American J Hematol - 2022 - Jabbour CML

Received: 16 June 2022 Accepted: 18 June 2022
DOI: 10.1002/ajh.26642
ANNUAL CLINICAL UPDATES IN

HEMATOLOGICAL MALIGNANCIES
Chronic myeloid leukemia: 2022 update on diagnosis,

therapy, and monitoring
Elias Jabbour | Hagop Kantarjian
Department of Leukemia, The University of

Texas M. D. Anderson Cancer Center, Abstract
Houston, Texas, USA Disease Overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative
Correspondence neoplasm with an incidence of 1–2 cases per 100 000 adults. It accounts for approxi-
Elias Jabbour, Box 428, 1515 Holcombe Blvd mately 15% of newly diagnosed cases of leukemia in adults.
Houston, Texas 77030, USA.
Email: ejabbour@mdanderson.org Diagnosis: CML is characterized by a balanced genetic translocation, t (9;22) (q34;
q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with
the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrange-
ment is known as the Philadelphia chromosome. The molecular consequence of this
translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn trans-
lates into a BCR::ABL1 oncoprotein.
Frontline Therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosuti-
nib, and nilotinib are approved by the United States Food and Drug Administration
for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical
trials with second generation TKIs reported significantly deeper and faster responses
but had no impact on survival prolongation, likely because of the availability of effec-
tive TKIs salvage therapies for patients who have a cytogenetic relapse with frontline
TKI therapy.
Salvage Therapy: For CML post failure on frontline therapy, second-line options
include second and third generation TKIs. Although potent and selective, these TKIs
exhibit unique pharmacological profiles and response patterns relative to different
patient and disease characteristics, such as patients' comorbidities, disease stage, and
BCR::ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation
display resistance to all currently available TKIs except ponatinib, asciminib, and
olverembatinib. Allogeneic stem cell transplantation remains an important therapeu-
tic option for patients with CML-CP and failure (due to resistance) of at least two
TKIs, and for all patients in advanced phase disease. Older patients who have a cyto-
genetic relapse post failure on all TKIs can maintain long-term survival if they con-
tinue a daily most effective/least toxic TKI, with or without the addition of non-TKI
anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine,
busulfan and others).
1236 © 2022 Wiley Periodicals LLC. wileyonlinelibrary.com/journal/ajh Am J Hematol. 2022;97:1236–1256.

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JABBOUR AND KANTARJIAN 1237
1 | D I S E A S E OV E R V I E W circumstances and phases of the disease. Allo-SCT is an important

treatment option in CML chronic phase (CP) post TKIs failure and
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm in advanced CML phases, and its role will be reviewed. Cytoge-
with an incidence of 1–2 cases per 100 000 adults. It accounts for netic and molecular benchmarks for patients on therapy will be
approximately 15% of newly diagnosed adult leukemia cases.1 In discussed. Finally, appropriate monitoring strategies for patients
2022, an estimated 8860 new CML cases will be diagnosed in the on TKIs will be addressed.
United States (US), and about 1220 patients will die of CML (due to
its high prevalence today). Since the introduction of imatinib in 2000,
the annual mortality in CML has decreased from 10–20% to 1–2%.1 2 | M A N I F E S T A T I O N S A N D ST A G I N G
Consequently, the prevalence of CML in the US, estimated at about
30 000 cases in 2000, has increased by approximately 8600/year to About 50% of patients diagnosed with CML in the US are asymp-
an estimated 150 000+ cases in 2022. Early estimates indicated the tomatic. The diagnosis of CML often occurs during a routine physical
CML prevalence to reach a plateau of about 180 000 cases by 2030– examination or blood tests. CML can be classified into three phases:
2040.2 However, based on the current incidence of near 9000 cases/ CP, accelerated phase (AP), and blast phase (BP). Most (90–95%)
year in the US (population expansion), and an estimated annual overall patients present in CML-CP. Common signs and symptoms of CML-
mortality of 1–2%, the prevalence plateau (annual incidence equal to CP, when present, result from anemia and splenomegaly. These
annual mortality of 9000 cases) is now estimated to be include fatigue, weight loss, malaise, easy satiety, and left upper
9000 100/2 = 400–450 000 cases in the US, which may not be quadrant fullness or pain. Rare manifestations include bleeding
reached until 2040–2050 with TKI optimal treatment. Considering a (associated with a low platelet count and/or platelet dysfunction),
world population of 8 billion and optimal CML management world- thrombosis (associated with thrombocytosis and/or marked leukocy-
wide with the availability of affordable generic tyrosine kinase inhibi- tosis), gouty arthritis (from elevated uric acid levels), priapism (usu-
tors (TKIs), the world prevalence of CML (25 times that of the US) ally with marked leukocytosis or thrombocytosis), retinal
might reach above 10 million cases. These projections depend on hemorrhages, and upper gastrointestinal ulceration and bleeding
difficult-to-estimate variables like the population growth in the US (from elevated histamine levels due to basophilia). Leukostatic symp-
and worldwide, and TKIs treatment penetration, optimization, and toms (dyspnea, drowsiness, loss of coordination, confusion) due to
affordability. leukemic cells sludging in the pulmonary or cerebral vessels, are
Central to the pathogenesis of CML is the fusion of the Abelson uncommon in CP despite white blood cell (WBC) counts exceeding
murine leukemia (ABL1) gene on chromosome 9 with the breakpoint 100 109/L. Splenomegaly is the most consistent physical sign
cluster region (BCR) gene on chromosome 22. This results in expres- detected in 20–40% of cases. Hepatomegaly is less common (<10%).
sion of an oncoprotein termed BCR::ABL1,3 a constitutively active Lymphadenopathy and infiltration of skin or other tissues are rare.
tyrosine kinase that promotes the growth and survival of CML cells When present, they favor Ph-negative CML or AP or BP of CML.
through downstream signaling pathways such as RAS, RAF, JUN Headaches, bone pain, arthralgias, pain from splenic infarction, and
kinase, MYC and STAT.4–10 This influences leukemogenesis by creat- fever are more frequent with CML transformation. Most patients
ing a cytokine-independent cell cycle with aberrant apoptotic signals evolve into AP prior to BP, but historically (before the availability of
in response to cytokine withdrawal. TKIs) 20% of patients developed a sudden BP without AP warning
Until the end of the last century, drug therapy for CML was lim- signals. This dreaded sudden evolution to BP has become rare with
ited to nonspecific agents such as busulfan, hydroxyurea, and TKI therapy, occurring mostly in the first 1–2 years of TKI therapy,
interferon-alfa (IFN-a).11 IFN-a therapy resulted in suppression of the often as a lymphoid BP in a younger patient.13 Otherwise, beyond
Ph-positive cells and improved survival, but had modest efficacy and 2 years of TKI therapy and in complete cytogenetic response
significant toxicities. Allogeneic stem cell transplantation (allo-SCT) is (CCyR), patients usually manifest a loss of cytogenetic response
curative but carries the risks of morbidities and mortality. Allo-SCT is (BCR::ABL1 transcript levels increasing to >1%), a loss of hematologic
an option for younger patients with good performance status and response and AP findings as prelude warnings to BP development.
organ functions, and who have an appropriate donor. CML-AP might be insidious or present with worsening anemia,
The CML therapeutic landscape changed dramatically with the splenomegaly and organ infiltration. CML-BP presents as an acute
development of the small molecule BCR::ABL1 TKIs that potently leukemia (myeloid in 60%, lymphoid in 30%, megakaryocytic or
interfered with the interaction between the BCR::ABL1 oncoprotein undifferentiated in 10%) with worsening constitutional symptoms,
and adenosine triphosphate (ATP), blocking cellular proliferation of bleeding, fever and infections.
the malignant clone. This “targeted” approach altered the natural his-
tory of CML, improving the 10-year survival rate from approximately
20% to 80–90%.1,2,12 3 | DI AGN OS I S
In this review, we will highlight the evidence supporting the
use of each of the available TKIs in frontline and subsequent-line The diagnosis of typical CML is simple and consists of documenting,
therapy, including how to select an agent under various in the setting of persistent unexplained leukocytosis (or occasionally
1238 JABBOUR AND KANTARJIAN
thrombocytosis), the presence of the Philadelphia (Ph) chromosome appropriately followed when assessing for response to TKI therapy.
abnormality, the t(9;22)(q34;q11), by routine cytogenetics, or the The typical translocations of BCR::ABL1 result in e13a2 or e14a2
Ph-related molecular BCR::ABL1 abnormalities by fluorescence in situ transcripts, producing the p210 oncoproteins. About 1% of patients
hybridization (FISH) or by molecular studies.14–16 may have e1a2/a3 transcript, resulting in a shorter p190 oncopro-
A FISH analysis relies on the co-localization of large genomic teins. These patients may have a worse prognosis. About 2–5% of
probes specific to the BCR and ABL1 genes. Comparison of simulta- patients have e13a3 or e14a3 variants of p210 BCR::ABL1 or e19a2
neous marrow and blood samples by FISH analysis shows high con- transcripts (p230) (rare; indolent) that may yield a false negative PCR
cordance. FISH studies may have a false positive range of 1% to 5% by routine probes. If not tested at diagnosis, this would give the false
depending on the probes used. impression that a patient may be in complete molecular response on
Reverse transcriptase-polymerase chain reaction (RT-PCR) TKI therapy.
amplifies the region around the splice junction between BCR and
ABL1. It is highly sensitive in detecting minimal residual disease. PCR
testing can either be qualitative (QPCR), providing information 4 | DI FF E R E N T I A L D I A G NO S I S
about the presence of the BCR::ABL1 transcript, or quantitative,
assessing the amount of BCR::ABL1 transcripts. Qualitative PCR is CML must be differentiated from leukemoid reactions, which usually
useful for diagnosing CML; quantitative PCR is ideal for monitoring produce white blood cell counts lower than 50 109/L, toxic granulo-
residual disease. Simultaneous peripheral blood and marrow QPCR cytic vacuolation, and Döhle's bodies in the granulocytes. These show
studies show a high level of concordance. False-positive and false- absence of basophilia and normal or increased LAP levels. The clinical
negative results can happen with PCR. False-negative results may be history and physical examination generally suggest the origin of the
from poor-quality RNA or failure of the reaction; false-positive leukemoid reaction. Corticosteroids can rarely cause extreme neutro-
results can be due to contamination. A 0.5–1 log difference in some philia with a left shift, but this abnormality is transient and of short
samples can occur depending on testing procedures, sample han- duration.
14–16
dling, and laboratory experience. For correlative purpose and CML may be more difficult to differentiate from other myelopro-
monitoring without necessarily performing repeat marrow studies, a liferative or myelodysplastic syndromes. Patients with agnogenic mye-
CCyR (0% Ph-positive metaphases by cytogenetic analysis) is equiv- loid metaplasia with or without myelofibrosis frequently have
alent to a negative FISH test (+/ 2%) and BCR::ABL1 transcripts splenomegaly, neutrophilia, and thrombocytosis. Polycythemia vera
by International Standard [IS] <1%. A partial cytogenetic response with associated iron deficiency, which causes normal hemoglobin and
(Ph-positive metaphases ≤35%) is equivalent to BCR::ABL1 hematocrit values, can manifest with leukocytosis and thrombocyto-
transcripts ≤10% [IS]. sis. Such patients usually have a normal or increased LAP score, a
The Ph chromosome is usually present in 100% of metaphases, WBC count <25 109/L, and no Ph abnormality.
often as the sole abnormality. Ten to 15% of patients have additional The greatest diagnostic difficulty lies with patients who have
chromosomal abnormalities usually co-occurring in the Ph-positive splenomegaly and leukocytosis but who do not have the Ph chromo-
cells (clonal evolution) involving trisomy 8, isochromosome 17, addi- some. In some, the BCR::ABL1 hybrid gene can be demonstrated
tional loss of material from 22q or double Ph, or others. despite a normal or atypical cytogenetic pattern. Patients who are Ph
Ninety percent of patients have a typical t (9;22); 5% have variant negative and BCR::ABL1 negative are considered to have Ph-negative
translocations which can be simple (involving chromosome 9 and a CML or chronic myelomonocytic leukemia. Rarely, patients have mye-
chromosome other than chromosome 22; i.e., still an ABL1 transloca- loid hyperplasia, which involves almost exclusively the neutrophil,
tion), or complex (involving one or more chromosomes in addition to eosinophil, or basophil cell lineage. These patients are described as
chromosomes 9 and 22). Patients with Ph-variants have response to having chronic neutrophilic, eosinophilic, or basophilic leukemia, and
therapy and prognosis like Ph-positive CML. About 2–5% of patients do not have evidence of the Ph chromosome or the BCR::ABL1 gene.
present with a morphologic picture of CML without the Ph-positivity Isolated megakaryocytic hyperplasia can be seen in essential thrombo-
by cytogenetic studies. If the FISH and PCR studies document Ph- cythemia, with marked thrombocytosis and splenomegaly. Occasional
negative BCR::ABL1 rearranged CML, then such patients have similar patients who present with clinical characteristics of essential throm-
response and outcome on TKI therapy as patients with Ph- bocythemia (thrombocytosis but without leukocytosis) may have
positive CML. CML; cytogenetic and molecular studies showing the Ph chromosome,
Bone marrow aspiration is mandatory for all patients in whom the BCR::ABL1 rearrangement, or both, lead to the appropriate diagno-
CML is suspected, as it will confirm the diagnosis (e.g., cytogenetic sis and treatment.
analysis), and will provide information needed for staging in terms of
the blast and basophil percentages. Baseline cytogenetic analysis will
allow the detection of clonal evolution, particularly i (17)(q10)-7/ 5 | FR O NT L I N E T R EA T M E N T O P T I O N S
del7q, and 3q26.2 rearrangements, associated with a relatively poor
prognosis.17 Baseline reverse transcriptase-polymerase chain reaction The four commercially available TKIs for the frontline treatment of
is needed to identify the specific type of rearrangement that can be CML include imatinib, dasatinib, nilotinib, and bosutinib. Current
TABLE 1 Summary of pivotal phase III trials of approved tyrosine kinase inhibitors for the frontline treatment of chronic myeloid leukemia
BCR::ABL1 < 10% Longest

