Chronic Myeloid Leukemia: 2020 Update On Diagnosis, Therapy and Monitoring

10968652, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.25792 by Nat Prov Indonesia, Wiley Online Library on [23/02/2023].
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Received: 12 March 2020 Accepted: 18 March 2020
DOI: 10.1002/ajh.25792
ANNUAL CLINICAL UPDATES

IN HEMATOLOGICAL MALIGNANCIES
Chronic myeloid leukemia: 2020 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 Disease overview: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm
Correspondence with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately
Elias Jabbour, MD Anderson Cancer Center, 15% of newly diagnosed cases of leukemia in adults.
Box 428, 1515 Holcombe Blvd, Houston, TX
77030. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2),
Email: ejabbour@mdanderson.org involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the
breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is
known as the Philadelphia chromosome. The molecular consequence of this transloca-
tion is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a
BCR-ABL oncoprotein.
Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib,
and bosutinib 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 they
had no impact on survival prolongation, likely because of the existence of highly effec-
tive salvage therapies for patients who have a cytogenetic relapse with frontline TKI.
Salvage Therapy: For CML post failure on frontline therapy, second-line options
include second and third generation TKIs. Although potent and selective, these
exhibit unique pharmacological profiles and response patterns relative to different
patient and disease characteristics, such as patientsʼ comorbidities, disease stage,
and BCR-ABL1 mutational status. Patients who develop the T315I “gatekeeper”
mutation display resistance to all currently available TKIs except ponatinib. Allogeneic
stem cell transplantation remains an important therapeutic option for patients with
CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase dis-
ease. Even among older patients who have a cytogenetic relapse post failure on all
TKIs, they can maintain long-term survival if they continue on a daily most effective/
less toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxy-
urea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others).
1 | D I S E A S E OV E R V I E W In 2020, it is estimated about 8450 new CML cases will be diagnosed

in the United States, and about 1080 patients will die of CML. Since
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm the introduction of imatinib in 2000, the annual mortality in CML has
with an incidence of 1-2 cases per 100 000 adults. It accounts for decreased from 10%-20% to 1%-2%.1 Consequently, the prevalence
1
approximately 15% of newly diagnosed cases of leukemia in adults. of CML in the United States (US), estimated at about 30 000 in 2000,
Am J Hematol. 2020;95:691–709. wileyonlinelibrary.com/journal/ajh © 2020 Wiley Periodicals, Inc. 691

10968652, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.25792 by Nat Prov Indonesia, Wiley Online Library on [23/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
692 JABBOUR AND KANTARJIAN
has increased by approximately 7000-8800/year to an estimated with a low platelet count and/or platelet dysfunction), thrombosis
150-180 000+ in 2020, based on an incidence of 5000 cases/year in (associated with thrombocytosis and/or marked leukocytosis), gouty
2020. Early estimates indicated the CML prevalence to reach a pla- arthritis (from elevated uric acid levels), priapism (usually with marked
teau of about 180 000 cases by 2030-2040.2 However, based on the leukocytosis or thrombocytosis), retinal hemorrhages, and upper gas-
current incidence of 9000 cases/year in the US (US population expan- trointestinal ulceration and bleeding (from elevated histamine levels
sion), and an annual overall mortality of 2%, the prevalence plateau due to basophilia). Leukostatic symptoms (dyspnea, drowsiness, loss
(annual incidence equal to annual mortality of 9000 cases) is now esti- of coordination, confusion) due to leukemic cells sludging in the pul-
mated to be 9000 × 100/2 = 400 000-450 000 cases in the US, monary or cerebral vessels, are uncommon in CP despite white blood
which may not be reached until 2040-2050. cell (WBC) counts exceeding 100 × 109/L. Splenomegaly is the most
Central to the pathogenesis of CML is the fusion of the Abelson consistent physical sign detected in 20-40% of cases. Hepatomegaly
murine leukemia (ABL1) gene on chromosome 9 with the breakpoint is less common (less than 10%). Lymphadenopathy and infiltration of
cluster region (BCR) gene on chromosome 22. This results in expres- skin or other tissues are rare. When present, they favor Ph-negative
sion of an oncoprotein termed BCR-ABL1.3 Thus, BCR-ABL1 is a con- CML or AP or BP of CML. Headaches, bone pain, arthralgias, pain
stitutively active tyrosine kinase that promotes growth and replication from splenic infarction, and fever are more frequent with CML trans-
through downstream signaling pathways such as RAS, RAF, JUN formation. Most patients evolve into AP prior to BP, but 20% transi-
kinase, MYC and STAT.4-10 This influences leukemogenesis by creat- tion into BP without AP warning signals. Therefore, CML-AP might be
ing a cytokine-independent cell cycle with aberrant apoptotic signals insidious or present with worsening anemia, splenomegaly and organ
in response to cytokine withdrawal. infiltration; CML-BP presents as an acute leukemia (myeloid in 60%,
Until the end of the last century, drug therapy for CML was lim- lymphoid in 30%, megakaryocytic or undifferentiated in 10%) with
ited to nonspecific agents such as busulfan, hydroxyurea, and worsening constitutional symptoms, bleeding, fever and infections.
interferon-alfa (INF-a).11 The INF-a therapy resulted in disease regres-
sion and improved survival, but had modest efficacy and a multitude
of toxicities. Allogeneic stem cell transplantation (allo-SCT) is curative, 3 | DI AGN OS I S
but carries risks of morbidities and mortality. So, allo-SCT is an option
only for younger patients with good performance status and organ The diagnosis of typical CML is simple and consists of documenting,
functions, and who have an appropriate donor. in the setting of persistent unexplained leukocytosis (or occasionally
The CML therapeutic landscape changed dramatically with the thrombocytosis), the presence of the Philadelphia (Ph) chromosome
development of small molecule tyrosine kinase inhibitors (TKIs) that abnormality, the t(9;22)(q34;q11), by routine cytogenetics, or the Ph-
potently interfered with the interaction between the BCR-ABL1 related molecular BCR-ABL1 abnormalities by fluorescence in situ
oncoprotein and adenosine triphosphate (ATP), blocking cellular pro- hybridization (FISH) or by molecular studies.13-15
liferation of the malignant clone. This “targeted” approach altered the A FISH analysis relies on the co-localization of large genomic pro-
natural history of CML, improving the 10-year survival rate from bes specific to the BCR and ABL1 genes. Comparison of simultaneous
approximately 20% to 80%-90%.1-2,12 marrow and blood samples by FISH analysis shows high concordance.
In this review, we will highlight the evidence supporting the use Fluorescence in situ hybridization studies may have a false positive
of each of the available TKIs, including how to select an agent under range of 1% to 5% depending on the probes used.
various circumstances and phases of the disease. Allo-SCT is an Reverse transcriptase-polymerase chain reaction (RT-PCR)
important treatment option in CML chronic phase (CP) post TKIs fail- amplifies the region around the splice junction between BCR and
ure and in advanced CML phases, and its role will be reviewed. Cyto- ABL1. It is highly sensitive in detecting minimal residual disease. The
genetic and molecular benchmarks for patients on therapy will be PCR testing can either be qualitative (QPCR), providing information
discussed. Finally, appropriate monitoring strategies for patients on about the presence of the BCR-ABL1 transcript, or quantitative,
TKIs will be addressed. assessing the amount of BCR-ABL1 transcripts. Qualitative PCR is use-
ful for diagnosing CML; quantitative PCR is ideal for monitoring resid-
ual disease. Simultaneous peripheral blood and marrow QPCR studies
2 | M A N I F E S T A T I O N S A N D ST A G I N G show a high level of concordance. False-positive and false-negative
results can happen with PCR. False-negative results may be from
About 50% of patients diagnosed with CML in the United States are poor-quality RNA or failure of the reaction; false-positive results can
asymptomatic. The diagnosis of CML often occurs during a routine be due to contamination. A 0.5-1 log difference in some samples can
physical examination or blood tests. CML can be classified into three occur depending on testing procedures, sample handling, and labora-
phases: CP, accelerated phase (AP), and blast phase (BP). Most (90%- tory experience.13-15 For correlative purpose and monitoring without
95%) patients present in CML-CP. Common signs and symptoms of necessarily performing repeat marrow studies, a complete cytogenetic
CML-CP, when present, result from anemia and splenomegaly. These response (CCyR; 0% Ph-positive metaphases by cytogenetic) is equiv-
include fatigue, weight loss, malaise, easy satiety, and left upper quad- alent to a negative FISH test (+/− 2%) and BCR-ABL1 transcripts by
rant fullness or pain. Rare manifestations include bleeding (associated International Standard (IS) <1%. A partial cytogenetic response (PCyR)
JABBOUR AND KANTARJIAN 693
(Ph-positive metaphases ≤35%) is equivalent to BCR-ABL1 tran- have a normal or increased LAP score, a WBC count less than
scripts ≤10% IS. 25 × 109/L, and no Ph abnormality.
The Ph chromosome is usually present in 100% of metaphases, The greatest diagnostic difficulty lies with patients who have
often as the sole abnormality. Ten to 15% of patients have additional splenomegaly and leukocytosis but who do not have the Ph chromo-
chromosomal changes (clonal evolution) involving trisomy 8, isochro- some. In some, the BCR-ABL1 hybrid gene can be demonstrated
mosome 17, additional loss of material from 22q or double Ph, or despite a normal or atypical cytogenetic pattern. Patients who are Ph
others. negative and BCR-ABL1 negative are considered to have Ph-negative
Ninety percent of patients have a typical t(9;22); 5% have variant CML or chronic myelomonocytic leukemia. Rarely, patients have mye-
translocations which can be simple (involving chromosome 22 and a loid hyperplasia, which involves almost exclusively the neutrophil,
chromosome other than chromosome 9), or complex (involving one or eosinophil, or basophil cell lineage. These patients are described as
more chromosomes in addition to chromosomes 9 and 22). Patients having chronic neutrophilic, eosinophilic, or basophilic leukemia, and
with Ph-variants have response to therapy and prognosis similar to do not have evidence of the Ph chromosome or the BCR-ABL1 gene.
Ph-positive CML. About 2%-5% of patients present with a morpho- Isolated megakaryocytic hyperplasia can be seen in essential
logic picture of CML without the Ph-positivity by cytogenetic studies. thrombocythemia, with marked thrombocytosis and splenomegaly.
Fluorescent in situ hybridization and PCR document Ph-negative BCR- Some patients who present with clinical characteristics of essential
ABL1 rearranged CML. Such patients have similar response and out- thrombocythemia (with marked thrombocytosis but without leukocy-
come on TKI therapy as patients with Ph-positive CML. tosis) have CML; cytogenetic and molecular studies showing the Ph
Bone marrow aspiration is mandatory for all patients in whom CML chromosome, the BCR-ABL1 rearrangement, or both lead to the
is suspected, as it will confirm the diagnosis (eg, cytogenetic analysis), and appropriate diagnosis and treatment.
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/del7q, and 3q26.2 rearrangements, 5 | FR O NT L I N E T R EA T M E N T O P T I O N S
16
associated with a relatively poor prognosis. Baseline reverse
transcriptase-polymerase chain reaction is imperative to identify the spe- The four commercially available TKIs for the frontline treatment of
cific type of rearrangement that can be appropriately followed when CML include imatinib, dasatinib, nilotinib, and bosutinib. Current
assessing for response to TKI therapy. The typical translocations of BCR- guidelines endorse all four TKIs as options for the initial management
ABL1 result in e13a2 or e14a2 transcripts, producing the p210 of CML in the chronic phase (CML-CP, Table 1).
oncoproteins. About 1% of patients may have e1a2/a3 transcript,
resulting in a shorter p190 oncoproteins. These patients may have a
worse prognosis. About 2%-5% of patients have e13a3 or e14a3 (not 5.1 | Imatinib
e13a2 or e14a2) variants of p210 BCR-ABL1 or p230 transcripts (indo-
lent), that may yield a false negative PCR by routine probes, and (if not Imatinib mesylate was the first TKI to receive approval by the Food
tested at diagnosis) would give the false impression that a patient may be and Drug Administration (FDA) for the treatment of patients with
in complete molecular response on TKI. CML-CP. It acts via competitive inhibition at the ATP-binding site of
the BCR-ABL1 oncoprotein, which results in the inhibition of phos-
phorylation of proteins involved in cell signal transduction. It effi-
4 | DIFFERENTIAL DIAGNOSIS ciently inhibits the BCR-ABL1 kinase, but also blocks the platelet-
derived growth factor receptor (PGDFR) and the C-KIT tyrosine
CML must be differentiated from leukemoid reactions, which usually kinase.17
produce white blood cell counts lower than 50 × 10 /L, toxic granulo-
9
The International Randomized Study of Interferon and STI571
cytic vacuolation, Döhleʼs bodies in the granulocytes; they also show (IRIS) study is considered a landmark clinical trial for TKIs and CML.18
absence of basophilia and normal or increased LAP levels. The clinical Investigators randomized 1106 patients in CML-CP to receive
history and physical examination generally suggest the origin of the imatinib 400 mg/day or INF-a plus low-dose cytarabine. After a
leukemoid reaction. Corticosteroids can rarely cause extreme neu- median follow-up of 19 months, outcomes for patients receiving
trophilia with a left shift, but this abnormality is transient and of short imatinib were significantly better than in those treated with INF-a plus
duration. cytarabine. Notably, the rates of CCyR rate (74% vs 9%, P < .001), and
Chronic myeloid leukemia may be more difficult to differentiate freedom-from-progression to AP or BP at 12 months (99% vs 93%,
from other myeloproliferative or myelodysplastic syndromes. P < .001). Further highlighting the challenge of using IFN-a was the
Patients with agnogenic myeloid metaplasia with or without myelo- high crossover rate to imatinib due to intolerance. With a median
fibrosis frequently have splenomegaly, neutrophilia, and follow-up of almost 11 years, the estimated overall survival rate for
thrombocytosis. Polycythemia vera with associated iron deficiency, patients who had been randomly assigned to receive imatinib was
which causes normal hemoglobin and hematocrit values, can mani- 83.3%, with a cumulative CCyR rate of 83% and a 10-year major
fest with leukocytosis and thrombocytosis. Such patients usually molecular response (MMR) rate of 93%.12 Despite the high rate of
TABLE 1 Summary of pivotal phase III trials of approved tyrosine kinase inhibitors (TKIs) for the frontline treatment of chronic myeloid
leukemia (CML)
BCR-ABL < 10% Longest

