Chronic Myeloid Leukaemia

Seminar
Chronic myeloid leukaemia

Jorge Cortes, Carolina Pavlovsky, Susanne Saußele
Tyrosine-kinase inhibitors have changed the natural history of chronic myeloid leukaemia in such a way that patients Published Online
with adequate access to these agents, who are properly managed, and who respond well to this treatment can expect August 20, 2021
https://doi.org/10.1016/
a near-normal life expectancy. Achieving this goal requires an adequate understanding of the patient’s treatment
S0140-6736(21)01204-6
goals, careful monitoring for the achievement of optimal response hallmarks, implementation of proper interventions
Georgia Cancer Center, Augusta
according to the attainment of such endpoints, adequate recognition and management of adverse events, and University, Augusta, GA, USA
acknowledgment of the relevance of comorbidities. Treatment with tyrosine-kinase inhibitors, once considered (Prof J Cortes MD); FUNDALEU,
lifelong, has become terminable for at least some patients, and promising new agents are emerging for those whose Buenos Aires, Argentina
(Prof C Pavlovsky MD);
disease does not respond to any of the multiple therapeutic options currently available. If these advances reach
University Hospital Mannheim,
all patients with chronic myeloid leukaemia, cure might eventually become a reality in most instances. Heidelberg University,
Mannheim, Germany
Introduction commonly in Philadelphia chromosome-positive acute (Prof S Saußele MD)
In 1960, Nowell and Hungerford1 discovered, in blood lymphoblastic leukaemia, the breakpoint occurs proximal Correspondence to:
Prof Jorge Cortes, Georgia Cancer
samples from patients with chronic myeloid leukaemia, to exon 2 (in the minor breakpoint cluster region),
Center, Augusta University,
what was then called a minute chromosome—a discovery generating an e1a2 transcript that translates into a Augusta, GA 30912, USA
that marked the beginning of a new era in haematology, BCR-ABL1 protein of 190 kDa. An e19a2 transcript jorge.cortes@augusta.edu
which led to the current focus on molecular medicine. resulting in a BCR-ABL1 protein of 230 kDa (and other
This abnormality was later identified as a balanced transcripts such as e13a3, e14a3, e6a2, and e8a2) are less
translocation between chromosomes 9 and 22,2 resulting common.
in the fusion of Abelson tyrosine-protein kinase 1 (ABL1) Additional molecular abnormalities frequently emerge
and breakpoint cluster region protein (BCR), the product at the time of transformation to accelerated phase or
of which was a tyrosine kinase with increased activity.3 blast phase. Other cancer-associated mutations, most
The development of specific tyrosine-kinase inhibitors commonly in ASXL1, IKZF1, and RUNX1, are identified
drastically changed the natural history of chronic myeloid at diagnosis in some patients. Although some studies
leukaemia. Presently, patients with chronic myeloid have suggested that these abnormalities correlate with
leukaemia who are properly treated with tyrosine-kinase poor outcomes,8 others have found no such association.9
inhibitors, adequately monitored, and who respond well
to treatment can expect a near-normal life expectancy.4,5 Prognostic factors
Yet, challenges to the understanding and management The prognostic scores currently used rely on clinical
of this disease persist, such as the newly recognised factors obtained before the start of any therapy. The first
molecular complexity of chronic myeloid leukaemia, the universally adopted scoring system was proposed by
optimal sequencing of drugs, the management of adverse Sokal and colleagues,10 in 1984, and is still widely used.
events, and the criteria for successful discontinuation of The EuroSCORE was introduced to better predict out For more on the EuroSCORE see
treatment. A key goal of ongoing research is ensuring come probabilities for patients treated with interferon http://www.euroscore.org/calc.
html
that no patient dies of chronic myeloid leukaemia.
Pathogenesis of chronic myeloid leukaemia Search strategy and selection criteria

The hallmark of chronic myeloid leukaemia is the We searched PubMed for manuscripts published between
Philadelphia chromosome, t(9;22)(q34;q11.2), which Jan 1, 2015, and March 30, 2020. Relevant manuscripts
results in the BCR-ABL1 chimeric gene. This fusion published between Jan 1, 1960, and Dec 31, 2014, were
eliminates a myristoyl group that has an autoregulatory included in this Seminar if they provided the best available
function, resulting in a constitutively activated tyrosine evidence or support for the concepts presented. Key reviews
kinase. The breakpoint in chromosome 9 is relatively or reference manuscripts were included in the reference list if
constant between exons 1 and 2, whereas the breakpoint they provided the best evidence, consensus, or additional
in chromosome 22 can occur in various regions, usually at sources of reference for the readers of this Seminar. The terms
the major breakpoint region. These variable breakpoints used for this search were “chronic myeloid leukaemia”,
in chromosome 22 produce two distinct products, e13a2 “Philadelphia chromosome”, “BCR-ABL1”, “tyrosine-kinase
(formerly b2a2) and e14a2 (formerly b3a2), both generating inhibitors”, “imatinib’, “nilotinib”, “dasatinib”, “bosutinib”,
a BCR-ABL1 protein of 210 kDa molecular weight. e14a2 is “ponatinib”, “stem-cell transplant”, “treatment-free
more common, expressed in approximately two-thirds remission”, “major molecular response”, and “deep molecular
of all patients, and might be associated with a better response”. Manuscripts included in the reference lists of those
probability of deep molecular response and survival; initially investigated or others known to the authors from
5–10% of all patients co-express e13a2 and e14a2.6,7 personal experience or involvement were also considered.
Occasionally in chronic myeloid leukaemia and more
www.thelancet.com Published online August 20, 2021 https://doi.org/10.1016/S0140-6736(21)01204-6 1

Descargado para Ronald Eduardo Lozano Acosta (loacro@yahoo.com) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en septiembre
01, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.
Seminar
When left untreated or if the disease does not respond to

