Written in Blood
Nilotinib Plus Chemotherapy Yields Encouraging Results for Patients
with Ph-Positive ALL
Nilotinib, when used in combination with multi-agent chemotherapy, achieved “deep” molecular responses similar or better than those
achieved with imatinib in patients
with Philadelphia-positive acute
lymphocytic leukemia (Ph-ALL),
according to results of a phase II
trial recently published in Blood.
In a previous phase III, randomized clinical trial nilotinib
– a highly selective BCR-ABL1
tyrosine kinase inhibitor (TKI)
– helped patients with chronic
myeloid leukemia achieve significantly higher rates of molecular
response compared with imatinib,
the authors of the current study,
led by Dae-Young Kim, MD,
PhD, wrote. Given this outcome,
Dr. Kim, from the University
of Ulsan College of Medicine
in Seoul, Korea, and colleagues
sought to evaluate the feasibility,
efficacy, and safety of nilotinib
plus multi-agent chemotherapy
compared with imatinib in adult
patients with Ph-ALL.
daunorubicin, and prednisone)
with nilotinib started eight days
following induction therapy at
a dose of 400 mg administered
twice daily. Nilotinib therapy
was continued until the start of
allogeneic hematopoietic cell
transplantation (alloHCT) or
until the end of consolidation
therapy. After achieving complete
hematologic remission (CHR),
patients received either five
courses of consolidation followed
by two-year maintenance therapy
with nilotinib, or alloHCT. Minimal residual disease (MRD) was
assessed at CHR and then every
three months.
A total of 90 patients from
17 centers were included in the
study, 82 of whom achieved CHR,
for a CHR rate of 91 percent.
Median time to CHR was 27 days
(range, 13-72 days). Fifty-seven of
these patients (70%) later went on
to receive alloHCT; median time
to alloHCT was 3.8 months after
CHR (range, 1.4-8 months).
Although the combination
of nilotinib and chemotherapy was feasible, the adverse
events cannot be overlooked,
including a “relatively high”
rate of non-relapse mortality.
“Nilotinib achieved deeper
molecular response [in the postremission setting] than imatinib,
and the adverse events were tolerable,” Dr. Kim told AS H Clinical
News. “We highly recommend
the use of nilotinib as a firstline agent for the treatment of
Philadelphia-positive ALL, if it
is approved by the U.S. Food and
Drug Administration.”
Patients were eligible for inclusion in the multicenter, singlearm, prospective study if they
were 15 years of age or older, were
diagnosed with ALL or biphenotypic acute leukemia, and carried
the Philadelphia chromosome.
All patients received induction chemotherapy (vincristine,
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ASH Clinical News
More than half of patients
who achieved CHR also achieved
complete molecular remission
(CMR; 53%, or 48 patients),
defined as a negative MRD when
the BCR-ABL1/G6PDH ratio
was <1x10-5. Cumulative rates of
CMR were 86 percent among all
patients and 94 percent among
patients who achieved CHR. At
two years, the rate of hematologic
relapse-free survival (HRFS) was
72 percent among patients who
achieved CHR; two-year molecular relapse-free survival rate was
63 percent among the 76 patients
who achieved CMR.
The 57 patients who underwent alloHCT had a lower
incidence of overt hematologic
relapse than those who did not:
19 percent and 41 percent,
respectively. In addition, patients
receiving alloHCT had a significantly higher estimated two-year
HRFS rates than non-recipients
(78% vs. 49%; p=0.045). The twoyear overall survival, however,
was similar between those receiving alloHCT and those who did
not (80% vs. 72%, respectively;
p=0.227).
A significant portion of
patients who failed to achieve a
good molecular response (defined
as a BCRABL1/G6PDH ratio of
≤1×10-3) at three months after
HCR could be rescued successfully with alloHCT, Dr. Kim and
investigators stressed, suggesting that alloHCT continued to
play a significant role in treating
Ph-positive ALL – even after the
advent of potent TKIs.
Adverse events associated with nilotinib (including
jaundice, gastrointestinal issues,
serum lipase elevations, and pancreatitis) occurred mostly during
the induction phase of therapy
and were reversible with dose reduction or transient interruption
of nilotinib. Most of the adverse
events were tolerable, according
to the researchers.
Because the study was not
performed in a randomized, comparative fashion, the advantages
of treatment with nilotinib over
other TKIs were not definitively
demonstrated. “Although the
combination of nilotinib and
chemotherapy was feasible,” they
noted, “the adverse events cannot
be overlooked.” Future studies
should evaluate whether nilotinib
– compared with other TKIs imatinib and dasinitib – improves the
outcome of Ph-ALL by decreasing
rates of hematologic relapse and
the need for alloHCT, they added.
“Although the non-relapse
mortality rate was relatively high,
due to high doses of anthracycline and nilotinib during
induction,” Dr. Kim and authors
concluded, “we found a high
cumulative incidence of complete
molecular response (negative
MRD) and hematologic relapsefree survival rates, comparable to
those reported previously with
imatinib or dasatinib.”
Reference
Kim DY, Joo YD, Lim SN, et al. Nilotinib combined
with multi-agent chemotherapy for newly diagnosed
Philadelphia-positive acute lymphoblastic leukemia.
Blood. 2015 June 11. [Epub ahead of print]
July 2015