Trial Treatment CCyR (%) MMR (%) at 3 mo (%) EFS/PFS (%) OS (%) follow-up (y)
IRIS At 10 y At 10 y
Imatinib (n = 304) 83 93 NR 80 83 11
DASISION At 2 y At 5 y At 5 y
Dasatinib (n = 259) 86 76 84 85 91 5
Imatinib (n = 260) 82 64 64 86 90
ENESTnd At 2 y At 5 y At 10 y
Nilotinib 300 mg (n = 282) 87 77 91 86 88 10
Nilotinib 400 mg (n = 281) 85 77 89 90 90
Imatinib (n = 283) 77 60 67 87 98
BEFORE By 2 y At 2 y
Bosutinib 400 mg (n = 268) 82 66 75 96 99 24 mo
Imatinib (n = 268) 76 57 57 93 97
crossover among patients who had been randomly assigned to receive At our institution, we reported on 38 patients who switched therapy
INF-a plus cytarabine (66%) and the short duration of therapy before from branded imatinib to generics. Before the switch, all patients were in
crossover in these patients (median, 0.8 years), the 10-year survival CCyR and 36 (95%) were in MMR, including 28 (74%) in molecular
rates favored the imatinib therapy arm (83.3% vs 78.8%).12 response (MR .4.5). Patients have received generic imatinib for a median
While the results using imatinib are impressive, only 48% of of 19.4 months. Molecular responses after switching were stable in 89%,
patients enrolled in the IRIS study remained on therapy at the 10-year improved in 8%, and worsened in 3% of patients. No patient lost MMR.21
follow-up time. This underscored the need for additional treatment
options for patients with CML and failure or intolerance to imatinib.
This led to the rational development of second generation TKIs that 5.3 | High-dose imatinib and imatinib-based
would effectively treat patients unable to continue on imatinib combinations
therapy.
Other strategies for frontline therapy include using higher doses of
imatinib or combining a TKI with an additional agent, such as inter-
5.2 | Imatinib generics feron. In the Tyrosine Kinase Inhibitor Optimization and Selectivity
(TOPS) study, patients were randomized to receive imatinib 400 mg
Imatinib generics entered the market recently after the Novartisʼs pat- once daily or twice daily (800 mg).22 The MMR rate at 12 months was
ent for Gleevec expired. Several groups have reported on the efficacy the study primary endpoint, with cytogenetic response and time to
and safety of generic imatinib compared with the branded one. The such responses collected as secondary outcomes. Patients in the high-
two largest series are from Poland and India. The Polish Adult Leuke- dose group achieved faster CCyR and MMR, but rates were not signif-
mia Group (PALG) imatinib generics registry reported on 726 patients icantly different at 12 months.
who started therapy with imatinib generics (multiple manufacturers) Interferon has re-emerged as an interesting therapeutic option in
after the diagnosis of CML (group A, n = 99), or who were switched to CML with the advent of pegylated formulations requiring less fre-
generic from branded imatinib (group B, n = 627) and were observed quent administration and having improved tolerability. In a phase III
for at least 12 months.19 Among patients treated in the frontline set- randomized study, patients with newly diagnosed CML-CP were
ting (group A), the rates of 3-month PCyR, 6 month CCyR, and assigned to one of four treatment arms (imatinib 400 mg once daily,
12 month MMR were 66%, 53%, and 50%, respectively. These rates imatinib 600 mg once daily, imatinib 400 mg once daily plus
were similar to the expected rates achieved with branded imatinib. peginterferon alfa-2a, or imatinib 400 mg once daily plus subcutane-
The rates of resistance and intolerance were also similar (26% and ous cytarabine).23 Patients were initially assigned to receive
28%, respectively). Among patients who switched therapy, responses peginterferon alfa-2a at a dose of 90 mcg once weekly. Because of a
were maintained in the vast majority with only 0.3% and 1% of high rate of discontinuation due to toxicity, the dose was later modi-
patients losing their CCyR and MMR, respectively. Similar data were fied to 45 mcg once weekly. At 12 months, rates of CCyR were similar
reported from India. Among 174 patients treated with imatinib among the four groups. The imatinib plus peginterferon alfa-2a
generics, response and survival rates were similar to those observed treated group achieved higher rates of MMR and deeper molecular
among 1193 patients treated with the branded imatinib. The safety responses, but follow-up was not sufficient to define the impact on
profile was similar as well.20 long-term outcomes.
The CML-study IV was designed to explore whether treatment with showed the 12-month MMR rates were higher with dasatinib (58% vs
imatinib at 400 mg/day (n = 400) could be optimized by doubling the 43%;P < .001). The 12-month CCyR rates were 51% and 40%
dose (n = 420), or by adding interferon (n = 430) or cytarabine (n = 158) (P < .002), respectively. Progression rate to CML-AP was 0.7% with
or by using imatinib after interferon-failure (n = 128).24 From July 2002 imatinib and 0.5% with dasatinib. The progression rate to CML-BP
to March 2012, 1551 newly diagnosed patients with CML-CP were ran- was 1.7% vs 1%. Pleural effusions occurred more frequently with
domized into a five-arm study. The study was powered to detect a sur- dasatinib (19% vs <1%). Other side effects of dasatinib included
vival difference of 5% at 5 years. After a median observation time of myelosuppression (20%), and rare pulmonary hypertension (1-2%).
9.5 years, 10-year overall survival rate was 82%, 10-year progression-
free survival (PFS) rate was 80%, and 10-year relative survival rate was
92%. Despite a faster response with imatinib 800 mg, the survival differ- 5.5 | Lower dose dasatinib
ence between standard-dose and higher dose imatinib was only 3% at
5 years (less than 5%). In a multivariate analysis, standard-dose imatinib In early clinical trials evaluating dasatinib, the drug was active at lower
was equivalent to other treatment arms. Patients who reached the doses with better safety profile.33 In a randomized trial reported later,
6-month BCR-ABL1 transcripts IS <1% milestone, had a significant sur- dasatinib 100 mg daily was as effective as 140 mg daily with a better
vival advantage of about 6% after 10 years regardless of therapy. safety profile.34 Investigators from the DASISION trial reported on the
ability to maintain the efficacy of dasatinib among patients who had the
dose reduced while improving its safety profile.35 Based on this rationale,
5.4 | Dasatinib we treated 81 patients with early CML-CP with dasatinib 50 mg daily.
With a minimal follow-up of 12 months,36,37 the cumulative rates for a
Dasatinib is an oral, second generation TKI that is 350 times more MMR, a MR4, and a MR4.5 by 12 months were 81%, 55%, and 49%,
potent than imatinib in vitro.25-27 It also inhibits the Src family of respectively. Twenty-one patients (25%) had treatment interruptions for a
kinases, which may be important in blunting critical cell signaling path- median of 13 days (range, 4-64 days). Five patients (6%) developed pleural
28
ways. It was initially evaluated in patients in the salvage setting, and effusions; four of them required a dose reduction. Two patients (2%) failed
later compared to imatinib in frontline CML to test the possibility that to achieve any cytogenetic or molecular response and were taken off the
frontline use of the more potent TKIs might improve outcomes. study. At a median follow-up time of 24 months, none of the patients had
The DASISION trial was a phase III randomized study comparing disease transformation to an accelerated or blastic phase.37 The 2-year
imatinib 400 mg once daily to dasatinib 100 mg once daily in newly diag- event-free and overall survival rates were 100%. Such a strategy may have
nosed patients with CML-CP.29 The primary outcome was confirmed a significant impact on our future practice mainly due equivalent efficacy,
CCyR (cCCyR) at 12 months. A total of 519 patients were randomized better safety profile and lower cost of care.37
(1:1). Patients assigned to dasatinib achieved cCCyR at 12 months more
often than those assigned to imatinib (77% vs 66%, P = .007). Many of
the secondary endpoints of interest also favored the dasatinib arm. A 5.6 | Nilotinib
five-year follow-up showed that dasatinib induced more rapid and
deeper responses (12-month CCyR, MMR, MR4.5) at early time points Nilotinib is a structural analog of imatinib. Its affinity for the ATP bind-
30
compared with imatinib. At 3 months, a higher proportion of patients ing site on BCR-ABL1 is 30-50 times more in vitro.38 Like dasatinib,
treated with dasatinib achieved BCR-ABL1 transcripts IS ≤ 10% (84% vs nilotinib initially demonstrated the ability to induce hematologic and
64%, P < .0001). Meeting this threshold in either arm predicted better cytogenetic responses in patients who had failed imatinib.
PFS and overall survival. Transformations to CML-AP or CML-BP were Similar to dasatinib, nilotinib was also compared to imatinib in a
fewer among patients treated with dasatinib vs imatinib (4.6% vs 7.3%). large, international, randomized study (ENEST-nd). In ENEST-nd, two
However, with a minimum follow-up time of 5 years, the estimated doses of nilotinib (300 mg or 400 mg twice daily) were compared to
5-year survival was similar with imatinib and dasatinib (90% vs 91%).30 imatinib 400 mg once daily.39 The primary endpoint was the rate of
In another multicenter trial, several North American cooperative MMR at 12 months. This was significantly higher for both doses of
groups randomized patients with newly diagnosed CML-CP to either nilotinib compared with imatinib (44% and 43% vs 22%, P < .001). The
dasatinib 100 mg once daily or imatinib 400 mg once daily.31 Similar cumulative incidence of CCyR by 24 months was 87% with nilotinib
to the results of the DASISION study, patients treated with dasatinib 300 mg twice daily, 85% with nilotinib 400 mg twice daily, and 77%
achieved a higher rate of CCyR compared to patients receiving with imatinib 400 mg daily (P < .001).39
imatinib (84% vs 69%, P = .04). There was more toxicity experienced With a median follow-up of 10 years,40,41 the cumulative incidences
in the dasatinib arm (Grades 3 or 4 adverse events 58% with dasatinib of MMR by 10 years were 77.7% with nilotinib 300 mg twice daily and
and 35% with imatinib), mostly hematologic toxicity.31 62.5% with imatinib (P < .0001%).40 The 10-year cumulative rates of
A third phase III randomized study, SPIRIT 2, compared imatinib MR4.5 were 61% and 39.2%, respectively (P < .0001%).40 There was no
32
400 mg daily with dasatinib 100 mg daily. The primary endpoint of significant difference in outcome among patients treated with nilotinib
the trial was event-free survival (EFS) at 5 years, with the rate of and imatinib.40 The estimated 10-year PFS rates were 86.2%, 89.9%, and
achievement of MMR a key secondary endpoint. The interim results 87.2% with nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and
imatinib respectively.40 The estimated 10-year survival rates were 87.6%, 400 mg with either imatinib 800 mg, dasatinib, or nilotinib in randomised
90.3%, and 88.3%, respectively.40 In a second randomized trial with the trials, our study provided a comparative analysis of four TKI modalities
same design that enrolled 267 Chinese patients, the MMR rate was 52% after a long follow-up time. The analysis included 482 patients treated
at 12 months with nilotinib compared with 28% with imatinib.42 How- (July 2000-September 2013) in consecutive or parallel clinical trials, with
ever, the rates of both CCyR (84% vs 87%) and PFS (95% each) were imatinib 400 mg daily (n = 68), imatinib 800 mg daily (n = 200), dasatinib
similar at 24 months. Overall, six patients in each arm progressed to 50 mg twice daily or 100 mg daily (n = 106), or nilotinib 400 mg twice
AP/BP. In both arms, the estimated 2-year survival rate was 98%. daily (n = 108). More patients receiving imatinib 800 mg or second-
While nilotinib therapy was overall well tolerated, there was an generation TKIs (ie, dasatinib or nilotinib) achieved CCyR (87% with
increased risk of accumulated vascular events on therapy. The 10-year imatinib 400 mg; 90% with imatinib 800 mg; 96% with dasatinib; and
cumulative cardiovascular event rates were 24.8%, 33.4%, and 6.3% with 93% with nilotinib). The overall MMR rates were 76%, 86%, 90%
nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib and, 91%, respectively. The overall MR4.5 rates were 57%, 74%, 71%, and
400 mg daily, respectively.40 Other notable side effects were headache 71%, respectively. This finding was consistent over time (3-60 months),
and skin rashes (common 20%-30% but mild to moderate; alleviated by where at any time point, imatinib induced lower rates of cytogenetic and
dose reduction), self-limited elevation of indirect bilirubin (10%), eleva- molecular responses. This landmark assessment contrasts with previous
tions of blood sugar (10%-20%), and pancreatitis (1%-2%). reports where results were reported cumulatively (“by” not “at”) and can
be misleading. The 5-year EFS significantly differed between the imatinib
400 mg group and the other TKI groups (imatinib 800 mg, P = .029;
5.7 | Bosutinib dasatinib, P = .003; nilotinib, P = .031). However, there was no significant
difference in the 5-year rates of failure-free survival (P = .32, P = .075,
Bosutinib is a potent dual SRC/ABL kinase inhibitor.13 The drug was first P = .332), transformation-free survival (P = .053, P = .038, P = .493), or
approved for treating adults with Philadelphia chromosome-positive overall survival (P = .563, P = .162, P = .981). We also compared event-
CML and resistance and /or intolerance to prior therapy. It was recently free and overall survival according to whether or not MMR or MR4.5
approved for first-line treatment of chronic-phase CML.43 In a multina- response was achieved, in addition to CCyR. As expected, among patients
tional, phase III study, 536 patients with newly diagnosed chronic-phase who achieved CCyR, no difference in outcomes was observed regardless
CML were randomized to bosutinib 400 mg once daily (n = 268) or of by whether MMR or MR4.5 response was additionally achieved.44 The
imatinib (n = 268). The MMR rate at 12 months (primary end-point) was long-term results of frontline nilotinib and dasatinib therapy were
significantly higher with bosutinib vs imatinib (47% vs 37%, respectively; recently reported.45,46 Among 122 patients treated with nilotinib with a
P = .02), as was the CCyR rate by 12 months (77% vs 66%, respectively;
median follow-up of 78 months, the cumulative CCyR and MMR rates
P = .007). At 2 years, six patients (2.2%) receiving bosutinib and seven
were 91%. Seventy-five percent and 59% of patients achieved MR4.5
patients (2.6%) receiving imatinib experienced disease progression to
and a sustained MR4.5 beyond 2 years, respectively. The estimated
accelerated/blastic phase. Among treated patients, 22% of patients
5-year EFS and OS rates were 89% and 93%, respectively, and the
receiving bosutinib and 27% of patients receiving imatinib discontinued
corresponding rates at 10 years were 85% and 88%, respectively.45
treatment, most commonly for drug-related toxicity (13% and 9%,
Among 149 patients treated with dasatinib with a median follow-up of
respectively).43 Grade ≥ 3 diarrhea (8% vs 0.8%) and increased ALT (19%
6.5 years, the cumulative CCyR, MMR, and MR4.5 rates at 11 years were
vs 1.5%) and AST (10% vs 2%) levels were more common with bosutinib.
92.6%, 88.2%, and 79.5% (sustained beyond 2 years 55%), respectively.
Cardiac and vascular toxicities were uncommon. The 2-year cumulative
The 10-year overall survival, transformation-free survival, EFS, and
rates of CCyR were 76% and 66%, among patients treated with
bosutinib and imatinib (P = .005) respectively. The 2-year cumulative failure-free survival rates were 89%, 95%, 86%, and 65%, respectively.46
rates of MMR, MR4 and MR4.5 were 57% and 34% (P = .0036), 27% Given the equivalent efficacy and lower toxicity of lower dose
and 10% (P = .0249), and 15% and 3% (P = .0542), respectively.43 The dasatinib in our phase 2 study, frontline dasatinib 50 mg daily has
estimated 2-year survival rates were similar (99% vs 97%). become our standard of care for frontline therapy of patients with
CML-CP, including patients with high-risk disease.
5.8 | The MD Anderson Cancer Center (MDACC)

