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lyzed outcomes of 760 adult patients (median age at diagnosis
= 52.0 years; range = 11.2-85.5 years) with chronic-phase
CML who stopped TKI treatment to define prognostic markers of durable molecular response after withdrawal.
All patients received TKI treatment for at least three
years and were in MR4 (defined by at least 4-log reduction
in BCR-ABL transcripts) for at least one year (confirmed by
3 consecutive PCR results during the last 12 months prior to
study inclusion). Patients who had disease progression after
prior TKI treatment were excluded. One patient decided not
to stop therapy after inclusion.
Before discontinuing TKIs, patients were screened for
at least six weeks; if MR4 was confirmed, TKI therapy was
stopped and patients were followed every four weeks for six
months, followed by every six weeks until two years postwithdrawal, then every three months.
The majority of patients were treated with imatinib as
their first-line TKI (94%), followed by nilotinib (4%) and
dasatinib (2%). One-hundred and fifteen patients switched
to alternate TKIs as their second therapy due to intolerance,
prior to discontinuation in MR4: 57 to dasatinib, 47 to nilotinib, and seven to imatinib.
The median time from diagnosis to stopping TKI treatment was 7.7 years (range = 3.1-22.6 years); median duration
of TKI treatment was similar, at 7.6 years (range = 3.0-14.2
years).
MR4 was reached by a median of 21 months (range =
3.0-140.0 months) and, prior to stopping TKIs, patients
were in MR4 for a median of 4.7 years (range = 1.0-13.3
years). The median patient age at the time of withdrawal
was 60.3 years (range = 19.5-89.9 years).
After a median follow-up of 10 months (range = 1-36
months), 717 patients had evaluable molecular data. Of
these, 381 patients were still in major molecular remission (MMR; BCR-ABL1 ≤0.1% according to the International Scale), 331 patients lost MMR, and four died in
remission. The molecular relapse-free survival after stopping TKI treatment (the study’s primary endpoint) was:
• 62% (95% CI 58-65%) at 6 months
• 56% (95% CI 52-59%) at 12 months
• 51% (95% CI 47-55%) at 24 months
Dr. Richter and colleagues also looked at 448 patients
treated with first-line imatinib to identify prognostic factors of MMR at six months after discontinuing imatinib,
finding no significant correlation between sex, age, or risk
score and post-TKI success. They did, however, find that
treatment duration and MR4 duration increased the likelihood of MMR at six months.
The odds ratio for treatment duration was 1.16 (95% CI
1.08-1.25), “meaning that one additional year of imatinib
treatment increases the odds to stay in MMR by 16 percent,” Dr. Richter said. “We also identified a cutoff suitable
for stopping imatinib therapy, which is around six years,”
Dr. Richter said. Molecular relapse-free survival at six
months was 65.5 percent for imatinib treatment >5.8 years
and 42.6 percent for treatment ≤5.8 years (p<0.001).
Stopping TKI treatment, he added, would eliminate
the associated toxicities (including “financial toxicity”) and
improve patients’ quality of life. These associations would
need to be analyzed in further detail.
Additional follow-up is needed to reach definitive
conclusions about the long-term responses and risk of
recurrence after stopping TKI therapy.
REFERENCE
Richter J, Mahon FX, Guilhot J, et al. Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial. Abstract #S145. Presented at
the EHA 21st Congress, June 10, 2016; Copenhagen, Denmark.
32
ASH Clinical News
Caplacizumab Plus Standard Care
Reduces Thromboembolic Events,
Mortality in Patients with Thrombotic
Thrombocytopenia Purpura
The standard of care for thrombotic thrombocytopenia purpura (TTP) is plasma exchange and
immunosuppression, though many patients remain at risk for thrombotic complications until
remission is achieved. Caplacizumab, an investigational anti-von Willebrand factor nanobody for the
treatment of acquired TTP, was previously shown to shorten the time to resolution of TTP episodes,
compared with placebo, in the phase II, randomized TITAN trial.
Flora Peyvandi, MD, PhD, associate professor of internal medicine at the Angelo Bianchi
Bonomi Hemophilia and Thrombosis Center in Milan, Italy, and TITAN investigators presented
post-hoc data at the European Hematology Association’s 21st Congress, reporting that caplacizumab
lowered the incidence of major thromboembolic events and mortality.
In TITAN, a total of 75 patients were randomized 1:1 to receive:
• caplacizumab plus standard care (plasma exchange; n=36)
• placebo plus standard of care (n=39)
Thirty-five caplacizumab-treated patients and 37 placebo-treated patients were included in the safety
analysis.
Four major thrombotic events were reported in four patients in the caplacizumab group (TABLE),
including one pulmonary embolism (PE) and three TTP exacerbations (defined as recurrences
of TTP during the treatment period). The number of thrombotic events in the placebo group was
higher, with 20 thrombotic events occurring in 14 patents, including 13 TTP exacerbations. The p
value was not reported.
TABLE.
Treatment-Emergent Adverse Events
Caplacizumab
(n=35)
Placebo
(n=37)
Events
Patients, n (%)
Events
Patients, n (%)
Acute myocardial
infarction
0
0
2
2 (5.4%)
Deep-vein thrombosis
0
0
1
1 (2.7%)
Venous thrombosis
0
0
1
1 (2.7%)
Pulmonary embolism
1
1 (2.9%)
1
1 (2.7%)
Ischemic stroke
0
0
1
1 (2.7%)
Hemorrhagic stroke
0
0
1
1 (2.7%)
Thrombotic thrombocytopenic purpura
exac erbations
3
3 (8.6%)
13
11 (29.7%)
Deaths related to TTP
0
0
2
2 (5.4%)
TOTAL
4
4 (11.4%)
22
16 (43.2%)
“Compared [with patients] who received placebo and standard care, a lower proportion of those
treated with caplacizumab and standard care had one or more major thromboembolic adverse events
(AEs) or died,” the authors noted.
Overall, 11.4 percent of patients treated with caplacizumab and 43.2 percent of patients treated
with placebo experienced ≥1 thromboembolic events or died (p=0.006). Two deaths related to TTP
occurred in the placebo group (one related to refractory TTP and one to cerebral hemorrhage), while
no patients died in the caplacizumab cohort.
“The results suggest that treatment with caplacizumab has the potential to reduce the significant
morbidity and mortality associated with acquired TTP,” the authors concluded.
The results are limited by the post-hoc analysis and need to be confirmed in other prospective
studies. Dr. Peyvandi and colleagues noted that a phase III confirmatory study is ongoing and will
include a prospectively defined assessment of TTP-associated morbidity and mortality. ●
REFERENCE
Peyvandi F, Scully M, Kremer Hovinga JA, et al. Impact of caplacizumab treatment on mortality and major thromboembolic events in acquired TTP: Phase II TITAN study
results. Abstract LB418. Presented at the EHA 21st Congress, June 10, 2016; Copenhagen, Denmark.
August 2016