Panel: Chronic myeloid leukaemia phases according to the treatment, it eventually progresses to the blast phase,
European LeukemiaNet19 which has a median survival of 12 months, even after the
Chronic phase advent of tyrosine-kinase inhibitors—an improvement
• Blast cells: <15% of total in blood over the historical 3–6 month survival, but still
• Blast cells and promyelocytes: <30% of total in blood and unquestionably inadequate.18 The accelerated phase has
bone marrow an intermediate prognosis that has improved substan
• Basophils: <20% of total in blood and bone marrow tially with tyrosine-kinase inhibitors. There are various,
• Platelets: >100 × 10⁹ cells per L slightly varying, definitions of these stages. The European
• No additional chromosomal abnormalities at the time of LeukemiaNet definition19 (panel) has been used in all
diagnosis major tyrosine-kinase inhibitor studies, thus giving a
more accurate indication of the expected outcomes that
Accelerated phase cannot be extrapolated when other definitions are used.
• Blast cells: ≥15% of total in blood or bone marrow
• Blast cells and promyelocytes: ≥30% of total in blood or Diagnosis
bone marrow Most patients are diagnosed while asymptomatic, when
• Basophils: ≥20% of total in blood or bone marrow a blood test is done for other purposes. Typical findings
• Persistent thrombocytopenia (<100 × 10⁹ platelets per L) are leucocytosis with a left shift (ie, increased number
unrelated to therapy of immature cells) and, occasionally, thrombocytosis.
• Clonal chromosomal abnormalities in Philadelphia In rare cases, patients can have only thrombocytosis;
chromosome-positive cells, major route, on treatment therefore, patients with increased blood cell counts should
Blast phase always be assessed for the presence of the Philadelphia
• Blast cells: ≥30% of total in blood or bone marrow chromosome. Patients with symptoms might have night
• Extramedullary disease with immature blast cells sweats or fever, left upper quadrant discomfort (due to
splenomegaly), or symptoms of hyperviscosity such as
headaches, visual disturbance, or priapism. Diagnosis
alfa. The EUTOS score11 was later developed to better requires the identification of the Philadelphia chromo
predict survival free from progression to the accelerated some. Although a diagnosis of chronic myeloid leukaemia
phase or blast phase (ie, progression-free survival) and can be made in peripheral blood, a bone marrow aspir
the probability of a complete cytogenetic response at ation (and biopsy, in case of a dry tap) is needed to stage
18 months with tyrosine-kinase inhibitors. The EUTOS the patient and assess for additional chromosomal
Long-Term Survival Score was subsequently designed abnormalities. At least one qualitative PCR test for
with a focus on defining the risk of dying from causes BCR-ABL1 is also recommended to confirm that a
related to chronic myeloid leukaemia.12,13 typical transcript is present. Atypical transcripts, such as
The distribution of patients in various risk groups e13a3, e14a3, or e19a2, cannot be detected by the standard
varies across the world. In high-income countries, PCR done in most clinical laboratories, but multiplex
few patients (typically <10%) have high-risk disease at approaches that can detect most rearrangements are
diagnosis, whereas in low-income countries, approxi available in many laboratories.20 A patient with the
mately 20–25% of patients present with high-risk disease. Philadelphia chromosome but undetectable transcripts
Comorbidities at the time of diagnosis are some of the might have atypical transcripts. Some specialised labora
most important predictors of long-term survival.14 tories can quantitate atypical transcripts, but these are not
The presence of chromosomal abnormalities in amenable to international standardisation.
addition to the Philadelphia chromosome, whether
observed at the time of diagnosis15 or during the course Monitoring and response criteria
of therapy, worsens the prognosis. High-risk chromo Regular monitoring is required to assess response to
somal abnormalities include—besides the Philadelphia treatment and determine the need for interventions at
chromosome—i(17)(q10), abnormalities involving 3q26.2, crucial times (eg, to assess and address adherence and
abnormalities involving 11q23, trisomy 8, trisomy 17, adverse events, and to consider treatment change or dose
trisomy 19, trisomy 21, chromosome 7 abnormalities optimisation).
(including monosomy 7 and deletions of the long arm of
chromosome 7), chromosome 3 abnormalities, and other Response assessment
complex abnormalities.16,17 A routine complete blood count is indicated periodically
to assess normalisation of leukocyte concentrations and
Staging to identify myelosuppression, a common side-effect
Chronic myeloid leukaemia has a triphasic course. Most observed with tyrosine-kinase inhibitors.
patients present in the chronic phase, which is frequently The main goal of therapy is to eradicate the malignant
asymptomatic and associated with the best outcome. clone, characterised by the Philadelphia chromosome and
2 www.thelancet.com Published online August 20, 2021 https://doi.org/10.1016/S0140-6736(21)01204-6

Seminar
BCR-ABL1. There are three main methods of assessing

Approximate Molecular response BCR-ABL1 Undetectable transcripts
this endpoint: cytogenetic analysis, fluorescence in-situ complete transcript levels (minimum number of copies
hybridisation, and quantitative PCR (qPCR). response in the of reference gene)
Cytogenetic analysis should always be done at diagnosis equivalent International
Scale
to confirm the presence of the Philadelphia chromosome
and additional chromosomal abnormalities. Guidelines Baseline ·· ·· 100% ··
diverge on how often to do a cytogenetic analysis. When 1·0 log PCyR ·· ≤10% ··
standardised qPCR is available, cytogenetic analysis is 2·0 log CCyR ·· ≤1% ··
less essential for response assessment. Cytogenetic 3·0 log ·· Major molecular response ≤0·1 % ··
analysis can, however, detect emerging additional 4·0 log ·· Molecular response 4·0 ≤0·01% ≥10 000 ABL (≥24 000 GUSB)
chromosomal abnormalities in the context of progression 4·5 log ·· Molecular response 4·5 ≤0·0032% ≥32 000 ABL (≥77 000 GUSB)
to the accelerated phase (ie, clonal evolution). Clonal 5·0 log ·· Molecular response 5·0 ≤0·001% ≥100 000 ABL (≥240 000 GUSB)
evolution, however, rarely occurs without increasing CCyR=complete cytogenetic response. PCyR=partial cytogenetic response. *Log reduction is calculated in relation to a
transcript concentrations and probably inducing a loss of standardised baseline.
haematological response. In such instances, a bone
Table 1: Response criteria and equivalence by log reduction*
marrow aspiration for cytogenetic analysis is required.
One study17 suggested that the emergence of high-risk
additional chromosomal abnormalities in patients in every 3–6 months until a stable major molecular
the chronic phase is a harbinger of the blast phase, response is reached, and then every 6 months. When
particularly among patients with low blast cell counts. access to or the cost of qPCR tests preclude testing with
Additionally, in 10–15% of patients treated with tyrosine- this frequency, qPCR should be done as frequently as
kinase inhibitors, additional chromosomal abnormalities possible, ideally at least once per year. Minor variations
emerge in Philadelphia chromosome-negative cells as in transcript levels are common because the test has a
patients respond to therapy.21 A cytogenetic analysis every coefficient of variability of at least 0·5 log. Therefore,
6–12 months for the first 1–3 years of treatment can minor changes in transcript levels should not prompt
identify these abnormalities in most patients because major changes in therapy without confirmation of a fixed
they usually occur at an early stage. Patients with such tendency. Undetectable transcript levels should be
abnormalities have worse survival than those without considered with caution. qPCR results express the ratio
these abnormalities and some develop acute myeloid of BCR-ABL1 to a control gene. Thus, an undetectable
leukaemia or myelodysplastic syndrome.21 There is no level is highly dependent on the number of copies of
consensus about the proper management of these the control gene. Because it is more precisely defined,
patients, but a change of therapy is not indicated solely MR4·5 (ie, BCR-ABL1 ≤0·0032% as measured on the
because of the identification of such changes. Therefore, International Scale) is more commonly used as the most
some experts do not recommend regular cytogenetic reliable measure of the deepest molecular response
analysis during therapy unless other clinical features (table 1).
suggest disease progression.
Fluorescence in-situ hybridisation can be done in Response criteria
peripheral blood samples to assess the number of A complete haematological response is defined as
BCR-ABL1-positive cells. Although this technique normalisation of peripheral blood cell counts with no
has not been formally validated for cytogenetic palpable splenomegaly and no signs or symptoms of
response assessment, most experts consider it adequate the disease.
for this purpose.22 However, fluorescence in-situ Cytogenetic remission became relevant and achievable
hybridisation cannot identify additional chromosomal during the era of interferon alfa therapy. Reaching
abnormalities unless specific probes are used for each a complete cytogenetic response (0% Philadelphia
abnormality being investigated, and although it is not chromosome-positive metaphases) improves overall
as sensitive as PCR, it can be valuable in the case survival and translates to a near-normal life expectancy.
of patients with atypical transcripts. Nonetheless, A complete cytogenetic response together with a partial
decisions about treatment discontinuation cannot be cytogenetic response (≤35% Philadelphia chromosome-
made on the basis of fluorescence in-situ hybridisation positive metaphases) is considered a major cytogenetic
alone. response. With tyrosine-kinase inhibitors, a complete
qPCR is the most used monitoring test. The poor cytogenetic response is the minimum acceptable
correlation of results from different labora tories has response, at least in the first-line setting.
been largely addressed by the International Scale,23 which Molecular responses require normalisation of results
allows standardisation. Commercial stan dardisation to the International Scale (table 1). A major molecular
reagents have made this process more feasible. qPCR response, when reached within 18 months, is associated
transcripts correlate partly with cytogenetic response with improved event-free survival, but deeper molecular
criteria (table 1). During therapy, qPCR is recommended responses, ideally MR4·5, are required for consideration