Trial Treatment CCyR (%) MMR (%) at 3 months (%) EFS/PFS (%) OS (%) Follow-up (years)
At 10 years At 10 years
IRIS12 Imatinib (n = 304) 92 93 – 80 83 11
At 2 years At 5 years At 5 years
DASISION31–33 Dasatinib (n = 259) 86 76 84 85 91 5
Imatinib (n = 260) 82 64 64 86 90
ENESTnd45–47 Nilotinib 300 mg (n = 282) 87 78 91 86 88 10
Nilotinib 400 mg (n = 281) 85 80 89 90 90
Imatinib (n = 283) 77 63 67 87 88
BFORE50,51 Bosutinib 400 mg (n = 268) 83 74 81 93 95 5
Imatinib (n = 268) 77 65 61 91 95
Abbreviations: CCyR, complete cytogenetic response; EFS, event-free survival; MMR, major molecular response; PFS, progression-free survival; OS, overall
survival.
guidelines endorse all four TKIs as options for the initial management 5.2 | Imatinib generics
of CML in the chronic phase (CML-CP) (Table 1).
Imatinib generics entered the market recently after the patent for Glee-
vec expired. Several groups have reported on the efficacy and safety of
5.1 | Imatinib generic imatinib compared with Gleevec. The Polish Adult Leukemia
Group (PALG) imatinib generics registry reported on 726 patients who
Imatinib mesylate was the first TKI to receive approval by the Food started therapy with imatinib generics (multiple manufacturers) after
and Drug Administration (FDA) for the treatment of patients with the diagnosis of CML (n = 99) or who were switched to generic from
CML-CP. It acts via competitive inhibition at the ATP-binding site of Gleevec (n = 627) and were observed for at least 12 months.20 Among
the BCR::ABL1 oncoprotein, which results in the inhibition of phos- patients treated in the frontline setting, the rates of 3-month partial
phorylation of proteins involved in cell signal transduction. It effi- cytogenetic response (PCyR), 6-month CCyR, and 12-month MMR
ciently inhibits the BCR::ABL1 kinase, and also blocks the platelet- were 66%, 53%, and 50%, respectively. These rates were similar to the
derived growth factor receptor (PGDFR) and the C-KIT tyrosine expected rates achieved with Gleevec. The rates of resistance and intol-
kinase.18 erance were also similar (26% and 28%, respectively). Among patients
The International Randomized Study of Interferon and STI571 who switched therapy, responses were maintained in the vast majority,
(IRIS) in CML19 randomized 1106 patients in CML-CP to receive imati- with only 0.3% and 1% of patients losing their CCyR and MMR, respec-
nib 400 mg/day or IFN-a plus low-dose cytarabine. The outcomes tively. In a study from India, among 174 patients treated with imatinib
with imatinib therapy were significantly better, notably the rates of generics, response and survival rates were like those observed among
CCyR (74% vs. 9%, p < .001), and freedom-from-progression to AP or 1193 patients treated with Gleevec. The safety profiles were similar as
BP at 12 months (99% vs. 93%, p < .001). Highlighting the challenge well.21 Similar results were reported from our institution.22
of using IFN-a was the high crossover rate to imatinib due to intoler-
ance. With a median follow-up of almost 11 years, the estimated
overall survival rate on imatinib therapy was 83.3% with a cumulative 5.3 | High-dose imatinib and imatinib-based
CCyR rate of 83% and a 10-year major molecular response (MMR; combinations
PCR <0.1% or 3-log reduction of BCR::ABL1 transcripts[IS]) rate of
93%.12 Despite the high rate of crossover among patients assigned to Other strategies for frontline therapy include using higher doses of imati-
receive IFN-a plus cytarabine (66%) and the short duration of therapy nib or combining a TKI with an additional agent, such as IFN-a. In the
before crossover (median, 0.8 years), the 10-year survival rates Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study,
favored the imatinib therapy arm (83.3% vs. 78.8%).12 Still, only 48% patients were randomized to receive imatinib 400 mg once daily or twice
of patients enrolled remained on therapy at the 10-year follow-up daily (800 mg).23 Patients in the high-dose group achieved faster CCyR
time. This underscored the need for additional treatment options for and MMR, but rates were not significantly different at 12 months.
patients who had failed or were intolerant to imatinib. This led to the In a phase III randomized study, patients with newly diagnosed
rational development of second generation TKIs. CML-CP were assigned to one of four treatment arms (imatinib
400 mg once daily, imatinib 600 mg once daily, imatinib 400 mg once 5.5 | Lower dose dasatinib
daily plus peginterferon alfa-2a, or imatinib 400 mg once daily plus
subcutaneous cytarabine).24At 12 months, the rates of CCyR were In early clinical trials, dasatinib was active at lower doses with better
similar among the four groups. safety profile.36 In a randomized trial, dasatinib 100 mg daily was as
The CML-study IV explored whether treatment with imatinib at effective as 140 mg daily with a better safety profile.37 Investigators
400 mg/day (n = 400) could be optimized by doubling the dose from the DASISION trial reported on the ability to maintain the effi-
(n = 420), or by adding IFN-a (n = 430) or cytarabine (n = 158) or by cacy of dasatinib among patients who had the dose reduced while
using imatinib after interferon-failure (n = 128).25 After a median improving its safety profile.38 Based on this rationale, we treated
observation time of 9.5 years, the 10-year overall survival rate was 81 patients with early CML-CP with dasatinib 50 mg daily. With a
82%, 10-year progression-free survival (PFS) rate was 80%, and minimal follow-up of 12 months,39,40 the cumulative rates for MMR,
10-year relative survival rate was 92%. Despite a faster response with MR4, and MR4.5 by 12 months were 81%, 55%, and 49%, respec-
imatinib 800 mg, the survival difference between standard-dose and tively. Twenty-one patients (25%) had treatment interruptions for a
higher dose imatinib was only 3%. In a multivariate analysis, standard median of 13 days (range, 4–64 days). Five patients (6%) developed
dose imatinib was equivalent to other treatment arms. Patients who pleural effusions; 4 of them required a dose reduction. Two patients
reached the 6-month BCR::ABL1 transcripts [IS] <10% milestone had a (2%) failed to achieve any cytogenetic or molecular response and were
survival advantage of about 6% after 10 years regardless of therapy. taken off the study. At a median follow-up time of 24 months, none
Based on the above data, high-dose imatinib or imatinib combina- of the patients had disease transformation to AP or BP.40 The 2-year
tions (with IFN-a) should not be used a standard of care in frontline event-free and overall survival rates were 100%.40
CML-CP therapy. A propensity score analysis with 1:1 matching compared the
responses and outcomes of patients with CML-CP treated with front-
line dasatinib 50 mg/d or 100 mg/d (77 patients identified in each
5.4 | Dasatinib cohort).41 The median follow-up was 60 months. At 12 months, the
MMR rate was 82% with low-dose dasatinib and 75% with standard-
Dasatinib is an oral, second generation TKI that is 350 times more potent dose dasatinib (p = .229). Within the first year of therapy, higher
than imatinib in vitro.26–28 It also inhibits the Src family of kinases, which cumulative rates of MR4 (63% vs. 43%, p = .009), MR4.5 (53%
may be important in blunting critical cell signaling pathways.29 vs. 36%, p = .031), and complete molecular response (CMR) (46%
The DASISION trial was a phase III randomized study (1:1) vs. 33%, p = .060) were observed with low-dose dasatinib compared
comparing imatinib 400 mg once daily to dasatinib 100 mg once daily with standard-dose dasatinib. Dasatinib 50 mg/d resulted in a signifi-
in 519 newly diagnosed patients with CML-CP.30–32 The primary out- cantly lower incidence of Grade 3–4 pleural effusion (3% vs. 10%,
come was confirmed CCyR (cCCyR) at 12 months. Dasatinib therapy p = .016). No significant difference was observed in the EFS and OS
was associated with a higher cCCyR rate at 12 months (77% vs. 66%, rates. Such a strategy may have a significant impact on our future
p = .007). A five-year follow-up showed that dasatinib induced more practice mainly due equivalent efficacy, better safety profile, and
rapid and deeper responses (12-month CCyR, MMR, MR4.5) at early lower cost of care.
time points compared with imatinib.33 Transformations to CML-AP or The DAVLEC phase II study evaluated dasatinib 20 mg daily as
CML-BP were fewer with dasatinib versus imatinib (4.6% vs. 7.3%). frontline CML-CP treatment in patients >70 years of age. Among
However, the estimated 5-year survival rate was similar with imatinib 52 patients treated (median age 77.5 years; range, 73.5–83 years;
and dasatinib (90% vs. 91%).33 median follow-up 12 months), 38 patients (73%) had BCR::ABL1 IS
A second multicenter trial randomized patients with newly diag- <10% at 3 months. The 12-month cumulative rates of MMR, MR4,
nosed CML-CP to dasatinib 100 mg once daily or imatinib 400 mg and MR4.5 were 60%, 27%, and 14%, respectively. Three patients dis-
once daily.34 Patients treated with dasatinib achieved a higher rate of continued therapy due to treatment failure, and one patient due to
CCyR (84% vs. 69%, p = .04). There was more toxicity experienced drug-related adverse event (long QT syndrome). Four patients had
with dasatinib (Grades 3–4 adverse events 58% with dasatinib and pleural effusions (Grade 1–2).42 The results from this study suggest
34
35% imatinib), mostly hematologic toxicity. that using dasatinib 20 mg daily is safe and feasible among older
A third phase III randomized study, SPIRIT 2, compared imatinib patients, often with medical comorbidities, allowing the achievement
400 mg daily with dasatinib 100 mg daily.35 The interim results of molecular remissions with a lower incidence of adverse events
showed the 12-month MMR rates were higher with dasatinib (58% compared with higher doses.
vs. 43%, p < .001). The 12-month CCyR rates were 51% and 40%
(p < .002), respectively. The progression rate to CML-AP was 0.5%
with dasatinib and 0.7% with imatinib. The progression rate to CML- 5.6 | Nilotinib
BP was 1% vs. 1.7%. Pleural effusions occurred more frequently with
dasatinib (19% vs. <1%). Other side effects of dasatinib included mye- Nilotinib is a structural analog of imatinib. Its affinity for the ATP bind-
losuppression (20%), and rare pulmonary hypertension (1–2%). ing site on BCR::ABL1 is 30–50 times more than imatinib in vitro.43
Nilotinib was compared with imatinib as frontline CML-CP more commonly diarrhea (75%), nausea (37.3%), thrombocytopenia
therapy in a large, international, randomized study (ENEST-nd). Two (35.8%) and increased ALT (33.6%); patients on imatinib mostly
doses of nilotinib (300 mg or 400 mg twice daily) were compared with reported diarrhea (40.4%), nausea (42.3%), and muscle spasms
imatinib 400 mg once daily.44–46 The primary endpoint, MMR at (30.6%). The most frequent side effects leading to bosutinib discontin-
12 months, was significantly higher for both doses of nilotinib com- uation were increased ALT (4.9%) and diarrhea (1.5%), while imatinib
pared with imatinib (44% and 43% vs. 22%, p < .001). The cumulative therapy was mainly discontinued due to thrombocytopenia (1.5%) and
incidence of CCyR by 24 months was 87% with nilotinib 300 mg diarrhea (1.1%).51
twice daily, 85% with nilotinib 400 mg twice daily, and 77% with
imatinib 400 mg daily (p < .001).46
With a median follow-up of 10 years,47,48 the cumulative inci- 5.8 | The MD Anderson Cancer Center experience
dences of MMR by 10 years were 77.7% with nilotinib 300 mg twice
daily and 62.5% with imatinib (p < .0001).47 The 10-year cumulative We published the long-term responses and outcomes of patients with
rates of MR4.5 were 61% and 39.2%, respectively (p < .0001).47 There CML-CP and provided a comparison of four commonly used TKI
was no significant difference in outcome among patients treated with modalities.52 Unlike previous reports, our study provided a compara-
47
nilotinib and imatinib. The estimated 10-year progression-free sur- tive analysis of four TKI modalities after a long follow-up time. The
vival (PFS) rates were 86.2%, 89.9%, and 87.2% with nilotinib 300 mg analysis included 482 patients treated (July 2000–September 2013) in
twice daily, nilotinib 400 mg twice daily, and imatinib, respectively.47 consecutive or parallel clinical trials, with imatinib 400 mg daily
The estimated 10-year survival rates were 87.6%, 90.3%, and 88.3%, (n = 68), imatinib 800 mg daily (n = 200), dasatinib 50 mg twice daily
respectively. 47
or 100 mg daily (n = 106), or nilotinib 400 mg twice daily (n = 108).
In a second randomized trial with the same design that enrolled More patients receiving imatinib 800 mg or second-generation TKIs
267 Chinese patients, the MMR rate was 52% at 12 months with nilo- (i.e., dasatinib or nilotinib) achieved CCyR (87% with imatinib 400 mg;
tinib compared with 28% with imatinib.49 However, the rates of both 90% with imatinib 800 mg; 96% with dasatinib; and 93% with niloti-
CCyR (84% vs. 87%) and PFS (95% each) were similar at 24 months. nib). The overall MMR rates were 76%, 86%, 90% and, 91%, respec-
Overall, 6 patients in each arm progressed to AP/BP. In both arms, tively. The overall MR4.5 rates were 57, 74%, 71%, and 71%,
the estimated 2-year survival rate was 98%. respectively. This finding was consistent over time (3–60 months),
While nilotinib therapy was overall well tolerated, there was an where at any time point, imatinib induced lower rates of cytogenetic
increased risk of arterio-occlusive events (AOEs) on therapy. The and molecular responses. This landmark assessment contrasts with
10-year cumulative rates were 24.8%, 33.4%, and 6.3% with nilotinib previous reports where results were reported cumulatively (“by” not
300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg “at”) and can be misleading. The 5-year event-free survival signifi-
daily, respectively.40 Other notable side effects were headache and cantly differed between the imatinib 400 mg group and the other TKI
skin rashes (common—20–30%—but mild to moderate; alleviated by groups (imatinib 800 mg p = .029, dasatinib p = .003, nilotinib
dose reduction), self-limited elevation of indirect bilirubin (10%), ele- p = .031). However, there was no significant difference in the 5-year
vations of blood sugar (10–20%), and pancreatitis (1–2%). rates of FFS, transformation-free survival, or overall survival. Among
patients who achieved CCyR, no difference in outcomes was
observed regardless of whether MMR or MR4.5 response was addi-
5.7 | Bosutinib tionally achieved.52 The long-term results of frontline nilotinib and
dasatinib therapy were reported as well.53,54 Among 122 patients
Bosutinib is a potent dual SRC/ABL kinase inhibitor.14 The drug was treated with nilotinib with a median follow-up of 78 months, the
first approved at 500 mg daily to treat CML-CP following resistance cumulative CCyR and MMR rates were 91%, each. Seventy-five per-
and/or intolerance to prior TKI therapy. It was recently approved at cent and 59% of patients achieved MR4.5 and a sustained MR4.5
400 mg daily as first-line treatment of CML-CP. In a multinational, beyond 2 years, respectively. The estimated 5-year EFS and OS were
phase III study, 536 patients with newly diagnosed CML-CP were ran- 89% and 93%, respectively, and the corresponding rates at 10 years
domized to bosutinib 400 mg once daily (n = 268) or imatinib were 85% and 88%, respectively.53 Among 149 patients treated with
(n = 268). 50
The MMR rate at 12 months (primary endpoint) was dasatinib with a median follow-up of 6.5 years, the cumulative CCyR,
higher with bosutinib (47% vs. 37%; p = .02), as was the CCyR rate by MMR, and MR4.5 rates at 11 years were 92.6%, 88.2%, and 79.5%
12 months (77% vs. 66%; p = .0075). The favorable outcome with (sustained beyond 2 years 55%), respectively. The 10-year overall sur-
50
bosutinib was maintained at 2 and 5 years. At 5 years, bosutinib vival, transformation-free survival, event-free survival, and FFS rates
resulted in higher cumulative rates of MMR (73.9% vs. 64.4%), MR4 were 89%, 95%, 86%, and 65%, respectively (Table 2).54
(58.2% vs. 48.1%), and MR4.5 (47.4% vs. 36.6%) compared with imati- In a study from Japan, 454 patients with newly diagnosed CML-
nib. No additional transformation events (AP/BP) were recorded with CP were randomized to receive dasatinib 100 mg daily or nilotinib
this longer follow-up (6 patients in the bosutinib arm, and 7 patients 300 mg BID.55 No differences were noted in the 3-year rates of CCyR
51
in the imatinib arm). The 5-year OS rates were similar: 94.5% with (79% vs. 78%), MR4.5 (44% vs. 40%), or survival (99% vs. 99%). Given
bosutinib and 94.6% with imatinib. Patients on bosutinib experienced the equivalent efficacy and lower toxicity of lower dose dasatinib in
T A B L E 2 Frontline TKIs therapy:

