CLINICAL NEWS
in a Different Vein
Research from ASH’s online peer-reviewed
journal, Blood Advances
Aggressive Imatinib Dose Escalation Shows
No Improvement Over Standard Escalation in CML
For patients with newly diagnosed chronic myeloid
leukemia (CML), aggressive dose escalation of
imatinib failed to improve response and survival
rates compared with a standard dose escalation fol-
lowing European LeukemiaNet (ELN) guidelines,
according to results from a phase III study pub-
lished in Blood Advances. However, the researchers
identified a subset of younger patients who may
benefit from aggressive dose escalation if they have
tolerated imatinib well.
Because up to 20 percent of patients with
CML have disease that is resistant to imatinib at
the standard 400-mg dose, research groups like
ELN have published dose-escalation guidelines
for patients with suboptimal responses. With this
prospective randomized study, Koichi Miyamura,
MD, of the Japanese Red Cross Nagoya First Hos-
pital and colleagues evaluated whether using more
sensitive assessments of clinical response than
those outlined in the ELN criteria could improve
outcomes for patients taking imatinib.
The trial included 245 patients with previously
untreated Philadelphia chromosome (Ph)–positive
chronic-phase CML. All participants had adequate
liver and kidney function, normal heart and lung
function, and an Eastern Cooperative Oncology
Group performance status of 0 to 3.
Patients began treatment with imatinib 400 mg/day
and were randomized to one of two dose-escalation
strategies based on measurements of response at three
and six months:
• In group A, dose escalation was performed
according to ELN criteria: Imatinib dose was
increased from 400 to 600 mg if a patient did
not achieve complete hematologic response
within 3 months or a partial cytogenetic
response (PCyR) within 6 months of treatment
initiation (n=122)
• In group B, imatinib dose was increased from
400 to 600 mg if a patient did not achieve a
complete cytogenetic response (CCyR) within
3 months or a major molecular response
(MMR) within 6 months of treatment initiation
(n=123).
Cytogenetic responses were evaluated by G banding
of ≥20 marrow cells in metaphase; CCyR was defined
as no Ph-positive cells, and PCyR was defined as 1
to 35 percent Ph-positive cells. Molecular responses
were measured by reverse-transcription real-time
quantitative polymerase chain reaction. MMR was
achieved when <100 BCR-ABL mRNA copies were
detected per 1 mg of RNA, corresponding to a 3-log
reduction from the standardized baseline.
In the first year of treatment, several patients
in each group required dose reductions or discon-
tinuations of imatinib 400 mg (31 in group A and
19 in group B), leading to median dose intensities
of 375.1 mg/day in group A and 424.2 mg/day in
group B (ranges not reported).
At six months post-treatment initiation, there
was trend in cytogenetic response that favored ag-
gressive dose escalation (78.7% vs. 69.4%; p=0.09),
the authors reported. However, at 12 months, the
CCyR rate was comparable between both groups
(81.8% for group A vs. 84.3% for group B; p value
not reported).
Rates of MMR at 12 months and 24 months (the
study’s primary and secondary endpoints) also were
similar between groups A and B:
• 12-month MMR: 52.1% vs. 58.7% (p=0.3)
• 24-month MMR: 70% vs. 68.3% (p value not
reported)
Per study protocol, 56 patients in group B were
intended to increase their dose to 600 mg at three
months because they did not achieve CCyR; how-
ever, only 28 of these patients (50%) increased
their dose. The 65 patients who achieved CCyR
maintained their dose through assessment at
six months, when 34 patients were intended to
increase their dose because they did not achieve
MMR. Again, only half of patients (n=17) under-
went a dose increase. (Two patients did not receive
a molecular response test.)
“In contrast, in group A, only four and six
patients failed to increase the dose at three and six
months, respectively,” the researchers reported.
Dose-escalation strategy did not appear to
affect survival outcomes: The three-year overall
survival rate was high and similar between groups
A and B (99.3% vs. 97.4%; p value not reported),
with no difference observed between groups
for three-year progression-free survival (PFS;
89.1% vs. 94.2%; p=0.17; median follow-up not
provided).
The primary reason for maintaining a 400-mg
dose was adverse events (AEs), with a higher inci-
dence of grade 3/4 lymphocytopenia and anemia in
group B than group A (11 vs. 6 and 9 vs. 3, respec-
tively). “However, in this study, the incidence of
nonhematologic AEs was equivalent in both groups,
and the aggressive dose-escalation group did not
show a higher frequency of withdrawal due to drug
toxicity, compared with the standard dose-escalation
group (21% and 20%, respectively),” Dr. Miyamura
commented.
They also observed that the dose-escalation
protocol in group B was associated with higher rates
of molecular response: “Among the 42 patients who
received increased dose according to the protocol,
25 (60%) achieved MMR at 12 months, whereas
only 14 of 40 patients (35%) who did not receive an
increased dose achieved MMR (p<0.05).”
Based on these findings, the authors proposed
that, although “the early aggressive dose escalation
failed to produce a better molecular response at 12
months, … for patients who tolerate imatinib well
but show inadequate response at an early time point,
aggressive dose escalation may contribute to achiev-
ing a better outcome.”
Dr. Miyamura also noted that certain patients
would benefit from switching to another medica-
tion, rather than increasing imatinib dose, and that
the findings from this study could aid clinicians in
identifying those patients. “Before making changes
to other medicines, dose escalation at an early stage
could confirm whether the drug currently being
used has reached the optimal individual concentra-
tion,” he said. “The strategy of starting imatinib
at 400 mg, carefully observing disease response
and AEs, and increasing imatinib to 600 mg in
patients who do not have a major response (CCyR
at 3 months and MMR at 6 months) is an effective
means of finding this concentration.”
During the study, only half of the patients com-
pleted dose-escalation per study protocol, which the
authors noted may limit the implications of these
findings.
The authors report relationships with Novartis, the
manufacturer of imatinib. ●
REFERENCE
Miyamura K, Ohnishi K, Ohtake S, et al. Randomized study of imatinib for chronic myeloid
leukemia: comparing standard dose escalation with aggressive escalation. Blood Adv.
2019;3:312-9.
PERSPECTIVES
“While this study suggests that an aggressive
escalation in imatinib dose may offer a modest
benefit for improving rates of MMR at 12 months
in patients with CML, this subtle trend evapo-
rated by 24 months and did not translate into a
difference in PFS – which was excellent for both
groups. According to the analysis, a starting dose
ASHClinicalNews.org
of imatinib 400 mg may be appropriate in most
patients and following standard ELN escalation
recommendations is sufficient for achieving
long-term PFS. For a subset of younger patients
who are tolerating imatinib well, the as-treated
analysis within this study suggests that aggres-
sive dose escalation may shorten the time to
achieving an MMR. This finding may have impli-
cations for successfully stopping tyrosine kinase
inhibitor therapy in the future.”
Alexandra Stevens MD, PhD
Baylor College of Medicine
Texas Children’s Hospital
Houston, TX
ASH Clinical News
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