Seminar
cytarabine resulted in a significantly higher major

Optimal response Warning or subopotimal Intolerance or resistance
response cytogenetic response rate with imatinib (85·2% vs 22·1%,
p<0·001), and a significant improvement in progression-
Baseline Not applicable High-risk ACA, high-risk Not applicable
ELTS score free survival at 18 months (92·1% vs 73·5%; p<0·0001).27
3 months BCR-ABL1 ≤10% BCR-ABL1 >10% BCR-ABL1 >10% confirmed A 10·9 year follow-up study28 showed a 10 year overall
within 1–3 months survival of 83·3% with imatinib and 78·8% with
6 months BCR-ABL1 ≤1% BCR-ABL1 >1% to 10% BCR-ABL1 >10% interferon alfa plus cytarabine (p=0·04). Molecular
12 months BCR-ABL1 ≤0·1% BCR-ABL1 >0·1% to 1·0% BCR-ABL1 >1% monitoring was scarce in this study, but the CML
Any time after 12 months BCR-ABL1 ≤0·1% BCR-ABL1 >0·1% to 1·0% BCR-ABL1 >1%; emergence Study IV29 showed that the 5 year probability of a major
and loss of major of resistance mutations; molecular response was 86·3%, increasing to 92·2% at
molecular response* high-risk ACA 10 years, while the 5 year probability of MR4·5 was
For patients aiming at treatment-free remission, the optimal response (at any time) is BCR-ABL1 ≤0·01% (molecular 49·4%, increasing to 67·2% at 10 years, in all evaluable
response 4·0). A change of treatment can be considered if a major molecular response is not reached within patients. Generic imatinib is now available in most
36–48 months. Adapted from Hochhaus et al.19 ACA=additional chromosomal abnormalities in Philadelphia
chromosome-positive cells. ELTS=European Treatment Outcome Study Long-Term Survival Score. *Loss of major countries and has become a cost-effective alternative
molecular response (BCR-ABL1 >0·1%) indicates relapse after treatment-free remission. to the branded version of the drug. Most case series
have reported that good quality generic imatinib has
Table 2: Treatment milestones suggested by the European LeukemiaNet19
equivalent efficacy and safety to branded imatinib.30–32
After the emergence of resistance and intolerance to
of elective treatment discontinuation. A deep molecular imatinib in some patients, second-generation tyrosine-
response refers to MR4·0 or MR4·5. kinase inhibitors were developed, and three are approved
The European LeukemiaNet has defined optimal for clinical use in various parts of the world: dasatinib,
times for the attainment of various levels of response, nilotinib, and bosutinib.
which correlate with the best long-term outcomes Dasatinib inhibits ABL1 and SRC and, because of its
or with treatment failure (table 2). An intermediate short half-life (approximately 5 h), was initially used on a
category (warning or suboptimal response) represents a schedule of 70 mg twice daily. A subsequent randomised
response that requires close monitoring and assessment trial33 showed that a lower frequency (once daily) yielded
of the patient’s long-term goals and plans. The optimal equivalent efficacy and lower toxicity, and this schedule
management plan for patients in this inter mediate thus became the standard of care. Among patients who
category has not yet been defined. The early molecular developed intolerance or resistance to imatinib, dasatinib
response (ie, BCR-ABL1 [as measured on the Inter 100 mg once daily resulted in a major cytogenetic
national Scale] ≤10% at 3 months) is of particular response rate of 63% (complete cytogenetic response
interest. Patients with an early molecular response have of 50%),34 and to a major molecular response of 46%.33
significantly better overall survival and progression-free MR4·5 was reported in 20% of patients. The 7 year
survival (although differences are relatively small in progression-free survival was 42% and overall survival
magnitude), and a better probability of having a deep was 65%.33
molecular response than patients with no early Similarly to dasatinib, nilotinib is a substantially more
molecular response. 30–35% of patients treated with potent ABL1 inhibitor than imatinib, but has no SRC
first-line imatinib and 10–15% of those treated with a inhibitory activity. Although no formal maximum
first-line second-generation tyrosine-kinase inhibitor tolerated dose was identified and despite a relatively long
do not have an early molecular response. half-life (approximately 17 h), 400 mg twice daily was
used for patients who developed intolerance or resistance
Treatment to imatinib. A major cytogenetic response was reached
Tyrosine-kinase inhibitors in 59% of patients (complete cytogenetic response 45%)
The first major breakthrough in the medical management with a 48 month progression-free survival of 57% and an
of chronic myeloid leukaemia was the introduction overall survival of 78%.35 Molecular response rates were
of interferon alfa. When combined with low-dose not reported.
cytarabine, 25–30% of treated patients have a complete Bosutinib inhibits both ABL1 and SRC, but has no
cytogenetic response,24 which has led to an overall activity against SCFR (also known as proto-oncogene
survival probability of 78% at 10 years for those who have c-Kit) or PDGFR alpha and PDGFR beta, which are
such a response.24 inhibited by imatinib, dasatinib, and nilotinib. No
Imatinib was the first available tyrosine-kinase formal maximum tolerated dose of bosutinib has been
inhibitor, initially approved for patients who did not identified, but a dose of 500 mg once daily was used for
respond to interferon alfa.25 The major cytogenetic patients who developed intolerance or resistance to
response seen in these patients was 60% (complete imatinib. The major cytogenetic response rate was 58%,
cytogenetic response of 41%), with a progression-free and the complete cytogenetic response was 46%.36
survival of 89% at 18 months.26 A randomised trial The cumulative rate of major molecular response
comparing first-line imatinib to interferon alfa plus was 42% and 5 year overall survival was 84%.36