experience 5.9 | Dasatinib and venetoclax combination
We published the long-term responses and outcomes of patients with While TKIs are effective in CML, they may not eliminate the dormant
CML-CP and provided a comparison of four commonly used TKI modali- CML stem cells which may result in disease relapse after treatment
ties (Table 2).44 Unlike previous reports that compared only imatinib discontinuation.47 The BCR-ABL1 tyrosine kinase regulates several
TABLE 2 Frontline TKIs therapy:

% Cumulative Imatinib 400 mg Imatinib 800 Nilotinib Dasatinib
MDACC experience
CCyR 85 90 99 97
MR4.5 56 74 80 78
BCL-2 family proteins that confer resistance to apoptosis in CML 6 | SELECTING A FRONTLINE THERAPY
cells.47 Targeting BCR-ABL1 and BCL-2 could have therapeutic bene-
fits in quiescent CML CD34+ cells that are insensitive to TKI.48 6.1 | Patient age and comorbidities, and TKI
Carter and colleagues demonstrated increased BCL-2 expression toxicity profile
at the protein level in bone marrow cells, particularly in Lin(−)Sca-1(+)
cKit(+) cells of inducible CML in mice.48 Selective inhibition of BCL-2, While multiple TKIs are available to treat newly diagnosed CML in CP,
aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly each has a distinct toxicity profile to consider when deciding on ther-
decreased leukemic Lin(−)Sca-1(+)cKit(+) cell numbers and long-term apy. Most TKIs are reasonably well tolerated with adequate monitor-
stem cell frequency and prolonged survival in a murine CML model.48 ing and supportive care. For patients at risk of developing pleural
This combination effectively eradicated CD34(+)CD38(−), CD34(+) effusions (existing lung injuries), TKI other than dasatinib should be
CD38(+), and quiescent stem/progenitor CD34(+) cells from BP CML selected. This might be relevant for patients with a history of lung dis-
patient samples.48 ease (eg, chronic obstructive pulmonary disease), cardiac disease (eg,
These results suggest that BCL-2 is a key survival factor for CML congestive heart failure), or uncontrolled hypertension. Pulmonary
stem/progenitor cells and that combined inhibition of BCL-2 and arterial hypertension (PAH) is a rare yet important complication of
BCR-ABL1 tyrosine kinase has the potential to improve the depth of dasatinib,49 and patients with preexisting PAH may be considered for
48
response and cure rates of CML-CP. We are evaluating the combi- alternative TKIs in the frontline setting. Dasatinib also inhibits plate-
nation of venetoclax with dasatinib 50 mg daily in the frontline ther- lets function,50 and patients taking concomitant anticoagulants may
apy of CML-CP. be at an increased risk of hemorrhagic complications.51
Current guidelines recommend any of the four TKIs, imatinib, Nilotinib has been associated with hyperglycemia, caution should
dastinib nilotinib or bosutinib as good therapeutic options with a cat- be exercised in patients with uncontrolled diabetes when initiating
egory 1 recommendation for initial treatment of CML-CP. Second therapy. Niloinib should be avoided or prescribed with caution in
generation TKIs produced higher rate of early optimal responses, but patients with diabetes or history of pancreatitis. During preclinical
had no impact on long-term survival (probably because of available development, nilotinib was shown to potentially prolong the QT inter-
effective salvage therapies). There were also associated with higher val, and parameters were put in place to monitor for this complication
rates of serious adverse events (10-year cumulative rate of cardio- after the drug was approved. Potassium and magnesium should be
vascular events with nilotinib is 33%). Second generation TKI may repleted to appropriate serum levels before starting nilotinib or deter-
benefit patients with high-risk disease; a relevant decrease in the mining an individual patientʼs QT interval. Patients should always be
rate of transformation to AP and a BP was achieved with nilotinib, counseled to take nilotinib in a fasting state to avoid excess drug
dasatinib, and bosutinib. Thus, second generation TKIs in the front- exposure. Nilotinib has also been associated with vasospastic and
line setting could be reserved to patients with higher risk disease. vaso-occlusive vascular events, such as ischemic heart disease, ische-
Higher dose imatinib and combination approaches in the frontline mic cerebrovascular events, and peripheral artery occlusive disease
setting are investigational. These strategies are also not benign inter- (PAOD).40 In the 10-year follow-up on the ENEST-nd trial,40 approxi-
ventions, as they add to the economic and toxicity burden of the mately 33.4% of patients experienced vascular events. Nilotinib use
overall treatment plan. Allo-SCT or other chemotherapy agents are should be limited or avoided in patients with risk factors such as dia-
not recommended as upfront treatments for CML-CP given the excel- betes mellitus or coronary or cerebrovascular artery disease. Avoiding
lent outcomes and long-term survival achieved with the TKIs. An nilotinib in patients with significant past vascular histories is
exception may be in emerging nations where allo-SCT is a one-time warranted with the availability of other viable options. Bosutinib and
procedure costing $ 14-20 000, accessible to most patients. On the imatinib are the safest TKIs in relation to cardiovascular events.
other hand generic imatinib in such geographies (eg, India) costs only Imatinib causes bothersome quality-of-life side-effects including
less than $400 per year of therapy, arguing for always delaying allo- weight gain, fatigue, peripheral and periorbital edema, bone and muscle
SCT to post-frontline CML therapy. At MDACC, patients are cur- aches, nausea and others. However, most are mild to moderate. Less
rently offered therapy with dasatinib 50 mg daily +/− venetoclax. than 5%-10% experience elevations in creatinine with long-term therapy.
Lower dose dasatinib (50 mg daily) showed sustained efficacy com- Boustinib side-efffects are gastro-intestinal, hepatic, and renal.
pared with standard dose, and had a better safety profile. This cost- Among patients with such comorbidities, boustinib should be avoided
effective strategy may achieve an optimal response at a lower cost or used cautiously. Boustinib should be avoided in patients with
(higher rate of complete molecular responses; see below). Because of inflammatory bowel disease or renal dysfunction.52
the higher rates of durable complete molecular responses with second Finally, the patient age plays an important role in the treatment
generation TKIs (which could lead to discontinuation of TKI therapy decision. Patients younger than 50 years are expected to live 30+
and potential molecular cures discussed later), considerations of sec- more years. Therefore, inducing a durable CMR may potentially lead
ond generation TKIs in younger patients with CML (eg, age to therapy discontinuation. Second generation TKIs induce a signifi-
<50 years) may be entertained if offered at appropriate cost (price at cantly higher rate of CMR compared with imatinib. The issue of dura-
most 3 times higher than generic imatinib and not exceeding ble CMR and potential therapy discontinuation plays a less important
$25.000 per year). role in older patients in whom discontinuing therapy is less relevant.
6.2 | Cost outcomes. Patients with low-risk disease or intermediate-risk disease

