Blood Reviews xxx (xxxx) xxx

Contents lists available at ScienceDirect

Blood Reviews
journal homepage: www.elsevier.com/locate/issn/0268960X

Review

Long-term safety review of tyrosine kinase inhibitors in chronic myeloid

leukemia - What to look for when treatment-free remission is not an option
Jeffrey H. Lipton a, *, Tim H. Brümmendorf b, Carlo Gambacorti-Passerini c,
Valentin Garcia-Gutiérrez d, Michael W. Deininger e, Jorge E. Cortes f
a
Princess Margaret Cancer Centre, Toronto, Canada
b
Universitätsklinikum RWTH Aachen, Aachen, Germany
c
University of Milano-Bicocca, Monza, Italy
d
Servicio de Hematología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
e
Versiti Blood Research Institute, Milwaukee, WI, USA
f
Division of Hematology and SCT, Georgia Cancer Center, Augusta, GA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients
Adverse events with chronic myeloid leukemia (CML). Although there are some common class-wide side effects, differences in
Chronic myeloid leukemia safety profiles between TKIs allow physicians and patients to personalize treatment plans. Treatment selection
Long-term
depends on several factors, such as age, disease risk, comorbidities, and concomitant medications. In second- and
Safety
later-line settings, response to previous TKIs and mutation analyses should also be used to guide TKI selection.
Tyrosine kinase inhibitors
Several strategies can be used to manage adverse events (AEs) that emerge during treatment, e.g., dose re­
ductions/interruptions, monitoring, treatment of AEs, lifestyle modifications, prophylactic therapy, and other
supportive care strategies. This review summarizes the safety profiles of the currently approved TKIs and how
they impact treatment selection in the first- and later-line settings of CML, particularly regarding patient
comorbidities and concomitant medications. Additionally, strategies to manage AEs of special interest with TKIs
are reviewed.

1. Introduction
Five ATP-competitive and one allosteric BCR::ABL1 tyrosine kinase
inhibitors (TKIs)—imatinib, dasatinib, nilotinib, bosutinib, ponatinib,
and asciminib (US Food and Drug Administration [FDA] only)—are
approved for the treatment of chronic myeloid leukemia (CML) [1–11].
Although preclinical studies have shown that TKIs may not eradicate
leukemic stem cells (LSCs), some studies have suggested that LSC burden
at diagnosis and other factors such as telomere shortening that correlate
with a high proportion of LSCs, are important prognostic and response-
predictive markers in CML [12–15].
Initial TKI selection is dependent on several factors, such as comor­
bidities, concomitant medications, risk factors, cost, reimbursement
policies, availability, and administration schedule and the possible
impact on adherence (e.g., once [QD] vs twice [BID] daily administra­
tion, and/or restrictions for food intake) [16–22]. Switching to another
TKI and/or later-line treatment also requires consideration of response
to prior therapies, BCR::ABL1 kinase domain mutation status, and prior
or anticipated adverse events (AEs) based on known toxicity profiles in
the framework of the patients’ comorbidities and past medical history
[16–18]. Additionally, an increasing number of patients with CML have
attempted or would like to attempt treatment-free remission (TFR)
[23,24]; however, only 20–40% of patients are thought to be eligible for
TFR based on current criteria, and the rate of successful TFR is
approximately 50% [25–30]. This means that the majority of patients
with CML will remain on long-term therapy; therefore, there are a
number of factors to consider for patients who are unable to attempt TFR
or who did not accomplish a successful TFR. The current status of TKI
therapy for CML has recently been reviewed in this journal [31].
This review describes and discusses treatment selection in the first-
and later-line settings of CML, with a focus on the long-term safety
profiles of the currently approved TKIs, and dovetails the caveats of
treatment into the success story previously reviewed. AEs of special
interest, including potential risk factors and underlying mechanisms for

* Corresponding author at: Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON M5G 2A1, Canada.
E-mail address: Jeff.Lipton@uhn.ca (J.H. Lipton).

https://doi.org/10.1016/j.blre.2022.100968

Available online 6 May 2022

0268-960X/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: Jeffrey H. Lipton, Blood Reviews, https://doi.org/10.1016/j.blre.2022.100968
J.H. Lipton et al.
these AEs, as well as suggested management strategies are also
reviewed.
2. Long-term clinical experience with TKIs
Outcomes from clinical trials of the approved TKIs have been re­
ported and, for most, long-term clinical follow-up data are also available
(Table 1) [32–62]. Long-term experiences are important because,
although many AEs occur mostly during the first few weeks or months of
therapy and frequently improve over time, some AEs (notably pleural
effusions and arterio-occlusive events [AOEs]) may appear for the first
time after many years of therapy, and thus the cumulative incidence
continues to increase after many years of follow-up. Other AEs have not
been recognized or reported in initial studies and have only been
recognized in subsequent studies (e.g., renal dysfunction). Comparisons
across studies regarding AEs (all grade and grade 3–4) and discontinu­
ations or dose modifications are hampered by the differing study designs
and eligibility criteria/patient populations. Additionally, AEs reported
from various studies are inconsistent and frequently subjective. Some
studies reported only AEs considered by the investigator to be treatment-
related rather than all-causality. The selection of what AEs are reported
or the search criteria for defining certain events is also variable. Others
such as hematologic AEs were commonly reported with all TKIs. Across
trials, cardiac/vascular AEs and pulmonary AEs, although not initially
recognized, have more recently been reported as AEs of special interest
for most TKIs; however, some reports focus on a few specific diagnoses,
while others offer a wide range of signs and symptoms that could
represent these important events (Table 2). In addition, long-term reg­
istries and observational analyses (≥12 months) of TKIs in the off-
protocol setting have been reported (Table 3).
With imatinib, both after interferon failure and in IRIS (first-line
chronic phase [CP] CML), common non-hematologic short-term AEs
included superficial edema (peripheral and periorbital), nausea, diar­
rhea, and muscle cramps [32]. Over 10.9 years follow-up, cardiac
serious AEs (SAEs) and other neoplasms (i.e., second benign or malig­
nant neoplasms) SAEs were reported in 7.1% and 11.3% of patients,
respectively [33]. Most common cardiac SAEs were coronary ischemia,
myocardial infarction, atrial fibrillation, and cardiac arrest [33]. The
incidence of such cardiac SAEs is common in the ‘normal’ population;
therefore, it is difficult to assess whether the incidence of these SAEs was
increased or attributable to imatinib or other TKIs to which patients may
have been switched.
With dasatinib in CA180-034 (imatinib-resistant/intolerant CP CML)
and DASISION (first-line CP CML), hematologic AEs were the most
common AEs reported [34–37]. Pleural effusion is of particular concern
with dasatinib and is one AE that may occur for the first time after many
years of therapy. In the CA180-034 7-year analysis, 28% and 35% of
patients reported pleural effusion with dasatinib 100 mg QD and other
dasatinib doses, respectively [37]. Pleural effusion occurred in 28% of
dasatinib-treated patients in the final DASISION 5-year analysis [35].
Other important AEs reported in some patients with dasatinib included
hemorrhage (even in the absence of thrombocytopenia) and pulmonary
hypertension [34–37].
In ENESTnd (first-line CML) and a phase 2 study (imatinib-resistant/
intolerant CP CML), AEs with nilotinib included rash, pruritis, headache,
and nausea [38–42]. After at least 10 years’ follow-up in ENESTnd,
cardiovascular events occurred at a higher rate with nilotinib (16.5% for
300 mg BID and 23.5% for 400 mg BID) versus imatinib (3.6%) [39,40].
A similar trend was present for the development of hyperglycemia and
diabetes. The frequencies of some AEs, including rash and grade 3–4
hematologic AEs, were lower in ENEST1st (single-arm first-line CP CML)
compared with what was reported in ENESTnd, despite an older patient
population in ENEST1st [63].
In a phase 1/2 study of bosutinib in TKI-resistant/intolerant CML,
diarrhea, nausea, vomiting, and increased transaminases were among
the most commonly reported AEs [47]. Cardiac and vascular AEs were
2
Blood Reviews xxx (xxxx) xxx
uncommon with bosutinib [46,49,64,65]. A 10-year follow-up of the
phase 1/2 study and extension study reported a consistent safety profile,
with diarrhea, nausea, and thrombocytopenia the most common
treatment-emergent AEs (TEAEs), which occurred in 86%, 46%, and
42% of patients, respectively [61]. Pleural effusion and cardiac and
vascular TEAEs occurred in 13%, 12%, and 11% of patients, respectively
[61]. Data from the phase 4 BYOND study were consistent with the
phase 1/2 study in the second-, third-, and fourth-line settings [48].
Furthermore, long-term analyses of the BFORE (5 years) and BELA (≥30
months) trials in first-line CP CML reported distinct safety profiles for
bosutinib and imatinib; gastrointestinal AEs and elevated transaminases
were more common with bosutinib, whereas neutropenia, muscle
spasms, and edema occurred more frequently with imatinib
[43,49–51,66].
In PACE (heavily pretreated CML or acute lymphoblastic leukemia
[ALL]), the three most common non-hematologic treatment-related all
grade AEs with ponatinib were rash, dry skin, and abdominal pain [52].
This was the first study that reported AOEs associated with TKI therapy.
In the final 5-year PACE analysis, the cumulative incidence of AOEs
increased over time to 31% [53]. In EPIC (first-line CP CML), the
ponatinib safety profile was consistent with previous reports; however,
the study was prematurely terminated due to concerns about the risk of
AOEs [54].
Asciminib has a different mechanism of action than the other TKIs by
binding to the myristate pocket rather than the ATP-binding pocket of
the kinase domain [67]. This could potentially reduce the incidence of
some AEs. In a phase 1 study (CP or accelerated phase [AP] CML after ≥2
TKIs), the most common AEs were fatigue, headache, and increased
lipase [55]. Asciminib was investigated in ASCEMBL (patients with CP
CML resistant or intolerant to ≥2 TKIs) versus bosutinib. The three most
frequent grade ≥3 AEs with asciminib were thrombocytopenia, neu­
tropenia, diarrhea, and increased alanine aminotransferase [56]. There
was a higher incidence of AOEs with asciminib versus bosutinib, and this
will need to be monitored carefully in long-term studies. Due to the
limited information on long-term safety and AEs with asciminib, it will
not be discussed in detail in this review.
Radotinib is currently approved only in South Korea, based on results
from RERISE (first-line CML) [68,69]. Common AEs were hematologic
AEs and biochemical abnormalities. No new safety signals were detected
after ≥48 months follow-up [68,69]. Since limited information is
available for radotinib, it will not be discussed further in this review.
Overall, all TKIs have manageable safety profiles, although some
TKIs are associated with specific AEs. Low-grade chronic AEs occur with
all TKIs, leading to discontinuation or treatment switching. However,
many AEs occur early in treatment and are dose-dependent, and thus
they can be managed by dose modifications and/or supportive care
strategies. Nevertheless, some AEs may linger or appear for the first time
after several months or years of therapy. Several long-term studies re­
ported that the safety profiles of TKIs remained consistent with earlier
reports. Some common AEs may persist and need to be managed over
years, given that many patients with CML require long-term treatment.
AE management strategies for common AEs associated with TKIs are
discussed later in this review. Across long-term study reports, rates of
late-emerging cardiac, vascular, or pulmonary AEs of special interest
were generally low, but highlighted as AEs that physicians should be
mindful of throughout TKI treatment [35,37,40,46,53]. Unfortunately,
many pivotal trials are being terminated after only 5 years of follow-up,
which limits the understanding of late-occurring AEs. Careful consid­
eration of risk factors (such as cardiovascular, metabolic, and pulmo­
nary) [70] prompt identification of any new signs and symptoms, and
ongoing management of comorbidities is important to mitigate the risk
of these potentially late-emerging AEs.
2.1. Patient-reported outcomes (PROs), cross-intolerance, and switching
Limited information on PROs, treatment switching, and cross-
J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 1
Key clinical safety experience of TKIs in CML
Study Discontinuations and dose Most common non-hematologic AEs Most common Deaths
interruptions or reductions hematologic AEs

Imatinib
Phase 3 IRIS study (median 19 months) in newly diagnosed CP CML [32]
All grades:

All grades:
• Anemia: 44.6%
• Neutropenia: 60.8%
• Superficial edema: 55.5%
• Thrombocytopenia:
• Nausea: 43.7%
56.6%
Imatinib 400 mg QD: Discontinued: 12.3% • Muscle cramps: 38.3%
Grade 3–4:
n=553 Discontinued due to AEs: 2.2% Grade 3–4:

• Neutropenia: 14.3%
• Musculoskeletal pain: 2.7%
• Thrombocytopenia:
• Abdominal pain: 2.4%
7.8%
• Joint pain: 2.4% Imatinib: n=6
• ALT or AST increased:
IFN + LDAC: n=2
5.1%
Reasons: cardiac events (n=4); car
All grades:
accident, pneumococcal sepsis, pulmonary
All grades: edema, and liver metastasis (n=1 each)
• Anemia: 54.8%
• Neutropenia: 67.2%
• Fatigue: 65.5%
• Thrombocytopenia:
• Nausea: 61.4%
78.6%
Discontinued: 31.6% • Headache: 42.6%
IFN + LDAC: n=553 Grade 3–4:
Discontinued due to AEs: 6.0% Grade 3–4:

• Neutropenia: 25.0%
• Fatigue: 24.4%
• Thrombocytopenia:
• Depression: 12.8%
16.5%
• Musculoskeletal pain: 8.3%
• ALT or AST increased:
6.8%
IRIS study follow-up (median: 10.9 years) in newly diagnosed CP CML [33]
Imatinib-related SAEs: n=89

• Abdominal pain: 0.7% • CML: n=50

Imatinib 400 mg QD: Discontinued: 49.2%
• Anemia: 0.5% N/A • Secondary malignancy: n=11
n=553 Discontinued due to AEs: 6.9%
• Congestive cardiac failure: 0.5% • Cardiac disorder or CV disease: n=7
• GI hemorrhage: 0.5% • Infectious disease: n=5
• Vomiting: 0.5% • Other: n=16
IFN + LDAC: n=553,
Discontinued: 51.8%
with n=363 in crossover N/A N/A N/A
Discontinued due to AEs: 9.4%
to imatinib group