Seminar
Although cross-trial comparisons are not possible,

Dasatinib* Nilotinib† Bosutinib
the study designs were similar, particularly regarding
definitions of imatinib resistance. The primary endpoint Complete haematological 89% 77% 86%
response
for all these studies33,35,36 was major cytogenetic response,
Major cytogenetic response 59% 56% 57%
and most of these responses were reached by 24 months,
Complete cytogenetic response 44% 41% 44%
although more recently the objective of treatment has
Progression-free survival‡ 80% 64% 81%
shifted to deeper cytogenetic (complete cytogenetic
Overall survival 91% 87% 91%
response) and even molecular responses. When analysing
the results for patients with imatinib resistance only, the All data shown for 24 months’ follow-up. *Major molecular response at
7 years: 43%; progression-free survival at 7 years: 42%; overall survival at
major cytogenetic response rates at 24 months are very 7 years: 65%; treatment discontinuation at 7 years: 78%. †Progression-free survival
similar: 59% for dasatinib, 56% for nilotinib, and 57% for at 4 years: 57%; overall survival at 4 years: 78%; treatment discontinuation at
bosutinib (table 333,35,36). The choice of second-generation 4 years: 70%. ‡In all patients (those resistant and intolerant to imatinib).
tyrosine-kinase inhibitor after resistance or intolerance to Table 3: Treatment responses in patients with chronic-phase chronic
imatinib is, therefore, influenced by other factors. An myeloid leukaemia treated with second-generation tyrosine-kinase
important consideration is the presence of ABL1 muta inhibitors after resistance or intolerance to imatinib
tions. The patterns of resistance to, and efficacy of, the
various tyrosine-kinase inhibitors for many of the most
common mutations are known.37 Using a tyrosine-kinase used. All three second-generation tyrosine-kinase
inhibitor with preclinical efficacy against the mutation inhibitors have been compared with imatinib 400 mg in
detected in a given patient is predictive of a better randomised trials and shown improved efficacy.
probability of response and improved progression-free In the DASISION study,41 which was regrettably
survival.38 Mutations, how ever, are not present in all terminated after only 5 years of follow-up, patients
patients. In a prospective analysis of mutations among treated with dasatinib 100 mg had earlier responses and
patients with no response or warning response, showed an early molecular response rate of 84%, versus
25% of patients had mutations detectable by Sanger 64% with imatinib. There was a trend for fewer
sequencing, which is still considered the gold standard for transformations to accelerated phase or blast phase, and
the detection of BCR-ABL1 mutations.39 With next- the cumulative 5 year major molecular response rates
generation sequencing, however, more mutations were (76% vs 64%) and MR4·5 rates (42% vs 33%) were better
identified, frequently at low expression levels.39 Whether with dasatinib. Even so, similar proportions of patients
changes to treatment at the time of detection of low-level discontinued dasatinib (39%) and imatinib (37%), and
mutations alter long-term outcomes is, however, unknown. the study did not show a difference in progression-free
No first-generation or second-generation tyrosine- survival or overall survival.41 A single-arm study of
kinase inhibitor has preclinical or clinical activity dasatinib with a longer follow-up reported a cumulative
against the Thr315Ile mutation in BCR-ABL1. This 11 year MR4·5 rate of 79·5%, and a sustained (ie, lasting
shortcoming has led to the development of ponatinib, a for at least 2 years) MR4·5 was reached in 55% of
potent tyrosine-kinase inhibitor with activity against patients.42 Although the standard dose of dasatinib in this
unmutated BCR-ABL1 and against the most common indication is 100 mg once daily, a recent study suggests
mutations, including Thr315Ile. In a phase 2 study of that a starting dose of 50 mg once daily might yield
patients who had previously received multiple tyrosine- similar results with reduced toxicity.43
kinase inhibitors (93% had received two or more and Two different dose schedules of nilotinib, 400 mg
56% had received three or more), 60% of patients in versus 300 mg, twice daily, were investigated in the
the chronic phase had a major cytogenetic response ENESTnd study.44 Because the two schedules showed a
(and 54% had a complete cytogenetic response). The similar efficacy, 300 mg twice daily became standard for
cumulative rate of major molecular response was first-line therapy. When compared with imatinib 400 mg
40% and that of MR4·5 was 24%.40 Among patients with once daily, nilotinib 300 mg twice daily resulted in a
a Thr315Ile mutation, 72% had a major cytogenetic higher early molecular response rate (90·7% vs 66·7%)
response (70% had a complete cytogenetic response), and fewer transformations from chronic phase to
58% had a major molecular response, and 38% had accelerated or blast phase (0·7% vs 4·2%). The 5 year
MR4·5. The overall 5 year progression-free survival was cumulative major molecular response rate was 77% for
53% and overall survival was 73%.40 nilotinib (MR4·5 of 54%) and 60·4% for imatinib
(MR4·5 of 31%). However, after 5 years of follow-up,
First-line therapy 40·1% of patients had discontinued nilotinib and
Imatinib, dasatinib, nilotinib, and bosutinib are approved 50·2% had discontinued imatinib. There was no
for the first-line treatment of patients with chronic difference in progression-free survival or overall survival
myeloid leukaemia in the chronic phase in several at 5 years.44 A longer-term report from a single-arm
countries. Imatinib was the first tyrosine-kinase inhibitor study reported 10 year rates of MR4·5 of 75% and
available as an initial therapy and continues to be widely sustained MR4·5 of 60% with nilotinib.45

