Page 1215 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 67 Chronic Myeloid Leukemia 1061

Randomized studies show an improvement in survival rates in Imatinib Mesylate
patients receiving IFN compared with patients receiving BU or HU.
An Italian multicenter study randomly assigned 218 patients to Imatinib mesylate is a small, 2-phenylaminopyrimidine molecule that
receive IFN and 104 patients to receive HU or BU (the control inhibits the kinase activity of all proteins that contain ABL, ABL-
group). Cytogenetic remissions were significantly more common in related gene (ARG) protein, or platelet-derived growth factor recep-
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the IFN group. After a median follow-up of 68 months, the observed tor, as well as the KIT receptor, at micromole concentrations.
6-year survival rate was 50% for IFN-treated patients and 29% for Imatinib is a competitive inhibitor that acts at the ATP-binding site
controls, with median survivals of 72 and 52 months, respectively. in the kinase domain to inhibit the normal binding of ATP and
The time for progression from CP to accelerated or blast phase was blocks the ability of BCR-ABL to phosphorylate tyrosine residues on
lengthened from 45 months to more than 72 months. In a German its substrates (Fig. 67.5).
multicenter study, 622 patients were randomized to receive IFN, BU, Initial phase I and phase II trials established that imatinib was well
or HU. The 5-year survival rate in the IFN group (59%) exceeded tolerated and induced hematologic as well as cytogenetic response in
that of the BU group (32%) but was not significantly higher than the majority of patients with CP CML in whom other treatments
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that of the HU group (44%). Much of the discrepancy between the had failed. In a phase II study, 532 CP patients who were refractory
Italian and German findings can be explained by differences in case to or intolerant of IFN-α were treated with imatinib at a dose of
mix and treatment regimens. Two other randomized trials also showed 400 mg daily. A CHR was achieved in 95% of patients, MCR in
benefit for IFN treatment compared with chemotherapy. The UK 60% of patients, and CCR in 41% of patients. With a median
Medical Research Council randomly assigned 293 patients to receive follow-up of 18 months, the estimated PFS was 89%. Only 2% of
IFN and 294 patients to receive HU or BU. The 5-year survival rate patients discontinued therapy because of adverse events.
was 52% for the IFN group and 34% for the control group. A Japa- Subsequently the International Randomized Interferon and
nese randomized control trial compared IFN (80 patients) with BU STI571 (IRIS) study compared imatinib at 400 mg daily with IFN-α
(79 patients). Hematologic and cytogenetic remission rates did not plus cytosine arabinoside in 1106 newly diagnosed patients in first
differ significantly. After a median follow-up of 50 months, the CP. This study was closed with the conclusion that imatinib is the
predicted 5-year survival rate was 54% for patients receiving IFN and initial nontransplant treatment of choice for patients with newly
32% for those receiving BU. diagnosed CP CML. This conclusion was based primarily on a higher
The added value of combining IFN with cytosine arabinoside was rate of disease progression in the patient group receiving IFN plus
shown in a French multicenter trial, wherein 360 patients were cytosine arabinoside. In the initial report from this study, after a
randomly assigned to receive IFN combined with cytosine arabino- median follow-up of 19 months, the estimated rate of an MCR at
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side (20 mg/m /day for 10 days) and 361 patients to receive only 18 months was 87.1% (95% confidence interval [CI]: 84.1–90.0) in
IFN. After 3 years, the survival rate was 86% with IFN and cytosine the imatinib group and 34.7% (95% CI: 29.3–40.0) in the IFN plus
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arabinoside and 79% with IFN alone. The rate of hematologic cytosine arabinoside group (p < .001). The estimated rates of CCR
response was higher in the IFN–cytosine arabinoside group than in were 76.2% (95% CI: 72.5–79.9) and 14.5% (95% CI: 10.5 18.5),
the IFN group. Major cytogenetic responses were observed 12 months respectively (p < .001). At 18 months, the estimated rate of freedom
