2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Abl suppression; and 3) the early enthusiasm regarding the
positive results with imatinib should be tempered because
historic experiences in oncology have often resulted in disappointing
long-term results.
The long-term positive experience with imatinib in CML
has in fact been beyond our original expectations. Currently,
the annual mortality related to CML is reduced from the
historic rate of 10% to 20% to less than 1%. We also learned
multiple important lessons that were unanticipated based
on previous cancer treatment experience: 1) the importance
of early therapy with targeted agents to achieve optimal
outcome; 2) the importance of an optimal biologic dose of the
targeting agent, rather than a classical maximum-tolerated
dose; 3) the rate of transformation was low, and if it
occurred, it did so early rather than late; 4) the development
of mutations in the targeted kinase as a resistant mechanism
to TKIs; and 5) rationally designed and more potent
KEY POINTS
Table 1. Comparison of Response Rates with Matched Targeted Agents in CML and Solid Tumors
● Chronic myelogenous leukemia (CML) is the poster
child for the future of oncology, having been transformed
from a disease that was rapidly fatal (median
survival of 3 to 6 years) to one that is functionally
cured (estimated survival of 25 years).
● In CML blastic phase (advanced stage), responses to
imatinib are transient, development of resistance
common, and survival is still only 1 year.
● Targeted therapies in solid tumors are typically evaluated
in patients with advanced disease and achieve
responses similar to imatinib in CML blastic phase.
● The effectiveness of targeted therapies in solid tumors
may be underestimated by evaluation at a stage
analogous to CML blastic phase.
● In order to realize the same response outcomes in
solid tumors as have occurred in CML, it may be
necessary to use the high successful strategy of treating
the earliest stage of the disease with targeted
therapy.
Complete Cytogenetic
Response Rate (%) with
Bcr-Abl TKIs* References
CML blastic phase 0 to 30 8–11, 17
CML accelerated phase 17 to 24 12
CML relapsed chronic phase 13–49 3, 24
CML Newly-diagnosed chronic phase 65 to �80 3,14,15
Response Rate (%)
with vemurafenib
(BRAF inhibitor)
Partial Complete
Melanoma: relapsed metastatic V600E BRAF mutation 75 6 26
Melanoma: untreated metastatic V600E BRAF mutation 47# 1# 32
PR rate with crizotinib
(ALK inhibitor)
CR rate with crizotinib
(ALK inhibitor)
Lung Cancer: relapsed, advanced, ALK-rearranged 56% 1% 27
Abbreviations: CML, chronic myelogenous leukemia; TKI, tyrosine kinase inhibitor.
* Bcr-ABl TKIs include imatinib, dastatinib and nilotinib, #: Response rate reported with median follow up of 3.8 months, tumor regression rate was approximately
95%.
180
WESTIN, KANTARJIAN, AND KURZROCK
TKIs can be developed to overcome some of the mechanisms
of CML resistance to imatinib.
Importance of Treating Newly Diagnosed CML
The use of targeted agents in the earliest phases of the
disease is likely the most important lesson from the CML
experience that could be directly applied to other solid
tumors. With imatinib and other TKIs (nilotinib, dasatinib),
therapeutic outcome is most strongly associated with the
phase of CML (ie, chronic versus blastic phase) during which
TKI therapy is introduced (Table 1). In patients with blastic
phase CML, TKI therapy produces complete cytogenetic
response rates of only 10% to 20%, with transient cytogenetic
responses and a median survival that increased from a
median of 3–6 months to 9–18 months. Invariably, in most
patients with blastic-phase CML resistance develops rapidly
to TKI therapy and patients die from complications of their
disease. 8-11 These poor responses to TKI are assumed to be
related to the multiple additional resistance mechanisms
(cytogenetic clonal evolution, mutations, and multiple parallel
and additional molecular abnormalities causing CML
transformation).
Even delaying therapy moderately so that it is given in
late chronic phase or accelerated phase markedly compromises
complete cytogenetic response rates. For instance,
patients with newly diagnosed chronic phase CML have a
complete cytogenetic response rate of over 80% with Bcr-Abl
TKI treatment. 7 The cytogenetic response rates drop to
approximately 40% in patients with previously treated
chronic phase CML. 3 By the time disease is in acceleratedphase
CML, complete cytogenetic responses occur in approximately
20% of cases. 12,13
In addition, deeper levels of (molecular) responses are
achieved at a greater frequency in early chronic-phase CML
compared with more advanced disease, attesting to the
increased efficacy of TKI therapies in early chronic-phase
CML. Achieving a major molecular response (defined as
BCR-ABL transcript levels less than 0.1%) is noted in 40% to
70% of patients with newly diagnosed CML, with higher
molecular response rates observed with the more potent
second-generation TKIs (eg, dasatinib and nilotinib) compared
with imatinib. 14,15 The major molecular response rate
rates were lower in accelerated-phase CML (20% to 30%),