Seminar
Despite the benefits of bosutinib 500 mg once daily Although no direct comparison between second-
shown in the BELA trial46 for most endpoints, the generation tyrosine-kinase inhibitors in the first-line
primary endpoint (complete cytogenetic response at setting is available, the differences in outcome compared
12 months) was not met. A second study of bosutinib with imatinib are generally similar in favour of second-
400 mg once daily with a primary endpoint of major generation tyrosine-kinase inhibitors, suggesting that
molecular response at 12 months (the BFORE trial47) they are somewhat equivalent (table 4). No second-
yielded a higher early molecular response rate with generation tyrosine-kinase inhibitor prolongs overall
bosutinib (75·2%) than with imatinib 400 mg once survival or progression-free survival compared with
daily (57·3%), and a lower rate of transformation imatinib. The main benefit of these agents is the higher
from chronic phase to accelerated or blast phase rate, and earlier achievement, of deep molecular
(1·6% vs 2·5%). The follow-up for this study, at the time response. These are important objectives when con
of writing of this Seminar, was short, but the major sidering treatment-free remission, although according to
molecular response rate at 12 months was superior the ENESTnd trial,44 the probability of achieving MR4·5
with bosutinib than with imatinib (47·2% vs 36·9%). after 10 years is only approximately 60%, and the 5 year
By 12 months, 18·3% of patients had discontinued probability of a sustained MR4·5 is 41–44% with second-
bosutinib and 17·7% had discontinued imatinib.47 generation tyrosine-kinase inhibitors. Other studies,
however, have shown higher rates of response with
second-generation tyrosine-kinase inhibitors in the first-
First-line Imatinib First-line Imatinib First-line Imatinib line setting.42,45,48 Therefore, other factors, such as the
dasatinib control nilotinib control bosutinib control
patient’s goals, should be considered when making the
BCR-ABL1 ≤10% at 3 months 84·0% 64·0% 91·0% 67·0% 75·0% 57·0% decision on what treatment to use (figure). For a patient
Complete cytogenetic response 83·0% 72·0% 80·0% 65·0% 77·0% 66·0% interested in pursuing treatment-free remission, a
at 12 months second-generation tyrosine-kinase inhibitor offers the
Major molecular response at 46·0% 28·0% 44·0% 22·0% 47·0% 37·0% best probability of achieving this objective. For a patient
12 months
not primarily interested in treatment-free remission and
Treatment discontinuation by 23·0% 25·0% 26·0% 33·0% 29·0% 34·0%
24 months more interested in reaching a near-normal life expectancy,
Transformation to accelerated 3·5% 5·8% 0·7% 4·2% 2·2% 2·6%
or those with substantial comorbidities and an increased
or blast phase at 24 months risk of arterial-occlusive events, imatinib is a valuable
alternative. Considering the dosing schedule, availability,
Table 4: Treatment responses in patients with chronic-phase chronic myeloid leukaemia treated with comorbidities and their possible influence on known
second-generation tyrosine-kinase inhibitors in the first-line setting (compared with imatinib)
adverse events, and other factors can be helpful when
Newly diagnosed chronic-phase chronic myeloid

leukaemia
• Comorbidities
• Patient goals
• Availability of treatment
• Cost and schedule
Imatinib (first-generation tyrosine-kinase Second-generation tyrosine-kinase inhibitors

inhibitor) • More molecular responses
• Once daily, with food • Deep molecular response
• Most experience in clinical setting • More sustained deep molecular response
• Most follow-up and general use data available • Faster molecular responses
• Lowest risk of arterial-occlusive events • Lower rate of transformation from chronic phase
• More treatment-free remission data to accelerated phase or blast phase
• Some renal toxicity • More prospective treatment-free remission data
• Official generic formulations (but also copies) (nilotinib superior to dasatinib; no data with
available bosutinib)
Dasatinib Nilotinib Bosutinib

• Once daily, with or without food • Twice daily on an empty stomach • Once daily, with food
• Only 5 year follow-up data available • Longest follow-up data available • Only 5 year follow-up data available
• Risk of pleural effusion, pulmonary hypertension • Higher risk of arterial-occlusive events • Lower risk of arterial-occlusive events
• Higher risk of arterial-occlusive events • Risk of metabolic syndrome • Frequent diarrhoea, usually mild
• Optimal dose uncertain
Figure: Decision algorithm for newly diagnosed patients with chronic-phase chronic myeloid leukaemia
Considerations for the various first-line therapy options are shown.

Seminar
choosing between second-generation tyrosine-kinase be curative and should be considered for patients aiming
inhibitors. For example, for a patient for whom a second- for a more definitive approach; for some patients, a
generation tyrosine-kinase inhibitor is desirable but complete cytogenetic response or major molecular
who wants to minimise the risk of arterial-occlusive response might be the most realistic expectation.
events, bosutinib might be the best choice. For patients Bosutinib and ponatinib have been prospectively
with intestinal issues or ongoing diarrhoea, however, evaluated in patients who have previously received two or
bosutinib might not be optimal; in patients with more tyrosine-kinase inhibitors. Among patients with
pulmonary problems, dasatinib should be avoided; and resistance or intolerance to imatinib and either dasatinib
for patients with diabetes, nilotinib might not be the first or nilotinib, the 4 year cumulative major cytogenetic
choice. Ultimately, decisions should be individualised response rate with bosutinib was 40% (and the complete
and discussed with the patient to understand their goals cytogenetic response rate was 32%). Responses were
and concerns, and to provide information that can help durable, particularly in those with intolerance to dasatinib
them to make informed decisions. or resistance to nilotinib.53 Some responses have been
reported in patients treated with dasatinib or nilotinib
Subsequent therapy after imatinib and a second-generation tyrosine-kinase
Second-generation tyrosine-kinase inhibitors are the inhibitor (ie, third-line treatment) but these data are
standard therapy for patients who develop intolerance or mostly from retrospective case series.54
resistance to imatinib. 40–45% of patients with resistance Ponatinib is a third-generation tyrosine-kinase inhibitor
to imatinib can reach a complete cytogenetic response with potent activity against all ABL1 kinase domain
with nilotinib, dasatinib, or bosutinib.33,35,36 When a mutations tested. Among patients who had previously
mutation is detected, a tyrosine-kinase inhibitor with in- received two or more tyrosine-kinase inhibitors, 60% had
vitro efficacy against that mutation should be selected. a major cytogenetic response. Responses occurred rapidly
For those with no mutations or with mutations for which (median time to major cytogenetic response: 2·8 months;
such guidance is not available (ie, most patients), since major molecular response: 5·5 months) and were
all three second-generation tyrosine-kinase inhibitors durable.54 Therefore, ponatinib might be preferable in
have a similar efficacy, factors such as possible adverse this setting. For those with safety concerns because of the
events, schedule, availability, and familiarity can be risk of arterial-occlusive events, bosutinib might be the
considered to select the most suitable agent. A more best alternative.
complex scenario is if a patient has been initially treated A more controversial scenario is that of patients with a
with a second-generation tyrosine-kinase inhibitor,49 but suboptimal or warning response, particularly those with
there are presently no prospective data addressing this a ratio of BCR-ABL1 to ABL1 higher than 10% at
question. The usual approach is to change to another 3 months. The LASOR trial55 randomly assigned patients
second-generation tyrosine-kinase inhibitor. If the receiving imatinib and with a suboptimal response at
reason for treatment discontinuation was intolerance to 3 months, 6 months, or 12 months to change to nilotinib
the first second-generation tyrosine-kinase inhibitor, or continue with imatinib. The complete cytogenetic
trying a different second-generation tyrosine-kinase response rate at 6 months was better with nilotinib than
inhibitor or imatinib is a reasonable option. For those with imatinib (50% vs 36%, adjusting for crossover).55
who develop resistance, changing to another second- However, this study used European LeukemiaNet 2009
generation tyrosine-kinase inhibitor can be considered if criteria, which did not consider a ratio of BCR-ABL1
there are no other options that offer potentially better to ABL1 higher than 10% at 3 months a suboptimal
outcomes. Several models have predicted benefits for response. The DASCERN study56 randomly assigned
various tyrosine-kinase inhibitors. For example, a patients receiving imatinib without an early molecular
matching-adjusted indirect comparison model suggests response to continue imatinib or change to dasatinib.
that bosutinib might have improved progression-free The major molecular response rate at 12 months was
survival compared with dasatinib or nilotinib in this better with dasatinib than with imatinib (29% vs 13%).56
setting,50 whereas a retrospective worldwide chart review Although both studies suggest a benefit with changing
suggested that nilotinib had a better MR4·5 probability from imatinib, the endpoints reported are of short term.
than dasatinib.51 These models have caveats and should To ascertain whether the change in treatment will
be considered with caution. In case of resistance to a translate into long-term benefits (ie, deep molecular
second-generation tyrosine-kinase inhibitor as first-line response, progression-free survival, and overall
therapy, ponatinib might yield better results, but the data survival), longer follow-ups are required. For the time
are scarce52 and this indication falls outside the approval being, these treatment changes are not standard of care.
of ponatinib in most instances. Stem-cell transplantation The current recommendation for patients without an
can also be considered for patients who develop early molecular response is not to make decisions on
resistance to second-generation tyrosine-kinase inhibi the basis of one single measure but instead testing
tors, taking into account the patient’s goals and realistic repeatedly, monitoring closely, and reviewing treatment
response expectations. Stem-cell transplantation might adherence.19