Dasatinib
Phase 3 DASISION study in newly diagnosed CP CML [34]
TRAEs, all grades:
TRAEs, all grades:
• Anemia: 90%
• Fluid retention: 19% • Thrombocytopenia:
• Diarrhea: 17% 70%
Dasatinib 100 mg QD:
Discontinued: 15.5% • Headache: 12% • Neutropenia: 65%
n=259 (median 14.0
Discontinued due to AEs: 5.0% TRAEs, grade 3–4: TRAEs, grade 3–4:
months)

• Fluid retention: 1% • Neutropenia: 21%

• Diarrhea: <1% • Thrombocytopenia:
• Fatigue: <1% 19%
• Anemia: 10% Dasatinib: n=4
TRAEs, all grades: TRAEs, all grades: Imatinib: n=1

• Fluid retention: 42% • Anemia: 84%

• Nausea: 20% • Thrombocytopenia:
• Diarrhea: 17% 62%
Imatinib 400 mg QD:
Discontinued: 18.6% • Muscle inflammation: 17% • Neutropenia: 58%
n=260 (median 14.3
Discontinued due to AEs: 4.3% • Rash: 17% TRAEs, grade 3–4:
months)
TRAEs, grade 3–4:
• Neutropenia: 20%
• Fluid retention: 1% • Thrombocytopenia:
• Diarrhea: 1% 10%
• Rash: 1% • Anemia: 7%
Final 5-year analysis of DASISION study in newly diagnosed CP CML [35]
Grade 3–4:
n=26
Discontinued: 39%
Dasatinib 100 mg QD: Discontinued due to intolerance: • Neutropenia: 29%
N/A • CV disease: n=2
n=259 16% • Thrombocytopenia:
• Disease progression: n=9
Discontinued due to AEs: 5% 22%
• Infection: n=11
• Anemia: 13%
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J.H. Lipton et al.
Table 1 (continued )
Study Discontinuations and dose
interruptions or reductions
Imatinib 400 mg QD: Discontinued: 37%
n=260 Discontinued due to intolerance:
7%
Discontinued due to AEs: 2%
Phase 3 CA180-034 study (median 8 months) of dasatinib in imatinib-resistant and -intolerant CP CML [36]
• 100 mg QD: n=167 Discontinued: 16–23%
• 50 mg BID: n=168 Discontinued due to treatment-
• 140 mg QD: n=167 related toxicity: 4–11%
• 70 mg BID: n=168 Discontinued due to AEs
unrelated to treatment: <1 to
2%
Dose interruptions: 51–68%
Dose reductions: 30–55%
Final 7-year analysis of CA180-034 in imatinib-resistant and -intolerant CP CML [37]
• 100 mg QD: n=167 Discontinued due to AE
• 50 mg BID: n=168 unrelated to study drug: 2–6%
• 140 mg QD: n=167 Discontinued due to TRAEs:
• 70 mg BID: n=168 24–31%
Nilotinib
Phase 3 ENESTnd study (median 14 months) in newly diagnosed CML [38]
Nilotinib 300 mg BID: Discontinued due to AEs: 5%
n=282 Dose reductions / interruptions:
59%
Nilotinib 400 mg BID: Discontinued due to AEs: 9%
n=281 Dose reductions / interruptions:
66%
Blood Reviews xxx (xxxx) xxx
Most common non-hematologic AEs Most common Deaths
hematologic AEs
• Other malignancy, septic shock; cardiac
failure, multiorgan failure; whole-body
swelling: n=1 each
N/A Grade 3–4: n=26
• Neutropenia: 24% • CV disease: n=1
• Thrombocytopenia: • Disease progression: n=17
14% • Infection: n=1
• Anemia: 9% • Stem-cell transplantation complications
and unknown: n=2 each
• Severe chest pain, clinical deterioration;
decrease in performance status; fatal
bleeding: n=1 each
TRAEs, all grades: TRAEs, all grades: n=21
CML disease: n=6
• Headache: 19–30% • Anemia: 89–93% Infection: n=4
• Fluid retention: 21–28% • Neutropenia: 63–75% CV disease: n=1
• Nausea: 15–25% • Thrombocytopenia: Bleeding: n=1
TRAEs, grade 3–4: 60–75% Study drug toxicity: n=1
TRAEs, grade 3–4: Other: n=5
• Fluid retention: 1–4% Not reported: n=2
• Diarrhea: 2–4% • Neutropenia: 33–44% Unknown: n=1
• Dyspnea: 1–5% • Thrombocytopenia:
• Fatigue: 0–3% 22–40%
• Headache: 0–3% • Leukocytopenia:
16–25%
Cumulative rates of all grade AESI for N/A n=184
100 mg QD vs other treatment arms:
• Hemorrhage: 26% vs 28%
• Pleural effusion: 27% vs 36%
• Diarrhea: 42% vs 47%
• Nausea/vomiting: 27% vs 43%
• Fatigue: 37% vs 34%
• Myalgias/arthralgias: 38% vs 33%
• Rash: 33% vs 36%
Cumulative rate of grade ≥3 AESIs for
100 mg QD vs other treatment arms:
• Hemorrhage: 3% vs 4%
• Pleural effusion: 5% vs 9%
• Diarrhea: 4% vs 6%
• Nausea/vomiting: 1% vs 2%
• Fatigue: 4% vs 3%
• Myalgias/arthralgias: 2% vs 3%
• Rash: 2% vs 2%
All grades: All grades: n=3
• Increased ALT: 66% • Thrombocytopenia: • Small intestine obstruction: n=1
• Increased bilirubin: 53% 48% • Suicide: n=1
• Increased AST: 40% • Neutropenia: 43% • Post bone marrow transplant: n=1
Grade 3–4: • Anemia: 38%
Grade 3–4:
• Increased glucose: 6%
• Increased lipase: 6% • Neutropenia: 12%
• Decreased phosphate: 5% • Thrombocytopenia:
10%
• Anemia: 3%
All grades: All grades: n=2
• Increased ALT: 73% • Thrombocytopenia: • Disease progression: n=1
• Increased bilirubin: 62% 49% • Gastric cancer: n=1
• Increased AST: 48% • Neutropenia: 38%
Grade 3–4: • Anemia: 38%
Grade 3–4:
• Increased ALT: 9%
• Increased bilirubin: 8% • Thrombocytopenia:
• Increased lipase: 6% 12%
• Neutropenia: 10%
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Table 1 (continued )
Study Discontinuations and dose Most common non-hematologic AEs Most common Deaths
interruptions or reductions hematologic AEs

• Anemia: 3%
Imatinib 400 mg QD: Discontinued due to AEs: 7% All grades: All grades: n=4
n=283 Dose reductions / interruptions:
52% • Decreased phosphate: 45% • Neutropenia: 68% • Disease progression: n=4
• Increased alkaline phosphatase: • Thrombocytopenia:
33% 56%
• Nausea: 31% • Anemia: 47%
Grade 3–4: Grade 3–4:

• Decreased phosphate: 8% • Neutropenia: 20%

• Increased lipase: 3% • Thrombocytopenia:
• Increased ALT: 2% 9%
• Anemia: 5%
ENESTnd study (≥10 years of follow-up) in newly diagnosed CML [39,40]
Nilotinib 300 mg BID: Discontinued due to AEs: 24.0% All grades: All grades: n=84
n=282 Discontinued due to SAEs:
40.1% • Rash: 39.4% • Thrombocytopenia: • Nilotinib 300 mg: n=32
• Headache: 33.7% 19.4% • Nilotinib 400 mg: n=23
• Nasopharyngitis: 29.0% • Neutropenia: 16.1% • Imatinib: n=29
Grade 3–4: • Anemia: 14.0%
Grade 3–4: Most common reasons overall:
• Headache: 3.2%
• Nausea: 2.5% • Neutropenia: 11.8% • CML: n=26
• Back pain: 1.8% • Thrombocytopenia: • Infections / infestations: n=16
• Hypertension: 1.8% 10.0%
• Anemia: 5.7%
Nilotinib 400 mg BID: Discontinued due to AEs: 35.4% All grades: All grades:
n=281 Discontinued due to SAEs:
45.8% • Rash: 45.1% • Thrombocytopenia:
• Headache: 37.9% 21.3%
• Nausea: 31.8% • Anemia: 17.3%
Grade 3–4: • Neutropenia: 10.8%
Grade 3–4:
• Hypertension: 4.7%
• Rash: 2.5% • Thrombocytopenia:
• Headache: 2.5% 11.9%
• Back pain: 2.5% • Neutropenia: 9.0%
• Diarrhea: 2.5% • Anemia: 6.1%
Imatinib 400 mg QD: Discontinued due to AEs: 20.0% All grades: All grades:
n=283 Discontinued due to SAEs:
34.6% • Diarrhea: 48.2% • Anemia: 23.9%
• Nausea: 42.1% • Neutropenia: 21.1%
• Muscle spasms: 35.0% • Thrombocytopenia:
Grade 3–4: 18.9%
Grade 3–4:
• Diarrhea: 3.6%
• Rash: 1.8% • Neutropenia: 15.0%
• Nausea: 1.4% • Thrombocytopenia:
• Back pain: 1.4% 8.9%
• Fatigue: 1.4% • Anemia: 7.1%
Phase 3b ENEST1st study (≥24 months of follow-up) in newly diagnosed CP CML [63]
Nilotinib 300 mg BID: Discontinued: 19.1% All grades: All grades: n=13
N=1089 Discontinued due to AEs: 10.7%
Dose changes / interruptions: • Rash: 21.4% • Anemia: 71.1%
45.2% • Pruritus: 16.5% • Thrombocytopenia:
Dose changes / interruptions • Headache: 15.2% 40.2%
due to AEs/laboratory Grade 3–4: • Lymphopenia: 37.1%
abnormalities: 36.7% Grade 3–4:
• Headache: 0.7%
• Abdominal pain: 0.7% • Thrombocytopenia:
• Fatigue: 0.6% 6.0%
• Neutropenia: 4.8%
• Lymphopenia: 3.7%
Phase 2 study (median ≥6 months) in imatinib-resistant and -intolerant CP CML [41]
Nilotinib 400 mg BID: Discontinued due to AEs: 15% TRAEs, all grades: Grade 3–4: n=4
N=280
• Rash: 28% • Neutropenia: 29% • Myocardial infarction: n=1
• Nausea: 24% • Thrombocytopenia: • Coronary artery disease: n=1
• Pruritus: 24% 29% • Sepsis: n=2
• Headache: 19%
• Fatigue: 19%
TRAEs, grade 3–4:

• Rash: 3%
• Headache: 2%
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J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 1 (continued )
Study Discontinuations and dose Most common non-hematologic AEs Most common Deaths
interruptions or reductions hematologic AEs

• Diarrhea: 2%
Phase 2 study (48 months of follow-up) in imatinib-resistant and -intolerant CP CML [42]
Nilotinib 400 mg BID: Discontinued: 69.8% TRAEs, all grades: Grade 3–4: n=9
N=280 Discontinued due to AEs: 20.6%
Discontinued due to TRAEs: • Rash: 30.8% • Neutropenia: <1%
16.5% • Pruritis: 26.2% • Thrombocytopenia:
• Nausea: 24.6% <1%
TRAEs, grade 3–4:

• Rash: 1.9%
• Diarrhea: 1.9%
• Headache: 1.6%

Bosutinib
Phase 3 BFORE study (minimum 12 months of follow-up) in newly diagnosed CP CML [43]
Bosutinib 400 mg QD: Discontinued: 22.0% All grades: All grades: n=1
n=268 Discontinued due to treatment-
related toxicity: 12.7% • Diarrhea: 70.1% • Thrombocytopenia: • Spindle cell lung carcinoma: n=1
Discontinued due to AEs: 14.2% • Nausea: 35.1% 35.1%
Dose interruptions / reductions • Increased ALT: 30.6% • Anemia: 18.7%
due to AEs: 56.3% Grade ≥3: • Neutropenia: 11.2%
Grade ≥3:
• Increased ALT: 19.0%
• Increased AST: 9.7% • Thrombocytopenia:
• Increased lipase: 9.7% 13.8%
• Neutropenia: 6.7%
• Anemia: 3.4%
Imatinib 400 mg QD: Discontinued: 26.8% All grades: All grades: n=6
n=268 Discontinued due to treatment-
related toxicity: 8.7% • Nausea: 38.5% • Neutropenia: 20.8% • Disease progression: n=3
Discontinued due to AEs: 10.6% • Diarrhea: 33.6% • Thrombocytopenia: • CV failure / cerebrovascular accident:
Dose interruptions / reductions • Muscle spasms: 26.4% 19.6% n=1
due to AEs: 35.8% Grade ≥3: • Anemia: 18.9% • Pneumonia: n=1
Grade ≥3: • Septicemia: n=1
• Increased lipase: 5.3%
• Increased AST: 1.9% • Neutropenia: 12.1%
• Increased ALT: 1.5% • Thrombocytopenia:
5.7%
• Anemia: 4.5%
Final 5-year analysis of BFORE in newly diagnosed CP CML [51]
Bosutinib 400 mg QD: Discontinued due to AEs: 25.0% All grades: All grades: N/A
n=268
• Diarrhea: 75.0% • Thrombocytopenia:
• Nausea: 37.3% 35.8%
• Increased ALT: 33.6% Grade 3–4:
Grade 3–4:
• Thrombocytopenia:
• Increased ALT: 20.9% 14.2%
• Increased AST: 10.4% • Neutropenia: 7.5%
• Increased lipase: 13.4%
Imatinib 400 mg QD: Discontinued due to AEs: 12.5% All grades: Grade 3–4:
n=268
• Nausea: 42.3% • Neutropenia: 13.6%
• Diarrhea: 40.4% • Thrombocytopenia:
• Muscle spasms: 30.6% 6.0%
Grade 3–4: • Anemia: 5.7%