% Cumulative Imatinib 400 mg Imatinib 800 Nilotinib Dasatinib
MDACC experience52
CCyR 87 90 93 96
MR4.5 57 74 71 73
Abbreviation: CCyR, complete cytogenetic response.
our phase 2 study, frontline dasatinib 50 mg daily has become our Current guidelines recommend any of the four TKIs, imatinib,
standard of care for frontline therapy of patients with CML-CP, dasatinib, nilotinib or bosutinib as good therapeutic options with a
including patients with high-risk disease. category 1 recommendation for the initial treatment of CML-CP.
Second generation TKIs produced higher rates of early optimal
responses but had no impact on long-term survival (probably because
5.9 | Investigating combinations of dasatinib with of available effective salvage therapies). They were also associated
venetoclax or oral decitabine with higher rates of serious adverse events (10-year cumulative rate
of AOEs with nilotinib 33%). Second generation TKI may benefit
While TKIs are effective in CML, they may not eliminate the dormant patients with high-risk disease; a relevant decrease in the rate of
CML stem cells which may result in disease relapse after treatment transformation to AP and a BP was achieved with nilotinib, dasatinib,
discontinuation.56 The BCR::ABL1 tyrosine kinase regulates several and bosutinib. In our opinion, higher dose imatinib regimens should
BCL-2 family proteins that confer resistance to apoptosis in CML not be used as frontline CML-CP therapy anymore. Combination
cells.56 Targeting BCR::ABL1 and BCL-2 could have therapeutic bene- approaches in the frontline setting are investigational. These strate-
fits in quiescent CML CD34+ cells that are insensitive to TKI.57 gies are also not benign interventions, as they add to the economic
Carter and colleagues demonstrated increased BCL-2 expression and toxicity burden of the overall treatment plan. Allo-SCT or other
at the protein level in bone marrow cells, particularly in Lin()Sca-1(+) chemotherapy agents are not recommended as frontline therapy
cKit(+) cells of inducible CML in mice.57 Selective inhibition of BCL-2, CML-CP, given the excellent outcomes and long-term survival
aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly achieved with the TKIs. Even considering the possible low cost of
decreased leukemic Lin()Sca-1(+)cKit(+) cell numbers and long-term allo-SCT as a one-time procedure in some geographies ($14000–
57
stem cell frequency and prolonged survival in a murine CML model. 20 000 in India and Mexico), generic imatinib now costs <$400–500
This combination effectively eradicated CD34(+)CD38(), CD34(+) per year of therapy (total cost even with 40 years of life expectancy
CD38(+), and quiescent stem/progenitor CD34(+) cells from blast about $20000), arguing for always delaying allo-SCT to postfrontline
phase CML patient samples.57 CML therapy. Lower dose dasatinib (50 mg daily) showed sustained
These results suggest that BCL-2 is a key survival factor for CML efficacy compared with standard dose and had a better safety profile.
stem/progenitor cells and that combined inhibition of BCL-2 and At MD Anderson, patients are currently offered therapy with dasati-
BCR::ABL1 tyrosine kinase has the potential to improve the depth of nib 50 mg daily +/ ASTX727. Because of the higher rates of durable
response and cure rates of CML-CP.57 We have completed a study deep/complete molecular responses with second generation TKIs
combining dasatinib 50 mg daily with venetoclax added 3 months into (which could lead to discontinuation of TKI therapy and potential
therapy. The results are under evaluation. molecular cures discussed later), considerations of second generation
Decitabine was initially tested as monotherapy among TKIs in younger patients with CML (e.g., age < 50 years) may be
123 patients with CML: 64 in BP, 51 in AP, and eight in CP. The entertained if offered at appropriate cost (price at most 3 times higher
58
objective response rates were 28%, 51%, and 63%, respectively. than generic imatinib and not exceeding $10000–25 000 per year).
The subsequent combination of decitabine and imatinib in patients
with AP or BP was active and well tolerated. More recently, a phase
I/II trial was conducted to determine the safety and efficacy of the 6 | SELECTING A FRONTLINE TKI
combination of decitabine and dasatinib among 30 patients with CML THERAPY
in AP or BP. The respective rates of major hematologic response,
major cytogenetic response (MCyR) and MMR were 48%, 44%, and 6.1 | Aims of frontline CML-CP therapy
33%. The median OS was 13.8 months.59 Based on these promising
results, a novel combination of oral decitabine/cedazuridine Selecting particular TKIs as frontline therapy depends on several con-
(ASTX727) with low dose dasatinib (50 mg/d) is under evaluation in siderations including: (1) the aim of therapy, (2) the patient age and
newly diagnosed CML-CP(NCT05007873). This strategy has the co-morbidities, (3) the cost and affordability of the TKI under consid-
potential to induce deeper and faster responses compared with TKI eration, and (4) the CML risk profile. The two major aims of CML ther-
monotherapy, which might ultimately increase the proportion of apy are normalization of survival and possibly the achievement of a
patients eligible for TKI discontinuation at 3 years and improve the durable deep molecular response (DMR; MR4 or MR4.5 lasting for 2+
rate of treatment-free remission (TFR). years) and TFR status. For survival prolongation/normalization, at
least 16 randomized trials have shown on average the equivalence of inflammatory bowel disease or renal dysfunction.63 In order to avoid
imatinib and second-generation TKIs, provided patients are treated the early self-limited gastrointestinal toxicities (diarrhea), it is recom-
optimally, and treatment is changed from imatinib to second genera- mended to start bosutinib at 100 mg daily 1 week, then escalate to
tion TKI promptly when there is evidence of treatment failure (imati- 200 mg daily 1 week, 300 mg daily 1–2 weeks, then settle at
nib toxicities or CML resistance). If the aim of therapy is durable 400 mg daily in the frontline therapy or at the optimal individual dose.
DMR/TFR, second generation TKIs may achieve such results faster Finally, the patient age plays an important role in the treatment
than imatinib. Thus, they may be considered among younger patients decision. Patients younger than 50 years are expected to live 30+
with CML-CP in whom TKI discontinuation and a TFR status are more years. Therefore, inducing a durable DMR-CMR may potentially
important. lead to therapy discontinuation. Second generation TKIs induce signif-
icantly faster DMRs compared with imatinib. The issue of durable
DMR-CMR and potential therapy discontinuation plays a less impor-
6.2 | Patient age, comorbidities, and TKI toxicity tant role in older patients in whom discontinuing therapy is less
profile relevant.
While multiple TKIs are available to treat newly diagnosed CML in CP,
each has a distinct toxicity profile to consider when deciding on ther- 6.3 | Cost and affordability of a TKI
apy. Most TKIs are reasonably well tolerated with adequate monitor-
ing and supportive care. The cost of cancer drugs has risen drastically over the past two
Imatinib causes bothersome quality-of-life side-effects including decades.64,65 All anticancer agents approved in the recent years were
weight gain, fatigue, peripheral and periorbital edema, bone and mus- priced (Average Whole Sale Price [AWP]; what the patient pays on
cle aches, nausea and others. However, most are mild to moderate. average) at over $120000–270 000 annually.66–68 Unlike TKIs in
Less than 5–10% experience elevations in creatinine with long-term CML, most of these therapies do not provide a substantial improve-
therapy. Rare neurologic toxicities were reported (worsening of Par- ment in survival or other objective measures to justify the cost. The
kinsonism, dementia-like findings). BCR: ABL1 TKIs transformed CML from a fatal cancer into a chronic
For patients at risk of developing pleural effusions (existing lung cancer with a near-normal life expectancy. When an international
injuries), dasatinib should be avoided. This might be relevant for group of CML experts called attention to the high prices of TKIs, the
patients with a history of lung disease (e.g., chronic obstructive pul- cost history of imatinib (the first small-molecule targeted therapy in
monary disease), cardiac disease (e.g., congestive heart failure), or cancer) was used to illustrate the problem with the high cancer drug
uncontrolled hypertension. Pulmonary arterial hypertension (PAH) is a prices.68,69 When first approved in the US, the AWP price of imatinib
rare yet important complication of dasatinib,60 and patients with pre- was <$30 000/year, a price set by the drug company to make the
existing PAH should be considered for alternative TKIs. Dasatinib also development and commercialization of imatinib profitable when it
inhibits platelets function,61 and patients taking concomitant antico- was expected that most patients would be treated for an estimated
agulants may be at an increased risk of hemorrhagic complications.62 5 to 10 years. Patients with CML now live a near-normal lifespan and
Nilotinib has been associated with hyperglycemia; caution should remain on imatinib therapy.68,69 Paradoxically, with a higher number
be exercised in patients with uncontrolled diabetes when initiating of patients and a longer duration of therapy, the AWP of imatinib had
therapy. Nilotinib should be avoided or prescribed with caution in quadrupled to $132 000/year. This AWP is in the same range as dasa-
patients with diabetes or history of pancreatitis. During preclinical tinib, nilotinib, and bosutinib, all priced above $200 000/year of
development, nilotinib was shown to potentially prolong the QT inter- therapy.
val, and parameters were put in place to monitor for this complication Based on market forces, the availability of 4–5 generics would
after the drug was approved. Patients should take nilotinib in a fasting generally reduce significantly the Wholesale Acquisition Price (WAP;
state to avoid excess drug exposure. Nilotinib has also been associ- roughly the price a drug manufacturer would charge). In 2022, 15 ima-
ated with AOEs, such as ischemic heart disease, ischemic cerebrovas- tinib generics were available in the US. Their WAP ranges from $1500
47
cular events, and peripheral artery occlusive disease (PAOD). In the to $55 600 per year of treatment (median WAP 44400/year). How-
10-year follow-up on the ENEST-nd trial,47 24.8% of patients experi- ever, because of the market intermediaries (wholesalers, Group Pur-
enced AOEs with nilotinib 300 mg BID. Nilotinib use should be limited chase Organizations, Pharmacy Benefit Managers) that mark up the
or avoided in patients with risk factors such as diabetes or coronary, drug price along its journey from the drug manufacturer to the
cerebrovascular, or peripheral artery disease. Avoiding nilotinib in patient, the AWP of imatinib remains astoundingly high, above
patients with significant past history of AOEs is warranted with the $130 000/year for 12 of the 15 generics (the other three have AWPs
availability of other viable options. Bosutinib and imatinib are the saf- of $5300, $54 700 and 466 700/year, respectively). Outside of the
est TKIs in relation to AOEs. US, generic imatinib is commonly priced at a range of $400–8000/
Boustinib side-effects are gastro-intestinal, hepatic, and renal. year. Physicians will then have to assess the “treatment value” of sec-
Among patients with such comorbidities, bosutinib should be avoided ond generation TKIs (dasatinib, nilotinib, bosutinib) in the frontline
or used cautiously. Bosutinib should be avoided in patients with setting against generic imatinib in relation to benefits versus cost.
Second generation TKIs may be offered for patients with high-risk TABLE 3 Important response categories in CML
disease, while imatinib and/or its generic formulation are offered for Response Translates into:
patients with low- and intermediate-risk disease. Generic second gen-
BCR::ABL1 ≤ 10% at Significantly improved survival
eration TKIs, offered at lower costs (<$10 000/year) may make them 6 months; CCyR later
more cost effective as frontline TKIs therapy in younger patients MMR Modest improvement in EFS; possible
based on different modeled scenarios considered.70–72 longer duration CCyR; no survival
The billionaire Mark Cuban created a generic company, Cost- benefit
Plus, that offers generic drugs directly to patients (thus avoiding the DMR Possibility of therapy discontinuation
classical drug supply chains of intermediary suppliers) at cost Abbreviations: CCyR, complete cytogenetic response; DMR, deep
+15%.73 Therefore, a safe and effective generic imatinib is now molecular response (≤4.5-log reduction to ≤4-log reduction of BCR::ABL1
available at $47 per month ($565 per year) in the US through transcript levels); EFS, event-free survival; IS, international scale; MMR,
generic companies that supply imatinib. Considering the median age major molecular response.
of 60 years at diagnosis, the total cost of imatinib therapy for