Seminar
Some studies have explored changing therapy for pioneering STIM61 and TWISTER62 studies enrolled
patients with a good response but who have not had a patients with undetectable BCR-ABL1 or ABL1 transcripts
deep molecular response. In the ENESTcmr trial,57 patients (with a 4·5–5·0 log reduction) sustained for at least
receiving imatinib who had a complete cytogenetic 2 years during therapy with imatinib. These studies
response but not a deep molecular response were reported a 40% or higher probability of treatment-free
randomly assigned to either continue imatinib or receive remission, and multiple subsequent studies have
nilotinib. The MR4·5 rate at 48 months was 53·8% with confirmed these observations.
nilotinib and 44·7% with imatinib (13 [28%] of 46 patients Some basic principles should be considered before
initially assigned to imatinib had MR4·5 after crossing attempting treatment-free remission.19,63,64 Patients must
over to nilotinib). However, 12·9% of patients treated with have reached and maintained a deep molecular response.
nilotinib had arterial-occlusive events, compared with Current recommendations are to consider patients with an
1·9% of patients taking imatinib.57 Changing from MR4·5 response sustained for at least 2 years (with testing
imatinib to nilotinib for absence of a deep molecular every 6 months); some studies have explored different
response is not standard of care but can be considered approaches for treatment-free remission. In the EURO-SKI
for selected patients aiming to reach a deep molecular trial,65 an MR4·0 response sustained for at least 1 year was
response for treatment-free remission. used as a criterion for attempting treatment discon
tinuation, and treatment-free remission at 24 months was
Stem-cell transplantation reported in 50% of patients. Although the initial studies
Stem-cell transplantation was a mainstay of chronic only included patients treated with imatinib, there are now
myeloid leukaemia therapy for many years, providing studies of treatment-free remission in patients receiving
the best option for long-term remission and a possible nilotinib66–69 or dasatinib.70–72 Treatment-free remission rates
cure for eligible patients. Since the introduction of appear to be similar regardless of the tyrosine-kinase
tyrosine-kinase inhibitors, stem-cell transplantation is inhibitor used to reach a sustained deep molecular
rarely used as initial therapy. Stem-cell transplantation response, although the probability of achieving a deep
as first-line treatment yielded a 10 year overall survival molecular response is superior with second-generation
of 58% and a leukaemia-free survival of 50%.58 Trans tyrosine-kinase inhibi tors than with imatinib. Among
plantation outcomes have substantially improved since patients who discontinue a second-generation tyrosine-
then. In 56 patients transplanted in the chronic phase kinase inhibitor, those who received these agents as a
after resistance or intolerance to imatinib, overall first-line therapy or after imatinib intolerance have a better
survival at 3 years was 91%.59 Still, the availability of treatment-free remission probability than those who
second-generation, third-generation, or investigational received them after resistance or suboptimal response to
tyrosine-kinase inhibitors has relegated stem-cell trans imatinib (probability of treatment-free remission at
plantation to subsequent lines of therapy. The European 48 months: 62·36% vs 23·08%).73 To consider treatment
LeukemiaNet recommends assessing patients for discontinuation, patients should have access to high-quality
stem-cell transplantation if there is resistance to second- qPCR testing standardised on the International Scale with
generation tyrosine-kinase inhibitors and especially if a rapid turnaround of results.
there is no response to ponatinib.19 Other factors such as The criteria for resuming therapy have evolved, from
patient characteristics (eg, age and comorbidities), donor the initial approach to resume treatment when patients
availability and type (ie, matched sibling, matched developed detectable transcripts61 to the current recom
unrelated, umbilical cord, or haploidentical), and disease mendation to resume treatment if BCR-ABL1 transcripts
stage (ie, chronic phase, accelerated phase, or blast reach higher than 0·1% (ie, loss of major molecular
phase) also play an important role in deciding when response) at any time, or if BCR-ABL1 transcripts reach
stem-cell transplantation should be considered and in higher than 0·01% on the International Scale (ie, loss
which patients. For patients with a Thr315Ile mutation, a of MR4·0) on any two occasions. With this approach,
comparison of outcomes with ponatinib versus with treatment-free remission is approximately 50–60%.64
stem-cell transplantation suggests that overall survival is Most cases of increases in BCR-ABL1 transcripts
better with ponatinib for patients in the chronic phase requiring treatment resumption (approximately 70–85%)
(72·7% vs 55·8% at 48 months).60 Outcomes are similar occur within 6 months of discontinuing treatment, with
with either modality in the accelerated phase, and better the remaining cases usually occurring by 24 months, but
(albeit still poor) with stem-cell transplantation in the some patients might lose response even after 24 months;
blast phase. Therefore, ponatinib might be the preferred close monitoring is therefore mandatory. The European
option for patients in the chronic phase and should also LeukemiaNet recommends monitoring monthly for the
be considered for patients in the accelerated phase. first 6 months, every 2 months between months 6 and 12,
and every 3 months thereafter.19 Less frequent monitoring
Treatment-free remission might be adequate in some instances,74 but should not be
Treatment discontinuation has become a feasible option less frequent than every 2–3 months for the first 1–2 years
for a subset of patients, and a goal for many more. The and every 6 months after that. Identification of the