are expected to have optimal responses with imatinib, dasatinib,
53-55
The cost of cancer drugs has risen drastically over the past decade. nilotinib, or boustinib. However, selecting a second generation TKI as
All anticancer agents approved in the recent years were priced at over frontline therapy based upon the Sokal or Hasford scores was proven
$120-160 000 annually.53-55 Unlike TKIs in CML, most of these thera- more beneficial in patients with intermediate or high-risk disease, as
pies do not provide a substantial improvement in survival or other objec- shown in the pivotal randomized trials.29,39,43 Patients with higher risk
tive measures to justify the cost. When an international group of CML disease have a lower likelihood of achieving the early milestones of
experts called attention to the high prices of TKIs, the cost history of CCyR and MMR and, particularly, higher chances of disease transfor-
imatinib was used to illustrate the problem with the high cancer drug mation to AP-CML or BP-CML.
prices.55-57 When first approved in the United States, the annual price Any of the the TKIs currently approved for frontline CML therapy
for imatinib was less than $30 000. This was the price set to make the may be selected. These include imatinib, dasatinib, nilotinib, or bosutinib.
development and commercialization of imatinib profitable when it was While second generation TKIs have demonstrated superiority over
expected that most patients would be treated for an estimated 5 to imatinib in relation to early surrogate markers, imatinib is still highly
10 years. Patients compliant with their treatment regimen now live a effective in a large number of patients with CML. At MDACC, when
“normal” lifespan and remain on imatinib therapy. 55-57
Paradoxically, with choosing an agent, we consider issues such as comorbidities, patient age,
a higher number of patients and a longer duration of therapy, the annual adverse events profile, risk stratification score, and cost. Kinase domain
price of imatinib had quadrupled to $ 132 000. This price is in the same mutation profile plays no role in selecting an initial TKI, but becomes rele-
range as dasatinib, nilotinib, and bosutinib, all priced above $ 150 000/ vant in the relapse setting.
year of therapy.
Imatinib has been available in the United States in generic formula-
tions since February 2016, and ranges in price from $4400 to $82 000 7 | M O N I T O R I N G T R E A T M E N T RE S P ON S E :
per year of treatment. Outside of the USA, generic imatinib is commonly 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
priced at a range of $2000-8000 per year of treatment. In some coun-
tries such as India, multiple versions of generic imatinib are available at Because patients with CML on TKI therapy are expected to live for
an annual price as low as $400 a year. Physicians will then have to assess their expected lifetime, surrogate markers of outcome are important
the “treatment value” of second generation TKI (dasatinib or nilotinib or (Table 3). In general, achieving a deeper response faster has been
bosutinib) in the frontline setting against generic imatinib in relation to associated with improved outcome, although the result of molecular
benefits vs cost. Second generation TKIs may be offered for patients testing is dependent on individual laboratories and techniques. Due to
with high-risk disease, while imatinib and/or its generic formulation are advances in technology, there are less invasive tests available for
offered for patients with low-risk disease and intermediate-risk disease. monitoring than the traditional bone marrow examinations (except
We recently assessed the treatment value of second-generation BCR- when changing TKI; or in unusual situations like unexpected
ABL1 TKIs compared with imatinib to achieve treatment-free remission myelosuppression, in order to exclude transformation or the develop-
(TFR) in patients with CML using a decision analytical model.58 Different ment of myelodysplastic syndrome or other marrow conditions).
modeled scenarios were considered. We calculated incremental cost-
effectiveness ratios (ICERs) and assessed cost-effectiveness by consider-
ing two societal willingness-to-pay thresholds: $50 000 per quality- 7.1 | Important points for monitoring and
adjusted life-year (QALY) in all markets and $200 000 per QALY in the determining treatment failure
United States. None of the explored scenarios showed a good treatment
value for using second-generation TKIs at the current prices in the At baseline, all patients should undergo a bone marrow examination to
United States, or at the price of $30.000-40.000 per year elsewhere. To establish the diagnosis, assess percentage of blasts and basophils, and
be cost-effective, the cost of second-generation TKIs should be less than perform cytogenetic analysis to confirm the presence of the Philadelphia
$25.000 per year.58-60 Under the same conditions in developing nations, chromosome and to assess for cytogenetic clonal evolution, particularly i
the annual price of second-generation TKIs should not exceed $10 000 (17)(q10) -7/del7q, and 3q26.2 rearrangements, associated with a
per year of therapy.
Finally, lower dose dasatinib and generic second generation TKIs
TABLE 3 Important response categories in CML
may offer a solution to the ongoing discussions of frontline CML ther-
apy and the need to achieve TFR. Response Translates into:
BCR-ABL1 ≤ 10% Significantly improved survival
at 6 mo; CCyR later
6.3 | Disease characteristics MMR Modest improvement in EFS;