after randomization in 41% of patients treated with IFN-cytosine from progression to AP or BC CML was 96.7% in the imatinib group
arabinoside and in 24% of patients treated with IFN only. and 91.5% in the IFN group (p < .001). Imatinib was better tolerated
Thus, accumulated evidence from randomized trials suggests that than combination therapy. In a subsequent 60-month follow-up
IFN improves survival in CP patients with favorable features com- report for this study, the estimated cumulative incidence rate of
pared with BU and HU. Metaanalysis suggests that the pooled 5-year CHR, MCR, and CCR for patients on first-line imatinib was 98%,
survival rate is 57% (50–59%) for IFN and 42% (29–44%) for 92%, and 87% at 60 months (Fig. 67.6). Only 7% of patients pro-
chemotherapy, which results from a delay in the onset of BC. The gressed to advanced phase, and the estimated overall survival (OS)
controlled trials suggest that IFN increases life expectancy by a was 89%. Crossover between arms was permitted for treatment
median of approximately 20 months compared with BU and HU. failure, and 382 (69%) of 553 patients originally allocated to the
There is no direct evidence that IFN has a greater impact on survival IFN/cytarabine arm crossed over to the imatinib arm at a median of
than does HU for patients who are in the later stages of CP (e.g., 60 months from start of treatment. The main reason for crossover
more than 1 year after diagnosis) or for those who are more ill (e.g., from IFN to imatinib was intolerance of treatment, but reasons also
more than 10% to 30% blasts in peripheral blood). Adding cytosine included disease progression and failure to achieve hematologic or
arabinoside to IFN appears to add further survival benefit but also cytogenetic response. During the 6th year of study treatment, there
increases toxicity. Although IFN clearly is beneficial in patients with were no further reports of disease progression and the toxicity profile
CML patients, benefit is limited by low levels of cytogenetic response remained unchanged. Of all patients randomized to receive imatinib
and considerable toxicity. As discussed later, the use of IFN in the and still on study treatment, 63% showed CCR at last assessment.
modern treatment of CML patients has been replaced by use of The estimated event-free survival (EFS) at 6 years was 83%, and the
imatinib and other TKIs. estimated OS was 88%. 9
A dose of 400 mg of imatinib daily is currently the standard dose
for initiating therapy in newly diagnosed CP patients. Nonrandom-
Tyrosine Kinase Inhibitor Treatment ized studies suggested that patients receiving initial therapy with
800 mg imatinib daily will achieve CCR more rapidly than patients
Because the tyrosine kinase activity of BCR-ABL plays a critical role receiving standard 400-mg daily doses. The Tyrosine Kinase Inhibi-
in cellular transformation, it is an attractive target for inhibition. tor Optimization and Selectivity study compared imatinib 800 mg/
The introduction of TKIs into clinical practice has dramatically day (n = 319) to 400 mg/day (n = 157). Higher dose imatinib
changed CML treatment. TKI therapy, now the mainstay of treat- provided faster response CCR rates at 6 months (57% vs. 45%,
ment, is remarkably effective for CP CML, inducing remissions in respectively), but there was no significant difference between the
most patients and leading to excellent survival. TKI resistance can arms at 12 months (70% vs. 66%, respectively) or 24 months (76%
occur, especially in AP and BC CML, usually as a result of tyrosine in both groups). Similarly, no difference in EFS, PFS, or OS was
kinase domain point mutations. Resistance to imatinib can often seen. However, a subset of patients who can tolerate higher doses
be treated by “second-generation” TKIs dasatinib or nilotinib, and of imatinib, without interruptions for side effects, can have a better
there is evidence that these drugs may be even more effective than response. 10
imatinib for front-line treatment of CML. Molecular endpoints Cumulative response estimates do not take into account patients
that correlate with long-term outcomes have been developed and who have left the study for a variety of reasons. It is also clear that
have been incorporated into guidelines to monitor response to TKIs the results of imatinib therapy in the community setting are less
treatment. favorable. Thus, only 55% of patients treated with first-line imatinib