|
|
|
Second-Generation Tyrosine Kinase Inhibitors Are Safe and Effective as First-Line Treatment for CML
December 7, 2009—During the 51st ASH Annual Meeting and Exposition
in New Orleans, data were presented demonstrating the efficacy and
safety of second-generation tyrosine kinase inhibitors in patients with
newly diagnosed, previously untreated Philadelphia chromosome–positive
(Ph+) chronic myelogenous leukemia (CML) in early chronic phase.
Imatinib
is the current standard of care for patients with newly diagnosed CML,
but intolerance or development of resistance are limiting factors.
Highly potent inhibitors of BCR-ABL are currently indicated for adults
with Ph+ CML in chronic phase (CP) or accelerated phase (AP) who are
resistant or intolerant to imatinib.
Efficacy of nilotinib as first-line therapy
Jorge
Cortes, MD (The University of Texas, M. D. Anderson Cancer Center,
Houston, Texas, United States), presented data from a phase II trial
evaluating the efficacy of nilotinib as initial therapy in patients
with Ph+ CML. The primary objective of this study was to estimate the
proportion of patients attaining major molecular response (MMR) at 12
months. Secondary objectives included rate of complete cytogenetic
response (CCyR) and time to response, duration of response, event-free
survival (EFS), and overall survival (OS). A total of 67 patients with
untreated CML-CP received nilotinib 400 mg bid.
The following results were obtained from this trial:
- 100%
(55/55) of patients with CML in early CP who were not in complete
hematologic response (CHR) at the start of treatment achieved CHR
- 98% (57/58) of patients with CML in early CP who had at least 3 months of follow-up and evaluable karyotype achieved CCyR
- 95% of patients achieved CCyR at 12 months
- Rate
of CCyR at different time points (up to 42 months) was favorable when
compared to historical data with imatinib 400 mg qd or imatinib 800 mg
qd
- 88% (53/60) of patients with CML in early CP achieved MMR
- 71% of patients achieved MMR at 12 months
- Among 7 patients evaluated with CML in AP, 4 achieved MMR, 2 achieved CCyR, and 1 had no response
Grade
3/4 nonhematologic adverse events included elevation of bilirubin (7%)
and lipase (4%), while grade 3/4 hematologic adverse events included
thrombocytopenia (13%), neutropenia (11%), and anemia (6%). Event-free
survival at 48 months was 93%. These data demonstrated that first-line
treatment with nilotinib in patients with CML in early CP induced rapid
CCyR with a favorable safety profile; in addition, MMR rates at 12
months were higher than had been demonstrated with imatinib.
Blood. 2009;114(22): Abstract 341.
Dose delivered and safety profile of nilotinib as first-line therapy
Gianantonio
Rosti, MD (University of Bologna, Italy), presented a detailed analysis
of the safety profile of nilotinib 800 mg daily as front-line therapy
in patients with previously untreated Ph+ CML in early CP. In this
phase II trial, 73 patients received nilotinib 400 mg bid.
The following results were obtained from this study:
- 96% of patients achieved CCyR at 12 months
- 85% of patients achieved MMR at 12 months
- The mean daily dose of nilotinib received was 600-800 mg (74%
of patients), 400-599 mg (18% of patients), and <400 mg (8% of
patients)
- At 12 months, the CCyR rate was similar for all mean daily doses of nilotinib
- Grade 3/4 hematologic adverse events included neutropenia (4% of patients) and thrombocytopenia (3% of patients)
- 4 adverse events (≥ grade 2) accounted for the majority of dose interruptions:
- Bilirubin increase (38%; no grade 4)
- Skin rash and/or pruritus (37%; no grade 4)
- Asymptomatic amylase and/or lipase increase (16%; 4% grade 4)
- Transaminases increase (19%, no grade 4)
Data from this trial further demonstrated the feasibility and
safety, as well as the efficacy, of nilotinib 800 mg daily as
front-line therapy in patients with previously untreated Ph+ CML in
early CP. Indeed, the authors state that nilotinib may represent an
important advance in the management of this patient population.
Blood. 2009;114(22): Abstract 2205.
Efficacy of dasatinib as first-line therapy
Dasatinib,
another second-generation BCR-ABL inhibitor, is indicated for the
treatment of adults with all phases of CML who exhibit resistance or
intolerance to prior therapy, including imatinib. Jorge Cortes, MD (The
University of Texas, M. D. Anderson Cancer Center), reported data from
a phase II trial evaluating the efficacy and safety of front-line
dasatinib in patients with previously untreated CML in early CP. The
primary objective of this study was to estimate the proportion of
patients attaining MMR at 12 months. A total of 62 patients were
randomized to either dasatinib 50 mg bid or dasatinib 100 mg qd.
The following results were obtained from this trial:
- 95% (62/65) of patients with CML in early CP who were not in CHR at the start of treatment achieved CHR
- 96% (67/70) of patients with CML in early CP who had at least 3 months of follow-up achieved CCyR
- 79% (55/70) of patients with CML in early CP achieved MMR
- 74% of patients achieved MMR at 12 months
Grade 3/4 nonhematologic adverse events included muscle or
joint pain (14%), fatigue (11%), dyspnea (8%), and neuropathy (7%);
grade 3/4 hematologic toxicity included neutropenia (25%),
thrombocytopenia (24%), and anemia (10%). Pleural effusion occurred in
17% of evaluable patients, with grade 3/4 pleural effusion observed in
3% of patients. Data from this study demonstrated the safety and
efficacy of dasatinib as front-line therapy in patients with previously
untreated CML in early CP. The dasatinib 100 md qd arm continues to
accrue patients due to improved response and toxicity.
Blood. 2009;114(22): Abstract 338
Taken
together, data from these phase II studies demonstrate that
second-generation tyrosine kinase inhibitors can be used safely and
efficaciously in the front-line treatment of patients with CML-CP.
Several phase III clinical trials are currently underway to further
define the optimal use of second-generation tyrosine kinase inhibitors
in patients with CML.
|
|
| |
|
|
 |
|
|
|
|
|