possible longer duration CCyR;
no survival benefit
For patients with CP-CML it is common to use one of the available
CMR Possibility of therapy discontinuation
risk stratification scores, such as Sokal61 or Hasford62 to help predict
relatively worse prognosis.16 The current recommendation that patients have a worse outcome; still the 4-year survival with BCR-ABL1 tran-
have a follow up bone marrow study at 3, 6, and 12 months after scripts IS >10% vs <10% are 100% vs 74%. The CML-study IV has
63
starting therapy are not necessary. An alternative method to determine established the 6-month BCR-ABL1 transcripts IS <1% response as an
cytogenetic response is with the use of FISH and PCR on peripheral optimal milestone. Patients who reached the 6-month milestone, had
blood.64 If a patient is responding optimally, and the FISH study is nega- a significant survival advantage of about 6% after 10 years regardless
tive at 6 or 12 months and or BCR-ABL1 transcripts IS <1%, it may be of therapy.24 Thus it may be reasonable to change the TKI from
reasonable to omit marrow exams, as the patient is likely to be in imatinib to second generation TKI for BCR-ABL1 transcripts IS >10%
CCyR.65 after 6 months. However, a similar situation in a patient on second
For patients in durable CCyR receiving TKI therapy, periodic generation TKI does not imply consideration of allo-SCT, since the
molecular monitoring using RT-Q-PCR is acceptable and useful, but estimated 5-year survival if they continue TKI therapy is 81%.30
may lead to erroneous changes in well-tolerated treatment due to dis-
cordant results between laboratories or even within the same labora-
tory. One strategy to minimize this is to use interphase FISH as a 7.2 | When to switch therapy
complementary diagnostic test along with the molecular test to detect
possible false positive or negative results generated by either assay, Achievement of CCyR at 12-month and maintaining a CCyR status
until PCR levels are less than 1%.65 For patients in CCyR, the achieve- thereafter is associated with a relative normal lifespan. For survival as
ment and maintenance of a MMR is of debatable significance. Several an endpoint in CML, the aim of therapy should be the achievement of
studies evaluating patients receiving imatinib or second generation CCyR or MR2 (PCR <1% IS) within 12 months and to continue to be
TKIs have found that patients in CCyR have similar survival regardless in CCyR at any time beyond 12 months, especially with standard dose
of whether or not they achieved MMR.66,67 imatinib therapy. For second generation TKIs, CCyR may need to be
Early molecular response has been shown to have strong prog- achieved sooner for an optimal outcome, for example, within
nostic value (Table 4). This has been shown with each of the four TKIs 6 months.74 Patients who do not achieve a complete hematologic
used in the frontline setting. A BCR-ABL1 transcripts IS < 10% at response by 3 months should be considered for a change of therapy.
3 months separates patients into high and low risk categories for long One question is whether to change therapy at 3 months based on
term outcomes (ie, progression, survival).29,39,43,68 The important the level of BCR-ABL1 transcripts IS. This was discussed earlier. For
question is: how should we advise a patient who does not meet the patients on imatinib therapy, if the 3-month transcript level is greater
3-month benchmark? One option is to switch TKIs early, but there are than 10%, we suggest to perform serial molecular monitoring between
no data indicating this will alter long-term outcome. In the DASCERN, 3 and 6 months to determine the response precisely. If patients still
a randomized, open-label, international phase 2b trial in adults with have greater than 10% BCR-ABL1 transcripts IS at 6 months, the
CML-CP with CHR but BCR-ABL1 > 10% IS at 3 months after initial chances of attaining CCyR are low, and a change of therapy might be
treatment with imatinib 400 mg QD, patients were randomized to in indicated. A 3-month value of 10% IS may not be accurate: in a
early switch to dasatinib 100 mg daily or ≥400 mg daily of imatinib report in 1 sample collected at 3 months and tested 96 times, the
(option for dose escalation).69 While early switch induced a higher mean value was 11% (range, 5%-16%), with only 31% of tests being
rate of 12-month MMR (29% vs 13%; P = .005), there was no differ- ≤10%.75 This approach also applies to patients on second generation
69
ence in OS and PFS with a median follow-up of 30 months. There- TKIs, because, as mentioned earlier, very early switching has not
fore, a follow-up measurement at 6 months will help define patients shown to influence long-term outcome.76 Another study randomized
clearly in need of a change in therapy. This strategy has been retro- patients in CCyR on imatinib for at least 2 years to continue imatinib
spectively analyzed by several large groups.70-74 The results of two or switch to nilotinib.77 Switching to nilotinib induced deeper molecu-
independent study groups have suggested that all patients with BCR- lar responses, but did not translate into an improvement in PFS or in
ABL1 transcripts >10% at 3 months do not necessarily have an inferior other meaningful outcomes. The ELN guidelines updated recently
outcome.71,72 Patients who continued on therapy and achieved tran- (2020) are complex and may confuse or not allow physicians to deci-
scripts levels less than 10% by 6 months had the same long-term pher the correct approach at specific time points.78 Our recommenda-
favorable outcome as those with optimal molecular responses at tions are summarized in Table 5 and reflect a practical approach based
3 months. Patients with BCR-ABL1 transcripts IS >10% after 6 months on our clinical experience.
Patients who meet all the relevant benchmarks in the first
12 months are monitored periodically using molecular testing +/−
TABLE 4 Percentage of survival by early molecular response FISH (molecular testing only if BCR-ABL1 IS transcripts consistently
Study Q-PCR < 10% Q-PCR > 10% below 0.1%). If there are clear signs of possible failure, patients should
undergo a bone marrow examination with cytogenetic analysis, and
UK (8-y) 93 54
molecular testing, including analysis for mutations. Any degree of
MDACC (10-y) 98 94
cytogenetic relapse calls for a change of therapy. Fluctuating molecu-
ENEST-nd 97 87
lar levels during continuous CCyR would only prompt closer monitor-
DASISION 97 86
ing and a compliance assessment. Some CML experts advocate a
TABLE 5 MDACC criteria for response/failure and change available TKIs. Second generation TKIs overcome most of the muta-
of therapy tions that confer resistance to imatinib, though novel mutations ren-
Time (mo) Imatinib Second generation TKIs dering the leukemia resistant to second generation TKIs have
3-6 MCyR; PCR≤10% IS CCyR; PCR ≤1% IS emerged. One important mutation, T315I, known as the “gatekeeper”
mutation, displays resistance to all currently available TKIs except
12 CCyR; PCR ≤1% IS CCyR; PCR ≤1% IS
ponatinib.
Later CCyR; PCR ≤1% IS CCyR; PCR ≤1% IS
Before defining a patient as having TKI resistance and modifying
therapy, treatment compliance and drug-drug interactions should be
change of therapy for a documented consistent loss of MMR after assessed. Rates of imatinib adherence have been estimated to range
3-4 years of therapy (BCR-ABL1 transcripts >0.1% IS), particularly if from 75% to 90%, and lower adherence rates correlated with worse
transcript levels are consistently above 0.3-0.5%. outcome.79-81 In a study of 87 patients with CML-CP treated with
The new ELN 2020 guidelines propose the achievement of TFR imatinib 400 mg daily, an adherence rate of 90% or less resulted in
as an important goal of therapy in CML. This will be discussed later in MMR rate of 28% compared with 94% with greater than 90% adher-
detail. ence rate (P < .001).79 The CMR rates were 0% vs 44% (P = .002), and
In several studies, the achievement of a CCyR (Ph-positive meta- no molecular responses were observed when adherence rates were
phases 0%; BCR-ABL1 transcripts IS ≤ 1%) at 12 months or later on TKI 80% or lower. Lower adherence rates have been described in younger
therapy was associated with significant survival benefit, compared with patients, those with adverse effects of therapy, and those who have
achievement of lesser degrees of response. Achievement of CCyR is the required dose escalations.79
primary endpoint of TKI therapy. Achievement of BCR-ABL1 transcripts
IS ≤ 0.1% (MMR) was associated with modest improvements in event-free
survival rates, possible longer durations of CCyR, but not with a survival 8.1 | Second and third generation TKIs
benefit. The achievement of CMR (non-measurable BCR-ABL1 transcripts)
offers the possibility of treatment discontinuation. Lack of achievement Before their approval to treat first-line CML-CP, second generation
of MMR or of CMR should not be interpreted as a need to change TKI TKIs were approved for use in second-line CML-CP following prior
therapy or to consider allo-SCT. Response assessments at earlier times on therapy including imatinib. Clinical studies of second-line and third
frontline TKI therapy (3-6 months) have shown better outcomes with line TKIs are summarized in Table 6. Based on these studies, several
achievement of a major cytogenetic response by 3 to 6 months on noteworthy ideas have emerged. First, second-line treatment with
imatinib therapy (Ph-positive metaphases ≤35%; BCR-ABL1 transcripts nilotinib, dasatinib, or bosutinib can yield high rates of responses in
IS ≤ 10%). While this is interpreted to mean that a change to second TKI patients who have inadequate response to imatinib, including high
therapy may be considered if such outcome is not obtained, no studies rates of MMR. Second, dose escalation of imatinib can improve
have shown that changing therapy from imatinib to second TKIs has response rates in patients with inadequate response to standard-dose
