On Location
TABLE.
Response Rates According to FLT3 Mutation Status
Response
Complete remission (CR)
CR, incomplete platelet recovery (CRp)
ASH Clinical News
n (%)
4 (5%)
3 (5%)
0
4 (5%)
4 (6%)
0
27 (33%)
25 (38%)
3 (8%)
Partial remission (PR)
12 (15%)
10 (15%)
1 (3%)
Composite CR
35 (43%)
32 (49%)
3 (8%)
Overall response rate (CR+PR)
47 (57%)
42 (65%)
4 (11%)
A New Indication for Ruxolitinib?
The JAK2 inhibitor ruxolitinib was initially approved in 2011 for the treatment of
myelofibrosis, but may offer a promising
Meeting attendees take in a session during the ASCO meeting.
new treatment for patients with CMML,
according to results from a phase I trial
conducted through the Myelodysplastic
Syndromes Clinical Research Consortium
(MDS CRC) and presented by Eric W.
Padron, MD, from H. Lee Moffitt Cancer
Center in Tampa, Florida.2
CMML is an aggressive myelodysplastic/
myeloproliferative neoplasm (MDS/MPN)
characterized by peripheral monocytosis and bone marrow dysplasia with limited therapeutic
In early-phase trials conducted in patients with acute
options. JAK2 inhibitors, though, have shown promise
myeloid leukemia (AML) and chronic myelomonocytic
as therapeutic candidates in preclinical studies. “Overall
leukemia (CMML), two investigational agents (ASP2215
survival with CMML is about 34 months, so there is a real
and CPI-613) and one previously approved JAK2 inhibiunmet treatment need for these patients,” Dr. Padron told
tor demonstrated good clinical activity.
ASH Clinical News. “This phase I trial, we hope, is a start
toward addressing that.”
ASP2215 in Relapsed or Refractory AML
Nineteen patients with CMML-1 – with no regard to
In patients with relapsed or refractory AML, ASP2215,
prior therapies – were enrolled into the trial in four coa selective, potent inhibitor of FLT3/AXl, produced high
horts, Dr. Padron explained, with doses ranging from 5 mg
composite complete remission (CR) rates.1 This first-intwice daily to 20 mg twice daily in 5-mg dose escalations.
human phase I/II trial also showed ASP2215 to be well
Median age among the 19 patients was 71 years, and 67
tolerated in doses up to 300 mg/day, according to senior
percent had the proliferative form of CMML. Mean duraauthor Mark J. Levis, MD, from Johns Hopkins University
tion of therapy was 122 days (range, 28-409 days).
in Baltimore, Maryland, who presented the study findings
Of the 15 patients evaluable for response, three had
at the American Society of Clinical Oncology meeting.
hematologic improvement and one had a partial response
Noting that activating mutations of FLT3, some of which
per 2006 International Working Group (IWG) criteria.
confer a poor prognosis, are found in about 30 percent of
Among the nine patients with splenomegaly, six experiAML patients, Dr. Levis said that FLT3 inhibitors exhibit
enced a >50 percent reduction in spleen size. Ruxolitinib
clinical promise but may have potency, safety, and tolerability
was particularly beneficial for patients with CMML-relatissues. With the current trial, investigators sought to identify
ed B symptoms (fever, night sweats, weight loss, pruritis):
a safe, tolerable dose that fully inhibits FLT3 in all patients.
14 of 15 patients had clinically meaningful or complete
At the time of Dr. Levis’ presentation, ASP2215 had
been administered to 198 patients with relapsed or refrac- resolution. No dose-limiting toxicities for ruxolitinib
were identified, Dr. Padron noted.
tory AML (127 of whom were FLT3-mutant positive), in
doses ranging from 20 mg/day to 450 mg/day.
CPI-613 for High-Risk AML Patients
The investigational drug was also associated with consisCPI-613, a first-in-class, non-redox, active lipoate derivative, is
tent, potent, and sustained inhibition of FLT3 at all doses
a promising salvage regimen in combination with high-dose
≥80 mg/day, Dr. Levis reported (TABLE). In general, FLT3–
Ara-C (HDAC) and mitoxantrone – particularly for older pamutant-positive patients responded better to treatment
tients with AML and patients with high-risk AML – according
than FLT3–wild-type patients, with an overall response rate
to research presented by Timothy S. Pardee, MD, PhD, from
(complete and partial remissions) of 57 percent versus 11
Wake Forest University in Winston-Salem, North Carolina.3
percent, respectively.
Median overall survival (OS) was highest in the 80 mg/
Outcomes in these patient groups are “dismal,” said Dr.
day group (201 days), followed by the 120 mg/day group
Pardee, but in this phase I trial, treatment with CPI-613,
(199 days), 200 mg/day group (161 days), 20 mg/day group
which works by inhibiting mitochondrial metabolism, led
(128 days), and 40 mg/day group (105.5 days). The reported
to favorable overall response rates.
50
FLT3-wild-type
≥80 mg/day, n (%)
CR, incomplete hematologic recovery (CRi)
adverse events were similar to those of other
FLT3 inhibitors.
Dr. Levis noted that combination studies are ongoing in newly diagnosed AML,
and that phase III trials with ASP2215 at
120 mg/day are planned.
Early Trials in AML
and CMML Offer
Promising Results
FLT3-mutated
20-300 mg/day, n (%)
Among the 48 patients (median age = 60 years; range
21-79) in this trial, 14 had refractory disease and 11 had
received one or more lines of prior salva ge therapy.
Compared with a historic cohort treated with HDAC,
mitoxantrone, and asparaginase, the overall response rates
(ORR) in this trial were favorable (48% vs. 25%), with
19 CR and 4 CRi. Surprisingly, Dr. Pardee said, the 11
patients with poor-risk cytogenetics and the 26 patients
60 years old or older also had high ORR, compared with
the historic cohort (48% vs. 25%; 46% vs. 33%). As in the
historic cohort, 13 percent of patients died on or before day
30 of treatment. Twenty-three percent of patients went on
to receive stem cell transplantation.
“We are very excited by these preliminary results, especially for high-risk patients,” Dr. Pardee concluded, adding
that a randomized phase II study is under development. ●
REFERENCES
1. Levis MJ, Perl AE, Altman JK, et al. Results of a first-in-human, phase I/II trial of ASP2215,
a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute
myeloid leukemia (AML). Abstract #7003. Presented at the 2015 American Society of
Clinical Oncology Annual Meeting, Chicago, IL, May 30, 2015.
2. Padron E, Dezern AE, Vaddi K, et al. A multi-institution phase I trial of ruxolitinib in chronic
myelomonocytic leukemia (CMML). Abstract #7021. Presented at the 2015 American
Society of Clinical Oncology Annual Meeting, Chicago, IL, May 30, 2015.
3. Pardee TS, Stadelman K, Isom S, et al. Activity of the mitochondrial metabolism inhibitor cpi-613
in combination with high dose Ara-C (HDAC) and mitoxantrone in high risk relapsed or refractory
acute myeloid leukemia (AML). Abstract #7015. Presented at the 2015 American Society of
Clinical Oncology Annual Meeting, Chicago, IL, May 30, 2015.
Watch our
interview with
Mark J. Levis,
MD, about
ASP2215 in
relapsed or
refractory AML
by scanning the
QR code.
Watch our
interview with
Eric W. Padron,
MD, about
ruxolitinib in
the treatment
of CMML by
scanning the
QR code.
July 2015