• Increased lipase: 5.7%

Phase 3 BELA study (≥12 months of follow-up) in newly diagnosed CP CML [50]
Bosutinib 500 mg QD: Discontinued due to AEs: All grades: All grades: n=4
n=250 19%
Dose interruptions and • Increased ALT: 69% • Anemia: 81% • CML: n=3
reductions due to AEs, 61% and • Diarrhea: 68% • Thrombocytopenia: • Mesenteric embolism / intestinal
39%, respectively • Increased AST: 56% 66% necrosis: n=1
Grade 3–4: • Neutropenia: 28%
Grade 3–4:
• Increased ALT: 22%
• Diarrhea: 11% • Thrombocytopenia:
• Increased AST: 11% 14%
• Neutropenia: 11%
Imatinib 400 mg QD: Discontinued due to AEs: 6% All grades: All grades: n=10
n=252 Dose interruptions and
reductions due to AEs, 42% and • Hypophosphatemia: 63% • Anemia: 84% • CML: n=8
18%, respectively • Edema: 38% • CV disease: n=1
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Table 1 (continued )
Study Discontinuations and dose Most common non-hematologic AEs Most common Deaths
interruptions or reductions hematologic AEs

• Nausea: 35% • Thrombocytopenia: • Lung embolism: n=1

Grade 3–4: 63%
• Neutropenia: 54%
• Hypophosphatemia: 15% Grade 3–4:
• Increased lipase: 5%
• Increased ALT: 3% • Neutropenia: 24%
• Increased AST: 3% • Thrombocytopenia:
14%
• Anemia: 7%
Phase 3 BELA study (≥30 months of follow-up) in newly diagnosed CML [49]
Bosutinib 500 mg QD: Discontinued due to AEs: 25% All grades: All grades: n=4
n=248 Dose interruptions and
reductions due to AEs, 67% and • Diarrhea: 70% • Thrombocytopenia: • Mesenteric embolism / intestinal
42%, respectively • Vomiting: 33% 28% necrosis: n=1
• Increased ALT: 33% • Anemia: 25% • Congestive heart failure: n=1
• Nausea: 32% • Neutropenia: 13% • Gastric carcinoma with lung metastases:
Grade 3–4: Grade 3–4 AEs: n=1
• Respiratory failure: n=1
• Increased ALT: 19% • Thrombocytopenia:
• Diarrhea: 12% 13%
• Increased lipase: 9% • Anemia: 9%
• Neutropenia: 8%
Imatinib 400 mg QD: Discontinued due to AEs: 8% All grades: All grades: n=3
n=251 Dose interruptions and
reductions due to AEs, 46% and • Nausea: 36% • Neutropenia: 30% • CV disease: n=1
21%, respectively • Diarrhea: 26% • Thrombocytopenia: • Lung embolism: n=1
• Muscle cramps: 22% 28% • Pneumonia: n=1
Grade 3–4: • Anemia: 23%
Grade 3–4:
• Hypophosphatemia: 10%
• Increased lipase: 6% • Neutropenia: 16%
• Increased creatine phosphokinase:• Thrombocytopenia:
5% 14%
• Anemia: 6%
• Leukopenia: 6%
Phase 4 BYOND study (~85% with ≥2 years of follow-up) in CML with resistance/intolerance to prior TKIs [48]
Bosutinib 500 mg QD: Discontinued due to AEs: 25.8% All grades: All grades: n=12
N=163 Dose interruptions and
reductions due to AEs, 75.5% • Diarrhea: 87.7% • Thrombocytopenia: • Acute kidney injury
and 77.3%, respectively • Nausea: 39.9% 11.0% • Respiratory insufficiency due to
• Vomiting: 32.5% Grade 3–4: aspiration
Grade 3–4: • Cerebral tumor
• Thrombocytopenia: • Chronic bridenileus (ileus from
• Diarrhea: 16.0% 8.0% adhesions)
• Increased ALT: 14.1% • Hemorrhagic shock
• Increased lipase: 6.7% • Lymphoma
• Metastatic lung cancer
• Multiorgan failure
• Prostate adenocarcinoma
• Sepsis
• CML
• Unknown
Phase 1/2 study (median 24.2 months of follow-up) in imatinib-resistant and -intolerant CP CML [47]
Bosutinib 500 mg QD: Discontinued due to AEs: 21% All grades: All grades: N/A
N=288 Dose interruptions and
reductions due to AEs, 66% and • Diarrhea: 84% • Anemia: 90%
47%, respectively • Nausea: 44% • Thrombocytopenia:
• Rash: 44% 66%
Grade 3–4: • Neutropenia: 40%
Grade 3–4:
• Diarrhea: 9%
• Rash: 9% • Thrombocytopenia:
• Vomiting: 3% 24%
• Neutropenia: 18%
• Anemia: 13%
Final 5-year analysis of Phase 1/2 study in imatinib-resistant and -intolerant CP CML [46]
Bosutinib 500 mg QD: Discontinued due to AEs: 24% All grades: All grades: n=45
N=288 Dose interruptions and
reductions due to AEs, 74% and • Diarrhea: 85.6% • Thrombocytopenia:
50% respectively: • Nausea: 46.1% 41.5%
• Vomiting: 37.3% • Anemia: 29.2%
Grade 3–4: • Neutropenia: 16.2%
Grade 3–4:
• Diarrhea: 9.5%
• Rash: 9.2%
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Table 1 (continued )
Study Discontinuations and dose Most common non-hematologic AEs Most common Deaths
interruptions or reductions hematologic AEs

• Increased ALT: 8.5% • Thrombocytopenia:

25.4%
• Anemia: 13.4%
• Neutropenia: 9.9%
Long-term extension study (≥8 years) in CML or ALL with ≥1 prior TKI [44]
Bosutinib: Discontinued due to AEs: All grades, across all groups: All grades, across all CP2L: n=55
CP2L: n=284 CP2L: 26% groups: CP3L: n=29
CP3L: n=119 CP3L: 30% • Diarrhea: 82% ADV: n=98
ADV: n=167 ADV: 18% • Nausea: 47% • Thrombocytopenia:
• Vomiting: 40% 41%
• Anemia: 32%
• Neutropenia: 19%
Final 10-year results of Phase 1/2 study and extension study in CP CML [61]
Bosutinib 500 mg QD: Discontinued due to AEs: 28% All grades: All grades: N/A
N=284
• Diarrhea: 86% • Thrombocytopenia:
• Nausea: 46% 42%

Ponatinib
Phase 2 PACE study (median 15 months) in CML or ALL with prior TKI [52]
Ponatinib 45 mg QD: Discontinued due to AEs: 12% All grades: All grades: n=18
N=267 Dose interruptions and
reductions due to AEs, 67% and • Rash: 34% • Thrombocytopenia:
55%, respectively • Dry skin: 32% 37%
• Abdominal pain: 22% • Neutropenia: 19%
• Anemia: 13%
Final 5-year analysis of PACE in CML or ALL with prior TKI [53]
Ponatinib 45 mg QD: Discontinued due to AEs: 18% All grades: All grades: n=56
N=267 Dose interruptions and Most common reasons:
reductions due to AEs, • Abdominal pain: 43% • Thrombocytopenia:
respectively: 71% and 68% • Rash: 42% 44% • Disease progression: n=26
• Constipation: 38% • Anemia: 25% • Sepsis/septic shock: n=5
• Headache: 38% • Neutropenia: 25% • Cardiac arrest: n=3
Grade 3–4: Grade 3–4:

• Hypertension: 12% • Thrombocytopenia:

• Increased lipase: 12% 36%
• Abdominal pain: 9% • Neutropenia: 22%
• Anemia: 16%
Phase 3 EPIC study (median 5.1 months) in newly diagnosed CP CML [54]
Ponatinib 45 mg QD: Discontinued due to AEs: 7% Grade 1–2: Grade 1–2: n=1
n=155 Dose reductions: 75%
• Abdominal pain: 33% • Thrombocytopenia: • Pneumonia: n=1
• Headache: 32% 12%
• Rash: 31% • Neutropenia: 2%
Grade 3 AEs: Grade 3 AEs:

• Increased lipase: 12% • Thrombocytopenia:

• Rash: 6% 6%
• Hypertension: 5% • Neutropenia: 3%
Imatinib 400 mg QD: Discontinued due to AEs: 1% Grade 1–2: Grade 1–2: n=2
n=152 Dose reductions: 7%
• Nausea: 34% • Thrombocytopenia: • Pneumonia: n=1
• Muscle spasms: 33% 7% • Paraspinal abscess: n=1
• Diarrhea: 26% • Neutropenia: 3%
Grade 3: Grade 3 AEs:

• Increased lipase: 2% • Thrombocytopenia:

• All others ≤1% 5%
• Neutropenia: 4%

Asciminib
Phase 1 dose escalation study (median 14 months of follow-up) in CML with resistance/intolerance to prior TKIs [55]
Asciminib: N=150 N/A All grades: All grades: n=1

• Fatigue: 29.3% • Thrombocytopenia:

• Headache: 28.0% 22.0%
• Increased lipase: 26.7% • Anemia: 11.3%
Grade 3–4: • Neutropenia: 10.7%
Grade 3–4:
• Increased lipase: 10.0%
• Hypertension: 9.3% • Thrombocytopenia:
• Increased ALT: 2.7% 9.3%
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Table 1 (continued )
Study Discontinuations and dose Most common non-hematologic AEs Most common Deaths
interruptions or reductions hematologic AEs

• Hypertriglyceridemia: 2.7% • Anemia: 7.3%

Phase 3 ASCEMBL study (median 14.9 months of follow-up) in CP CML with resistance/intolerance to prior TKIs [56]
Asciminib 40 mg BID: Discontinued due to AEs: 5.8%
n=157 Dose interruptions / reductions
due to AEs: 37.8%
Bosutinib 500 mg QD: Discontinued due to AEs: 21.1%
n=76 Dose interruptions / reductions
due to AEs: 60.5%
Phase 3 RERISE study in newly diagnosed CP CML [68]
Radotinib 300 mg BID: Discontinued before 12 months:
n=79 13%
Discontinued before 12 months
due to AEs: 0%
Dose interruptions / reductions: • AST elevation: 67%
67%
• Increased amylase: 2.7% • Neutropenia: 7.3%
• Vomiting: 2.7%
Grade ≥3: Grade ≥3: n=2
• Diarrhea: 0% • Thrombocytopenia: • Ischemic stroke: n=1
• Increased ALT: 0.6% 17.3% • Arterial embolism: n=1
• Neutropenia: 14.7%
Grade ≥3: Grade ≥3: n=1
• Diarrhea: 10.5% • Thrombocytopenia: • Septic shock: n=1
• Increased ALT: 14.5% 6.6%
• Neutropenia: 11.8%
All grades: All grades: n=0
• ALT elevation: 78% • Thrombocytopenia:
• Hyperbilirubinemia: 77% 67%
• Neutropenia: 41%
Grade 3–4: Grade 3–4:

• Hyperbilirubinemia: 27% • Neutropenia: 19%

Radotinib 400 mg BID: Discontinued before 12 months:
n=81 28%
Discontinued before 12 months
due to AEs: 7%
Dose interruptions / reductions:
73%
• ALT elevation: 20% • Thrombocytopenia:
• AST elevation: 6% 16%
All grades: All grades: n=3
• ALT elevation: 81% • Thrombocytopenia: • Unknown: n=1
• Hyperbilirubinemia: 80% 53% • Disease progression: n=2
• AST elevation: 77% • Neutropenia: 36%
Grade 3–4: Grade 3–4:

• Hyperbilirubinemia: 42% • Neutropenia: 24%

• ALT elevation: 26% • Thrombocytopenia:
• AST elevation: 6% 14%
Imatinib 400 mg QD: Discontinued before 12 months: All grades: All grades: n=1
n=81 19%
Discontinued before 12 months • Hyperglycemia: 56% • Thrombocytopenia: • Pneumonia: n=1
due to AEs: 4% • Hypophosphatemia: 43% 68%
Dose interruptions / reductions: • Lipase elevation: 33% • Neutropenia: 63%
52% Grade 3–4: Grade 3–4:

• Hypophosphatemia: 11% • Neutropenia: 30%

• Hyperglycemia: 4% • Thrombocytopenia:
20%
≥48-month follow-up of Phase 3 RERISE study in newly diagnosed CP CML [69]
Radotinib 300 mg BID: Discontinued: 47% All grades: All grades: n=0
n=79 Dose reductions: 68%
• Rash: 38% • Thrombocytopenia:
• Nausea: 27% 68%
• Headache: 24% • Leucopenia: 52%
• Neutropenia: 42%
Grade 3–4:

• Neutropenia: 19%
• Thrombocytopenia:
16%
• Leucopenia: 10%
Radotinib 400 mg BID: Discontinued: 51% All grades: All grades: n=0
n=81 Dose reductions: 84%
• Headache: 38% • Thrombocytopenia:
• Rash: 35% 58%
• Pruritis: 33% • Leucopenia: 40%
• Neutropenia: 37%
Grade 3–4:

• Neutropenia: 23%
• Thrombocytopenia:
15%
• Leucopenia: 14%
Imatinib 400 mg QD: Discontinued: 56% All grades: All grades: n=1
n=81 Dose reductions: 23%
• Nausea: 31% • Leucopenia: 74% • Acute respiratory failure: n=1
• Myalgia: 31% • Thrombocytopenia:
• Facial edema: 27% 72%
(continued on next page)