improved patientsʼ outcomes. When second generation TKIs are used in imatinib,82 but switching to second-line TKI can be more effective.83
front-line therapy, achievement of CCyR by 3-6 months of TKIs therapy Several studies that evaluated second-line nilotinib,84,85 dasatinib,83,85
has been associated with improved outcomes. or bosutinib,86 and high-dose imatinib (400 mg BID) have demon-
At MDACC, our major treatment milestones are at 6 and strated significantly higher rates of CCyR and MMR with the newer
12 months. Patients with lack of PCyR (BCR-ABL1 transcripts TKIs than with high-dose imatinib. Moreover, PFS was better with the
IS > 10%) at 6 months, or without CCyR (BCR-ABL1 transcripts newer TKIs than with high-dose imatinib. An earlier switch to second-
IS ≤ 1%) at 12 months, or with loss of response at any time are candi- line TKI may be more effective than a later switch. In the TIDEL-II
dates for a switch of therapy. The choice of TKIs is based on the study, patients who had suboptimal response to imatinib and were
mutation profiles and patients comorbidities. We do not consider a switched to nilotinib had a higher rate of CMR at 12 months, than
change of TKI therapy in patients in CCyR but without MMR. We also patients who had dose escalation of imatinib prior to being switched
do not consider a change of therapy at any time point in patients who to nilotinib.87 In a retrospective pooled analysis of three clinical stud-
do not achieve MR4 or more with the aim of inducing a TFR. Such ies of second-line dasatinib with CML with resistance or intolerance
strategy is not cost-effective and may be associated with serious new to imatinib, patients switched to dasatinib after the loss of MCyR
adverse events. (early intervention group) had higher rates of CCyR and MMR, as well
as 24-month EFS, TFS, and OS, than patients who were switched after
the loss of both MCyR and CHR (late intervention group).88 Although
8 | MANAGEMENT OF TKI RESISTANCE this analysis included studies with distinct study designs and various
dosing schedules of dasatinib, the essential finding is that earlier
With the widespread use of all commercially available TKIs and switch to dasatinib was associated with better outcomes.
increased CML prevalence, more patients are developing drug resis- Bosutinib was initially studied in patients with CML resistance to
tance. A common mechanism of resistance involves point mutations or intolerance of imatinib.86 After a dose escalation period, 500 mg
in the kinase domain of BCR-ABL1, which impairs the activity of the once daily was selected as the phase II dose, with the potential for
TABLE 6 Summary of second and third generation TKIs in CML- adverse events occurring in ≥40% of CP-CML patients were rash (47%),
CP post Imatinib resistance abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin
Percentage (42%), and constipation (41%).93 Other notable toxicities include severe
skin rashes (4%-7%), pancreatitis (7%), and severe hypertension (20%).
Response Dasatinib Nilotinib Bosutinib Ponatinib
As of early 2014, ponatinib labeling included a revised warning
Follow-up (months) >24 >24 >24 >24
regarding the risk of thrombotic events (13% per year), vascular occlu-
CHR 89 77 86 92
sions, heart failure, and hepatotoxicity.94 Vascular occlusion adverse
MCyR 59 56 54 60 events were more frequent with increasing age and in patients with
CCyR 44 41 41 54 prior history of ischemia, hypertension, diabetes, or hyperlipidemia.93
2-y PFS (%) 80 64 81 68 Factors associated with increased risk of vascular occlusion events
2-y OS (%) 91 87 91 86 include older age, higher dose, history of myocardial infarction or prior
vascular events, and longer duration of CML.93 Studies assessing
lower dose schedule of ponatinib are ongoing. In community practice,
dose escalation to 600 mg once daily for patients not meeting it may be safer to use ponatinib 30 mg daily (and lower the dose to
prespecified benchmarks. A total of 288 patients were enrolled in the 15 mg daily for toxicities and once a molecular response is obtained)
pivotal phase II trial; more than two thirds had imatinib-resistant dis- rather than use the FDA approved dose of 45 mg daily.
ease. The primary endpoint of MCyR at 6 months was achieved in
31%; 41% achieved a CCyR. Bosutinib appeared to retain activity
across most known mutations that confer imatinib resistance, except 8.2 | Novel TKIs
for T315I. Responses were independent of whether patients had
resistance to or intolerance of imatinib. The most common toxicities Asciminib is an allosteric inhibitor that binds a myristoyl site of the
were diarrhea, nausea, vomiting, and rash. Diarrhea occurred in 84% BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation
of patients, with 9% experiencing grade 3 diarrhea (there were no through a mechanism distinct from those for all other ABL kinase
grade 4 events documented). Other notable adverse events included inhibitors.95 Asciminib targets both native and mutated BCR-ABL1,
myelosuppression and liver function test abnormalities. In order to including the gatekeeper T315I mutant. In a Phase 1, dose-escalation
optimize the safety/efficacy of bosutinib in older patients with CML study, 141 patients with CML-CP and 9 with CML-AP who had failed
and failure on first-line therapy, a dose escalation was used with a at least two TKIs were treated.96 Asciminib was administered once or
starting dose of 200 mg daily increased to 300 mg daily at 2 weeks, twice daily (at doses of 10 to 200 mg). The median follow-up was
and to 400 mg daily at 3 months if transcripts are above 1%.89 Sixty- 14 months. Among patients with CML-CP, 34 (92%) with a hemato-
seven percent of patients had molecular improvement from baseline. logic relapse had a CHR; 31 (54%) without a CCyR at baseline had a
Treatment was well tolerated: diarrhea occurred in 16% of patients, CCyR. A MMR was achieved or maintained by 12 months in 48% of
with 8% experiencing grade 3 diarrhea; 22% had liver function test evaluable patients, including 8 of 14 (57%) deemed to have resistance
abnormalities (10% Grade 3 and 2% Grade 4).89 to or unacceptable side effects from ponatinib. A MMR was achieved
Ponatinib is a third generation TKI, and the first TKI in class to or maintained by 12 months in five patients (28%) with a T315I muta-
90
exhibit activity against CML with T315I mutation. It is 500 times as tion at baseline. Dose-limiting toxic effects included asymptomatic
potent than imatinib at inhibiting BCR-ABL1.91 The approval of elevations in the lipase level and clinical pancreatitis. Asciminib is
ponatinib was based on the phase II PACE trial, where 449 patients being evaluated in a Phase III randomized trial in patients who have
with heavily pretreated CML or Ph-positive acute lymphoblastic leu- failed two TKIs without T315I mutation and who are randomized to
92
kemia (ALL) were treated. Patients were considered for this trial if either bosutinib or asciminib.
they had resistance to or intolerance of dasatinib or nilotinib, or if HQP1351, a new orally active third generation TKI with low affin-
they had CML with T315I mutation. The dose of ponatinib was 45 mg ity against other kinases has completed a phase I trial in 101 patients
once daily, and patients were stratified by disease phase and by the (87 CML-CP, 14 CML-AP) who have failed prior TKIs and/or acquired
presence or absence of a T315I mutation. Among 267 patients who T315I mutation (63%).97 The drug was given every other day in
received ponatinib in CML-CP, 56% achieved a MCyR by 12 months, 28 days cycle with expansion cohorts at 30 mg, 40 mg, and 50 mg
which included 45/64 (70%) patients with a T315I mutation. Patients doses. With a median follow-up of 12 months, the overall CHR,
responded more favorably if they had received fewer TKIs. After a MCyR, CCyR, and MMR rates for patients with CML-CP were 95%,
median follow up of 5 years, 60% of patients achieved MCyR (primary 69%, 61%, and 37%, respectively. Grade 3/4 thrombocytopenia, grade
endpoint) at any time; 82% of those remained in MCyR at 5 years.93 Fur- 1 skin pigmentation and hypertriglyceridemia were common adverse
thermore, 40% of patients achieved a MMR or better. The 5-years OS events. A multicenter confirmatory trial is ongoing.
rate was 73%.93 Arterial occlusive events (AOEs) occurred in 31% of The results of an ongoing Phase I trial evaluating K0706, a third gen-
patients (26% serious). The exposure-adjusted incidence of new AOEs eration TKI with limited off-target activity were recently reported.98 The
(15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did recommended Phase II dose was 174 mg daily. Two dose limiting toxic-
not increase over time. The most common all-grade treatment-emergent ities were encountered at 240 mg/day including Grade 3 dyspnea +
Grade 2 non-cardiac chest pain and Grade 2 shortness of breath due to At MDACC, post imatinib failure, the choice of second or third gener-
fluid retention. The 6-month MCyR rate was 64%. ation TKI is based on the disease phase, mutation profile, and patientʼs
comorbidities. In advanced phases (AP or BP), we favor a combination of
chemotherapy and TKI (mainly ponatinib). In patients with CML-CP with
8.3 | How to select a second or third line option T315I mutation, ponatinib will be the first choice followed by allo-SCT if
a donor is available and an optimal response is not achieved. Outside the
At the time of treatment failure, patients should undergo bone mar- context of T315I mutations, the type of mutation will dictate the choice
row examination to allow proper determination of the CML phase and of therapy. Of note, patients with poor response to imatinib and com-
documentation of any clonal evolution. All patients should have CML pound mutations may not respond well to second generation TKI. A close
cells tested for BCR-ABL1 kinase domain mutations, as this will help monitoring should be offered.104 If an optimal response is not achieved, a
99-102
