lost MMR at ≤6 months 33/71 (46%)
Patients with MR4 >5 years 28/87 (32%)
p-value 0.07
MMR = major molecular response
* There was a trend for prognostic significance of MR4 duration.
• No significant difference was observed for relapse within 6 months according to
depth of molecular response at discontinuation (MR4 vs MR4.5 vs MR5).
243. Safety and Costs Associated with Discontinuation
of TKI Therapy
The discontinuation of TKI therapy was a safe procedure, but a
substantial proportion of patients reported transitory
musculoskeletal pain starting within weeks of imatinib
discontinuation.
This phenomenon was described in 30% of Swedish patients as a “TKI
withdrawal syndrome”
Taking into account the cost of imatinib in Europe and time
without treatment in the total study population at the most
recent analysis, total savings for the community within the
EURO-SKI trial were estimated at 7 million euros.
Mahon F-X et al. Proc ASH 2014;Abstract 151 (Abstract only).
244.
245.
246.
247. TFR phase
At week 48 of the TFR phase, 98 patients (51.6%)
remained in MMR without treatment reinitiation
of these 98 patients,
5 had confirmed loss of MR4 by 48 weeks (1 of these 5 patients
went on to lose MMR after 48 weeks but before the data cutoff
date),
3 had loss of MR4.5 without confirmed loss of MR4 and
90 (47.4% of all 190 patients who stopped treatment) had
MR4.5 or better at 48 weeks.
250. At 2 years, TFR was 46% in all patients,
51% in first-line patients, and
42% in subsequent-line patients
44% of patients resistant to prior TKI and
44% of patients intolerant of prior TKI.
251.
252.
253. Treatment of advanced-phase CML
End-phase CML comprises early progression with emerging high-risk
ACA and late progression with failing hematopoiesis and blast cell
proliferation.
BP is a late feature of progression.
Currently, diagnosis rests on the percentage of blasts (20% or 30%) in
blood or marrow.
Not all patients dying of CML reach the BP-defining blast levels.
Once BP has occurred, survival is generally <1 year with death due to
infection or bleeding.
254. Early indicators of progression are the appearance of
ACA, somatic mutations, and occasionally clinical
deterioration without obvious explanation.
Flow cytometry ---distinguishes between lymphoid and
myeloid BP allowing appropriate selection of treatment.
Lymphoid BP has more treatment options and a better
outcome than myeloid BP.
255. After KD-mutation analysis, treatment consists of intensive
combination chemotherapy with or without a TKI in
preparation for a prompt allo-SCT if possible.
In patients with resistance to a 2GTKI without specific mutations
ponatinib is preferred over change of 2GTKI, unless
cardiovascular risk factors are present.
In patients who cannot tolerate intensive chemotherapy regimens, a
more palliative approach with less intensive therapy should be
considered
256.
257. Allogeneic stem cell transplantation (allo- SCT):
In first CP (CP1) allo-SCT still has a place in :
Managing the small number of patients with disease resistant
or intolerant to multiple TKIs, and for the very rare patient
with inadequate recovery of normal hematopoiesis.
In resource-poor countries, allo-SCT may have priority over
TKI treatment as the one-time expenses of transplantation are
more economical than life-long drug costs
258. For a patient who is resistant to the initial 2GTKI given
either as first or second-line therapy,
the chance of achieving a durable response to an alternative
2GTKI is low, and ponatinib or an experimental agent should
be considered
At this juncture the patient should also be assessed for allo-
SCT.
Failure to respond to ponatinib after 3 months' treatment
indicates a patient at high risk of progression, and an early
transplant is indicated.
259. A patient presenting in AP should be treated as a high
risk patient, becoming eligible for allo-SCT if the
response is not optimal.
A patient progressing to AP during treatment should
immediately be considered for allo-SCT.
260. For patients presenting in, or progressing to BP, the longterm
outcome with any of the currently available TKI is poor---
every effort should be made to offer allo-SCT after initial control
of their disease.
Patients returning to a second CP (CP2) before allo-SCT have
improved transplantation outcomes.
The addition of a TKI to chemotherapy-based AML or ALL
regimens improves the chance of achieving CP2.
261. The choice of TKI should be based on prior therapies and BCR-
ABL1 KD-mutational status.
If CP2 is achieved, patients should proceed to allo-SCT
without delay, as PFS in BP is low and time to allo-SCT plays a
crucial role.
Transplantation in frank BP is not recommended
262. Ponatinib versus Allogeneic Stem Cell Transplant
(Allo SCT) for Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-
Positive Acute Lymphoblastic Leukemia (Ph+ ALL) with the T315I Mutation
Indirect comparison of ponatinib, a multitargeted tyrosine kinase inhibitor
(using data from the Phase II PACE trial) to allo SCT (using data from the EBMT
database)
N = 184 patients with CML and Ph+ ALL with the T315I mutation: N = 128
receiving ponatinib and N = 56 receiving allo SCT
Primary endpoint: Overall survival (OS) for patients with the T315I
mutation:
Nicolini FE et al. Proc ASH 2015;Abstract 480.
Leukemia type
Median OS
ponatinib (mo)
Median OS
allo SCT (mo) HR p-value
CP CML (N = 64, 26) NR 103.3 0.37 0.013
AP CML (N = 18, 8) NR 55.6 0.90 0.889
BP CML (N = 24, 17) 7.0 10.5 2.29 0.026
Ph+ ALL (N = 22, 5) 6.7 32.4 2.77 0.119
HR = hazard ratio; CP = chronic phase; NR = not reached; AP = accelerated phase;
BP = blast phase
265. Ponatinib versus Allo SCT: Conclusions
OS by leukemia type:
CP CML: Significantly longer with ponatinib; promising strategy
AP CML: Similar
BP CML and Ph+ ALL: Longer with allo SCT
Results warrant consideration of ponatinib as an
alternative to allo SCT for patients with T315I mutation-
positive CP CML.
Nicolini FE et al. Proc ASH 2015;Abstract 480.
266.
267. Pregnancy and parenting
For men taking imatinib, bosutinib, dasatinib, or nilotinib--
there is no increased risk of congenital abnormalities in their
offspring.
Changes in sperm quality and morphology can be present at
diagnosis and are unchanged after imatinib.
Therefore, men planning fatherhood do not need to
discontinue treatment with imatinib or 2GTKI.
268. For women, management of CML occurring during pregnancy must be
individualized.
TKI treatment should be discontinued in the first trimester, as soon as
pregnancy is confirmed.
Options of continuing or discontinuing treatment and continuation of pregnancy or
not ---exhaustively discussed.
The teratogenicity of TKI is due to off-target, most likely PDGFR, inhibition during
organogenesis.
The occurrence of hydrops fetalis when dasatinib was commenced in the second
trimester suggest all TKIs are contraindicated throughout pregnancy.
Although imatinib has been used safely in the second and third trimesters,
insufficient experience does not allow its routine use
269. Termination of the pregnancy is a consideration in more
advanced disease.
If the white blood cell count is low, CML treatment may
not be required before delivery.
Acetyl salicylic acid and/or low molecular weight heparin
are indicated for thrombocytosis.
270. Leucapheresis and/or IFNα are safe throughout
gestation.
Low-level secretion of TKI in breast milk
contraindicates their use during breast-feeding .
271. Women eligible for a trial of TFR can also safely
discontinue their TKI in order to conceive.
Women who lose MMR and are pregnant are likely to reach
term without a clinical need for restarting treatment.
Women who lose MMR and are not yet pregnant should
restart treatment, perhaps with a more potent TKI.