9
J.H. Lipton et al.
Table 1 (continued )
Study Discontinuations and dose Most common non-hematologic AEs
interruptions or reductions
AE adverse event, AESI adverse event of special interest, ALL acute lymphoblastic leukemia, ALT alanine aminotransferase, AP advanced phase, AST aspartate amino
transferase, BID twice daily, BP blast phase, CML chronic myeloid leukemia, CP chronic phase, CP2/3L xxxx second- and third-line treatment; CV cardiovascular; GI
gastrointestinal; IFN interferon; LDAC low-dose cytarabine; N/A not available, QD once daily, Ph Philadelphia chromosome; SAE serious adverse event, TKI tyrosine
kinase inhibitor, TRAE treatment-related adverse events
ADV: AP/BP CML or Ph+ ALL and prior imatinib (other prior TKIs permitted); CP2L: CP CML and no prior TKIs other than imatinib; CP3L: CP CML and prior imatinib +
dasatinib and/or nilotinib
intolerance within trials is available in the key TKI randomized clinical
trials. Health-related quality of life (HRQoL) was maintained or
improved from baseline in patients with CP CML following bosutinib
treatment in the phase 1/2, BFORE, and BYOND studies [48,71–75].
Interestingly, selected dimensions of HRQoL appeared to correlate with
molecular response to TKI treatment, although causality cannot be
established in these analyses [72]. Analyses of dasatinib, imatinib, and
nilotinib have also shown improvements in or maintenance of HRQoL
during treatment with these TKIs in patients with CML [76–81].
In the long-term follow-up of IRIS, 65.6% of patients receiving
interferon plus low-dose cytarabine crossed over to imatinib due to
disease progression or lack/loss of response (31.5%), AEs (26.2%), or
unwillingness to continue treatment (8.0%) [33]. In the DASISION 5-
year analysis, the three most common subsequent TKI treatments
following initial treatment discontinuation were imatinib (19%), nilo­
tinib (9%), and dasatinib (3%) in the dasatinib group, and dasatinib
(16%), imatinib (11%), and nilotinib (9%) in the imatinib group [35]. In
the CA180-034 7-year analysis, 54.8% and 50.5% of patients receiving
dasatinib 50 mg and 70 mg BID, respectively, switched to QD dosing
[37]. In ASCEMBL, 22 out of 24 patients who discontinued bosutinib due
to lack of efficacy switched to asciminib [56]. Overall, in the pivotal
randomized front-line studies of second-generation TKIs versus imati­
nib, approximately 40% of patients changed therapy for efficacy or
safety considerations. Thus, treatment changes are common for patients
with CML, and these are frequently prompted by AEs. Dose modifica­
tions to manage toxicity are also common, although the true frequency is
difficult to ascertain from study reports.
In most studies, cross-intolerance was generally defined as discon­
tinuation due to the same AE that led to prior TKI discontinuation [45];
however, a select few trials stipulated this as recurrence of grade ≥3 AEs
[41,46,47,82,83]. Cross-intolerance due to liver toxicity and gastroin­
testinal intolerance occurred in two patients with imatinib-intolerant CP
CML treated with nilotinib [41]. In a phase 1/2 study, 27% and 6% of
imatinib-intolerant patients, respectively, experienced the same grade
3–4 AE or discontinued bosutinib due to the same grade 3–4 AE [47].
Relevant AEs included myelosuppression-related AEs and rash [47]. In
the phase 1/2 study 5-year analysis, 14 patients had cross-intolerance to
bosutinib following imatinib, with AEs of thrombocytopenia, neu­
tropenia, diarrhea, vomiting, fatigue, and rash [46]. In an additional
long-term analysis of this study, cross-intolerance to bosutinib occurred
in 20% of imatinib-intolerant and 24% of dasatinib-intolerant patients
[45]. The most common AEs were thrombocytopenia and bone marrow
failure in imatinib-intolerant patients, and thrombocytopenia, pleural
effusion, and bone marrow failure in dasatinib-intolerant patients [45].
Pleural effusions in patients who previously suffered pleural effusions
with dasatinib may occur in patients subsequently treated with bosuti­
nib [84–87]. An analysis of 28 imatinib-intolerant patients (n=24 CML;
n=4 ALL) reported cross-intolerance to dasatinib in four patients who
had hematologic AEs (thrombocytopenia, anemia, and neutropenia) and
10
Blood Reviews xxx (xxxx) xxx
Most common Deaths
hematologic AEs
• Neutropenia: 64%
Grade 3–4:
• Neutropenia: 32%
• Thrombocytopenia:
20%
• Leucopenia: 11%
one patient who had a non-hematologic AE (hepatotoxicity) [83]. In an
analysis of cross-intolerance in imatinib-intolerant patients, no patients
discontinued nilotinib due to the same non-hematologic AE [88]. Of
hematologic AEs, 23% of patients discontinued nilotinib, all due to
grade 3–4 thrombocytopenia [88]. In a retrospective pooled analysis in
imatinib-intolerant patients, 17% had cross-intolerance to dasatinib: 2%
and 19% discontinued treatment due to non-hematologic and hemato­
logic AEs, respectively [82].
Overall, cross-intolerance was observed in no more than one-third of
patients across clinical trials. This suggests there are sufficient differ­
ences in TKI safety profiles to allow for personalized treatment selection
or switching based on an individual patient’s previous response to
treatment, medical history, comorbidities, and concomitant medica­
tions. Cross-intolerance was generally higher with hematologic
(particularly thrombocytopenia) versus non-hematologic AEs, given
that myelosuppression is mostly a class-wide effect of TKIs, whereas
non-hematologic toxicities may result from off-target effects [89]. In
most instances and based on known incidences of TEAEs, it is usually
recommended to switch to a TKI that is less likely to cause the same AE.
However, where a preferred TKI is associated with the same AE that led
to discontinuation, an attempt is warranted with proper monitoring and
management of the AEs. Based on the available published experience, in
most instances, patients seem to tolerate this subsequent TKI reasonably
well.
2.2. Standard practice
Several recent long-term registries and observational analyses (≥12
months) of TKIs in the off-protocol setting have been reported (Table 3).
Several analyses have reported on standard-practice imatinib, dasatinib,
and nilotinib [90–94]. In the observational SIMPLICITY study (N=1121;
CP CML) with ≥3 years’ follow-up, treatment discontinuations and in­
terruptions were common, with intolerance the most common reason for
discontinuation and/or TKI switching [90,91]. In the EUTOS registry
(N=2152; first-line CML), treatment switches were common and
occurred in 28%, 22%, and 20% of imatinib-, dasatinib-, and nilotinib-
treated patients, respectively, most commonly due to treatment failure
and AEs [92]. Similarly, dose reductions (25–31%) or interruptions
(9–14%) were common with imatinib, dasatinib, or nilotinib in a Dutch
nationwide registry (first-line CML); the most common reason for TKI
discontinuation was intolerance [93]. A Swedish cohort study reported
an increased risk for arterial and venous vascular events with imatinib,
dasatinib, or nilotinib versus a control population [94]. Two observa­
tional studies (US and France; CP CML) reported approximately one-
third of patients discontinued TKIs due to intolerance [95,96]. In a
real-world setting in Italy (CP CML), approximately one-third of patients
receiving dasatinib and nilotinib had permanent dose reductions [97].
Around one-third permanently discontinued dasatinib due to AEs, most
commonly due to pleural effusion. Approximately half discontinued
J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 2 Table 2 (continued )

Long-term follow-up of AEs of special interest Study Cardiac and Pulmonary AEs Other AEs of special
Study Cardiac and Pulmonary AEs Other AEs of special vascular AEs interest
vascular AEs interest
QT prolongation: effusion,
Imatinib 6.8% pericardial
IRIS study follow-up (median: 10.9 years) [33] effusion, and
• Imatinib Cardiac SAEs: 7.1% N/A Most common pulmonary
400 mg of patients neoplasm-related SAEs: edema: <4%
QD: receiving imatinib Nilotinib All CV events: Fluid retention: Hepatotoxicity: 53.1%
n=553 Most common • Prostate cancer: 400 mg 23.5% 27.1% Blood glucose
• IFN + cardiac SAEs: 2.0% BID: Ischemic heart Edema and other increased: 13.0%
LDAC: • Squamous cell n=281 disease: 13.0% fluid retention:
n=553, • Coronary carcinoma: 1.1% PAOD: 7.2% 26.4%
with ischemia: 1.8% • Basal cell carcinoma: Ischemic Severe fluid
n=363 in • Myocardial 1.1% cerebrovascular retention: 1.8%
crossover infarction: 1.5% disease: 7.6% Severe fluid
to • Atrial fibrillation Cardiac failure: retention,
imatinib and cardiac 2.5% including pleural
arrest: 0.9% QT prolongation: effusion,
7.9% pericardial
effusion, and
Dasatinib pulmonary
Final 5-year analysis of DASISION study [35] edema: <4%
Dasatinib Arterial ischemic Drug-related N/A Imatinib All CV events: 3.6% Fluid retention: Hepatotoxicity: 17.5%
100 mg events: 5% pleural effusion: 400 mg Ischemic heart 59.6% Blood glucose
QD: CV ischemic events: 28% QD: disease: 2.9% Edema and other increased: 2.9%
n=259 4% Pulmonary n=283 PAOD: 0% fluid retention:
TIA: 1% hypertension: Ischemic 59.6%
PAD: 0% 5% cerebrovascular Severe fluid
Imatinib Arterial ischemic Drug-related N/A disease: 0.4% retention: 2.5%
400 mg events: 2% pleural effusion: Cardiac failure: Severe fluid
QD: CV ischemic events: 0.8% 1.4% retention,
n=260 2% Pulmonary QT prolongation: including pleural
TIA: 0% hypertension: 3.9% effusion,
PAD: 1% 0.4% pericardial
Final 7-year analysis of CA180-034 [37] effusion, and
Dasatinib Dasatinib 100 mg Dasatinib 100 Cumulative incidence pulmonary
100 mg QD and other mg QD and other rate, dasatinib 100 mg edema: <4%
QD: dasatinib doses, dasatinib doses, QD and other dasatinib Phase 3b ENEST1st study (≥24 months of follow-up) [63]
n=167 respectively: respectively: doses, respectively: Nilotinib Ischemic Pleural effusion: Pancreatitis: 1.0%
Dasatinib 300 mg cardiovascular 0.6% Hepatotoxicity: 1.4%
50 mg • Overall • Pleural • Rash: 33% and 36% BID: events: 6.0% Fluid retention: 11.8%
BID: peripheral effusion: 28% • Myalgias/ N=1089 Peripheral artery
n=168 vascular events: and 35% arthralgias: 38% and disease: 1.9%
Dasatinib 0% and 1% • Pulmonary 33% Ischemic heart
140 mg • Overall hypertension: • Fatigue: 37% and disease: 3.4%
QD: cerebrovascular 2% and 3% 34% Ischemic
n=167 events: 3% and • Pulmonary • Nausea/vomiting: cerebrovascular
Dasatinib 1% arterial 27% and 43% events: 0.8%
70 mg • Overall CV hypertension: • Diarrhea: 42% and Congestive heart
BID: ischemic events: <1% and 0% 47% failure: 0.3%
n=168 4% and 4% • Hemorrhage: 26% Arrhythmia: 0.6%
• Myocardial and 28% Supraventricular
infarction: 2% Dasatinib 100 mg QD arrhythmia: 0.1%
and 1% and other dasatinib
• Angina pectoris: doses, respectively:
1% and 2% Bosutinib
• CAD: 1% and • Infections: 67% and BFORE study (median: 55 months) [64]
<1% 65% Bosutinib Cardiac AEs: 9.7% N/A N/A
400 mg Vascular AEs: 7.5%
QD: CV events: 4.9%
Nilotinib n=268 Cerebrovascular
Phase 2 study (48 months of follow-up) [42] events: 0.7%
Nilotinib Increased QTcF 460 Pleural effusion: N/A Peripheral vascular
400 mg ms from baseline: 0% events: 2.2%
BID: n=3 Hypertension:
N=280 10.4%
ENESTnd study (≥10 years of follow-up) [39,40] Most common
Nilotinib All CV events: Fluid retention: Hepatotoxicity: 48.4% cardiac, vascular,
300 mg 16.5% 23.7% Blood glucose and hypertension
BID: Ischemic heart Edema and other increased: 12.5% TEAEs:
n=282 disease: 7.9% fluid retention:
PAOD: 6.5% 22.6% • Sinus
Ischemic Severe fluid bradycardia:
cerebrovascular retention: 2.2% 2.2%
disease: 4.7% Severe fluid • Angina pectoris:
Cardiac failure: retention, 3.0%
3.2% including pleural
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Table 2 (continued ) Table 2 (continued )

Study Cardiac and Pulmonary AEs Other AEs of special Study Cardiac and Pulmonary AEs Other AEs of special
vascular AEs interest vascular AEs interest

