Biologic agents and novel chemotherapies in various stages of
clinical development hold promise for the treatment of hematologic
malignancies, but as past experience shows, results of preliminary
studies are not always confirmed in randomized controlled trials
and many drugs with promising phase II data do not gain FDA
approval. With that caveat, here are snapshots of some potentially
promising drugs for chronic myelogenous leukemia, lymphoma, and
multiple myeloma based on presentations at the 52nd Annual Meeting
of the American Society of Hematology (ASH), held December 4-7 in
Orlando, Florida.
Bosutinib for Chronic Myelogenous Leukemia
Imatinib is standard first-line therapy for chronic myelogenous
leukemia (CML), and both dasatinib (Sprycel) and nilotinib
(Tasigna) were recently approved by the FDA as first-line therapies
in CML. Bosutinib, a new tyrosine kinase inhibitor with a dual
mechanism of action, may be another option for first-line therapy
of CML if results of a phase III trial presented at ASH 2010
are confirmed.1 The randomized, phase III,
open-label BELA study showed that bosutinib reduced the number of
treatment failures compared with imatinib. At 1 year, treatment
failure rates were 3% on the bosutinib arm vs 10% on the imatinib
arm.
According to lead author Carlo Gambacorti-Passerini,
MD, Professor at the University of Milano Bicocca, Monza,
Italy, bosutinib's effect on treatment failure is the main message
of this study. The overall net benefit of 7% would translate to
about 500 patients newly diagnosed with CML in the United States
each year, he said.
Dr. Gambacorti-Passerini emphasized that it will be important to
determine which patients with CML would benefit from bosutinib
compared with other agents used in this setting. He and his
colleagues are currently doing genomic sequencing studies on
leukemic cells to try to identify characteristics of those
patients.
The study enrolled 502 newly diagnosed patients with CML. An
intent-to-treat analysis showed that at 1 year, the major molecular
response rate was 39% with bosutinib vs 26% with imatinib
(P = .002). The study failed to meet its primary endpoint
of superior complete cytogenetic response with bosutinib at 1 year:
70% for bosutinib vs 68% for imatinib, a difference that was not
statistically significant.
Bosutinib was associated with more diarrhea, nausea, vomiting,
and rash compared with imatinib; the most frequent grade 3 and 4
adverse events were diarrhea (8%) and rash (2%). More muscle
cramps, bone pain, and periorbital edema were associated with
imatinib therapy. Treatment discontinuation rates were 25.4% with
bosutinib and 13.5% with imatinib.
Dr. Gambacorti-Passerini concluded that the higher
discontinuation rate was mostly due to the lack of experience with
bosutinib of most participating centers (bosutinib is not yet
registered for any indication). Once it is reduced, the advantage
of bosutinib will be even greater.
Ponatinib for Chronic Myelogenous Leukemia
Despite the success of imatinib and its cousins dasatinib and
nilotinib in treating CML, a proportion of patients with CML will
experience treatment failure or develop resistance. Currently there
are no effective drugs for resistance due to the T315I mutation,
but ponatinib-a new tyrosine kinase inhibitor-appears to inhibit
the entire spectrum of mutations responsible for resistance to
tyrosine kinase inhibitors.
A dose-escalation, phase I study of 74 patients with refractory
hematologic malignancies (60 patients with CML), showed exciting
results in a cohort of patients with chronic-phase CML.2
(Among the 60 patients with CML, 44 were in chronic phase, 7 were
in accelerated phase, and 9 were in blast phase.)
Among 38 evaluable patients with chronic-phase CML, 95% had a
complete hematologic response, 66% a major cytogenetic response,
and 53% a complete cytogenetic response. In nine evaluable patients
from this group with chronic-phase CML and T315I mutations, 100%
had a complete hematologic response, 100% had a major cytogenetic
response, and 89% had a complete cytogenetic response.
"These are very exciting responses in these patients," said lead
author Jorge Cortes, MD, of The University of
Texas MD Anderson Cancer Center, Houston. If these preliminary
results are confirmed in future trials, this drug may be able to
prevent the emergence of resistance due to mutations.
Responses were less robust but still significant in patients
with accelerated- and blast-phase CML, with no complete hematologic
responses and major hematologic response observed in 35% of this
group.