30 years would be under $20 000. Since the long-term survival is
comparable with imatinib versus second-generation TKIs, all 7 | M O N I T O RI N G T R E A T M E N T RE S P O N S E :
patients with CML worldwide have access to affordable generic S U R R O G A T E E N D P O I N T S A N D M I L E S T O NE S
imatinib (at least 350-fold less expensive than dasatinib, nilotinib or
bosutinib). Raising awareness in the medical community of this Because patients with CML on TKI therapy are anticipated to live a
“Mark Cuban effect” can spare patients the out-of-pocket expenses near-normal life, surrogate markers of outcome are important
of second-generation TKIs, which can be as high as 20% to 25% of (Table 3). In general, achieving a deeper response faster has been
the treatment costs.73 associated with improved outcome, although the result of molecular
The dosing of TKIs can affect the cost of therapy, depending on testing is dependent on individual laboratories and techniques. Due to
the TKI used. Using dasatinib at the lower dose of 50 mg daily is not advances in technology, there are less invasive tests available for
only as effective and less toxic than 100 mg daily,41 but also cuts the monitoring than the traditional bone marrow examinations (except
price by half, from an average AWP of $228 000 to $127 000 per when changing TKI; or in unusual situations like unexpected myelo-
year. Unfortunately, ponatinib 45, 30, and 15 mg pills have the same suppression in order to exclude transformation or the development of
AWP. However, in treating T315I-mutated CML, ponatinib AWP is myelodysplastic syndrome or other marrow conditions).
$270 000 versus $1.3 million a year for asciminib 200 mg BID (the
effective dose in T315I-mutated CML). Finally, the advent of generic
second generation TKIs may offer a more affordable context to the 7.1 | Important points for monitoring and
ongoing discussions of frontline CML therapy and the need to determining treatment failure
achieve TFR.
At baseline, all patients should undergo a bone marrow examination
to establish the diagnosis, assess the percentage of blasts and baso-
6.4 | CML-CP risk status phils, and perform a cytogenetic analysis to confirm the presence of
the Philadelphia chromosome and to assess for cytogenetic clonal
For patients with CML-CP, several risk scores (Sokal74 or Hasford75) evolution, particularly i(17)(q10)-7/del7q, and 3q26.2 rearrange-
help predict outcomes. Patients with low- or intermediate-risk disease ments.17 The current recommendation that patients have a follow up
are expected to have optimal responses with imatinib, dasatinib, nilo- bone marrow study at 3, 6, and 12 months after starting therapy is
tinib, or bosutinib. However, second generation TKI as frontline ther- not necessary. An alternative method to determine cytogenetic
apy may be more beneficial in patients with high risk disease.31,46,50 response is with the use of FISH and PCR on peripheral blood.76 If a
Patients with higher risk disease have a lower likelihood of achieving patient is responding optimally, and the FISH study is negative at 6 or
the early milestones of CCyR and MMR and, particularly, higher risks 12 months and or BCR::ABL1 transcripts [IS] are <1%, it may be rea-
of disease transformation to AP-CML or BP-CML. sonable to omit marrow exams, as the patient is likely to be in
Any of the TKIs currently approved for frontline CML therapy CCyR.77
may be selected. These include imatinib, dasatinib, bosutinib, or niloti- In the first year of therapy, monitoring peripheral blood by PCR
nib. While second generation TKIs have demonstrated superiority every 3 months is reasonable. Once the patient is in a confirmed
over imatinib in relation to early surrogate markers, imatinib is still MMR (MMR for 2–3 times over a 6-month period), then monitoring
highly effective in most patients with CML. At MD Anderson, when PCR every 6 months is adequate and safe, provided patient compli-
choosing a BCR::ABL1 TKI, we consider issues such as comorbidities, ance is documented.77 For patients in CCyR, the achievement and
patient age, adverse events profile, risk stratification score, and cost. maintenance of a DMR is of debatable significance for survival (unless
Kinase domain mutation profile plays no role in selecting an initial TKI the treatment aim is a durable DMR and TFR). Several studies evaluat-
but becomes relevant in the relapse setting. ing patients receiving imatinib or second generation TKIs have found
TABLE 4 Percentage of survival by early molecular response TABLE 5 MDACC criteria for response/failure and change of
therapy
Study Q-PCR <10% Q-PCR >10%
80 Time (months) Imatinib Second generation TKIs
UK (8-year) 93 57
MDACC (10-year)52 98 94 3–6 MCyR; PCR ≤10% [IS] CCyR; PCR ≤1% [IS]
ENESTnd 44
97 87 12 CCyR; PCR ≤1% [IS] CCyR; PCR ≤1% [IS]
DASISION30 96 86 Later CCyR; PCR ≤1% [IS] CCyR; PCR ≤1% [IS]
Abbreviation: Q-PCR, quantitative polymerase chain reaction. Abbreviations: CCyR, complete cytogenetic response; IS, international
scale; MCyR, major cytogenetic response; PCR, polymerase chain reaction.
that patients in CCyR have similar survival regardless of whether or achievement of CCyR or MR2 (PCR <1% [IS]) within 12 months and
not they achieved MMR or DMR.78,79 to continue to maintain a CCyR at any time beyond 12 months, espe-
Early molecular response has been shown to have strong prog- cially with standard dose imatinib therapy. For second generation
nostic value (Table 4). This has been shown with each of the four TKIs TKIs, CCyR may need to be achieved sooner for an optimal outcome,
used in the frontline setting. A BCR::ABL1 transcripts [IS] <10% at 3– for example, within 6 months.86,87
6 months separates patients into high and low risk categories for long An important question is the variability of PCR testing results and
term outcomes (i.e., progression, survival).31,46,50,80 The important the possible erroneous treatment changes if we rely heavily on such
question is: how should we advise a patient who does not meet the results. In a report of one sample collected at 3 months and tested
3-month benchmark? One option is to switch TKIs early, but there are 96 times, the mean value was 11% (range, 5–16%), with only 31% of
no data indicating this will alter long-term outcome. In the DASCERN, tests being ≤10%.88 This approach also applies to patients on second
a randomized, open-label, international phase 2b trial in adults with generation TKIs, because, as mentioned earlier, very early switching
CML-CP with CHR but BCR::ABL1 > 10% IS at 3 months after initial has not shown to influence long-term outcome.89 One study random-
treatment with imatinib 400 mg QD, patients were randomized to ized patients in CCyR on imatinib for at least 2 years to continue ima-
early switch to dasatinib 100 mg daily or ≥400 mg daily of imatinib tinib or switch to nilotinib.90 Switching to nilotinib induced deeper
81
(option for dose escalation). While early switch induced a higher molecular responses, but did not translate into an improvement in
rate of 12-month MMR (29% vs. 13%; p = .005), there was no differ- PFS or in other meaningful outcomes. The 2020 updates of the ELN
81
ence in OS and PFS with a median follow-up of 30 months. A guidelines are complex and may confuse or not allow physicians to
follow-up measurement at 6 months will help define patients clearly interpret the correct approach at specific time points.91 Our recom-
in need of a change in therapy. This strategy has been retrospectively mendations summarized in Table 5 reflect a practical approach based
analyzed by several groups.82–86 The results of two independent on our clinical experience.
study groups have suggested that all patients with BCR::ABL1 tran- Patients who meet all the relevant benchmarks in the first
scripts >10% at 3 months do not necessarily have an inferior out- 12 months are monitored periodically using molecular testing +/
come.83,84 Patients who continued on therapy and achieved FISH (molecular testing only if BCR::ABL1 [IS] transcripts consistently
transcripts levels <10% by 6 months had the same long-term favor- below 0.1%). If there are clear signs of possible failure, patients should
able outcome as those with optimal molecular responses at 3 months. undergo a bone marrow examination with cytogenetic analysis and
Patients with BCR::ABL1 transcripts [IS] >10% after 6 months have a molecular testing, including analysis for mutations. Any degree of
worse outcome; still the 4-year survival with BCR::ABL1 transcripts cytogenetic relapse calls for a change of therapy. Fluctuating molecu-
[IS] >10% versus <10% are 100% versus 74%. The CML-study IV lar levels during continuous CCyR would only prompt closer monitor-
established the 6-month BCR::ABL1 transcripts [IS] <10% response as ing and a compliance assessment. Some CML experts advocate a
an optimal milestone. Patients who reached the 6-month milestone change of therapy for a documented consistent loss of MMR after 3–
had a survival advantage of about 6% after 10 years regardless of 4 years of therapy (BCR::ABL1 transcripts >0.1% [IS]), particularly if
therapy.25 Thus, it may be reasonable to change the TKI from imatinib transcript levels are consistently above 0.3–0.5%. This scenario could
to second generation TKI for BCR::ABL1 transcripts [IS] >10% after be justified if the goal is to achieve a durable DMR in order to offer a
6 months. However, a similar situation in a patient on second genera- TFR strategy. The ELN 2020 guidelines propose the achievement of
tion TKI does not imply consideration of allo-SCT, since the estimated TFR as an important goal of therapy in CML. This will be discussed
5-year survival if they continue TKI therapy is 81%.33 later in detail.
In several studies, the achievement of a CCyR (Ph-positive meta-
phases 0%; BCR::ABL1 transcripts [IS] ≤ 1%) at 12 months or later on
7.2 | When to switch therapy TKI therapy was associated with a significant survival benefit com-
pared with achievement of lesser degrees of response. Achievement
Achievement of CCyR at 12-month and maintaining a CCyR status of CCyR is the primary endpoint of TKI therapy. Achievement of
thereafter is associated with a relative normal lifespan. For survival as BCR::ABL1 transcripts [IS] ≤ 0.1% (MMR) was associated with modest
a treatment endpoint in CML, the aim of therapy should be the improvements in event-free survival rates, possible longer durations
of CCyR, but not with a survival benefit. The achievement of DMR assessed. The rates of adherence to imatinib therapy range from
offers the possibility of treatment discontinuation. Lack of achieve- 75% to 90%. Lower adherence rates correlate with worse
ment of MMR or of DMR should not be interpreted as a need to outcome.92–94 In a study of 87 patients with CML-CP treated with
change TKI therapy or to consider allo-SCT. Response assessments at imatinib 400 mg daily, an adherence rate of 90% or less resulted in
earlier times on frontline TKI therapy (3–6 months) have shown better MMR rate of 28% compared with 94% with >90% adherence rate
outcomes with achievement of a major cytogenetic response by 3– (p < .001).92 CMR rates were 0% versus 44% (p = .002), and no
6 months on imatinib therapy (Ph-positive metaphases ≤ 35%; BCR:: molecular responses were observed when adherence rates were
ABL1 transcripts [IS] ≤ 10%). When second generation TKIs are used 80% or lower. Lower adherence rates have been described in youn-
in front-line therapy, achievement of complete cytogenetic response ger patients, those with adverse effects of therapy, and those who
(BCR::ABL1 transcripts [IS] ≤ 1%) by 3–6 months of TKIs therapy has have required dose escalations.92
been associated with improved outcomes.
At MD Anderson, our major treatment milestones are at 6 and
12 months. Patients with lack of PCyR (BCR::ABL1 transcripts [IS] 8.1 | Second and third generation TKIs
> 10%) at 6 months, or without CCyR (BCR::ABL1 transcripts
[IS] ≤ 1%) at 12 months, or with loss of response at any time are can- Clinical studies of second line and third line TKIs are summarized in
didates for a change of TKI therapy. The choice of TKIs is based on Table 6. Based on these studies, several noteworthy ideas have
the mutation profiles and patients' comorbidities. We do not con- emerged. First, second-line treatment with dasatinib, bosutinib, or
sider a change of TKI therapy in patients in CCyR but without MMR. nilotinib can yield high rates of responses in patients who have inade-
We also do not consider a change of therapy at any time point in quate response to imatinib, including high rates of MMR.95–97 Second,
patients who do not achieve MR4 or more with the aim of inducing dose escalation of imatinib can improve response rates in patients
a TFR. Such strategy is not cost-effective and may be associated with inadequate response to standard-dose imatinib,98 but switching
with serious new adverse events. to second-line TKI can be more effective.99 Several studies that evalu-
ated second-line nilotinib,100,101 dasatinib,99,101 or bosutinib,102 and
high-dose imatinib (400 mg BID) have demonstrated significantly
8 | MANAGEMENT OF TKI RESISTANCE higher rates of CCyR and MMR with the newer TKIs than with high-
dose imatinib. Moreover, PFS was better with the newer TKIs. Third,
With the widespread use of all commercially available TKIs and earlier switch to second line TKI may be more effective than later
increased CML prevalence, more patients are developing drug resis- switch. In the TIDEL-II study, patients who had suboptimal response
tance. A common mechanism of resistance involves point mutations to imatinib and were switched to nilotinib had a higher rate of CMR at
in the kinase domain of BCR::ABL1, which impairs the activity of the 12 months than patients who had dose escalation of imatinib prior to
available TKIs. Second generation TKIs overcome most of the muta- being switched to nilotinib.103 In a retrospective pooled analysis of
tions that confer resistance to imatinib, though novel mutations three clinical studies of second-line dasatinib with CML with resis-
rendering the leukemia resistant to second generation TKIs have tance or intolerance to imatinib, patients switched to dasatinib after
emerged. One important mutation, T315I, known as the “gatekeeper” the loss of MCyR (early intervention group) had higher rates of CCyR
mutation, displays resistance to all currently available TKIs except and MMR, as well as 24-month EFS, TFS, and OS, than patients
ponatinib, asciminib, and olverembatinib (HQP1351). switched after the loss of both MCyR and CHR (late intervention
Before defining a patient as having TKI resistance and modifying group).104 Although this analysis included studies with distinct study
therapy, treatment compliance and drug–drug interactions should be designs and various dosing schedules of dasatinib, the essential
TABLE 6 Summary of 2nd and 3rd generation TKIs in CML-CP postimatinib resistance
Response Dasatinib97 Nilotinib96 Bosutinib95 Ponatinib110 Asciminib117