• Hypertension: vascular AEs: • Increased blood

9.7% creatine
Imatinib Cardiac AEs: 8.7% N/A N/A • Hypertension: phosphokinase: 8%
400 mg Vascular AEs: 3.4% 6%
QD: CV events: 0.4% • Hematoma: 2%
n=268 Cerebrovascular Imatinib Cardiac AEs: 6% Pleural Biochemical non-
events: 1.1% 400 mg Most common effusions: 1% hematologic laboratory
Peripheral vascular QD: cardiac AEs: AEs:
events: 2.3% n=252
Hypertension: • Palpitations: 2% • Increased ALT: 9%
10.9% • Pericardial • Increased AST: 10%
Most common effusion: 0% • Hypophosphatemia:
cardiac, vascular, Vascular AEs: 8% 20%
and hypertension Most common • Increased blood
TEAEs: vascular AEs: creatine
phosphokinase: 20%
• ECG QT • Hypertension:
prolongation: 4%
3.8% • Hematoma: 1%
• Peripheral
coldness: 1.1%
Ponatinib
• Hypertension:
Final 5-year analysis of PACE [53]
10.9%
Ponatinib • Arterial N/A SAEs reported in ≥5%
Final 5-year analysis of Phase 1/2 study [46]
45 mg QD: occlusive event: of CP CML patients:
Bosutinib Cardiac AEs: 13% Pleural effusion: Renal AEs: 13%
N=267 25%
500 mg Vascular AEs: 8% 11%
• CV event: 13% • Pancreatitis: 7%
QD: Hypertension: 9%
• Cerebrovascular • Atrial fibrillation:
N=288 Most common
events: 9% 6%
cardiac AEs:
• Peripheral • Pneumonia: 6%
vascular events: • Angina pectoris: 5%
• Pericardial
11%
effusion: 3%
• Congestive AE adverse event, ALL acute lymphoblastic leukemia, ALT alanine aminotrans­
cardiac failure, ferase, AP advanced phase, AST aspartate aminotransferase, BID twice daily, BP
atrial fibrillation,
blast phase, CAD coronary artery disease, CML chronic myeloid leukemia, CP
bradycardia, and
cardiac failure:
chronic phase, CP2/3L xxxx second- and third-line therapy, CV cardiovascular,
2% each ECG electrocardiogram, LDAC low-dose cytarabine, N/A not available, PAOD
Phase 1/2 study (follow-up of >7 years for CP3L and ADV, and >8 years for ADV) peripheral arterial occlusive disease, QD once daily, PAD peripheral arterial
[65] disease, Ph Philadelphia chromosome, QTcF corrected QT by Fredericia, SAE
Bosutinib Cardiac TEAEs: Effusion-related N/A serious adverse event, TEAE treatment-emergent adverse event, TKI tyrosine
500 mg 10.9% TEAEs: 13.3% kinase inhibitor
QD: Vascular TEAEs: Most common ADV: AP/BP CML or Ph+ ALL and prior imatinib (other prior TKIs permitted);
CP2L: 8.8% TEAEs in the
CP2L: CP CML and no prior TKIs other than imatinib; CP3L: CP CML and prior
n=284 Hypertension effusion cluster:
imatinib + dasatinib and/or nilotinib
CP3L: TEAEs: 9.1%
n=119 Most common • Pleural
ADV: TEAEs in the effusion: nilotinib due to AEs, most commonly due to peripheral arterial
n=167 cardiac, vascular, 11.9% obstructive disease [97]. In another Italian study (first-line CP CML),
and hypertension
clusters,
15.4% and 48.1% of patients permanently discontinued treatment due
respectively: to toxicity or had dose reductions, respectively, with dasatinib 100 mg
QD [98]. Across three real-world studies of bosutinib in CML, 12.1–16%
• Atrial of patients discontinued due to AEs/intolerance, most commonly due to
fibrillation: 3.0%
diarrhea [99–101]. Ponatinib has also been investigated in several real-
• Angina pectoris:
1.6% world studies (CML and ALL) [102–105]. Dose reductions and/or in­
• Hypertension: terruptions were common, and the most frequent AEs included derma­
8.2% tologic and hematologic AEs [102–105]. Dose reduction is possible
Final 10-year results of Phase 1/2 study and extension study in CP CML [61] without loss of efficacy [106–110]. In summary, real-world studies
Bosutinib Cardiac TEAEs: Pleural effusion: N/A
500 mg 12% 13%
provide additional and complementary safety data to those reported in
QD: Vascular TEAEs: clinical trials. Unfortunately, as is the case with clinical trials, compar­
N=284 11% isons across real-world studies are limited due to differences in reporting
Phase 3 BELA study (≥30 months of follow-up) [49] methods, patient populations, and outcomes (e.g., overall incidence vs
Bosutinib Cardiac AEs: 8% Pleural Biochemical non-
exposure time), as well as a lack of mechanistic research on certain AEs.
500 mg Most common effusions: 4% hematologic laboratory
QD: cardiac AEs: AEs:
n=250 3. Treatment considerations in the first-line and later-line
• Palpitations: 2% • Increased ALT: 33% settings
• Pericardial • Increased AST: 28%
effusion: 2% • Hypophosphatemia:
Vascular AEs: 10% 8% Treatment selection of TKIs is influenced by the patient’s medical
Most common history, comorbidities, and concomitant medications (Table 4). Addi­
tionally, there are other factors that should be considered during treat­
ment selection, e.g., disease risk score, age, mutational profile, and

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J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 3
Real-world safety experience of TKIs in CML
Study Discontinuations Dose interruptions or Treatment switching Additional AE data
reductions

SIMPLICITY observational study (2010–2017) [90]

Imatinib: n=370 Discontinuations due to Treatment interruptions: Treatment switches: N/A
Dasatinib: intolerance:
n=376 • Year 1: 16.4% • Year 1: n=146
Nilotinib: • Year 1: n=178 • Year 2: 4.0% • Year 2: n=54
n=375 • Year 2: n=51 Most common reasons for Most common reasons for
Most common reasons for treatment interruption: treatment switching:
discontinuations due to
intolerance: • Year 1: thrombocytopenia • Year 1: GI disorders (n=37) and
(n=45) and neutropenia general disorders (n=36)
• Year 1: general disorders (n=22) • Year 2: respiratory, thoracic,
(n=41) and GI disorders (n=40) • Year 2: dyspnea (n=8), and mediastinal disorders
• Year 2: respiratory, thoracic, pleural effusion (n=5), and (n=17) and GI disorders and
and mediastinal disorders fatigue (n=5) general disorders (n=12 each)
(n=18) and GI disorders (n=14)

3-year follow-up of SIMPLICITY observational study (2010–2017) [91]

Imatinib: n=147 Treatment discontinuations in
Years 1, 2, and 3: 25.2%, 9.5%,
and 2.7%, respectively
Across all years, intolerance and
primary resistance were the most
common reasons for treatment
discontinuation
Dasatinib: n=96 Treatment discontinuations in
Years 1, 2, and 3: 14.6%, 6.3%,
and 6.3%, respectively
Across all years, intolerance and
primary resistance were the most
common reasons for treatment
discontinuation
Nilotinib: n=127 Treatment discontinuations in
Years 1, 2, and 3: 11.8%, 7.9%,
and 4.7%, respectively
Across all years, intolerance and
primary resistance were the most
common reasons for treatment
discontinuation
Treatment interruptions in
Years 1, 2, and 3: 21.1%, 8.2%,
and 5.4%, respectively
Treatment interruptions in
Years 1, 2, and 3: 15.6%, 9.4%,
and 4.2%, respectively
Treatment interruptions in
Years 1, 2, and 3: 16.5%, 1.6%,
and 1.6%, respectively
Treatment switches in Years 1, 2, N/A
and 3: 23.8%, 8.8%, and 2.0%,
respectively
Across all years, intolerance and
primary resistance were the most
common reasons for treatment
switching
Treatment switches in Years 1, 2, N/A
and 3: 11.5%, 5.2%, and 4.2%,
respectively
Across all years, intolerance and
primary resistance were the most
common reasons for treatment
switching
Treatment switches in Years 1, 2, N/A
and 3: 9.4%, 6.3%, and 2.4%,
respectively
Across all years, intolerance and
primary resistance were the most
common reasons for treatment
switching

EUTOS registry (2008–2013) [92]

Imatinib: 80% N/A N/A Treatment switches: N/A
Nilotinib: 13%
Dasatinib: 4% • Imatinib: 28%
• Nilotinib: 20%
• Dasatinib: 22%
Most common reasons were
treatment failure and side effects

Dutch nationwide registry (2008–2013) [93]

Imatinib: 75% Overall, 44% discontinued within Dose reductions and N/A Most common AEs:
3 years: interruptions: 31% and 9%,
respectively • Rash: 11.1%
• Intolerance: 21% • Infection: 10.8%
• Failure: 19% • Thrombocytopenia: 9.8%
Nilotinib: 17% • Other: 3% Dose reductions and N/A Most common AEs:
interruptions: 25% and 12%,
respectively • Thrombocytopenia: 10.1%
• Rash: 7.2%
• Fatigue: 5.8%
Dasatinib: 6% Dose reductions and N/A Most common AEs:
interruptions: 27% and 14%,
respectively • Pleural effusion: 13.8%
• Thrombocytopenia: 10.3%
• Diarrhea: 9.5%

Retrospective cohort study in Sweden (2002–2012) [94]

N=896 N/A N/A • Imatinib then nilotinib: 11.5% Incidence rate per 1000 person-years of arterial
Imatinib: • Imatinib then dasatinib: 18.4% thromboembolic events, venous
87.1% • Imatinib, nilotinib, and thromboembolic events, and all arterial and
Nilotinib: dasatinib: 10.0% venous events, respectively:
26.9%

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13
J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 3 (continued )
Study Discontinuations Dose interruptions or Treatment switching Additional AE data
reductions

Dasatinib: • Imatinib: 13, 6, and 16

23.4% • Nilotinib: 29, 11, and 42
• Dasatinib: 19, 0, and 20

Observational, US multi-site cohort study (2014–2018) [95]

Imatinib: n=304 Discontinuations: 28% Dose reductions: 7% N/A N/A
Dasatinib: Discontinuations: 15% Dose reductions: 15% N/A N/A
n=309

French observational study (2011–2014) [96]

Imatinib Discontinuations: 29.5% N/A N/A AEs:
followed by Discontinuations due to
nilotinib: intolerance: 18.5% • Overall: 81.5%
N=146 • Grade 3: 30.8%
• Grade 4: 2.1%
Most common non-hematologic treatment-
related TEAEs:

• Pruritus: 16.4%
• Asthenia: 13.7%
• Dry skin: 13.0%

Real-world setting in Italy (48 months of follow-up) [97]

Dasatinib: n=95 Discontinuations due to AEs: 55% Permanent dose reductions: Switches after dasatinib (n=32): Most common AEs leading to permanent
29% discontinuation:
• Nilotinib: n=24
• Imatinib: n=2 • Pleural effusion: n=10
• Ponatinib: n=2 • Heart failure: n=2
• Bosutinib: n=2 • Arrhythmias: n=2
• Hydroxyurea: n=2
Nilotinib: n=68 Discontinuations due to AEs: 54% Permanent dose reductions: Switches after nilotinib (n=19): Most common AEs leading to permanent
31% discontinuation:
• Dasatinib: n=13
• Ponatinib: n=3 • PAOD: n=4
• Bosutinib: n=3 • CV events: n=3
• Cutaneous: n=2
• Fluid retention: n=2

Study across 26 Italian centers (2012–2015) [98]

Dasatinib: N=65 Permanent discontinuations due Dose reductions (100 mg QD N/A Grade 3–4 hematologic: 12.3%
to toxicity (100 mg QD group): group): 48.1% Grade 3-4 non-hematologic: 18.5%
15.4% Pleural effusions: 18.5%

Real-world study in UK and Netherlands (median duration 15.6 months) [99]

Bosutinib: N=53 Discontinuations: 38% N/A N/A All grades: 92%
Discontinuations due to AEs: 15% Grade 3–4: 26%
Most common, all grades:

• Diarrhea: 55%

Italian cohort study (median duration 18.1 months) [100]

Bosutinib: N=91 Permanent discontinuations: N/A N/A All grades and grade 3–4, respectively:
26.4%
Permanent discontinuations due • Hematologic: 13.1% and 5.4%
to AEs: 12.1% • Non-hematologic: 49.4% and 17.5%
Most common AEs leading to discontinuation:

• Rash: n=3
• GI: n=3
• Pleural effusion: n=2

Retrospective study in Spain and UK (2011–2016) [101]

Bosutinib: N=62 Discontinuations: 36%
Discontinuations due to
intolerance: 16%
Dose interruptions: 45–46% N/A Hematologic toxicities: 25%
Dose reductions: 64–66% Anemia: 21%
Thrombocytopenia: 21%
Neutropenia: 10%
Most common grades 2–4 non-hematologic
toxicities:

• Diarrhea: 39%

(continued on next page)

14
J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 3 (continued )
Study Discontinuations Dose interruptions or Treatment switching Additional AE data
reductions

• Elevated liver enzymes: 13%

• Pleural effusions: 11%

Nationwide Belgian Registry [102]

Ponatinib: N=50 Discontinuations due to AEs: 34% Dose reductions / interruptions N/A AEs: 68%
due to AEs: 74% Most common AEs:

Dose reductions / interruptions • Rash: 26%

to prevent AEs: 25% • Dry skin: 10%

PEARL observational study (2013–2014) [103]

Ponatinib: N=48 N/A N/A N/A Significant CV AEs: 46.8%
Most common AEs:

• Hypertension: 19.3%
• Thrombotic events: n=11
• Myocardial infarction: n=3
• DVT: n=3
• Cerebrovascular accidents: n=2
• PAOD: n=2
• Acute leg ischemia: n=1

Retrospective study [104]

Ponatinib: N=29 N/A Dose reduction due to N/A Most common AEs:
intolerance: n=2
Dose reduction to reduce CV • Grade 3 thrombocytopenia: n=5
risk: n=8 • Rash: n=5
• Hypertension: n=3
• Grade 3 neutropenia: n=3

Retrospective Italian study [105]

Ponatinib: N=49 Discontinued: n=13
Discontinued: 5/31 patients who
responded to treatment (n=2 due
to AEs)
Dose reduction: 11/31 patients
who responded to treatment
(n=8 due to AEs)
N/A AEs: 21/49 patients
Non-hematologic AEs:
• Dermatologic: n=9
• Arthralgia: n=2
• Hypercholesterolemia: n=2
• Diabetes: n=1
Hematologic AEs:

• Pancytopenia: n=3
• Thrombocytopenia: n=1
• MDS with trisomy 8: n=1
CV events:

• Hypertension: n=3
• Atrial fibrillation: n=1
• Carotid thrombosis: n=1
• Ischemic cardiopathy: n=1