guide the selection of the TKI. When selecting between switch of therapy to a third generation TKI and/or allo-SCT is warranted.
dasatinib, bosutinib, and nilotinib, in vitro and in vivo data have identi- In patients with no mutation or a mutation sensitive to all second genera-
fied distinct mutations that exhibit decreased sensitivity to each of tion TKIs, the choice is based on comorbidities. Patients with vascular risk
the agents.99-102 The physician may favor dasatinib or bosutinib if the factors and metabolic dysfunctions are not candidates for nilotinib, while
patient has the following mutations: Y253H, E255K/V, or F359C/V. patients with lung injuries are not candidates for dasatinib. Bosutinib may
Alternatively, nilotinib may be favored in the presence of the V299L be the best choice for patients with cardiac problems. In patients who
and F317L mutations. For patients lacking these mutations, the choice failed second generation TKIs, ponatinib is preferable over rotation of sec-
should be based on preexisting conditions, toxicity profiles, and cost. ond generation TKIs unless patients have severe cardiovascular com-
Bosutinib can be used for patients with most known mutations orbidities or develop a specific mutation that may be sensitive to another
that lead to imatinib failure.86 Like dasatinib and nilotinib, bosutinib second generation TKIs. Older patient post failure of multiple TKIs should
lacks activity against T315I. Bosutinib may be a reasonable choice for continue the most appropriate TKI regardless of molecular or cytogenetic
patients who fail imatinib who are not good candidates for dasatinib status. They can maintain long-term survival if they continue on a daily
or nilotinib. Bosutinib has a relatively distinct toxicity profile from the most effective/less toxic TKI, with or without the addition of non-TKI
other TKIs, with the predominant problem being diarrhea and other anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine,
gastrointestinal complaints. Recently, an analysis was conducted to cytarabine, busulfan, others).
closely characterize the toxicity of bosutinib and the management
strategy.103 Diarrhea was documented in 82% of patients (n = 570),
most being grades 1/2 in severity. Myelosuppression and liver func- 8.4 | Allogeneic stem cell transplantation
tion test abnormalities were also common. With appropriate support- (Allo-SCT)
ive care, monitoring, and dose reductions for persistent diarrhea, most
patients are able to continue therapy with periodic dose interruptions The number of patients undergoing allo-SCT for CML-CP has
or adjustment. Long-term bosutinib treatment is associated with an decreased significantly since TKIs were introduced, but will start to
apparently reversible decline in renal function with frequency and rise again as the prevalence of CML increases, as about 2% of patients
characteristics similar to renal decline observed with long-term become resistant to many TKIs every year and require allo-SCT. Allo-
imatinib treatment. Patients with risk factors for renal dysfunction SCT has a more important role when patients evolve into AP/BP (see
should be monitored closely.52 below).105,106 Allo-SCT remains an important therapeutic option for
Ponatinib should be considered the agent of choice in patient patients in CML-CP post failure of at least two TKIs or who are poten-
with CML and T315I mutation, and in instances where other TKIs are tially harboring the T315I mutation (after a trial of ponatinib ther-
not indicated (patients with resistance to at least one second genera- apy).105,106 Prior exposure to TKIs does not impact transplant
tion TKI). No other commercially available TKIs have activity against outcome negatively; patients referred to transplant may have a better
the T315I mutation. The risk for serious toxicities (vaso-occlusive dis- outcome if entering the transplant with a better response (lower CML
ease, pancreatitis, hypertension, severe skin rashes) and of thrombotic burden).107
events with ponatinib is significant, but the benefits outweigh the Finally, allo-SCT cost vs TKIs cost and availability should be con-
risks for most patients with a T315I mutation, as there are no other sidered. Allo-SCT, a curative one-time procedure costs $ 500 000 in
options for disease control. These side effects are lower with the United States, but only $12 000 to $20 000 in developing nations.
ponatinib 15-30 mg daily. Allo-SCT should not be offered as frontline therapy since generic
Second and third generation TKIs have not been compared head-to- imatinib cost can be as low as $ 400-1000/year. Considering the
head. Selection of one or the other is based on the side-effect profiles, median age of patients with CML and the projected survival of 30+
mutations profile, drug interactions, compliance issues and the patientʼs years ($400 X 30 years = $12000), generic imatinib frontline therapy
preexisting medical conditions. Mutational analysis is required following remains better than performing allo-SCT. In the salvage setting the
failure of imatinib or second generation TKIs or following progression to value of allo-SCT vs second/third generation TKI can be discussed in
AP/BP. Baseline mutational analysis on patients with newly diagnosed relation to geography, cost of care, and availability of second genera-
CML-CP are not done, as this does not help predict treatment outcome. tion TKIs. For example, in some geographies allo-SCT in first salvage
may cost $20 000 vs $120 000-$170 000/year for second-third gen- patients expected to live more year benefitting from TKI discontinua-
eration TKIs. In these circumstances, allo-SCT could be offered as a tion).119 However, when factoring in the number of patients who
108,109
first salvage option in nations with financial constraints. achieve deep enough molecular responses to be candidates for stop-
ping TKI therapy, the incidence of molecular cure remains relatively
low, about 20%-25% with imatinib and 30%-45% with second-
9 | T R E A T M E NT D U R A T I O N A N D generation TKIs. Although the use of second-generation TKIs certainly
D I S C O N T I NU A T I O N increases the likelihood of obtaining a sufficiently deep molecular
response in order to consider TKI discontinuation, the use of the
Several studies have evaluated whether TKIs can be safely discontinued second-generation agents comes at significant financial costs and tox-
in patients who have achieved long-term deep molecular responses. In icity.40,58 It has been estimated that even with the use of the least
the Stop Imatinib (STIM) study, 100 patients who had achieved complete expensive second-generation TKIs, it will cost an additional $917 056
molecular response (ie, >5-log reduction in BCR-ABL1 transcripts levels over 10 years to achieve this rather moderate magnitude of QALY
and undetectable transcripts on quantitative RT-PCR) after >2 years of improvement. Putting these numbers in the context of ICERs, it will
imatinib treatment discontinued TKI therapy and were followed prospec- cost more than $22 million to achieve a gain of 1 QALY from replacing
110
tively. Forty-two patients (61%) experienced molecular relapse, all but generic imatinib with second-generation TKIs for frontline therapy.
two within 6 months of TKI discontinuation. After reintroduction of The financial burden associated with frontline use of second-
imatinib, 26 patients again achieved CMR; the other 16 patients had generation TKIs should therefore be carefully weighed against the
decreases in BCR-ABL1 transcripts levels. Similar results were observed modest improvement in the potential cure fraction compared to
111-114
in other studies. imatinib.58-60
115
In the EURO-SKI trial, the largest study of TKI discontinuation, In order to increase the proportion of patients who may be
821 patients with CML treated with frontline imatinib, nilotinib or molecularly cured with long-term TKI therapy, combination strategies
dasatinib, who had achieved at least MR4 (BCR-ABL <0.01% on the Inter- are under evaluation. These focus on both inducing deeper molecular
national Scale) stopped TKI therapy. The molecular recurrence-free sur- responses and targeting the CML stem cell. Despite the presence of a
vival at 2 years was 52%. Among 321 (86%) patients who lost their MMR constitutively active BCR-ABL1 kinase, these leukemic stem cells may
and were restarted on TKI, 81% regained a molecular response be quiescent, which renders them relatively resistant to TKI ther-
(MMR/MR4). In a multivariate analysis, duration of MR4 for 3+ years was apy.120 This explains why a substantial proportion of patients relapse
the only significant factor for persistent deep molecular response after when TKI therapy is stopped. Future TKI-independent therapeutic
stopping therapy. Additional factors included duration of TKI therapy for approaches that target the leukemic stem cell will be imperative to
6+ years. Similar findings were reported from our institution with an addi- increasing the number of patients with CML who can be cured. These
tional important observation: longer duration of CML therapy resulted in strategies include the addition of pegylated interferon-α2b to imatinib,
significantly higher TFR rates. Discontinuing TKI after a sustained dasatinib, or nilotinib,121-123 and combining Bcl-2 inhibitors like ven-
MR4.5 ≥ 5 years was associated with higher TFR rates of 92%. 116
etoclax.48,124 Other combinations are exploring the addition of hyp-
Rousselot and colleagues reported a follow-up over 15 years of a omethylating agents,125 JAK2 inhibitors,126 and immune-based
single institution experience of treatment discontinuation among
128 patients treated with frontline imatinib (61%), frontline second
TABLE 7 Requirements for TKI discontinuation in clinical
generation TKI (11%), and second line second generation TKI (28%)
practice
and entering first treatment-free remission (TFR1).117 The median
follow-up in TFR1 was 6.5 years. The median duration of TKI therapy Discontinuation of TKI