Follow-up (months) 72 ≥48 ≥108 60 15
CHR (%) 89 77 86 92 NA
MCyR (%) 59 59 60 60 NA
CCyR (%) 44 45 48 54 6-month, 41
MMR (%) 40–43* NA 46 40 6-month, 25
PFS rate (%) 6-year, 48–56* 4-year, 57 NA 5-year, 53 2-year, 94
OS rate (%) 6-year, 76 4-year, 78 9-year, 74 5-year, 73 2-year, 97
Abbreviations: CHR, complete hematologic response; CCyR, complete cytogenetic response; MCyR, major cytogenetic response; MMR, major molecular
response; NA, not available; PFS, progression-free survival; OS, overall survival.
a
At different dasatinib dosing, ranging from 70 to 140 mg daily.
finding is that earlier switch to dasatinib was associated with better doses and with longer CML disease duration. Based on the results
outcomes. from the phase II OPTIC trial, an updated label was issued in
Bosutinib was initially studied in patients with CML resistance to December 2020 including an optimized, response-based dosing regi-
or intolerance of imatinib.102 After a dose escalation period, 500 mg men of ponatinib, aiming to maximize efficacy while decreasing the
once daily was selected as the phase II dose. A total of 288 patients risk of adverse events. In this study, 283 patients with CML-CP who
were enrolled in the pivotal phase II trial; more than two thirds had failed prior TKIs (55% received ≥3 prior TKIs) or who had a T315I
imatinib-resistant disease. The primary endpoint of MCyR at 6 months mutation (24%), were randomly assigned in a 1:1:1 ratio to receive a
was achieved in 31%; 41% achieved a CCyR. Bosutinib appeared to once-daily dose of ponatinib 45 mg (45 mg cohort), 30 mg (30 mg
retain activity across most known mutations that confer imatinib cohort), or 15 mg (15 mg cohort).112 Upon achievement of BCR::ABL1
resistance, except for T315I. Responses were independent of whether [IS] ≤1%, the dose of ponatinib was reduced to 15 mg daily. One third
patients had resistance to or intolerance of imatinib. In the phase of the patients had a least one cardiovascular risk factor at baseline.
4 BYOND study, 163 patients with CML-CP and resistance/ The rates of BCR::ABL1 [IS] ≤1% at 12 months (primary endpoint of
intolerance to prior TKIs received bosutinib 500 mg once daily. The the study) were 44%, 29%, and 23% in the 45 mg cohort, 30 mg
rates of MCyR by 12 months were 76% after one or two prior TKIs cohort and 15 mg cohort, respectively. Among patients with T315I
105
and 62% after three prior TKIs. The cumulative CCyR and MMR mutation, the 45 mg dosing resulted in higher rates of BCR::ABL1
rates by 12 months were 80.6% and 70.5%, respectively.105 [IS] ≤1% at 12 months compared with lower doses (60% vs. 25%
In order to optimize the safety and efficacy of bosutinib in older vs. 10.5%, respectively). The overall MMR rates were 34.4% in the
patients with CML and failure on first-line therapy, a dose escalation 45 mg cohort, 24.7% in the 30 mg cohort, and 23.1% in the 15 mg
was used with a starting dose of 200 mg daily increased to 300 mg cohort. The estimated 24-months PFS was 80%, 76%, and 78% in the
daily at 2 weeks and to 400 mg daily at 3 months if transcripts are 45, 30, and 15-mg cohorts, respectively. The median OS was not
above 1%.106 Sixty-seven percent of patients had molecular improve- reached in all cohorts, and the estimated 24-month OS was above
ment from baseline. Treatment was well tolerated: diarrhea occurred 90% in all three cohorts. The incidence of serious toxicities was signif-
in 16% of patients, with 8% experiencing grade 3 diarrhea; 22% had icantly less with the lower dose schedules. The exposure-adjusted
liver function test abnormalities (10% Grade 3 and 2% Grade 4).106 incidence of AOEs was 5.6% with 45 mg, 3.6% with 30 mg, and 2.1%
Ponatinib is a third generation TKI, and the first TKI in class to with 15 mg. When comparing the dose modification dynamics of
exhibit activity against CML with T315I mutation.107 It is 500 times as ponatinib from the PACE and OPTIC trials, the response-based dose-
108
potent than imatinib at inhibiting BCR::ABL1. The approval of reduction strategy in OPTIC resulted in comparable or better efficacy
ponatinib was based on the phase II PACE trial, in which 449 patients outcomes, fewer dose reductions related to AEs, fewer exposure-
with heavily pretreated CML or Ph-positive acute lymphoblastic leu- adjusted TE-AOEs, further demonstrating the benefit of the response-
kemia (ALL) were treated.109 Patients were considered for this trial if based dosing regimen used in OPTIC.113 We recommend using pona-
they had resistance to or intolerance of dasatinib or nilotinib, or if tinib 45 mg daily in T315I-mutated CML and 30 mg in non-T315I-
they had CML with T315I mutation. The dose of ponatinib was 45 mg mutated CML, with dose reductions to 15 mg daily once the BCR:
once daily, and patients were stratified by disease phase and by the ABL1 transcript [IS] is ≤1%.
presence or absence of a T315I mutation. Among 267 patients who A ponatinib real-life experience from Italy was recently reported
received ponatinib in CML-CP, 56% achieved a MCyR by 12 months, in which 666 patients with CML (515 CML-CP, 50 CML-AP,
which included 45/64 (70%) patients with a T315I mutation. Patients 101 CML-BP) were treated with ponatinib 45 mg daily. In CML-CP,
responded more favorably if they had received fewer TKIs. After a the incidences of CCyR, MMR and MR4 were 90%, 74% and 52%,
median follow-up of 5 years, 60% of patients achieved MCyR (primary respectively, Dose reductions were implemented in 20% of patients
110
endpoint) at any time; 82% of those remained in MCyR at 5 years. due to adverse events, and in 40% by physician's choice. Ponatinib
Furthermore, 40% of patients achieved a MMR or better. The 5-year was discontinued in 22% of patients (intolerance 7%, resistance 9%).
OS rate was 73%.110 AOEs occurred in 31% of patients (26% serious). The median time to treatment discontinuation in CML-CP was
The exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 47 months. This analysis confirms the high efficacy and safety of
100 patient-years in years 1 and 5, respectively) did not increase over ponatinib therapy in CML.114
time. The most common all-grade treatment-emergent adverse events Asciminib is an allosteric inhibitor that binds a myristoyl site of
occurring in ≥40% of CP-CML patients were rash (47%), abdominal the BCR::ABL1 protein, locking BCR::ABL1 into an inactive conforma-
pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), tion through a mechanism distinct from those for all other ABL kinase
110
and constipation (41%). Other notable toxicities include severe skin inhibitors.115 Asciminib targets both native and mutated BCR::ABL1,
rashes (4–7%), pancreatitis (7%), and severe hypertension (20%). including the gatekeeper T315I mutant. In a Phase I, dose-escalation
As of early 2014, ponatinib labeling included a revised warning study, 141 patients with CML-CP and 9 with CML-AP who had failed
regarding the risk of AOEs, heart failure and hepatotoxicity.111 The at least two TKIs were treated.116 Asciminib was administered once
AOEs were more frequent with increasing age and in patients with or twice daily (at doses of 10–200 mg). The median follow-up was
prior history of ischemia, myocardial infarction or prior vascular 14 months. Among patients with CML-CP, 34 (92%) with a hemato-
events, hypertension, diabetes, or hyperlipidemia, and with higher logic relapse had a CHR; 31 (54%) without a complete cytogenetic
response at baseline had a CCyR. An MMR was achieved or 8.2 | Third line therapy after failure of second-
maintained by 12 months in 48% of evaluable patients, including eight generation TKIs
of 14 (57%) deemed to have resistance to or unacceptable side effects
from ponatinib. Among patients with T315I mutation, CCyR was Rotating second-generation TKIs among patients who failed two prior
achieved in 11 patients (44%) without CCyR at baseline, and MMR lines of therapy (imatinib and one second generation TKI) is associated
was achieved or maintained by 12 months in five patients (28%). with lower response rates compared with the use of third generation
Dose-limiting toxic effects included asymptomatic elevations in the TKIs. In a systematic review of patients with CML-CP with resistance
lipase level and clinical pancreatitis. The recommended phase 2 doses or intolerance to previous second-generation TKIs, treatment with a
were 40 mg BID for non-T315I-mutated CML and 200 mg BID for different second-generation TKI in the third-line setting was associ-
T315I-mutated disease. ated with a CCyR rate of 22% to 26%. In contrast, treatment with
The ASCEMBL phase III trial randomized 233 patients (2:1) with ponatinib was associated with higher rates of CCyR of 60%. In a retro-
CML-CP post failure of 2+ TKIs to receive asciminib 40 mg twice spective analysis of 178 patients who failed two previous TKIs, the
daily or bosutinib 500 mg/day. The primary endpoint was the inci- 5-year OS rates were 57%, 68%, and 80% in patients treated in the
dence of MMR after 6 months of therapy, a new primary endpoint third line setting with imatinib, second-generation TKIs, and ponatinib,
not been confirmed to be associated with a survival benefit in CML respectively. In patients with prior resistance to second-generation
salvage. The 6-month MMR rate was 25.5% with asciminib versus TKIs, the respective 5-year OS rates were 38%, 56%, and 84%
13.2% with bosutinib (p = .029). The MMR rate of 13.2% obtained (p = .10). By multivariate analysis, ponatinib therapy as the third-line
with bosutinib is in contrast with the MMR rates of 50 + % TKI was the only prognostic factor for favorable survival (hazard ratio,
obtained in other bosutinib trials. 105
Based on the results, the FDA 0.36, 95% CI, 0.13–0.99, p = .047).124
approved asciminib 40 mg twice daily for the treatment of CML-CP Based on these observations, ponatinib should be favored as best
post failure of 2+ TKIs without T315I or V299L mutations.117 The TKI in patients with resistance to one second-generation TKI.
12-month CCyR rates in patients without CCyR at baseline was
50.8% with asciminib and 33.7% with bosutinib. An updated analy-
sis of the study at the European Hematology Association (EHA) 8.3 | Novel tyrosine kinase inhibitors
2022 annual meeting confirmed the persistent improvement of
MMR at 2 years (2-year MMR rate 38% with asciminib vs. 16% with Olverembatinib (formerly HQP1351), a new orally active third genera-
bosutinib). However, this did not translate into improved PFS tion TKI with low affinity against other kinases has completed a phase
(2-year PFS 94% vs. 91%) or improved survival (2-year survival 97% I trial in 101 patients (87 CML-CP, 14 CML-AP) who have failed prior
vs. 99%).118 TKIs and/or acquired T315I mutation (63%).125 The drug was given
Asciminib was also approved for patients with T315I mutation every other day in 28 days cycle with expansion cohorts at 30, 40,
based on a separate report, where 52 patients with CML-CP and and 50 mg dose. With a median follow-up of 31 months, the overall
T315I mutation who failed ≥2 prior TKIs received asciminib 200 mg CHR, CCyR, and MMR rates for patients with CML-CP were 97%,
twice daily (31 patients had prior ponatinib exposure, of whom 62%, and 51%, respectively. The 3-year PFS rate was 96.3% in
15 had ponatinib resistance).119 The estimated 2-year MMR rate was patients with CML-CP and 71.4% in those with CML-AP. Grade 3/4
57.8% in the ponatinib-naïve patients and 28.6% in ponatinib-treated thrombocytopenia, grade 1 skin pigmentation and hypertriglyceride-
patients. Arterial occlusive events were reported in 5.8% of patients mia were common adverse events.126 A multicenter confirmatory trial
with the current follow-up. is ongoing.
At the EHA 2022 annual meeting, the results of asciminib (free-
drug supply) in patients with CML post 3+ TKIs from different coun-
tries were reported (Russia, Canada, Italy, United Kingdom, Nether- 8.4 | How to select a second- or third-line option
land). In over 200 patients treated, the CCyR rates ranged from 57%
to 70%, the MMR rates ranged from 22% to 53%, and the DMR/MR4 At the time of treatment failure, patients should undergo bone mar-
120–123
rates ranged from 16% to 42%. row examination to allow proper determination of the CML phase and
Currently, there are no randomized head-to-head trials comparing documentation of any clonal evolution. All patients should have CML
ponatinib and asciminib in CML. As third-line therapy, among cells tested for BCR::ABL1 kinase domain mutations, as this will help
82 patients treated with asciminib 40 mg BID, the MMR rate was guide the selection of the TKI.127–130 When selecting between dasati-
117
30.5% and the CCyR rate was 40.8%. In the PACE trial, with pona- nib, bosutinib, and nilotinib, in vitro and in vivo data have identified
tinib therapy, the MMR rate was 45% and the CCyR rate was 65%. distinct mutations that exhibit decreased sensitivity to each of the
Among 64 patients with T315I-mutated CML treated with ponatinib, agents.127–130 Physician may favor dasatinib or bosutinib if the patient
the MMR rate was 58% and the CCyR rate was 70%. Based on the has the following mutations: Y253H, E255K/V, or F359C/V. Alterna-
above, studies that compare ponatinib and asciminib in similar salvage tively, nilotinib may be favored in the presence of the V299L and
settings (e.g., third-line therapy; T315I mutated or nonmutated CML) F317L mutations. For patients lacking these mutations, the choice
are needed.50,56 should be based on preexisting conditions, toxicity profiles, and cost.
For patients with T315I mutation ponatinib should be the preferred responses.137–143 In general, discontinuing a TKI after a durable DMR
option today. This is based on the larger experience and longer-term of 2+ years has been associated with a TFR rate of 40% to 50%.
follow-up with ponatinib compared with asciminib, the cost consider- In the EURO-SKI trial, the largest study of TKI discontinuation,142
ations, and the safer dose-adjusted ponatinib schedules. 728 patients with CML treated with frontline imatinib, nilotinib or
dasatinib, who had achieved at least MR4 (BCR::ABL1 [IS] <0.01% on
the International Scale) stopped TKI therapy. With a follow-up of
8.5 | Allogeneic stem cell transplantation 72 months, the 3-year molecular recurrence- and treatment-free sur-
vival rate was 45%. All patients who restarted TKI regained MMR
The number of patients undergoing Allogeneic stem cell transplanta- after a median of 5 months (range, 1–5 months). Prognostic factors
tion (allo-SCT) for CML-CP has decreased significantly since TKIs for a successful treatment discontinuation identified treatment dura-
were introduced but will start to rise again as the prevalence of CML tion and DMR duration as important. Findings from our institution
increases, as about 1–2% of patients become resistant to many TKIs confirmed the impact of a longer DMR duration on achieving a suc-
every year and require allo-SCT. Allo-SCT has a more important role cessful TFR among 284 patients who discontinued therapy.137 By
when patients evolve into AP/BP (see below).131,132 Allo-SCT remains multivariate analysis, durations of MR4 ≥ 5 years and MR4.5 ≥ 5 years
an important therapeutic option for patients in CML-CP post failure were independently associated with lower rates of loss of MMR. After
of at least two TKIs, or with resistance to a second generation TKI a median follow-up of 36 months, the 5-year TFR rates were 87% and
(and without a guiding mutation) or who are potentially harboring the 76% in patients with MR4.5 ≥ 5 years and MR4.5 < 5 years, respec-
T315I mutation (after a trial of ponatinib therapy).131132 Prior expo- tively. Patients with MR4 ≥ 5 years had a 5-year TFR rate of 88%
sure to TKIs does not impact transplant outcome negatively; patients compared with 64% in those with a duration of MR4 < 5 years. Two
referred to transplant may have a better outcome if entering the additional important observations were reported in our study: (1) a
transplant with a better response (lower CML burden).133 single RT-PCR fluctuation in the MR4 range in patients who discontin-
Allo-SCT cost versus TKIs cost and availability should be consid- ued therapy did not negatively affect the rate of successful TFR; and
ered. Allo-SCT, a curative one-time procedure costs $500 000+ in (2) the frequency of molecular monitoring following TKI discontinua-
the US, but only $20 000 in some nations. Allo-SCT should not be tion (every 4 weeks vs. every 6–8 weeks after stopping therapy) had
offered as frontline therapy since the cost of generic imatinib can be no impact on the rates of TFR.137
as low as $400–1000/year. In the salvage setting the value of allo- In order to increase the proportion of patients who may be
SCT versus second/third generation TKI can be discussed in relation molecularly cured with long-term TKI therapy, combination strategies
to geography, cost of care, and availability of second generation TKIs. are under evaluation. These focus on both inducing deeper molecular
For example, in some geographies, allo-SCT in first salvage may cost responses and targeting the CML quiescent stem cells.144 Strategies
$20 000 versus $120000–170 000/year for second-third generation that added IFN-a, JAK2 inhibitors, anti-PD1 antibodies and dendritic
TKIs. In these circumstances, allo- SCT could be offered as a first sal- cell vaccines did not improve the results. Other studies are investigat-
vage option in nations with financial constraints.134,135 ing adding venetoclax or hypomethylating agents.57,145–148
When should allo-SCT not be considered post TKIs failure/second- TKIs discontinuation studies in patients with durable DMR dem-
generation TKIs resistance? As experience accumulates, the dogma that onstrate that stopping TKI therapy is feasible, and that TFR status is
“patients must achieve a CCyR or be considered for allo-SCT” may not possible in a sizable proportion of patients. At MD Anderson, therapy
be as relevant in older patients. Shaya and colleagues reported that discontinuation is offered to patients in chronic phase with a quantifi-
among patients who did not achieve a CCyR at 2 years, 34% achieved able transcript, who have been on TKI for at least 5–6 years, who
later CCyR with continued TKI therapy. While their outcome was have achieved a durable DMR for at least 3–4 years, and in whom a
worse, after a median follow-up time of 8.1 years, their estimated sur- close follow-up is possible (Table 7). After TKI discontinuation, we
vival was still 85% versus 93% for those having achieved a CCyR at recommend close molecular monitoring every 6–8 weeks during the
2 years.136 Thus older patients with CML (e.g., age > 65–70 years) may first 12 months, every 2–3 months for next 2 years, and every 4–
consider forgoing the option of a curative allo-SCT in favor of a reason- 6 months thereafter.
ably long and near-normal life with continuation of TKI therapy while
not in CCyR. These patients may remain in chronic phase on an optimal
TKI therapy alone or with the addition of other agents to maintain a 10 | A D V A N C E D ST A G E C M L
hematologic response with or without a cytogenetic response.
Patients with CML-AP or CML-BP may receive initial therapy with
TKIs (newer generation TKIs like dasatinib or ponatinib preferred over
9 | T R E A T M E NT D U R A T I O N A N D imatinib) to reduce the CML burden, and be considered for early allo-
D I S C O N T I NU A T I O N SCT.109,149–154 The response rates with combinations of TKIs and
chemotherapy are 40% in nonlymphoid CML-BP and 70–80% in lym-
Several studies have evaluated whether TKIs can be safely discontin- phoid CML-BP.109,149–154 The median survival times are 6–12 and
ued in patients who have achieved long-term deep molecular 12–24 months, respectively. The addition of TKIs to chemotherapy
TABLE 7 Requirements for TKI discontinuation in clinical practice of cases, respectively. Another study of 216 CML patients showed
that ASXL1 mutations expanded at BP transformation and were inde-
Discontinuation of TKI
pendently associated with a poor prognosis.159 In a recent study con-
Parameter Yes No
ducted at MD Anderson, patients with CML-CP (n = 67), CML-AP
Sokal risk Low-intermediate High (n = 15), and CML-BP (n = 30) were evaluated for the presence of
BCR::ABL1 Quantifiable (e13a2 or Not quantifiable non-ABL1 mutations. The most frequent genetic abnormality was
transcripts e14a2)
ASXL1 in 13% and 40% of patients with CML-CP and CML-AP,
CML stage Chronic Accelerated/ respectively, and RUNX1 in 20% of patients with CML-BP. In the
blast phase
CML-CP cohort, the median EFS and FFS were significantly shorter
Response to first TKI Optimal Failure
with the presence of ASXL1 mutations. These findings suggest that
Duration of all TKIs >6–8 years <3 years
patients with CML-CP harboring somatic variants, particularly ASXL1
therapy
mutations, may require close monitoring and may benefit from the
Depth of molecular DMR Less than MR4
more potent TKIs or from combination therapies.160 Larger studies
response
are needed to assess more precisely the role of such mutations and
Duration of >3+ years <3 years
molecular their impact in CML.
response Allo-SCT should be considered early in patients in AP based on
Monitoring Ideal (every 2 months in Poor; response to TKI therapy. The only curative option for patients in BP
availability years 1–2) noncompliant disease is allo-SCT. TKIs combinations with chemotherapy should be
Abbreviations: CML, chronic myeloid leukemia; DMR, deep molecular