Seminar
minimum safe monitoring frequency is a matter of tyrosine-kinase inhibitors.87 Most adverse events are low-
ongoing studies.74 In case of unsuccessful treatment-free grade and can be managed with supportive care. More
remission, resumption of therapy results in recovery of a serious adverse events, usually grade 3 or 4, can require
major molecular response in more than 90% of patients, transient treatment interruptions, dose adjustments, or
most of whom reach an MR4·0 response or better. both. Alternative causes of, or contributors to, adverse
Treatment resumption is usually with the same tyrosine- events should be investigated. Altering the dose intensity
kinase inhibitor being used before discontinuation, might be more acceptable in patients with a good, stable
although a different tyrosine-kinase inhibitor can be response and who have low-grade adverse events, than in
considered if adverse events contributed to the decision those with poor disease control. In the ENRICH trial,88
to attempt treatment-free remission. Anecdotal instances patients receiving imatinib who had persistent low-
of relapse in the blast phase have been reported,75 grade (grade 1 or 2) non-haematological adverse events
underscoring the need for continued vigilance and switched to nilotinib. By 3 months, 62·9% of adverse
adequate education to allow patients to make informed events had resolved, and by 12 months at least 50% of
decisions. patients reported improve ments in quality of life.88
Second-line treatment discontinuation attempts can be However, 98% of patients had new or worsening adverse
successful in some patients, provided that the criteria for events and 15% discontinued nilotinib because of adverse
treatment discontinuation are met. The treatment-free events.88 Similarly, changing from imatinib to dasatinib
remission probability at 24 months is approximately resulted in resolution or improvement of 77% of grade 1
35% in this setting.76 Second-line treatment discon or 2 adverse events and improvements in patient-
tinuation attempts should be done in the context of clinical reported outcomes. Serious adverse events were observed
trials. Patients who have been in the accelerated or blast in 28% of patients, and 8% discontinued dasatinib
phases are generally not considered suitable candidates for because of adverse events.89 Therefore, such interventions
treatment-free remission attempts outside of clinical trials. should be carefully assessed for possible risks and
Some patients have a so-called withdrawal syndrome benefits.
upon treatment discontinuation. This is typically Some adverse events require specific attention.
characterised by myalgias, arthralgias, and generalised Arterial-occlusive events are associated with several
malaise,77 and is usually mild and transient. Patients tyrosine-kinase inhibitors. The risk appears to be greater
can be managed with non-steroidal anti-inflammatory with ponatinib, but also occurs with dasatinib and
agents and occasionally with corticosteroids. On rare nilotinib, and less frequently with bosutinib; imatinib
occasions, patients need to resume therapy with tyrosine- has the lowest risk of arterial-occlusive events.90,91 The
kinase inhibitors to resolve the symptoms of withdrawal. risk increases with age and is greater in those with
Factors that are predictive of successful treatment- additional comorbidities, and there is also a correlation
free remission include the duration of tyrosine-kinase between dose and risk. In the ENESTnd study,44 the
inhibitor therapy, the duration of deep molecular response, incidence of arterial-occlusive events was 13·4% with
the Sokal risk score, and previous interferon alfa use, with nilotinib 400 mg twice daily and 7·5% with nilotinib
the duration of deep molecular response being perhaps the 300 mg twice daily (compared with 2·1% with imatinib
most predictive factor.61,65,78 Immune mechanisms might 400 mg daily). As such, for patients with high-risk
contribute to maintenance of treatment-free remission.79,80 features, imatinib might be the safest choice. If a second-
generation tyrosine-kinase inhibitor is deemed necessary,
Safety bosutinib might be preferred.92
Tyrosine-kinase inhibitors are generally safe, but all are Renal dysfunction with a decrease in glomerular
associated with adverse events. Some adverse events filtration rate can also be observed, particularly with
(eg, myelosuppression) are common to all tyrosine- imatinib and bosutinib. This side-effect is typically mild
kinase inhibitors, whereas others are more closely linked and rarely needs any intervention.93,94 Pleural and
to specific tyrosine-kinase inhibitors, with imatinib pericardial effusions are more frequently seen with
having perhaps the lowest cumulative incidence of dasatinib,95 but have been reported with other tyrosine-
adverse events.81 A detailed description of all adverse kinase inhibitors as well. In contrast to most adverse
events reported with tyrosine-kinase inhibitors and events, which tend to occur first in the early weeks or
their management is beyond the scope of this Seminar, months of therapy, pleural effusion can first occur long
but a list of some of the most commonly reported after the start of therapy. Lower doses might decrease
adverse events is presented in the appendix;82 the the risk of occurrence or recurrence of pleural effusion. See Online for appendix
management of adverse events associated with tyrosine- Pulmonary artery hypertension can also be seen with
kinase inhibitors has been reviewed elsewhere.83–86 dasatinib. The true incidence of pulmonary artery
Patients should be followed up closely, educated about hypertension is unknown because few patients have
known adverse events, and managed properly. pulmonary catheterism.96 Pulmonary artery hyper
Comorbidities should be assessed and managed before tension or recurrent pleural effusions should prompt
and during therapy to minimise the risks associated with considerations for treatment change.