AE adverse event, CML chronic myeloid leukemia, CV cardiovascular, DVT deep vein thrombosis, GI gastrointestinal, MDS myelodysplastic syndrome, N/A not
available, PAOD peripheral arterial occlusive disease, TEAE treatment-emergent adverse event, TKI tyrosine kinase inhibitor

availability. In the first-line setting, second-generation TKIs are 3.1. Comorbidities

frequently advocated over imatinib, particularly for patients with in­
termediate- or high-risk scores, as response rates are significantly higher
with such agents in these groups [18,111]. Also, due to the increased
likelihood of faster and/or deeper molecular responses, bosutinib,
dasatinib, and nilotinib may be considered as first-line treatment for
female patients who may wish to become pregnant or other patients
interested in treatment discontinuation in the future [111]. In the first-
line setting, imatinib may be preferred for older patients with comor­
bidities, due to the lower risk of AOEs—the lowest among all TKIs [111].
Finally, mutation status should be assessed following failure of imatinib
or a second-generation TKI or following disease progression to AP or
blast phase (BP); a second-generation TKI may be preferred as first-line
therapy for patients with cytogenetic abnormalities or rare transcripts
[17,18,111].
Depending on the patient’s comorbidities, some TKIs may be
preferred to minimize the risk of AEs or exacerbation of any underlying
conditions, and/or reduce the possibility of drug-drug interactions
(DDIs) with concomitant medications (Table 4) [17,18,70,111,112].
Cardiac- and vascular-related comorbidities should be carefully
assessed and considered when selecting TKIs. In clinical practice, car­
diac and vascular risk factors should be assessed before initiating
treatment with any TKI (Table 5, Fig. 1) [22,70,113–119]. In patients
with existing cardiac or vascular comorbidities (e.g., diabetes, hyper­
tension), management should be in line with current guidelines for these
conditions, and the potential for DDIs between medications and TKIs
should be considered [70,112]. All necessary lifestyle modifications (e.
g., smoking, obesity) and management of cardiac or vascular risk factors
should be discussed (including the use of primary prophylactic drugs)
[119], and whenever possible controlled, prior to the start of TKI

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J.H. Lipton et al. Blood Reviews xxx (xxxx) xxx

Table 4 Table 4 (continued )

Summary of TKI treatment recommendations based on pre-existing comorbid­ Parameter TKI recommendations
ities and commonly administered concomitant medications in patients with CML
• Patients receiving imatinib should be
Parameter TKI recommendations administered low-molecular weight or stan­
Comorbidities dard heparin and should not receive warfarin
Cardiac and vascular • Bosutinib and imatinib are generally preferred P-glycoprotein substrates • Monitoring is recommended when co-
• Treatment of existing comorbidities should be administering with ponatinib
in line with current guidelines for that
CML chronic myeloid leukemia, CYP cytochrome P450, ECG electrocardiogram,
condition, and any potential drug-drug in­
TKI tyrosine kinase inhibitor
teractions considered
• Introduce lifestyle changes, manage any risk
factors, and correct serum electrolytes prior to
initiating TKI treatment, and monitor Table 5
throughout, e.g., smoking cessation, weight Suggested CV risk assessments during TKI treatment
loss, exercise, or control of
CV risk assessment Baseline 3-6 months Ongoing
hypercholesterolemia, hypertension, or
follow-up
diabetes
• Consider baseline ECG Ankle–brachial index Yes Yes Yes
• Additional monitoring, e.g., ECG and blood Blood pressure Yes Yes Yes
pressure, throughout treatment is necessary Echocardiogram Yes As clinically As clinically
for certain TKIs – bosutinib, dasatinib, indicated indicated
nilotinib, and ponatinib Electrocardiogram Yes As clinically As clinically
Pulmonary • Bosutinib, imatinib, and nilotinib are indicated indicated
generally preferred Fasting glucose Yes Yes Yes
Diabetes • Bosutinib, dasatinib, and imatinib are Fasting lipid panel Yes Yes Yes
generally preferred Fundoscopy Yes Yes Yes
Gastrointestinal • Dasatinib and nilotinib are generally preferred General CV assessment (e.g., Yes Yes Yes
Renal • Dasatinib and nilotinib are generally preferred Framingham Risk Score or SCORE
Hepatic • Dasatinib and imatinib are generally preferred Risk Chart) and physical
examination: personal and family
medical history of CV or vascular
Concomitant medications
disease; weight, height and BMI;
Strong CYP3A4/CYP3A5 • Co-administration with all TKIs should be
risk factors such as hypertension,
inhibitors or inducers avoided, where possible
dyslipidemia, diabetes, smoking,
• If co-administration is unavoidable, consider
obesity
dose modifications in line with product labels
General metabolic panel Yes Yes Yes
• Examples include the azole antifungal
Smoking cessation program Yes Yes Yes
medications (e.g., fluconazole, ketoconazole,
itraconazole, posaconazole, and Recommendations are based on published literature and author experience
voriconazole), antibiotics (e.g., rifampicin, [113–117]; they should also be considered alongside treatment guidelines.
clarithromycin, and erythromycin), and anti-
BMI body mass index, CML chronic myeloid leukemia, CV cardiovascular, TKI
epileptic medications (e.g., phenobarbital,
tyrosine kinase inhibitor
and phenytoin)
CYP2D6 substrates • Imatinib should be used with caution
• Examples include tricyclic antidepressants, e. therapy and monitored throughout [70,87,112]. Where appropriate,
g., amitriptyline and trimipramine
coordination with primary care and cardiologists should be considered,
Proton-pump inhibitors • Co-administration with all TKIs should be
avoided, where possible
to identify and manage AEs [22].
• Consider histamine 2 receptor antagonists and Establishing cardiovascular risk in patients with CML is particularly
antacids as alternatives important before initiating dasatinib, nilotinib, or ponatinib. Nilotinib is
• Examples include lansoprazole, omeprazole, associated with an increased risk of arterio-occlusive disease [6,7].
and pantoprazole
Possible mechanisms for these events have been reported for nilotinib
Histamine 2 receptor antagonists • Co-administration with all TKIs should be
and antacids avoided, where possible and include worsening of underlying risk factors such as hypertension
• If co-administration is unavoidable, consider and diabetes, modification of the lipid profile, as well as accelerated
separating the timing of administration of atherosclerosis and endothelial damage via upregulation of proathero­
these agents
genic adhesion proteins and inhibition of endothelial cell proliferation
Cardiovascular medications, e. • Caution should be exercised when co-
g., anti-arrhythmics and administering with all TKIs
and survival [113,119–122]. Ponatinib contains a label warning for
statins • Consider dose modifications in line with heart failure, hepatotoxicity, and vascular occlusion [9,10]. The mech­
product labels anistic basis for these warnings include ponatinib being a potent in­
• Consider alternative cardiovascular hibitor of vascular endothelial growth factor (VEGF) receptors and
medications
having prothrombotic effects, such as increased platelet activation and
• Co-administration of nilotinib should be
avoided with agents that may prolong the QT adhesion, as well as inhibiting proliferation and inducing apoptosis in
interval endothelial cells and cardiomyocytes via dysregulation of AKT and ERK
• Examples include anti-arrhythmic (e.g., signaling pathways [113,119,121,123–126]. The cardiovascular
amiodarone, diltiazem, and verapamil) and
toxicity of ponatinib is also thought to involve platelet-mediated
statin (e.g., atorvastatin and simvastatin)
Antidepressants • QT monitoring is recommended when co-
thrombotic microangiopathy, resulting in ischemic abnormalities
administering with all TKIs [126]. Ponatinib is thought to act as a platelet antagonist and has been
• Co-administration of nilotinib should be shown to inhibit platelet aggregation, likely through inhibition of
avoided platelet signaling pathways [127]. Dasatinib has also demonstrated an
• Examples include buproprion, citalopram, and
increased risk of cardiovascular and cerebrovascular events versus
fluoxetine
Anticoagulants • Dasatinib should be used with caution imatinib [35]. Generally, imatinib is associated with the lowest risk of
AOEs [111]. Among second-generation TKIs, bosutinib seems to have
the lowest risk of AOEs and may be the preferred first-line therapy for
patients with cardiovascular comorbidities considering a second-