used as a bridge to allo-SCT.
response (≤4.5-log reduction to ≤4-log reduction of BCR::ABL1 transcript At MD Anderson, patients with CML-BP are treated with a com-
levels); MR4, molecular response 4 (4-log reduction of BCR::ABL1 bination of chemotherapy (type depends on the immunophenotype)
transcript levels); TKI, tyrosine kinase inhibitor. and ponatinib followed by allo-SCT once a complete response is
achieved, then given maintenance TKI therapy post allo-SCT. Patients
with de-novo CML-AP are treated with frontline second generation
has improved the response rates and prolonged the survival in CML- TKI indefinitely if an optimal response (CCyR; BCR::ABL1 transcripts
BP.155 In an analysis of 477 patients in CML-BP the median survival [IS] < 1%) is achieved within 6 months of therapy. All other patients in
was 12 months. A multivariate analysis identified the following as CML-AP are treated with second/third generation TKI followed by
favorable: use of combinations of TKI and chemotherapy, lymphoid allo-SCT.
BP, and transition to allo SCT in CR.156 The combination of TKI with
intensive chemotherapy followed by stem cell transplantation
appeared to confer the best outcome. 11 | C O N C L U S I O N S A N D F U T U RE
Copland and colleagues reported the early results of FLAG-IDA DI RE C TION S
and ponatinib at a starting dose of 30 mg in 17 evaluable patients in
blast phase CML.157 Clinical responses were observed in 11/17 In 2022, CML experts and patients with CML have multiple treat-
patients (65%); five achieved MMR. Twelve patients received subse- ment options in the CML therapeutic armamentarium, including six
quent allo-SCT. The median overall survival was 12 months. TKIs (imatinib, dasatinib, bosutinib, nilotinib, ponatinib, asciminib),
At present, allo-SCT is the only curative therapy for CML-AP or omacetaxine (protein synthesis inhibitor), and several older agents
BP, with reported long-term survival rates of 15–40% and 10–20%, (hydroxurea, IFN-a, busulfan, 6-mercaptopurine, cytarabine, hypo-
respectively. Patients with cytogenetic clonal evolution as the only methylating agents, others). Most patients with CML would be
accelerated phase criterion have a long-term event-free survival rate expected to have a normal life span and be potentially functionally
of about 60%.133 De novo CML-AP has a better outcome with front- as well as molecularly cured with optimal TKI therapy. Future direc-
line TKI therapy than CML-AP evolving from CML-CP. The estimated tions will focus on strategies to increase the potential of molecular
8-year survival rate with TKI therapy in de novo CML-AP is 60– cure of CML (i.e., achievement of a durable DMR and TFR). This is
80%.133 Such patients may continue on TKI therapy as their long-term not a trivial issue since, with effective TKI therapy and full TKI treat-
treatment if they achieve a CCyR on TKI therapy. ment penetration worldwide, the prevalence of CML would increase
Various studies investigated the impact of genetic alterations, annually and plateau around 2040 at a rate of 35 times the inci-
notably non-ABL1 kinase domain mutations, on the risk of CML pro- dence. This may represent a considerable challenge in relation to
gression. In one study, 15 of 27 patients (56%) with CML-CP who pro- drug availability, compliance, long-term side effects, and costs. The
gressed to BP or had poor outcomes had cancer gene variants, TFR rates may increase with the current more potent new genera-
compared with three of 19 patients (16%) of optimal responders tion TKIs alone, or in combination with other available targeted ther-
(p = .007).158
The most frequently mutated genes were ASXL1 (nine apies. Further understanding of the pathophysiologic events
patients), IKZF1 (six patients), and RUNX1 (three patients); patients downstream of BCR::ABL1 may help in the development of new
with these mutations progressed to CML-BP in 67%, 83%, and 100% strategies to target them.
12 | THE MD ANDERSON APPROACH Patients with vascular risk factors and metabolic dysfunctions are not
candidates for nilotinib therapy, while patients with lung compromise are
All patients suspected to have CML undergo a bone marrow examina- not candidates for dasatinib therapy. Bosutinib may be the best choice
tion which will confirm the diagnosis and provide information needed for patients with cardiac problems. In patients with CML-CP with T315I
for staging. Baseline PCR is performed to identify the specific type of mutation, ponatinib is the first-choice treatment. In patients who failed
rearrangement that can be appropriately followed when assessing second generation TKIs, ponatinib is preferable over rotation of second
response to TKI therapy. generation TKIs unless patients have severe cardiovascular comorbidities
Waiting for confirmation, patients are placed on transient cytore- or developed a specific mutation that may be sensitive to another sec-
duction therapy with hydroxyurea. Tumor lysis syndrome prophylaxis ond generation TKIs. Asciminib represents an alternative third generation
is implemented as indicated. TKI in patients who failed two prior lines of therapy, including T315I
Patients are stratified into low/intermediate-risk and high-risk mutation, albeit associated with lower response rates than ponatinib.
disease. Outside of clinical trials, patients with lower-risk disease are However, studies directly comparing ponatinib and asciminib in similar
treated with imatinib; patients with higher-risk disease can be treated salvage settings are urgently needed. Also, in patients with T315I muta-
with either imatinib or with second generation TKI. Second generation tion, ponatinib is significantly more cost-effective than asciminib and
TKI may be preferred in patients with high-risk disease to reduce the should be favored in this setting. Allo-SCT remains an important thera-
rate of transformation to AP or BP. The choice of second generation peutic option for patients in CML-CP in the following situations: patients
TKI is based on patients' comorbidities. who fail at least two TKIs or are potentially harboring the T315I mutation
At MD Anderson, patients are currently offered therapy with after at least a trial of ponatinib therapy. Older patient post failure of
dasatinib 50 mg daily +/ oral decitabine. Lower dose dasatinib multiple TKIs should continue the most appropriate TKI regardless of
(50 mg daily) was as effective and less toxic than dasatinib 100 mg molecular or cytogenetic status. They can maintain long-term survival if
daily. Because of the faster rates of durable DMRs with second gener- they continue on a daily most effective/less toxic TKI, with or without
ation TKIs, considerations of second generation TKIs in younger the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine,
patients with CML (e.g., age < 50 years) may be offered more in the azacitidine, decitabine, cytarabine, busulfan, others).
future once their cost is lower (generic availability). Patients with CML-BP are treated with combination of chemo-
Following close monitoring for tumor reduction and side effects therapy (type depends on the immunophenotype) and ponatinib fol-
in the first 1–2 months, patients are then monitored (in addition to lowed by allo-SCT once a complete response is achieved and placed
routine blood tests) for BCR::ABL1 transcript levels every 3 months in on maintenance TKI therapy post allo-SCT. Patients with de-novo
the first year, and until the achievement of a stable confirmed MMR CML-AP are treated with frontline second generation TKI infinitely if
over 3–6 months, then they are monitored every 6 months. The major an optimal response (CCyR; BCR::ABL1 transcripts [IS] <1%) is
treatment milestones are at 6 and 12 months. Patients who do not achieved within 6 months of therapy. All other patients in CML-AP
achieve PCyR (BCR::ABL1 transcripts [IS] ≤10%) at 6 months, or CCyR are treated with second/third generation TKI followed by allo-SCT.
(BCR::ABL1 transcripts [IS] ≤1%) at 12 months, and those who have TKI discontinuation is offered only for patients with CML-CP with
later cytogenetic relapse at any time are candidates for a change of a quantifiable transcript, who have achieved a sustained DMR for at
therapy. The choice of TKI is based on mutation profile and patients' least 3–4+ years, and in whom a close follow-up can be performed.
comorbidities. We do not change therapy for patients in CCyR but After TKI discontinuation, we recommend close molecular monitoring
without MMR/DMR. Patients who meet all the relevant benchmarks every 6–8 weeks during the first 6 months, then every 3 months for
in the first 12 months are monitored periodically using molecular test- the next 3 years, then every 6 months thereafter.
ing (molecular testing only if BCR::ABL1 transcripts consistently below
0.1% [IS]). We do not consider a change of therapy at any time point FUNDING INF ORMATI ON
in patients who do not achieve DMR with the aim of inducing a TFR. The authors received research grants from BMS, Novartis, Takeda,
Such strategy is not cost-effective and may be associated with serious Pfizer, and Ascentage.
adverse events (e.g., vascular events with nilotinib).
Post imatinib failure, patients should undergo a bone marrow exami- CONFLIC T OF INT ER E ST
nation with cytogenetic and molecular testing, including analysis for The authors declare no conflict of interest.
BCR::ABL1 mutation. The choice of second or third generation TKIs is
based on the disease phase, the mutation profile, and the patient's DATA AVAILABILITY STAT EMEN T
comorbidities. Outside the context of a T315I mutation, the type of Data sharing is not applicable to this article as no new data were cre-
mutation dictates the choice of therapy. Patients with poor response to ated or analyzed in this study.
imatinib and compound mutations may not respond well to second gen-
eration TKI, and a close monitoring is indicated. If an optimal response is
OR CID
not achieved, a switch of therapy to a third generation TKI and/or allo-
Elias Jabbour https://orcid.org/0000-0003-4465-6119
SCT is warranted. In patients with no mutation or with mutations sensi-
Hagop Kantarjian https://orcid.org/0000-0002-1908-3307
tive to all second generation TKIs, the choice is based on comorbidities.
RE FE R ENC E S polish adult leukemia group imatinib generics registry. Am J Hematol.