Seminar
The incidence ratio for the risk of additional cancers has Patients with accelerated phase features at diagnosis
been reported to be between 0·88 and 1·52.97–100 Patients have a similar outcome with tyrosine-kinase inhibitors to
with chronic myeloid leukaemia treated with tyrosine- patients in the chronic phase, with complete cytogenetic
kinase inhibitors might have a slightly higher risk of response rates of 80% with imatinib and 90% with
developing additional cancers, but there is substantial dasatinib or nilotinib. Major molecular response rates of
variability for individual tumour types. Patients should be 63% with imatinib and 76% with dasatinib or nilotinib
advised to adhere to standard screening and cancer have been reported.108 With imatinib, progression-free
prevention recommendations. survival at 3 years is 91% and overall survival at 3 years
With regard to pregnancy and conception, some is 87%, whereas with second-generation tyrosine-kinase
(scarce) preclinical data and retrospective clinical data inhibitors progression-free survival is 78% and overall
and safety reports suggest that tyrosine-kinase inhibitors survival is 95%.108 Therefore, these patients can be treated
have a teratogenic effect.101–103 There is no formal with tyrosine-kinase inhibitor alone without the need for
contraindication for male patients to father children stem-cell transplantation.
while taking tyrosine-kinase inhibitors. A few adverse The blast phase has a poor outcome even when patients
outcomes during pregnancy have been reported, but are are treated with tyrosine-kinase inhibitors, with a median
not suggestive of a teratogenic effect when the father is overall survival of 12 months.18 Major haematological
taking tyrosine-kinase inhibitors. For female patients, response rates of 18–35%, usually of short duration,
although there have been anecdotal reports of successful have been reported with tyrosine-kinase inhibitors
outcomes despite continued treatment throughout alone.40,105,109 Tyrosine-kinase inhibitors in combination
pregnancy, tyrosine-kinase inhibitors should not be with chemotherapy yield higher response rates and more
administered during gestation. Reports of malformations durable responses.18,110,111 Patients with blast-phase chronic
such as exomphalos, fetal hydrops, craniosynostosis, myeloid leukaemia still require stem-cell transplantation,
and renal abnormalities frequently match the abnor although ideally after reaching at least some degree of a
malities observed in animal studies, suggesting a haematological response with tyrosine-kinase inhibitors,
teratogenic effect of tyrosine-kinase inhibitors. Patients which provides the best probability of long-term survival
should be reminded that the information in this regard (approximately 43% at 5 years).18,112
is scarce. Most patients can be monitored without
therapy during pregnancy.104 Transcript levels might Future research directions
increase but this observation alone does not warrant The main focus of future research is to understand the
therapy. Interferon alfa has been suggested as possibly role that molecular heterogeneity can have in the practical
safe, although mostly on the basis of anecdotal evidence. management of patients, to avoid and manage resistance
Interferon alfa also has adverse events and the median with fewer adverse events, to treat patients in the
time to a complete cytogenetic response is 16 months,24 advanced phase more effectively, and to improve the
and longer for a molecular response (which is also less success rate of treatment-free remission. Several new
likely to be reached), so it is unlikely to provide much tyrosine-kinase inhibitors are under development.
benefit for the management of chronic myeloid Asciminib is a novel, first-in-class allosteric inhibitor that
leukaemia during pregnancy. For patients needing binds to the N-terminal myristoyl site of ABL1. In a
therapy, the administration of tyrosine-kinase inhibitors phase 1 study of patients who had received multiple
during the third trimester (after embryo genesis has previous lines of therapy, including 70% who had
been completed) has been proposed to be a safe option. previously received three or more tyrosine-kinase
However, the safety of this approach has not been inhibitors (94% had received two or more tyrosine-kinase
prospectively tested and the risk–benefit ratio should be inhibitors), a major cytogenetic response was reported
considered and discussed with the patient. in 77% of patients in the chronic phase without a
Thr315Ile mutation, and in 60% of patients with a
Advanced-phase chronic myeloid leukaemia Thr315Ile mutation. In patients without the Thr315Ile
Some patients who have progressed to the accelerated mutation the major molecular response rate at 12 months
phase can have durable responses to tyrosine-kinase was 48%, whereas in patients with the mutation the
inhibitors, particularly with second-generation tyrosine- major molecular response rate was 28%.113 A randomised
kinase inhibitors or the third-generation tyrosine- trial in patients who had received two or more tyrosine-
kinase inhibitor ponatinib. The major haematological kinase inhibitors showed a greater probability of a major
response rate (the primary endpoint for studies with molecular response at 24 weeks with asciminib than with
tyrosine-kinase inhibitors in the advanced phase) was bosutinib (25·5% vs 13·2% [95% CI for the difference
54–67% with a tyrosine-kinase inhibitor, with an overall 2·19–22·3]; p=0·029). Other tyrosine-kinase inhibitors
survival at 4–5 years of 45–66%.40,105–107 Allogeneic stem- under development that have shown some efficacy in
cell transplantation provides similar overall survival early trials include PF-114,114 vodobatinib (K0706),115 and
and can be considered for younger patients with olverembatinib (HQP1351).116 Combining tyrosine-kinase
suitable donors. inhibitors with other agents such as ruxolitinib (a JAK2

Seminar
inhibitor), venetoclax (a BCL2 inhibitor), and interferon 18 Jain P, Kantarjian HM, Ghorab A, et al. Prognostic factors and
alfa is being investigated to improve the probability of survival outcomes in patients with chronic myeloid leukemia in
blast phase in the tyrosine kinase inhibitor era: cohort study of
successful treatment-free remission. 477 patients. Cancer 2017; 123: 4391–402.
Contributors 19 Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet
All authors wrote and reviewed the manuscript, did the literature search, 2020 recommendations for treating chronic myeloid leukemia.
and approved the final version for submission. Leukemia 2020; 34: 966–84.
20 Cross NC, Melo JV, Feng L, Goldman JM. An optimized multiplex
Declaration of interests polymerase chain reaction (PCR) for detection of BCR-ABL fusion
JC reports grants and personal fees from Novartis, Pfizer, Takeda, and mRNAs in haematological disorders. Leukemia 1994; 8: 186–89.
Sun Pharma; and grants from Bristol Myers Squibb, all outside the 21 Issa GC, Kantarjian HM, Gonzalez GN, et al. Clonal chromosomal
submitted work. CP reports grants and personal fees from Novartis and abnormalities appearing in Philadelphia chromosome-negative
Pint Pharma; and personal fees from Bristol Myers Squibb and Pfizer, metaphases during CML treatment. Blood 2017; 130: 2084–91.
all outside the submitted work. SS reports grants and personal fees from 22 Testoni N, Marzocchi G, Luatti S, et al. Chronic myeloid leukemia:
Novartis, Bristol Myers Squibb, and Incyte; and personal fees from a prospective comparison of interphase fluorescence in situ
Pfizer, all outside the submitted work. hybridization and chromosome banding analysis for the definition
of complete cytogenetic response: a study of the GIMEMA
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Chronic Myeloid Leukaemia

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Chronic myeloid leukaemia

Pathogenesis of chronic myeloid leukaemia Search strategy and selection criteria

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When left untreated or if the disease does not respond to

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BCR-ABL1. There are three main methods of assessing

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cytarabine resulted in a significantly higher major

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Although cross-trial comparisons are not possible,

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Newly diagnosed chronic-phase chronic myeloid

Imatinib (first-generation tyrosine-kinase Second-generation tyrosine-kinase inhibitors

Dasatinib Nilotinib Bosutinib

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