16
J.H. Lipton et al.
Fig. 1. Suggested guidelines and monitoring for CV risk factors in patients with CML
Recommendations are based on published literature and author experience [20,24,113–117,180]; they should also be considered alongside treatment guidelines.
CML chronic myeloid leukemia, CV cardiovascular, TFR treatment-free remission, TKI tyrosine kinase inhibitor.
generation TKI [18,112]. Regardless of the TKI selected, baseline elec­
trocardiograms are appropriate prior to initiating therapy [87].
QT interval prolongation has been reported with all TKIs; therefore,
serum levels of potassium and magnesium should be repleted prior to
initiating TKIs, and ongoing monitoring of electrolytes during treatment
is recommended [70]. Drug-induced QT interval prolongation is com­
mon with TKIs and is thought to involve inhibition of the potassium ion
channel – human ether-à-go-go (hERG) channel [128]. Nilotinib spe­
cifically contains a warning label for QT interval prolongation [6,7];
however, bosutinib and dasatinib should also be used with caution in
patients with any history, risk factors, or concomitant medications that
may lead to QT prolongation [3–5,8,70].
Pulmonary-related comorbidities should also be considered. Dasati­
nib has been associated with the highest risk of pleuro-pulmonary
toxicity and should be avoided in patients at risk of developing pleural
effusions (i.e., those with existing lung disorders or uncontrolled hy­
pertension and older patients) [129,130]. Alternatives to dasatinib
should be considered in patients with pulmonary arterial hypertension
[3,4]. Pleural effusion may be observed with other TKIs and can first
appear after years of ongoing treatment, albeit at significantly lower
rates than with dasatinib. Patients with symptoms suspicious for pleural
effusion (e.g., shortness of breath, chronic cough, and pleuritic chest
pain) should be evaluated for this AE. The pathogenesis of dasatinib-
induced pulmonary toxicity is thought to be multifactorial and involve
inhibition of Src family kinases, attenuation of vasoconstriction, auto-
immunity, inhibition of platelet-derived growth factor receptor
(PDGFR) beta, cardiac dysfunction, and endothelial cell apoptosis and
dysfunction via increased production of mitochondrial reactive oxygen
species [131–134]. The actual contribution of each of these factors has
not been studied, and further studies would be required not only to
clarify the mechanism of action but also to find the best approaches to
manage these events. A recent study suggested that the incidence of
pleural effusion is associated with dasatinib metabolism and may be
reduced by therapeutic drug monitoring and a dose reduction strategy
[135].
Other comorbidities should also be considered during TKI selection.
Due to increased risk of hyperglycemia, nilotinib should be used with
caution in patients with uncontrolled diabetes mellitus [6,7]. Nilotinib-
induced impairment of glucose and lipid metabolism is thought to
involve the development of insulin resistance and impaired insulin
secretion via c-Abl dysregulation of insulin receptor signaling and effects
17
Blood Reviews xxx (xxxx) xxx
on adipocytes and adiponectin secretion [136–140]. Bosutinib is asso­
ciated with an increased risk of gastrointestinal AEs; therefore, it should
be used with caution in patients with gastrointestinal comorbidities,
such as chronic inflammatory bowel disease, chronic diarrhea, or gastric
ulcer [16]. Mechanisms underlying bosutinib-induced diarrhea may
involve decreased intestinal barrier integrity, inhibition of kinases
within the intestinal epithelium, and changes to the gut microbiome
[141–143].
Patients with CML may often present with some baseline renal or
hepatic dysfunction. Analyses of patients with pre-existing liver and/or
renal dysfunction have demonstrated that dasatinib, imatinib, and
nilotinib can be safely administered and are effective in such settings;
however, patients with pre-existing renal dysfunction treated with these
TKIs may have an increased risk of worsening kidney function or other
AEs [144,145]. A decrease in glomerular filtration rate and elevated
serum creatinine has been reported with all TKIs but appears to be
higher with bosutinib and imatinib. However, there is no clear evidence
of renal injury with any TKI [112]. Monitoring of renal function is rec­
ommended during TKI administration, and dasatinib and nilotinib are
generally preferred in patients with renal comorbidities [112]. Addi­
tionally, dasatinib and imatinib are generally preferred in patients with
hepatic comorbidities [112]. Bosutinib should be administered with
caution in patients with hepatic comorbidities or risk factors, as trans­
aminase elevations have been reported more frequently with bosutinib
[16]. Other TKIs are also associated with increases in transaminases
and/or bilirubin. Therefore, all patients should be monitored periodi­
cally for liver function and avoid exposures to hepatotoxins, e.g., drugs
and alcohol. The mechanisms underlying the development of hepatic
toxicities during TKI treatment are unclear but may involve the devel­
opment of reactive metabolites, mitochondrial toxicity, and the inhibi­
tion of UGT1A1 (an enzyme involved in bilirubin metabolism)
[146,147].
3.2. Concomitant medications
It is important to consider concomitant medications during TKI se­
lection and use in patients with CML (Table 4). TKIs are primarily
metabolized via the cytochrome P450 (CYP) system; therefore, co-
administration of strong CYP3A4/CYP3A5 inhibitors or inducers
should be avoided. If co-administration is required, dose reductions (for
inhibitors) or increases (for inducers) of TKIs may be necessary per the
J.H. Lipton et al.
product labels [1–10]. Examples include azole antifungals, antibiotics,
and anti-epileptics [18,148]. However, specific data and guidelines as to
the optimal dosing in those circumstances are largely missing. Imatinib
should be used with caution in combination with CYP2D6 substrates
that have a narrow therapeutic index, e.g., tricyclic antidepressants
[1,2,148].
Decreases in bosutinib, dasatinib, and nilotinib exposure have been
reported in combination with proton pump inhibitors (PPIs) as a result
of a pharmacokinetic-based drug-drug interaction, which reduces TKI
absorption because of increased gastrointestinal pH [149]. Therefore,
co-administration should be avoided whenever possible. Short-acting
antacids could be considered as alternatives [3–8,18,148]. However,
decreases in bosutinib, dasatinib, and nilotinib exposure have also been
observed in combination with histamine 2 receptor antagonists (e.g.,
ranitidine) and antacids; therefore, simultaneous administration should
be avoided. If avoidance is not possible and acid-suppression therapy is
required [3–8,18], the administration times of these agents can be
separated (i.e., PPI administration 2 hours post-TKI administration
[150]). In addition, absorption of bosutinib, nilotinib, and asciminib
increases with food [151–154], whereas absorption of dasatinib, ima­
tinib, or ponatinib does not appear to be affected by food [155–157].
Cardiovascular medicines in combination with TKIs have been
associated with increased drug exposure, as well as an increased risk of
arrythmias and QT prolongation. Dose adjustments to TKIs or alterna­
tive cardiovascular medicines should be considered, except for nilotinib,
where co-administration with agents that may prolong the QT interval
should be avoided [6,7,18,148]. Similarly, certain statins have demon­
strated DDIs when co-administered with TKIs [148]. There appears to be
less interaction with pravastatin and rosuvastatin, and these agents may
be preferable when statins are indicated. Imatinib, nilotinib, and dasa­
tinib inhibited CYP3A4, leading to increased simvastatin exposure.
Additionally, atorvastatin inhibits P-glycoprotein, resulting in increased
imatinib and dasatinib exposure [148]. Therefore, caution should be
exercised when co-administering TKIs with these lipid-lowering medi­
cations [112,148].
Other common medications to consider are antidepressants, antico­
agulants, and P-glycoprotein substrates. Co-administration of all TKIs
with antidepressants has been associated with minor increases in
exposure. Therefore, QT monitoring is recommended when antidepres­
sants are co-administered with TKIs, except for nilotinib, where co-
administration should be avoided [18,148]. Furthermore, patients tak­
ing concomitant anticoagulants may be at an increased risk of bleeding
with dasatinib [111]. The pathophysiology of dasatinib-induced
bleeding is thought to involve impaired platelet function and aggrega­
tion, disruption of the vascular endothelium, inhibition of PDGFR, and
impaired thrombopoiesis. Patients receiving imatinib requiring anti­
coagulation therapy should be administered low-molecular weight or
standard heparin, avoiding warfarin if possible [1,2]. Ponatinib inhibits
P-glycoprotein or the transporter Breast Cancer Resistance Protein
(BCRP); therefore, monitoring is essential when ponatinib is co-
administered with P-glycoprotein or BCRP substrates, e.g., digoxin and
methotrexate [9,10]. In addition, a risk of drug-drug interaction has
been found in vitro between TKIs and direct oral anticoagulants [158];
however, a retrospective study of patients with atrial fibrillation and
cancer reported no increased risk of major bleeding associated with
concomitant use of direct oral anticoagulants and anticancer drugs
[159].
4. Ongoing treatment and the emergence and management of
AEs
The patient’s medical history, comorbidities, and concomitant
medications are potential factors affecting treatment tolerability and
that may predispose patients to developing particular TKI-associated
AEs [17,18,70,87,111,112]. These factors are also more likely to be
present in patients who are older, thus TKI intolerance may be more
18
Blood Reviews xxx (xxxx) xxx
common in older patients. Certain genetic polymorphisms affecting TKI
metabolism may also be a factor in the likelihood of AE development
[87]. Additionally, the kinetics of AEs and their dose-response rela­
tionship differ significantly between individual TKIs, as well as between
individual patients and ethnical/regional backgrounds, and have an
impact on treatment tolerability [106,160]. For example, all of the
following factors can influence the development of AEs: patient body
size and disease phase, the TKI administered, the dose, and dosing
schedule [87].
An important issue to highlight in terms of AE management is the
differences in AE perception between patients and physicians
[71,75,161–163]. Compared with patients with CML, physicians tend to
underestimate the impact and severity of TKI-related symptoms and
AEs, as well as overestimate overall health status [161–163]. Therefore,
physicians should consider the impact of any AEs and associated man­
agement strategies on patient quality of life [72,164,165].
AEs of special interest that may occur during treatment with TKIs are
outlined below, as well as additional pharmacologic and non-
pharmacologic strategies that could be considered for the manage­
ment of these AEs (Table 6). In addition, one of the most frequent AEs of
TKI treatment in patients with CML is fatigue [166,167]. While it may be
challenging to identify patients at risk of fatigue, including fatigue
reduction as a treatment goal has been highlighted [168]. In doing so,
physicians should consider other reasons for fatigue (e.g., depression,
thyroid hormone imbalance, or vitamin B12 deficiency) [169].
In the event of an AE, appropriate TKI dose reductions and/or
treatment interruptions, depending on AE severity, should be consid­
ered, as outlined in the product labels [1–10]. Many AEs can be
managed while continuing therapy and without compromising dose
optimization. Every attempt should be made to manage AEs with sup­
portive care, counseling, and/or use of proper medical or other in­
terventions as appropriate prior to changing therapy. Other causes or
contributors for TEAEs should be investigated and managed as appro­
priate. In some instances, dose reductions and/or interruptions need to
be considered and should be used when indicated, particularly for the
most clinically significant AEs (e.g., grade ≥3). It is important to note
that both hematologic and non-hematologic toxicities respond differ­
ently to dose reductions and are dependent on patient-specific factors (e.
g., BMI) [170].
Several studies are ongoing or have reported outcomes using dose
modification protocols in treating CML. Although the aim was treatment
discontinuation rather than mitigating the risk of AEs, DESTINY has
shown promising results through de-escalation of TKIs (imatinib, dasa­
tinib, or nilotinib) to half of the standard dose prior to treatment
discontinuation [171]. ENESTpath and ENESTswift reported tolerability
and deep molecular responses with a reduced dose of nilotinib (300 mg
BID) [172,173]. Fewer treatment interruptions due to AEs occurred
when patients initiated bosutinib via a dose-escalation protocol adjusted
by response and limited to a maximum dose of 400 mg QD, rather than
starting with the standard bosutinib dose [174]. Interestingly, in
BYOND, with a starting dose of bosutinib 500 mg QD, median dose in­
tensity was 405.9 mg/day versus 292.0 mg/day for TKI-resistant versus
TKI-intolerant patients [48]. The ongoing BODO study (NCT03205267)
is evaluating if reducing bosutinib dose during early treatment reduces
or prevents AEs while maintaining efficacy. DasaHIT (NCT02890784)
compares a 5-day holiday schedule with a 7-day standard schedule of
dasatinib to determine if the holiday schedule leads to a reduction in
toxicities while preserving efficacy. A study of a lower starting dose of
dasatinib 50 mg in patients with newly diagnosed CP CML demonstrated
that it was both safe and effective, with reduced rates of pleural effusion
[175]. In OPTIC IA, although slight reductions in ponatinib dose re­
ductions and interruptions due to AEs and in the rate of AOEs were
observed using lower doses (30 or 15 mg), there was a drop in efficacy,
particularly in patients with a T315I mutation, those who did not ach­
ieved a cytogenetic response to the immediate prior TKI, or had received
≥3 TKIs [176–178]. Importantly, by using a response-directed dose
J.H. Lipton et al.
Table 6
How to manage common AEs and/or AEs of special interest associated with TKIs
AE cluster AE management strategies
Cardiac and vascular • Patients should monitor and report any chest or leg
pain, palpitations, shortness of breath, dizziness,
fainting, or numbness
• Consider any underlying potential risk factors,
lifestyle modifications, or drug-drug interactions
between CV medications and TKIs
• Consider dose reductions and/or interruptions, or
potentially discontinuing TKI treatment
• Additional monitoring and/or assessments may be
necessary
Dermatologic • Suggest lifestyle modifications to mitigate the risk of
rash, e.g., avoid prolonged bathing, hot water when
washing/showering, and tight clothing
• Use of moisturizing creams, antihistamines, or
topical therapies in the event of an AE
• Consider systemic antibiotics and/or short-term
systemic steroids, and dermatologist consultation
for severe cases
Gastrointestinal • Suggest preventative measures to mitigate the risk
of these AEs, e.g., take medication with food, avoid
large meals and/or overly spicy, sweet, or fatty
foods
• Use of anti-diarrheal (e.g., loperamide or diphe­
noxylate/atropine), anti-emetic (e.g., pro­
chlorperazine or metoclopramide), or anti-nausea
(e.g., prochlorperazine or metoclopramide) treat­
ments, and/or fluid replacement, either prophylac­
tically or in the event of an AE
Hematologic • Patients should monitor and report any fever,
infection signs, bruising, unexpected bleeding or
blood in urine or stool
• Consider treatment with growth factors for
persistent myelosuppression
• Perform regular blood counts
Hepatic • Patients should monitor and report any jaundice or
‘tea-colored’ urine
• Consider dose reductions and/or interruptions, or
potentially discontinue TKI treatment
• Additional monitoring and/or assessments may be
necessary
Laboratory/biochemical • Consider any underlying potential risk factors,
abnormalities lifestyle modifications, or concomitant medications
• Additional monitoring and/or assessments may be
necessary
Muscle spasms • Evaluate and correct serum electrolytes
• Suggest non-pharmacologic management strategies,
e.g., maintaining adequate hydration, stretching/
gentle exercise, and drinking tonic water or sports
drinks
• Consider potassium and calcium supplements
Pulmonary • Patients should monitor and report any chest pain or
discomfort, cough, or dyspnea – signs of pleural
effusion
• Consider diuretics and/or oral corticosteroids for
pleural effusion
• Patients should monitor and report any dyspnea,
fainting, or fatigue – signs of pulmonary arterial
hypertension
• Patients should monitor and report any cough,
dyspnea, fever, or hypoxemia – signs of pneumonitis
• Consider oral corticosteroids for pneumonitis
Renal • Patients should monitor and report any changes in
urinary output or frequency
• Consider any underlying potential risk factors or
concomitant medications
• Consider dose reductions and/or interruptions, or
potentially discontinuing TKI treatment
• Additional monitoring and/or assessments may be
necessary
AE adverse event, CV cardiovascular, TKI tyrosine kinase inhibitor
19
Blood Reviews xxx (xxxx) xxx
reduction from 45 mg to 15 mg daily once patients achieved BCR-ABL1/
ABL1 ≤1%, the overall incidence of AOEs was greatly reduced versus the
historical reported rate, with a sustained dose of 45 mg daily [176,178].
Although these dose modification strategies appear to reduce the inci­
dence of certain AEs, long-term data on the impact of these protocols on
safety are needed.
Patients with serious or recurring AEs while on a TKI should consider
permanent discontinuation and switching to an alternative TKI that is
expected to have a lower probability of association with the offending
event [1–10]. Any new concomitant medications and the potential for
cross-intolerance should also be considered when selecting a new TKI.
4.1. Cardiac and vascular AEs
Rates of reported cardiac and vascular AEs across long-term clinical
studies are shown in Table 2. Long-term follow-up of these AEs is
becoming increasingly important due to the improved prognosis of CML
and near-normal life expectancy, with many patients taking TKIs for
many years and often for the rest of their lives. Furthermore, the inci­
dence of these events increases over time, with no clear evidence of a
plateau as late as 10 years after commencing therapy [39]. Unfortu­
nately, estimating the relative frequencies of these AEs across various
TKIs is difficult due to differences in analytical methods, cardiac
exclusion criteria across trials, definitions for categories of events, and
variability in reporting methods (e.g., some reports analyze multiple
Medical Dictionary for Regulatory Activities terms, whereas others only
use specific confirmed diagnoses) [179,180]. Additionally, there are
overlaps in the definitions of cardiovascular AEs using the Common