Toxicity was acceptable. The most common adverse events (10% or
greater) included thrombocytopenia, headache, nausea, arthralgia,
fatigue, anemia, increased lipase, muscle spasms, rash, myalgia,
and pancreatitis.
Pixantrone for Non-Hodgkin Lymphoma
Pixantrone, a novel aza-anthracenedione structurally related to
mitoxantrone and the anthracyclines, was superior to the
investigator's choice of therapy in the randomized, controlled,
phase III EXTEND trial of relapsed aggressive non-Hodgkin lymphoma
(NHL).3 In this pretreated, poor prognosis group of 140
patients previously treated with up to two lines of prior
chemotherapy, pixantrone achieved superior rates of complete
response/complete response unconfirmed, superior overall response
rate, and superior progression-free survival compared with
comparator agents.
At 18 months of follow-up, the complete response/complete
response unconfirmed rate was 20% for pixantrone vs 5.7% for
comparators (ie, vinorelbine, oxaliplatin, ifosfamide, etoposide,
mitoxantrone, gemcitabine, or rituximab [Rituxan]); overall
response rate was 37.1% vs 14.3%, respectively; median
progression-free survival at the end of the study was 5.3 vs 2.6
months, respectively (P = .005). Median overall survival
was 10.2 months with pixantrone vs 7.6 months for the other agents,
but this difference was not statistically significant.
Ruth Pettengell, MD, of St. George's Hospital in London,
presented these trial results at a poster session.
Carfilzomib for Multiple Myeloma
Although several effective therapies are available for multiple
myeloma, patients treated with these therapies typically relapse
and have limited treatment options. Carfilzomib, a novel highly
selective next-generation proteosome inhibitor, achieved durable
responses in a phase IIb study of 266 patients with
relapsed/refractory multiple myeloma previously treated with all
available therapies. The drug was generally well
tolerated.4
Carfilzomib has the potential to offer substantial clinical
benefit to patients who have relapsed or are refractory to other
therapies, said lead author David Siegel, MD, PhD,
of John Theurer Cancer Center, Hackensack, New Jersey.
Patients enrolled in the phase IIb trial received at least two
prior therapies, including bortezomib (Velcade) and either
thalidomide (Thalomid) or lenalidomide (Revlimid), plus an
alkylating agent. In 257 patients evaluable for response, overall
response rate was 24.1% and median duration of response was 8.3
months. The clinical benefit rate (complete or partial plus minimal
response rate) was 34.2%. The disease control rate, which includes
stable disease, was 69%. Median overall survival was 15 months.
The most common grade 3 or 4 toxicity was thrombocytopenia
(27%), anemia (22%), lymphopenia (18%), and neutropenia
(10%). Of particular note was the extremely low rate of
peripheral neuropathy.
Dr. Siegel said that these are good results in this group of
heavily pretreated patients, with a median number of five previous
lines of therapy, and multiple relapses and progressive disease at
study entry. Onyx Pharmaceuticals plans to file a New Drug
Application with FDA for carfilzomib in 2011. ■
References
1. Gambacorti-Passerini C, Kim D-W, Kantarjian H, et al: An
ongoing phase 3 study of bosutininb (SKI-606) versus imatinib in
patients with newly diagnosed chronic phase chronic myeloid
leukemia. 52nd ASH Annual Meeting. Abstract 208. Presented December 6, 2010.
2. Cortes J, Talpaz M, Bixby D, et al: A phase I trial of oral
ponatinib (AP24534) in patients with refractory chronic myelogenous
leukemia (CML) and other hematologic malignancies: Emerging safety
and clinical response findings. 52nd ASH Annual Meeting. Abstract 210. Presented December 6, 2010.
3. Pettengell R, Zinzani PL, Narayanan G, et al: Phase 3 trial
of pixantrone dimaleate compared with other agents as third-line,
single-agent treatment of relapsed aggressive non-Hodgkin lymphoma
(EXTEND): End of study results. 52nd ASH Annual Meeting. Abstract 2833. Presented December 5, 2010.
4. Siegel D, Martin T, Wang M, et al: Results of PX-171-003-A1,
an open-label, single-arm, phase 2 study of carfilzomib in patients
with relapsed and refractory multiple myeloma. 52nd ASH Annual
Meeting. Abstract 985. Presented December 7, 2010.