1. Society AC. Cancer Facts and Figures. Amercian Cancer Society; 2017;92(7):E125-E128.
2021. 21. Danthala M, Gundeti S, Kuruva SP, et al. Generic imatinib in chronic
2. Huang X, Cortes J, Kantarjian H. Estimations of the increasing preva- myeloid leukemia: survival of the cheapest. Clin Lymphoma Myeloma
lence and plateau prevalence of chronic myeloid leukemia in the era Leuk. 2017;17(7):457-462.
of tyrosine kinase inhibitor therapy. Cancer. 2012;118(12):3123- 22. Abou Dalle I, Kantarjian H, Burger J, et al. Efficacy and safety of
3127. generic imatinib after switching from original imatinib in patients
3. Rowley JD. A new consistent chromosomal abnormality in chronic treated for chronic myeloid leukemia in the United States. Cancer
myelogenous leukaemia identified by quinacrine fluorescence and med. 2019;8(15):6559-6565.
Giemsa staining. Nature. 1973;243(5405):290-293. 23. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-
4. Mandanas RA, Leibowitz DS, Gharehbaghi K, et al. Role of p21 RAS label study of daily imatinib Mesylate 400 mg versus 800 mg in
in p210 bcr-abl transformation of murine myeloid cells. Blood. 1993; patients with newly diagnosed, previously untreated chronic myeloid
82(6):1838-1847. leukemia in chronic phase using molecular end points: tyrosine
5. Okuda K, Matulonis U, Salgia R, Kanakura Y, Druker B, Griffin JD. kinase inhibitor optimization and selectivity study. J Clin Oncol.
Factor independence of human myeloid leukemia cell lines is associ- 2010;28(3):424-430.
ated with increased phosphorylation of the proto-oncogene Raf-1. 24. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus Peginter-
Exp Hematol. 1994;22(11):1111-1117. feron Alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;
6. Raitano AB, Halpern JR, Hambuch TM, Sawyers CL. The Bcr-Abl leu- 363(26):2511-2521.
kemia oncogene activates Jun kinase and requires Jun for transfor- 25. Hehlmann R, Lauseker M, Saußele S, et al. Assessment of imatinib as
mation. Proc Natl Acad Sci. 1995;92(25):11746-11750. first-line treatment of chronic myeloid leukemia: 10-year survival
7. Sawyers CL, Callahan W, Witte ON. Dominant negative MYC blocks results of the randomized CML study IV and impact of non-CML
transformation by ABL oncogenes. Cell. 1992;70(6):901-910. determinants. Leukemia. 2017;31(11):2398-2406.
8. Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL. Constitutive 26. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-
activation of STAT5 by the BCR-ABL oncogene in chronic myeloge- 6-methyl-phenyl)-2-(6-(4-[2-hydroxyethyl]- piperazin-1-yl)-
nous leukemia. Oncogene. 1996;13(2):247-254. 2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-
9. Carlesso N, Frank DA, Griffin JD. Tyrosyl phosphorylation and DNA 354825), a dual Src/Abl kinase inhibitor with potent antitumor activ-
binding activity of signal transducers and activators of transcription ity in preclinical assays. J med Chem. 2004;47(27):6658-6661.
(STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. 27. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-
J Exp Med. 1996;183(3):811-820. Abl inhibitors AMN107 and BMS-354825 against clinically relevant
10. Ilaria RL, van Etten RA. P210 and P190 induce the tyrosine phos- imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;
phorylation and DNA binding activity of multiple specific STAT fam- 65(11):4500-4505.
ily members. J Biol Chem. 1996;271(49):31704-31710. 28. Tokarski JS, Newitt JA, Chang CYJ, et al. The structure of Dasatinib
11. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis (BMS-354825) bound to activated ABL kinase domain elucidates its
of the effect of busulfan, hydroxyurea, interferon, and allogeneic inhibitory activity against imatinib-resistant ABL mutants. Cancer
bone marrow transplantation in treating the chronic phase of Res. 2006;66(11):5790-5797.
chronic myeloid leukemia: developed for the American Society of 29. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding
Hematology. Blood. 1999;94(5):1517-1536. imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;
12. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of 305(5682):399-401.
imatinib treatment for chronic myeloid leukemia. N Engl J Med. 30. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasati-
2017;376(10):917-927. nib or imatinib in chronic myeloid leukemia: 3-year follow-up from a
13. Jabbour E, Kantarjian H, O'Brien S, et al. Sudden blastic transforma- randomized phase 3 trial (DASISION). Blood. 2014;123(4):494-500.
tion in patients with chronic myeloid leukemia treated with imatinib 31. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib
mesylate. Blood. 2006;107(2):480-482. in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl
14. Jabbour E, Cortes JE, Kantarjian HM. Molecular monitoring in J Med. 2010;362(24):2260-2270.
chronic myeloid leukemia. Cancer. 2008;112(10):2112-2118. 32. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in
15. Kantarjian H, Schiffer C, Jones D, Cortes J. Monitoring the response newly diagnosed chronic-phase chronic myeloid leukemia: 2-year
and course of chronic myeloid leukemia in the modern era of BCR- follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;
ABL tyrosine kinase inhibitors: practical advice on the use and inter- 119(5):1123-1129.
pretation of monitoring methods. Blood. 2008;111(4):1774-1780. 33. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results
16. Schoch C, Schnittger S, Bursch S, et al. Comparison of chromosome of DASISION: the Dasatinib versus imatinib study in treatment-
banding analysis, interphase- and hypermetaphase-FISH, qualitative Naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;
and quantitative PCR for diagnosis and for follow-up in chronic mye- 34(20):2333-2340.
loid leukemia: a study on 350 cases. Leukemia. 2002;16(1):53-59. 34. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of
17. Wang W, Cortes JE, Tang G, et al. Risk stratification of chromosomal dasatinib 100 mg versus imatinib 400 mg in newly diagnosed
abnormalities in chronic myelogenous leukemia in the era of tyrosine chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898-
kinase inhibitor therapy. Blood. 2016;127(22):2742-2750. 3905.
18. Druker BJ, Lydon NB. Lessons learned from the development of an 35. O'Brien SG, Hedgley C, Adams S, et al. Spirit 2: an NCRI randomised
Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. study comparing Dasatinib with imatinib in patients with newly diag-
J Clin Investig. 2000;105(1):3-7. nosed CML. Blood. 2014;124(21):517.
19. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with inter- 36. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-
feron and low-dose Cytarabine for newly diagnosed chronic-phase resistant Philadelphia chromosome–positive leukemias. N Engl J
chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. Med. 2006;354(24):2531-2541.
20. Sacha T, Go ra-Tybor J, Szarejko M, et al. A multicenter prospective 37. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-
study on efficacy and safety of imatinib generics: a report from resistant or -intolerant chronic-phase, chronic myeloid leukemia
patients: 7-year follow-up of study CA180-034. Am J Hematol. 55. Matsumura I, Ohtake S, Atsuta Y, et al. Nilotinib vs. dasatinib in
2016;91(9):869-874. achieving MR4.5 for newly diagnosed chronic myeloid leukemia:
38. Cortes JE, Hochhaus A, Kantarjian HM, et al. Impact of dose reduc- results of the prospective randomized phase 3 study, JALSG
tions on 5-year efficacy in newly diagnosed patients with chronic CML212. Blood. 2020;136(Supplement 1):40-41.
myeloid leukemia in chronic phase (CML-CP) from DASISION. J Clin 56. Elrick LJ, Jorgensen HG, Mountford JC, Holyoake TL. Punish the
Oncol. 2017;35(15_suppl):7051. parent not the progeny. Blood. 2005;105(5):1862-1866.
39. Naqvi K, Jabbour E, Skinner J, et al. Early results of lower dose dasa- 57. Carter BZ, Mak PY, Mu H, et al. Combined targeting of BCL-2 and
tinib (50 mg daily) as frontline therapy for newly diagnosed chronic- BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem
phase chronic myeloid leukemia. Cancer. 2018;124(13):2740-2747. cells. Sci Transl med. 2016;8(355):355ra117.
40. Naqvi K, Jabbour E, Skinner J, et al. Long-term follow-up of lower 58. Kantarjian HM, O'Brien S, Cortes J, et al. Results of decitabine
dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed (5-aza-2?Deoxycytidine) therapy in 130 patients with chronic mye-
chronic-phase chronic myeloid leukemia. Cancer. 2019;126(1):67-75. logenous leukemia. Cancer. 2003;98(3):522-528.
41. Sasaki K, Jabbour EJ, Issa GC, et al. Low-dose dasatinib 50 mg/day 59. Abaza Y, Kantarjian H, Alwash Y, et al. Phase I/II study of dasatinib
versus standard-dose dasatinib 100 mg/day as frontline therapy in in combination with decitabine in patients with accelerated or blast
chronic myeloid leukemia in chronic phase: a propensity score analy- phase chronic myeloid leukemia. Am J Hematol. 2020;95(11):1288-
sis. Blood. 2021;138(Suppl 1):631. 1295.
42. Murai K, Ureshino H, Kumagai T, et al. Low-dose dasatinib in older 60. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hyperten-
patients with chronic myeloid leukaemia in chronic phase (DAVLEC): sion in patients treated by dasatinib. Circulation. 2012;125(17):
a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2021;8(12): 2128-2137.
e902-e911. 61. Quintás-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase
43. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of inhibitor–induced platelet dysfunction in patients with chronic mye-
AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer loid leukemia. Blood. 2009;114(2):261-263.
Cell. 2005;7(2):129-141. 62. Quintás-Cardama A, Kantarjian H, Ravandi F, et al. Bleeding diathe-
44. Hughes TP, Saglio G, Kantarjian HM, et al. Early molecular response sis in patients with chronic myelogenous leukemia receiving dasati-
predicts outcomes in patients with chronic myeloid leukemia in nib therapy. Cancer. 2009;115(11):2482-2490.
chronic phase treated with frontline nilotinib or imatinib. Blood. 63. Cortes JE, Gambacorti-Passerini C, Kim D-W, et al. Effects of Bosuti-
2014;123(9):1353-1360. nib treatment on renal function in patients with Philadelphia
45. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib chromosome-positive Leukemias. Clin Lymphoma Myeloma Leuk.
for the treatment of patients with newly diagnosed chronic phase, 2017;17(10):684-695.e686.
Philadelphia chromosome-positive, chronic myeloid leukaemia: 64. Vokinger KN, Hwang TJ, Grischott T, et al. Prices and clinical benefit
24-month minimum follow-up of the phase 3 randomised ENESTnd of cancer drugs in the USA and Europe: a cost–benefit analysis. Lan-
trial. Lancet Oncol. 2011;12(9):841-851. cet Oncol. 2020;21(5):664-670.
46. Saglio G, Kim D-W, Issaragrisil S, et al. Nilotinib versus imatinib for 65. Bach PB. Insights into the increasing costs of cancer drugs. Clin Adv
newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010; Hematol Oncol. 2019;17(5):287-298.
362(24):2251-2259. 66. Kantarjian H, Mathisen MS, Lipton JH. Having “skin in the game”
47. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes and allowing cross-border importation of drugs to lower high prices
with frontline nilotinib versus imatinib in newly diagnosed chronic of cancer drugs. JAMA Oncology. 2015;1(6):729.
myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leu- 67. Kantarjian H, Patel Y. High cancer drug prices 4 years later-progress
kemia. 2021;35(2):440-453. and prospects. Cancer. 2017;123(8):1292-1297.
48. Druker BJ, White BS, Obourn V, et al. Gene expression signature 68. Kantarjian H, Rajkumar SV. Why are cancer drugs so expensive in
predicts deep molecular response (DMR) in chronic myeloid leuke- the United States, and what are the solutions? Mayo Clin Proc. 2015;
mia (CML): an exploratory biomarker analysis from ENESTnd. Blood. 90(4):500-504.
2019;134(Suppl_1):665. 69. The price of drugs for chronic myeloid leukemia (CML) is a reflection
49. Wang J, Shen Z-X, Saglio G, et al. Phase 3 study of nilotinib vs imati- of the unsustainable prices of cancer drugs: from the perspective of
nib in Chinese patients with newly diagnosed chronic myeloid leuke- a large group of CML experts. Blood. 2013;121(22):4439-4442.
mia in chronic phase: ENESTchina. Blood. 2015;125(18):2771-2778. 70. Shih Y-CT, Cortes JE, Kantarjian HM. Treatment value of second-
50. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib generation BCR-ABL1 tyrosine kinase inhibitors compared with ima-
versus imatinib for newly diagnosed chronic myeloid leukemia: results tinib to achieve treatment-free remission in patients with chronic
from the randomized BFORE trial. J Clin Oncol. 2018;36(3):231-237. myeloid leukaemia: a modelling study. Lancet Haematol. 2019;6(8):
51. Brümmendorf TH, Cortes JE, Milojkovic D, et al. Bosutinib (BOS) e398-e408.
versus imatinib for newly diagnosed chronic phase (CP) chronic mye- 71. Yamamoto C, Nakashima H, Ikeda T, et al. Analysis of the cost-
loid leukemia (CML): final 5-year results from the Bfore trial. Blood. effectiveness of treatment strategies for CML with incorporation of
2020;136(Supplement 1):41-42. treatment discontinuation. Blood Adv. 2019;3(21):3266-3277.
52. Jain P, Kantarjian H, Alattar ML, et al. Long-term molecular and cyto- 72. Padula WV, Conti R, Larson R. What is the most cost-effective strat-
genetic response and survival outcomes with imatinib 400 mg, imati- egy for treating chronic myeloid leukemia after imatinib loses patent
nib 800 mg, dasatinib, and nilotinib in patients with chronic-phase exclusivity in Europe? Value Health. 2014;17(7):A636.
chronic myeloid leukaemia: retrospective analysis of patient data 73. Jones GH, Carrier MA, Silver RT, Kantarjian H. Strategies that delay
from five clinical trials. Lancet Haematol. 2015;2(3):e118-e128. or prevent the timely availability of affordable generic drugs in the
53. Masarova L, Cortes JE, Patel KP, et al. Long-term results of a phase United States. Blood. 2016;127(11):1398-1402.
2 trial of nilotinib 400 mg twice daily in newly diagnosed patients 74. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in
with chronic-phase chronic myeloid leukemia. Cancer. 2020;126(7): "good-risk" chronic granulocytic leukemia. Blood. 1984;63(4):
1448-1459. 789-799.
54. Maiti A, Cortes JE, Patel KP, et al. Long-term results of frontline 75. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score
dasatinib in chronic myeloid leukemia. Cancer. 2020;126(7):1502- for survival of patients with chronic myeloid leukemia treated with
1511. interferon Alfa writing Committee for the Collaborative CML
prognostic factors project group. J Natl Cancer Inst. 1998;90(11): 92. Marin D, Bazeos A, Mahon F-X, et al. Adherence is the critical factor
850-859. for achieving molecular responses in patients with chronic myeloid
76. Testoni N, Marzocchi G, Luatti S, et al. Chronic myeloid leukemia: a leukemia who achieve complete cytogenetic responses on imatinib.
prospective comparison of interphase fluorescence in situ hybridiza- J Clin Oncol. 2010;28(14):2381-2388.
tion and chromosome banding analysis for the definition of com- 93. Darkow T, Henk HJ, Thomas SK, et al. Treatment interruptions and
plete cytogenetic response: a study of the GIMEMA CML WP. non-adherence with imatinib and associated healthcare costs. Phar-
Blood. 2009;114(24):4939-4943. macoeconomics. 2007;25(6):481-496.
77. Kantarjian H, Cortes J. Considerations in the Management of 94. Noens L, van Lierde M-A, de Bock R, et al. Prevalence, determinants,
Patients with Philadelphia Chromosome–Positive Chronic Myeloid and outcomes of nonadherence to imatinib therapy in patients with
Leukemia Receiving Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113(22):
2011;29(12):1512-1516. 5401-5411.
78. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability- 95. Brümmendorf TH, Cortes JE, Goh YT, Yilmaz M, Klisovic RB,
adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus Purcell S, Viqueira A, Leip E, Gambacorti-Passerini C Bosutinib (BOS)
interferon-α in newly diagnosed chronic myeloid leukemia. J Clin for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib
Oncol. 2011;29(12):1634-1642. (IMA) failure: ≥8-y update of a phase I/II study. J Clin Oncol 2020;38-
79. Kantarjian HM, Shan J, Jones D, et al. Significance of increasing (15_suppl):7549–7549.
levels of minimal residual disease in patients with Philadelphia 96. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-
chromosome–positive chronic Myelogenous leukemia in complete resistant or imatinib-intolerant patients with chronic myeloid leuke-
cytogenetic response. J Clin Oncol. 2009;27(22):3659-3663. mia in chronic phase: 48-month follow-up results of a phase II study.
80. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 tran- Leukemia. 2012;27(1):107-112.
script levels at 3 months is the only requirement for predicting out- 97. Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasati-
come for patients with chronic myeloid leukemia treated with nib after imatinib failure in chronic-phase chronic myeloid leukemia:
tyrosine kinase inhibitors. J Clin Oncol. 2012;30(3):232-238. follow-up of a phase 3 study. Blood. 2014;123(15):2317-2324.
81. Cortes JE, Jiang Q, Wang J, et al. Dasatinib vs. imatinib in patients 98. Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose
with chronic myeloid leukemia in chronic phase (CML-CP) who have escalation is associated with durable responses in patients with
not achieved an optimal response to 3 months of imatinib therapy: chronic myeloid leukemia after cytogenetic failure on standard-dose
the DASCERN randomized study. Leukemia. 2020;34(8):2064-2073. imatinib therapy. Blood. 2009;113(10):2154-2160.
82. Jain P, Kantarjian H, Nazha A, et al. Early responses predict better 99. Kantarjian H, Pasquini R, Lévy V, et al. Dasatinib or high-dose imati-
outcomes in patients with newly diagnosed chronic myeloid leuke- nib for chronic-phase chronic myeloid leukemia resistant to imatinib
mia: results with four tyrosine kinase inhibitor modalities. Blood. at a dose of 400 to 600 milligrams daily. Cancer. 2009;115(18):
2013;121(24):4867-4874. 4136-4147.
83. Neelakantan P, Gerrard G, Lucas C, et al. Combining BCR-ABL1 tran- 100. Garcia-Gutierrez JV, Herrera P, Abalo LL, et al. Impact of second-
script levels at 3 and 6 months in chronic myeloid leukemia: implica- generation tyrosine kinase inhibitors as second line treatment for
tions for early intervention strategies. Blood. 2013;121(14):2739- patients with chronic myeloid leukemia. Blood. 2011;118(21):3780.
2742. 101. Goh H-G, Jootar S, Kim H-J, et al. Efficacy of nilotinib versus high-
84. Nazha A, Kantarjian H, Jain P, et al. Assessment at 6 months may be dose imatinib in early chronic phase CML patients who have subop-
warranted for patients with chronic myeloid leukemia with no major timal molecular responses to standard-dose imatinib (RE-NICE mul-
cytogenetic response at 3 months. Haematologica. 2013;98(11): ticenter study). Blood. 2011;118(21):2765.
1686-1688. 102. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and effi-
85. Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with cacy of bosutinib (SKI-606) in chronic phase Philadelphia
CML and >10% BCR-ABL1 after 3 months of imatinib depends on chromosome–positive chronic myeloid leukemia patients with resis-
the rate of BCR-ABL1 decline. Blood. 2014;124(4):511-518. tance or intolerance to imatinib. Blood. 2011;118(17):4567-4576.
86. Jabbour E, Kantarjian HM, O'Brien S, et al. Front-line therapy with 103. Yeung DT, Osborn M, White DL, et al. Upfront imatinib therapy in
second-generation tyrosine kinase inhibitors in patients with early CML patients with rapid switching to nilotinib for failure to achieve
chronic phase chronic myeloid leukemia: what is the optimal molecular targets or intolerance achieves high overall rates of
response? J Clin Oncol. 2011;29(32):4260-4265. molecular response and a low risk of progression: an update of the
87. Sasaki K, Kantarjian HM, Issa GC, et al. Impact of molecular response TIDEL-II trial. Blood. 2011;118(21):451.
at specific timepoints in patients with newly diagnosed chronic mye- 104. Quintás-Cardama A, Cortes JE, O'Brien S, et al. Dasatinib early inter-
loid leukemia treated with second generation tyrosine kinase inhibi- vention after cytogenetic or hematologic resistance to imatinib in
tors. Blood. 2020;136(Suppl 1):42-44. patients with chronic myeloid leukemia. Cancer. 2009;115(13):
88. Branford S. Monitoring and defining early response: where to draw 2912-2921.
the line? Best Pract Res Clin Haematol. 2016;29(3):284-294. 105. Hochhaus A, Gambacorti-Passerini C, Abboud C, et al. Bosutinib for
89. Cortes JE, de Souza CA, Ayala M, et al. Switching to nilotinib versus pretreated patients with chronic phase chronic myeloid leukemia:
imatinib dose escalation in patients with chronic myeloid leukaemia primary results of the phase 4 BYOND study. Leukemia. 2020;34(8):
in chronic phase with suboptimal response to imatinib (LASOR): a 2125-2137.
randomised, open-label trial. Lancet Haematol. 2016;3(12):e581- 106. Rosti G, Baccarani M, Pane F, et al. Dose optimization in elderly
e591. CML patients treated with bosutinib after intolerance or failure of
90. Hughes TP, Leber B, Cervantes F, et al. Sustained deep molecular first-line tyrosine kinase inhibitors. Blood. 2019;134(Suppl_1):496.
responses in patients switched to nilotinib due to persistent BCR- 107. O'Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL
ABL1 on imatinib: final ENESTcmr randomized trial results. Leuke- inhibitor for chronic myeloid leukemia, potently inhibits the T315I
mia. 2017;31(11):2529-2531. mutant and overcomes mutation-based resistance. Cancer Cell.
91. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2009;16(5):401-412.
2020 recommendations for treating chronic myeloid leukemia. Leu- 108. Zhou T, Commodore L, Huang W-S, et al. Structural mechanism of
kemia. 2020;34(4):966-984. the pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for
overcoming kinase inhibitor resistance. Chem Biol Drug des. 2011; sequential treatment with multiple tyrosine kinase inhibitors. Blood.
77(1):1-11. 2007;110(12):4005-4011.
109. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib 128. Jabbour E, Branford S, Saglio G, Jones D, Cortes JE, Kantarjian HM.
in Philadelphia chromosome–positive leukemias. N Engl J Med. Practical advice for determining the role of BCR-ABL mutations in
2013;369(19):1783-1796. guiding tyrosine kinase inhibitor therapy in patients with chronic
110. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Ponatinib efficacy and myeloid leukemia. Cancer. 2011;117(9):1800-1811.
safety in Philadelphia chromosome–positive leukemia: final 5-year 129. Müller MC, Cortes JE, Kim D-W, et al. Dasatinib treatment of
results of the phase 2 PACE trial. Blood. 2018;132(4):393-404. chronic-phase chronic myeloid leukemia: analysis of responses
111. Cambridge MAP, Inc. Iclusig (ponatinib) [prescribing information] according to preexisting BCR-ABL mutations. Blood. 2009;114(24):
2014. 4944-4953.
112. Cortes J, Apperley J, Lomaia E, et al. Ponatinib dose-ranging study in 130. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL
chronic-phase chronic myeloid leukemia: a randomized, open-label mutations on response to nilotinib in patients with chronic myeloid
phase 2 clinical trial. Blood. 2021;138(21):2042-2050. leukemia in chronic phase. J Clin Oncol. 2009;27(25):4204-4210.
113. Jabbour EJ, Deininger MW, Abruzzese E, et al. Dose modification 131. Jabbour E, Cortes J, Santos FPS, et al. Results of allogeneic hemato-
dynamics of Ponatinib in patients with chronic-phase chronic mye- poietic stem cell transplantation for chronic myelogenous leukemia
loid leukemia (CP-CML) from the PACE and Optic trials. Blood. patients who failed tyrosine kinase inhibitors after developing BCR-
2021;138(Suppl 1):2550. ABL1 kinase domain mutations. Blood. 2011;117(13):3641-3647.
114. Breccia M, Olimpieri PP, Celant S, et al. Ponatinib in a real-life set- 132. Nicolini FE, Basak GW, Kim D-W, et al. Overall survival with ponati-
ting: a retrospective analysis from the monitoring registries of the nib versus allogeneic stem cell transplantation in Philadelphia
italian medicines agency (AIFA). HemaSphere. 2022;6. chromosome-positive leukemias with the T315I mutation. Cancer.
115. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor 2017;123(15):2875-2880.
ABL001 enables dual targeting of BCR–ABL1. Nature. 2017; 133. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate
543(7647):733-737. on the outcome of hematopoietic cell transplantation for chronic
116. Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid myeloid leukemia. Blood. 2008;112(8):3500-3507.
leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019; 134. Ruiz-Argüelles GJ, Tarin-Arzaga LC, Gonzalez-Carrillo ML, et al.
381(24):2315-2326. Therapeutic choices in patients with Ph-positive CML living in
117. Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, ran- Mexico in the tyrosine kinase inhibitor era: SCT or TKIs? Bone Mar-
domized study of asciminib, a STAMP inhibitor, vs bosutinib in CML row Transplant. 2008;42(1):23-28.
after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. 135. Jaime-Pérez JC, Heredia-Salazar AC, Cantú-Rodríguez OG, et al.
118. Rea D, Hochhaus A, Mauro MJ, et al. Efficacy and safety results Cost structure and clinical outcome of a stem cell transplantation
from ASCEMBL, a phase 3 study of asciminib vs bosutinib in program in a developing country: the experience in northeast
patients with chronic myeloid leukemia in chronic phase after ≥2 Mexico. Oncologist. 2015;20(4):386-392.
prior tyrosine kinase inhibitors: wk 96 update. HemaSphere. 2022;6: 136. Shaya J, Pettit K, Kandarpa M, Bixby D, Mercer J, Talpaz M. Late
56-57. responses in patients with chronic myeloid leukemia initially refrac-
119. Cortes JE, Hughes TP, Mauro MJ, et al. Asciminib, a first-in-class tory to tyrosine kinase inhibitors. Clin Lymphoma Myeloma Leuk.
STAMP inhibitor, provides durable molecular response in patients 2022;22(1):17-23.
(pts) with chronic myeloid leukemia (CML) harboring the T315I 137. Haddad FG, Sasaki K, Issa GC, et al. Treatment-free remission in
mutation: primary efficacy and safety results from a phase 1 trial. patients with chronic myeloid leukemia following the discontinua-
Blood. 2020;136(Suppl 1):47-50. tion of tyrosine kinase inhibitors. Am J Hematol. 2022;97:856-864.
120. Breccia M, Rossi AVR, Martino B, et al. Asciminib Italian managed 138. Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission fol-
access program: efficacy profile in heavily pre-treated CML patients. lowing frontline nilotinib in patients with chronic myeloid leukemia
HemaSphere. 2022;6:607-608. in chronic phase: results from the ENESTfreedom study. Leukemia.
121. Innes A, Orovboni V, Claudiani S, et al. Asciminib use in CML: the 2017;31(7):1525-1531.
UKexperience. HemaSphere. 2022;6. 139. Mahon F-X, Réa D, Guilhot J, et al. Discontinuation of imatinib in
122. Khadadah F, Turkina AG, Lomaia E, et al. Canadian and Russian patients with chronic myeloid leukaemia who have maintained com-
experiences of asciminib in chronic myeloid leukemia (CML) patients plete molecular remission for at least 2 years: the prospective, multi-
who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy. centre stop imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029-
HemaSphere. 2022;6:603-604. 1035.
123. Kockerols CCB, Janssen JJWM, Blijlevens NMA, et al. Clinical out- 140. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imati-
come of asciminib treatment in a real-world multi-resistant CML nib cessation for CML patients with stable undetectable minimal
patient population. HemaSphere. 2022;6:604-605. residual disease: results from the TWISTER study. Blood. 2013;
124. Sasaki K, Jabbour E, Issa GC, et al. Outcomes of patients with 122(4):515-522.
chronic myeloid leukemia treated with third-line tyrosine kinase 141. Ross DM, Masszi T, Go mez Casares MT, et al. Durable treatment-
inhibitors. Blood. 2020;136(Suppl 1):25-26. free remission in patients with chronic myeloid leukemia in chronic
125. Zhai Y, Yang D, Hou Y, et al. An updated safety and efficacy results phase following frontline nilotinib: 96-week update of the ENEST-
of phase 1 study of HQP1351, a novel 3rd generation of BCR-ABL freedom study. J Cancer Res Clin Oncol. 2018;144(5):945-954.
tyrosine kinase inhibitor (TKI), in patients with TKI resistant chronic 142. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine
myeloid leukemia. Blood 2019;134(Suppl_1):493–493. kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a
126. Qian J, Shi D, Li Z, et al. Updated safety and efficacy results of phase prespecified interim analysis of a prospective, multicentre, non-ran-
1 study of olverembatinib (HQP1351), a novel third-generation domised, trial. Lancet Oncol. 2018;19(6):747-757.
BCR-ABL tyrosine kinase inhibitor (TKI), in patients with TKI- 143. Spentchian M, Cayuela J-M, Besson C, Delord M, Loiseau C,
resistant chronic myeloid leukemia (CML). Blood. 2021;138(Suppl Rousselot P. A report on 114 patients who experienced treatment
1):311. free remission in a single institution during a 15 years period: long
127. Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL term follow-up, late molecular relapses and second attempts. Blood
kinase domain mutations in chronic myeloid leukemia after 2019;134(Suppl_1):27–27.
144. Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: 154. Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine
stemming the tide of persistence. Blood. 2017;129(12):1595-1606. kinase inhibitors as initial therapy for patients with chronic myeloid
145. Erika Held S, Heine A, Mayer K, Kapelle M, Friedrich Wolf D, leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk. 2014;
Brossart P. Advances in immunotherapy of chronic myeloid leuke- 14(2):155-162.e151.
mia CML. Curr Cancer Drug Targets. 2013;13(7):768-774. 155. Strati P, Kantarjian H, Thomas D, et al. HCVAD plus imatinib or
146. Gallipoli P, Cook A, Rhodes S, et al. JAK2/STAT5 inhibition by niloti- dasatinib in lymphoid blastic phase chronic myeloid leukemia. Can-
nib with ruxolitinib contributes to the elimination of CML CD34+ cer. 2014;120(3):373-380.
cells in vitro and in vivo. Blood. 2014;124(9):1492-1501. 156. Jain P, Kantarjian HM, Ghorab A, et al. Prognostic factors and sur-
147. Ko TK, Chuah CTH, Huang JWJ, Ng K-P, Ong ST. The BCL2 inhibi- vival outcomes in patients with chronic myeloid leukemia in blast
tor ABT-199 significantly enhances imatinib-induced cell death in phase in the tyrosine kinase inhibitor era: cohort study of
chronic myeloid leukemia progenitors. Oncotarget. 2014;5(19):9033- 477 patients. Cancer. 2017;123(22):4391-4402.
9038. 157. Copland M, Slade D, McIlroy G, et al. Ponatinib with fludarabine,
148. Schnekenburger M, Grandjenette C, Ghelfi J, et al. Sustained expo- cytarabine, idarubicin, and granulocyte colony-stimulating factor
sure to the DNA demethylating agent, 20 -deoxy-5-azacytidine, leads chemotherapy for patients with blast-phase chronic myeloid leukae-
to apoptotic cell death in chronic myeloid leukemia by promoting mia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial. Lan-
differentiation, senescence, and autophagy. Biochem Pharmacol. cet Haematol. 2022;9(2):e121-e132.
2011;81(3):364-378. 158. Branford S, Wang P, Yeung DT, et al. Integrative genomic analysis
149. Apperley JF, Cortes JE, Kim D-W, et al. Dasatinib in the treatment reveals cancer-associated mutations at diagnosis of CML in patients
of chronic myeloid leukemia in accelerated phase after imatinib fail- with high-risk disease. Blood. 2018;132(9):948-961.
ure: the START a trial. J Clin Oncol. 2009;27(21):3472-3479. 159. Ochi Y, Yoshida K, Huang Y-J, et al. Clonal evolution and clinical
150. le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with implications of genetic abnormalities in blastic transformation of
Ph+ chronic myeloid leukemia in accelerated phase following imati- chronic myeloid leukaemia. Nat Commun. 2021;12(1):2833.
nib resistance or intolerance: 24-month follow-up results. Leukemia. 160. Nteliopoulos G, Bazeos A, Claudiani S, et al. Somatic variants in epi-
2011;26(6):1189-1194. genetic modifiers can predict failure of response to imatinib but not
151. Jabbour E, Cortes J, Kantarjian H, et al. Novel tyrosine kinase inhibi- to second-generation tyrosine kinase inhibitors. Haematologica.
tor therapy before allogeneic stem cell transplantation in patients 2019;104(12):2400-2409.
with chronic myeloid leukemia. Cancer. 2007;110(2):340-344.
152. Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesy-
late treatment before allogeneic transplantation for chronic myeloid
leukemia. Blood. 2006;109(4):1782-1789. How to cite this article: Jabbour E, Kantarjian H. Chronic
153. Carpenter PA, Snyder DS, Flowers MED, et al. Prophylactic adminis-
myeloid leukemia: 2022 update on diagnosis, therapy, and
tration of imatinib after hematopoietic cell transplantation for high-
risk Philadelphia chromosome–positive leukemia. Blood. 2006; monitoring. Am J Hematol. 2022;97(9):1236‐1256. doi:10.
109(7):2791-2793. 1002/ajh.26642

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Received: 16 June 2022 Accepted: 18 June 2022

ANNUAL CLINICAL UPDATES IN

Chronic myeloid leukemia: 2022 update on diagnosis,

Elias Jabbour | Hagop Kantarjian

Department of Leukemia, The University of

1236 © 2022 Wiley Periodicals LLC. wileyonlinelibrary.com/journal/ajh Am J Hematol. 2022;97:1236–1256.

1 | D I S E A S E OV E R V I E W circumstances and phases of the disease. Allo-SCT is an important

BCR::ABL1 < 10% Longest

T A B L E 2 Frontline TKIs therapy:

Abbreviation: CCyR, complete cytogenetic response.

of 60 years at diagnosis, the total cost of imatinib therapy for

Response Dasatinib97 Nilotinib96 Bosutinib95 Ponatinib110 Asciminib117

Abbreviations: CML, chronic myeloid leukemia; DMR, deep molecular

RE FE R ENC E S polish adult leukemia group imatinib generics registry. Am J Hematol.

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