Terminology Criteria for Adverse Events, leading to different assign­
ments of the same events. Therefore, there is increasing interest towards
central adjudication of cardiovascular outcomes [180,181]. The rela­
tively short follow-up in some studies, i.e., terminated after only 5 years,
is another limiting factor, since the incidence of these events continues
to increase over time, as demonstrated in the 10-year follow-up of the
ENESTnd study [39].
In an attempt to make reporting more in line with standard defini­
tions, a retrospective review of PACE with an independent adjudication
committee reported lower rates of AOEs versus those initially reported
[182]. The committee assessed events that met criteria for such events,
according to the American Heart Association and the American College
of Cardiology, and suggested many events originally reported may not
have been true AOEs [182]. Patients should be advised to contact their
doctor immediately for signs and symptoms of cardiac or vascular AEs,
e.g., chest or leg pain, palpitations, shortness of breath, dizziness,
fainting, or numbness. In the event of a cardiac or vascular AE, any
underlying potential risk factors, lifestyle modifications, or DDIs be­
tween cardiovascular medications (e.g., statins, amiodarone, diltiazem,
and verapamil) and TKIs should be considered. Although cardiac events
have been reported during therapy with all TKIs, imatinib and to some
extent bosutinib present a safer profile in patients with multiple cardiac
or vascular risk factors or comorbidities [16,70,111,112,183]. The
mechanism of AOEs is unknown, and it has been suggested to be an off-
target effect. Recent reports suggest thrombotic microangiopathy as a
possible cause and suggest the possibility that N-acetylcysteine might be
effective in managing these events [126,184].
For certain TKIs, additional monitoring throughout treatment may
be necessary due to the increased risk of some specific cardiac and
vascular AEs. Nilotinib contains a black box warning for QT prolonga­
tion; therefore, additional electrocardiogram monitoring is recom­
mended at baseline, seven days after initiation, and periodically
thereafter [6]. Furthermore, to reduce the risk of QT prolongation,
nilotinib should not be taken with food, particularly if fatty, as this may
increase absorption, leading to higher peak plasma concentrations
[6,7,70]. The risk of cardiovascular events with nilotinib has been
shown in a retrospective cohort study to be lowered by aggressive car­
diovascular risk factor modification [180]. The ponatinib label contains
J.H. Lipton et al.
a black box warning for heart failure; therefore, cardiac monitoring is
essential with ponatinib [9,10,70]. Recommendations have been pro­
posed for managing cardiovascular events with ponatinib [185], which
include applying European guidelines on cardiovascular disease pre­
vention in clinical practice for cardiovascular risk assessment and
management in patients with CML [186]. Cardiac monitoring is also
recommended with bosutinib, dasatinib, or nilotinib [3–8,70]. Blood
pressure should be monitored with ponatinib due to the potential for
hypertension [9,10,70], although increases in blood pressure
throughout the course of therapy have been reported with most TKIs
[179]. Patients administered ponatinib should also be routinely assessed
for AOEs and venous thromboembolism [9,10,70]. It will also be
important to ensure long-term monitoring of cardiac and vascular AEs
for newer agents such as asciminib.
4.2. Dermatologic AEs
Rash is a common dermatologic AE with TKIs [18,87]. The mecha­
nisms underlying dermatologic AEs are largely unclear; however, it has
been proposed that off-target effects of TKIs on PDGFR and c-kit, and
their subsequent downstream pathways within skin cells, may explain
these cutaneous side effects [187–191]. Physicians should advise pa­
tients on lifestyle modifications to mitigate the risk of rash (e.g., avoid
prolonged tub bathing or hot water when washing or showering) and co-
administer supportive therapies (e.g., moisturizing creams) [16,18]. In
severe cases, short-term systemic steroids can be administered, and
consultation with a dermatologist should be considered [16,18].
4.3. Gastrointestinal AEs
Gastrointestinal AEs such as nausea, vomiting, and diarrhea are
common during treatment with TKIs [18,87]. Bosutinib is associated
with the highest incidence of diarrhea and should be used with caution
in patients with gastrointestinal comorbidities [5,8,87,183]. Diarrhea is
usually mild, manageable, and improves over time during the first 2–3
months of treatment. Preventative measures can reduce the risk of
gastrointestinal AEs, e.g., taking medication with food and/or water
where recommended [16,87,183]. Patients should be assessed for
possible contributing comorbidities that may have been unrecognized
by the patient, such as gluten or lactose intolerance. A consultation with
a dietician may be valuable in selected cases. In daily practice, anti-
diarrheal, anti-emetic, or anti-nausea treatments, and/or fluid replace­
ment, are often used, either prophylactically or in the event of an AE
[16,87,183]. Diarrhea is also frequently managed with TKI dose
adjustments.
4.4. Hematologic AEs
Hematologic AEs are common across all TKIs (Tables 1 and 3) and
the most common cause of cross intolerance. The most common short-
and long-term AEs are anemia, neutropenia, and thrombocytopenia
[18,87]. Hematologic AEs are often limited to the initial treatment
period, with the severity of these AEs typically decreasing with longer
TKI exposure [87]. Recurrent or ongoing cytopenias can be problematic,
especially in patients with late chronic phase CML who received a
delayed diagnosis, prompting investigation of other possible etiologies
(e.g., myelodysplastic syndrome or myelofibrosis). This can be aided by
performing diagnostic cytogenetics, as well repeat cytogenetic assess­
ments at the time of recurrent cytopenias [192,193].
Patients should be advised to report potential signs or symptoms of
these AEs, e.g., fever, signs of infection, bruising, unexpected bleeding,
or blood in their urine or stool. In particular, bleeding and febrile neu­
tropenia are clinical manifestations of myelosuppression-related AEs.
For patients with persistent myelosuppression, treatment with growth
factors such as granulocyte colony-stimulating factor (G-CSF) and
erythropoietin could be considered [18,87,194], though no formal
20
Blood Reviews xxx (xxxx) xxx
guidelines currently exist. Although not approved for this indication, G-
CSF has been shown to overcome imatinib-induced neutropenia in pa­
tients with CML [195], while erythropoietin has been shown to be
effective in treating patients with CML who develop anemia following
imatinib therapy [196,197]. Although also not approved for this indi­
cation, studies have shown that interleukin-11 can improve thrombo­
cytopenia associated with TKIs [198,199]. Furthermore, a phase 2 study
involving 15 patients with CML reported that eltrombopag, a throm­
bopoietin receptor agonist, may be useful for patients with CML expe­
riencing persistent thrombocytopenia [200]. However, consideration
should be paid to the use of thrombopoietin receptor agonists since
myelofibrosis may be a long-term side effect [201]. Both bosutinib and
ponatinib product labels recommend complete blood counts be per­
formed upon initiation and the first few months of therapy, but this is
good practice for all TKIs [5,8–10]. There are no prospective studies
regarding the long-term use of growth factors in patients with persistent
cytopenias, and the theoretical concern that growth factors may stim­
ulate leukemia cells and increase relapse risk is not supported by data.
This suggests that it is acceptable to use growth factors to maintain
patients on an effective TKI dose to achieve optimal disease control.
4.5. Hepatic function and AEs
Elevations in amylase, bilirubin, and/or hepatic transaminases have
been reported during treatment with TKIs; therefore, monthly moni­
toring of liver function is important during the first year of treatment,
and every 3 months thereafter [5,6,9,18,87]. Dose adjustments for he­
patic impairment are recommended for all TKIs [1,2,5–10]. Ponatinib
contains a black box warning for serious hepatotoxicity [9,10]. Patients
should be advised to report symptoms such as jaundice or ‘tea-colored’
urine. Alcohol consumption and co-administration of other hepatotoxic
agents should be minimized or avoided to reduce the occurrence of these
events, particularly among patients with pre-existing mild abnormal­
ities, and avoided in patients who develop hepatic AEs. There is no
specific supportive care of proven efficacy; however, there have been
reports of glucocorticoids, essential phospholipids, glycyrrhizic acid,
milk thistle extract, ursodiol, and S-adenosylmethionine utilized for
hepatic AEs [16,87,183]. Patients receiving nilotinib, particularly those
with Gilbert syndrome, frequently develop asymptomatic elevation of
bilirubin, which typically does not require intervention [202].
4.6. Laboratory/biochemical abnormalities
Control of any underlying metabolic abnormalities, such as diabetes
or hypercholesterolemia, via lifestyle modifications and/or medication
is important prior to TKI initiation, requiring regular monitoring
throughout to mitigate the risk of metabolic AEs and their impact on the
risk of AOEs [70,87]. In patients with diabetes, treatments with bosu­
tinib, dasatinib, and imatinib are generally preferred over nilotinib, in
conjunction with the appropriate medication (e.g., metformin) and per
current guidelines [16,70,112]. More frequent glucose monitoring is
necessary before and during treatment with nilotinib in patients with
diabetes, due to the increased risk of hyperglycemia [70].
Other biochemical abnormalities to consider are those related to
lipid, phosphate, and calcium metabolism. Hyperlipidemia is common
with nilotinib [70,87]. Regular monitoring of lipid profiles prior to and
during nilotinib treatment is necessary [70,87]. For patients with
persistent hypercholesterolemia, a statin could be considered, in line
with current guidelines, with careful attention to possible DDIs [70].
Hypophosphatemia and, to a lesser extent, hypocalcemia have been
mostly reported with imatinib, dasatinib, and nilotinib [87]. Regular
monitoring of serum phosphate and calcium levels prior to and during
imatinib and nilotinib treatment is necessary [87]. There have been
suggestions of an effect on bone metabolism with imatinib and dasatinib
[203,204]. Hypophosphatemia, hypocalcemia, or hypovitaminosis D
should be corrected prior to and during TKI treatment [87]. Long-term
J.H. Lipton et al.
imatinib was reported to impair growth in children with CML
[205–207].
4.7. Muscle spasms
Muscle spasms are a common AE associated with imatinib [18]. The
pathophysiology of this AE is thought to involve disturbances in calcium
and phosphate homeostasis [208–210]. Levels of serum electrolytes
should be evaluated and corrected before and during treatment [87].
Non-pharmacologic management of muscle spasms includes maintain­
ing adequate hydration. Supplements can also be considered for patients
with low potassium or calcium levels [18,87].
4.8. Pulmonary AEs
Rates of reported pulmonary AEs across long-term clinical studies are
shown in Table 2. All TKIs have a risk of pleural effusions, particularly
over long-term therapy; however, the incidence is much higher with
dasatinib [70,87]. Importantly, in contrast to most other AEs that tend to
occur during the first weeks of therapy, pleural effusions may occur for
the first time at any time, even years after therapy initiation. In all pa­
tients with any new pulmonary symptoms, a chest X-ray should be
considered [70]. Patients should be advised to report any symptoms,
such as chest pain or discomfort, persistent cough, and dyspnea, that
could be associated with pleural effusions [70,87]. Pharmacologic
management includes administration of diuretics and/or oral cortico­
steroids [18,70,87,130]. An increased incidence of pulmonary arterial
hypertension has been reported with dasatinib and may be associated
with the occurrence of pleural effusion; patients with pleural effusion
frequently have echocardiographic evidence of increased pulmonary
artery pressure [70]. Patients should be encouraged to report symptoms
such as dyspnea, fainting, and fatigue [70,87]. Although rare, pneu­
monitis has been reported with imatinib; therefore, patients should
report symptoms of cough, dyspnea, fever, or hypoxemia [70,87].
Administration of oral corticosteroids could be considered for the
management of pneumonitis [70,87].
4.9. Renal function and AEs
A decrease in glomerular filtration rate has been reported with
imatinib and bosutinib [211,212]. Dose adjustments for renal impair­
ment are recommended for these agents [1,2,5,8]. In patients with
estimated creatinine clearance <50 mL/min or end-stage renal disease,
caution is advised with ponatinib therapy [9,10]. For patients receiving
bosutinib, renal function should be assessed at baseline and throughout
treatment, particularly in those with relevant risk factors, comorbidities,
or concomitant medications [5,8,16]. However, it has been suggested
that elevated serum creatinine can be caused by inhibition of tubular
reabsorption of creatinine and may not indicate a decrease in renal
function or kidney injury. Evaluation of blood urea nitrogen or inulin
clearance is indicated for questionable cases. Patients should be advised
to report any changes in urinary frequency and output. In the case of
renal AEs, concomitant medications or other nephrotoxic agents should
also be reviewed [16].
5. Conclusions and future considerations
Although they share common class-wide side effects, the differences
in the safety profiles of the approved TKIs for the treatment of CML al­
lows physicians and patients to choose the most suitable treatment for
individual patients. Treatment selection depends on several factors,
including age, disease risk, comorbidities, and concomitant medica­
tions. In second- and later-line settings, the response to previous TKIs,
especially AEs, and mutation status should also be used to guide TKI
selection. AEs that emerge with TKIs can frequently be managed through
dose reductions and/or interruptions, and supportive care strategies
21
Blood Reviews xxx (xxxx) xxx
tailored to the individual situation. Future directions should include
further studies on treatment-free remission and dose modification pro­
tocols, as well as the continued follow up of TKIs over the long-term,
particularly with regard to rarer AEs or AEs of special interest. These
studies will hopefully elucidate the underlying mechanisms behind the
differences in safety profiles between TKIs and how these differences can
be used to individualize and optimize treatment selection in patients
with CML.
Practice points
• Although BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs)
share common class-wide side effects, differences in safety profiles
allow physicians and patients to choose the most suitable treatment
for individual patients with chronic myeloid leukemia (CML).
• First-line TKI selection is dependent on several factors, such as age,
cost, reimbursement policies, availability, disease risk, comorbid­
ities, concomitant medications, and risk factors.
• Switching to another TKI and/or later-line treatment also requires
consideration of response to prior therapies, mutation status, and
prior and anticipated adverse events (AEs) based on known toxicity
profile in the framework of the patients’ comorbidities and past
medical history.
• Comparisons across long-term studies regarding AEs are difficult and
limited due to the differing study designs and eligibility criteria/
patient populations, and variability of reporting.
• Hematologic AEs are universally reported with all TKIs. Cardiac/
vascular AEs and pulmonary AEs have increasingly been reported as
AEs of special interest for most TKIs.
• Overall, all TKIs have manageable safety profiles, although they are
associated with specific AEs and low-grade chronic AEs, leading to
discontinuation or treatment switching.
• AEs that emerge with TKIs can be largely managed through dose
reductions and/or interruptions, alongside several supportive care
strategies.
• Most patients will not achieve a successful treatment-free remission
status and will remain on therapy indefinitely. This requires proper
monitoring and management of AEs.
Research agenda
• Continued long-term follow-up of patients with CML receiving TKIs,
particularly in real-world studies and regarding less frequently re­
ported and late-emerging AEs.
• Greater understanding of the underlying mechanisms of the most
common and serious AEs and the differences in safety profiles be­
tween TKIs, and how these can guide treatment selection in patients
with comorbidities and risk factors.
• Further studies on treatment-free remission and dose modification
protocols in patients with CML.
Author contribution
All authors participated equally in discussions and development of
the manuscript, contributed to correcting the draft manuscript, provided
additional recommendations, and have read and approved the final
manuscript.
Declaration of Competing Interest
Jeffrey Lipton: served as a consultant for Bristol-Myers Squibb,
Novartis, Pfizer, and Takeda; received research funding from Bristol-
Myers Squibb, Novartis, Pfizer, and Takeda; received honoraria from
Bristol-Myers Squibb, Novartis, Incyte, Pfizer and Takeda. Tim H
Brümmendorf: consultant for Janssen, Merck, Novartis, Pfizer, and
received research support from Novartis and Pfizer. Carlo Gambacorti-
J.H. Lipton et al.
Passerini: provides consultancy to Bristol-Myers Squibb and received
honoraria and research support from Pfizer. Valentin Garcia-Gutiérrez:
served as a consultant for Bristol-Myers Squibb, Incyte, Novartis and
Pfizer; received research funding from Pfizer, Novartis, Bristol-Myers
Squibb and Incyte. Michael Deininger: served as a paid consultant for
Blueprint, Ariad, Blueprint Medicine, Bristol-Myers Squibb, Galena
Biopharma, Incyte, Novartis, Fusion Pharma, Sangamo and Pfizer;
received research funding from Bristol-Myers Squibb, Celgene, Gilead
Sciences, Incyte, Novartis, SPARC, DisperSol, Pfizer and Blueprint. Jorge
E Cortes: served as a consultant for Amphivena Therapeutics, Astellas
Pharma, Bio-Path Holdings Inc, BiolineRx, Bristol-Myers Squibb, Daiichi
Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, and Takeda, and
received research funding from Astellas Pharma, Bristol-Myers Squibb,
Daiichi Sankyo, Immunogen, Jazz Pharmaceuticals, Merus, Novartis,
Pfizer, Sun Pharma, Takeda, Tolero Pharmaceuticals and Tovagene.
Acknowledgments
Pfizer provided a formal review of the publication, including for
medical accuracy, but the authors had final authority. The authors were
not compensated for manuscript preparation. Medical writing support
was provided by Anne Marie McGonigal, PhD, and Simon Stones, PhD,
of Engage Scientific Solutions and was funded by Pfizer Inc.
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