was 7.1 years. The 7-year TFR1 rate was 45.7%. The duration of TKIs Parameter Yes No
and the duration of MR4.5 were associated with a higher TFR1 rate. Sokal risk Low-intermediate High
Sixty-five patients had molecular relapse including nine patients (14%) BCR-ABL1 transcripts Quantifiable Not quantifiable
experiencing late molecular relapses (after 2 years). The latest molecu- (e13a2 or e14a2)
lar relapse was observed after 6.4 years. In late relapsing patients, CML stage Chronic Accelerated/blast
MR4.5 was lost after a median of 10 months and MR4 after a median phase
of 22 months with a long-lasting period of fluctuations of the BCR- Response to first TKI Optimal Failure
ABL1 ratio in-between MR4 and MR3. Furthermore, anecdotal cases Duration of all >6-8 y <3 y
of sudden myeloid blastic phase in patients in TFR were reported.118 TKIs therapy
These late relapses and sudden transformations suggest that a long- Depth of molecular CMR (MR4.5) Less than MR4
term molecular follow-up is mandatory for CML patients in TFR. response
The relatively higher TFR rates observed with patients initially Duration of molecular >3+ y <3 y
treated with second-generation TKIs suggests that second-generation response
TKIs may be preferred as initial therapy, for patients in whom even- Monitoring availability Ideal (every 2 mo Poor; non-compliant
in years 1-2)
tual TKI discontinuation may be particularly valued (eg, younger
therapies, including anti-PD-1 monoclonal antibodies and dendritic generation TKI followed by allo-SCT once a complete response is
cell vaccines.127 achieved, then given maintenance TKI therapy post allo-SCT. Patients
TKIs discontinuation studies in patients with durable CMR demon- with de-novo CML-AP are treated with frontline second generation TKI
strate that stopping TKI therapy is feasible, and some patients may be infinitely if an optimal response (CCyR; BCR-ABL1 transcripts [IS] <1%) is
cured. At MDACC, therapy discontinuation is offered only for patients in achieved within 6 months of therapy All other patients in CML-AP are
chronic phase with a quantifiable transcript, who have been on TKI for at treated with second/third generation TKI followed by allo-SCT.
least 6 years, who have achieved a sustained CMR for at least 3-4 years,
and in whom a close follow-up can be performed (Table 7).
11 | C O N C L U S I O N S A N D F U T U RE
DI RE C TION S
10 | A D V A N C E D ST A G E C M L
In 2020, CML experts and patients with CML have multiple treatment
Patients with CML-AP or CML-BP may receive initial therapy with options in the CML therapeutic armamentarium, including five TKIs
TKIs (newer generation TKIs like dasatinib or ponatinib preferred (imatinib, nilotinib, dasatinib, bosutinib, ponatinib), omacetaxine (protein
over imatinib) to reduce the CML burden, and be considered for early synthesis inhibitor), and several older agents (hydroxurea, interferon
allo-SCT.91,128-133 Response rates with combinations of TKIs and che- alpha, busulfan, 6-mercaptopurine, cytarabine, hypomethylating agents,
motherapy are 40% in non-lymphoid CML-BP and 70%-80% in lym- others). Most patients with CML would be expected to have a normal life
phoid CML-BP.91,128-133 Median survival times are 6-12 months, and span, and be potentially functionally, though not molecularly, cured. That
12-24 months, respectively. The addition of TKIs to chemotherapy is, as long as they continue therapy with TKI based regimens, are compli-
has improved the response rates and prolonged median survival in ant with the treatment, and are monitored closely for signs of resistance,
CML-BP.134 We recently assessed outcome of 477 patients with in order to change therapy in a timely manner and/or consider allo-SCT
CML-BP who were treated with a TKI at some point during the course before CML progression. Future directions will focus on the potential
135
of their CML. The median overall survival was 12 months. The molecular cure of CML (ie, achievement of a durable CMR and its persis-
combination of TKI with intensive chemotherapy followed by stem tence after discontinuation of TKI therapy). This is not a trivial issue
cell transplantation appeared to confer the best outcome. since, with effective TKI therapy, and full treatment penetration world-
Copland and colleagues reported the early results of FLAG-IDA wide (to 100% of all diagnosed patients and continuation of TKI therapy
and ponatinib at a starting dose of 30 mg in 16 evaluable patients in without interruptions) the prevalence of CML would increase annually
BP CML. Clinical responses were observed in 11/16 patients (69%). and plateau around 2040 at a rate of 35 times the incidence. The preva-
Five among them achieved MMR after first cycle. Nine patients lence is estimated to be close to 160 000 patients with CML in the
received subsequent allo-SCT. The 12-month survival rate was 50%. United States and about 3 million patients worldwide. This may repre-
At present, allo-SCT is the only curative therapy for AP and BP sent a considerable burden on patients and the healthcare systems in
CML: overall cure rates are 15%-40% and 10%-20%, respectively. relation to drug availability, compliance, potential development of long-
Patients with cytogenetic clonal evolution as the only AP criterion term side effects, and costs. Therefore it is important to continue
have a long-term EFS rate of about 60%.133 Otherwise, TKIs provide research into therapies that increase the rates of durable CMRs. This
hematologic responses in 80% of patients and an estimated 4-year may be achievable with the current more potent new generation TKIs
survival rates of 40% to 55% in CML-AP, but only a 40% response alone, or in combination with other available (Bcl-2 inhibitors, peg-
rate and a median survival of 9 to 12 months in CML-BP. Patients interferon alpha-2, omacetaxine, decitabine) or investigational therapies.
with de novo CML-AP have a better outcome with frontline TKI ther- Such strategies may improve the eradication of minimal residual disease,
apy than patients who evolve from CP to AP. The estimated 6-8 year and potentially obviate the need for indefinite therapy with TKIs. Further
survival rate with TKI therapy in de novo CML-AP is 60-80%.133 Such understanding of the pathophysiologic events downstream of BCR-
patients may continue on TKI therapy as their long-term treatment if ABL1 may help in the development of new strategies to target them.
they achieve a CCyR on TKI therapy.
Allo-SCT should be considered early in patients in AP based on
response to TKI therapy. The only curative option for patients in BP dis- 12 | MDACC APPROACH
ease is allo-SCT. Monotherapy with TKIs, or in combination with chemo-
therapy may serve as a good option for those who are not candidates for All patients suspected to have CML undergo bone marrow examina-
transplant, or as a bridge to allo-SCT. The role of TKIs before and after tion which will confirm the diagnosis and provide information needed
transplant is being evaluated. Accumulating data show that TKIs do not for staging. Baseline PCR is performed in order to identify the specific
increase transplant-related complications and when used after low inten- type of rearrangement that can be appropriately followed when
sity conditioning regimens, may delay relapse rates and need for donor assessing response to TKI therapy.
lymphocyte infusions. Waiting for confirmation, patients are placed on transient cyto-
At MDACC, patients with CML-BP are treated with a combination of reduction therapy with hydroxyurea. Tumor lysis syndrome prophy-
chemotherapy (type depends on the immunophenotype) and the third laxis is implemented as well.
Patients are stratified into low/intermediate-risk and high-risk infinitely if an optimal response (CCyR; BCR-ABL1 transcripts IS <1%)
disease. Outside clinical trials, patients with lower-risk disease are is achieved within 6 months of therapy. All other patients in CML-AP
treated with imatinib; patients with high-risk disease can be treated are treated with second/third generation TKI followed by allo-SCT.
with either imatinib or with second generation TKI. The choice of sec- Therapy discontinuation is offered only for patients with CML-CP
ond generation TKI is based on patientsʼ comorbidities. with a quantifiable transcript, who have been on TKI for at least
Patients are monitored regularly every 3 months in the first year, 6 years, have achieved a sustained CMR for at least 3-4 years, and in
and later every 6 months. Monitoring by the use of peripheral blood whom a close follow-up can be performed.
FISH and PCR are alternative to marrow examinations to determine
cytogenetic response. If a patient is responding optimally, and the OR CID
FISH study is negative at 6 or 12 months and or BCR-ABL1 transcripts Elias Jabbour https://orcid.org/0000-0003-4465-6119
IS <1%, patients may be monitored with peripheral blood PCR studies Hagop Kantarjian https://orcid.org/0000-0002-1908-3307
every 6 months. The major treatment milestones are at 6 and
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tor therapy before allogeneic stem cell transplantation in patients

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10968652, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.25792 by Nat Prov Indonesia, Wiley Online Library on [23/02/2023].

ANNUAL CLINICAL UPDATES

Chronic myeloid leukemia: 2020 update on diagnosis, therapy

Elias Jabbour | Hagop Kantarjian

Department of Leukemia, The University of

1 | D I S E A S E OV E R V I E W In 2020, it is estimated about 8450 new CML cases will be diagnosed

Am J Hematol. 2020;95:691–709. wileyonlinelibrary.com/journal/ajh © 2020 Wiley Periodicals, Inc. 691

BCR-ABL < 10% Longest

5.8 | The MD Anderson Cancer Center (MDACC)

TABLE 2 Frontline TKIs therapy:

6.2 | Cost outcomes. Patients with low-risk disease or intermediate-risk disease

6.3 | Disease characteristics MMR Modest improvement in EFS;

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