2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Treatment of Chronic Myelogenous Leukemia
as a Paradigm for Solid Tumors: How
Targeted Agents in Newly Diagnosed Disease
Transformed Outcomes
By Jason R. Westin, MD, Hagop Kantarjian, MD, and Razelle Kurzrock, MD
Overview: Although chronic myelogenous leukemia (CML) is
rare, with approximately 5000 new cases in the United States
annually, it may be the poster child for the future of oncology.
Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor
(TKI), transformed the course of CML from a rapidly fatal
disease (median survival, 3 to 6 years) to a functionally
curable, indolent disease with an estimated median survival of
more than 25 years. This transformation can be attributed to
several key factors: the identification of a causal and actionable
molecular aberration—BCR-ABL; the development of a
potent and selective Bcr-Abl TKI—imatinib; and, importantly
the application of imatinib in the earliest phase of CML. In
contrast, imatinib, if used in CML blastic phase, improves
median survival to only about 1 year. Similar to CML blastic
TARGETED THERAPY in cancer started long before the
imatinib era in chronic myelogenous leukemia (CML).
Examples of targeted therapies include hormone therapy
(tamoxifen) in estrogen- and progesterone-receptor positive
breast cancers, monoclonal antibodies in leukemias and
lymphomas (rituximab, gemtuzumab ozogamycin), and others.
However, the era of targeted therapy in cancer is
identified with imatinib as a result of several factors: 1) deciphering
the Philadelphia chromosome (Ph)-associated
and BCR-ABL-associated molecular abnormalities in CML;
2) defining a causal association between the BCR-ABL
molecular events and the development of CML in animal
models, thus proving that Bcr-Abl is a legitimate target for
therapeutic interventions; 3) discovering a relatively nontoxic,
orally available selective Bcr-Abl inhibitor, imatinib
mesylate; and 4) demonstrating the clinical efficacy of imatinib.
After positive clinical trials were reported, media
outlets suggested this new “magic bullet” could represent “A
New Hope For Cancer” and signal the dawn of a new phase
in the war on cancer. 1
Left untreated, CML will ineluctably progress from the
chronic phase to the accelerated phase, and eventually
transform to CML blastic phase. 2 This evolution is analogous
to the natural disease course believed to occur in most
cancers. In the time before imatinib, therapies for CML
improved blood counts but achieved complete cytogenetic
responses (0% Ph-positive [Ph�] metaphases in the bone
marrow) in only 15% of patients and improved median
survival from 3 years with busulphan or hydroxyurea to only
5–7 years with interferon alpha-based therapies. In contrast,
when treating the earliest phases of CML with a
therapy—imatinib—specific for the critical genetic abnormality,
the cumulative complete cytogenetic response rate
was greater than 80%, and the estimated 10-year survival
increased from less than 20% to 85% or more. Indeed, at
present, the estimated median survival of patients with
CML exceeds 25 years. 3-7 Because the median age of patients
with CML at the time of diagnosis is nearly 60 years,
it is now estimated that most patients with CML have a
normal life expectancy if treated appropriately with Bcr-Abl
phase, metastatic solid malignancies have undergone genetic
evolution, and their molecular aberrations are complex. As a
result, resistance is common and eradication is difficult. The
key to the dramatic improvement in the survival of patients
with CML involved using imatinib in newly diagnosed disease,
before blastic transformation. We hypothesize that metastatic
solid tumors are analogous to CML blastic phase, and that to
achieve improvements in solid tumor outcomes similar to
those seen in CML, application of targeted agents to newly
diagnosed disease may be required to prevent disease transformation
(i.e., metastases). Targeting driver mutations at the
time of diagnosis may be critical to the goal of markedly
changing the outlook for patients with cancer.
tyrosine kinase inhibitors (TKIs). These patients are therefore
“functionally cured.” Imatinib changed the course of
CML from a previously fatal disease (median survival, 3 to 6
years) to a functionally and molecularly curable disorder.
Patients diagnosed with chronic-phase CML today may be
reassured, with our current knowledge, that most can expect
to live decades and will likely die with, and not of, CML—
provided they comply with TKI therapy, there is a reasonable
observation for progression of the disease, and an
appropriate change is made to second- and third-generation
TKIs if disease resistance evolves.
Imatinib was approved by the Food and Drug Agency in
2001 for treatment of Ph� CML. During the decade to
follow, a sea change occurred in oncology with the approval
of dozens of agents to be used for targetable cancerassociated
molecular aberrations in both hematologic and
solid tumor malignancies. Unfortunately, in solid tumors,
these new targeted therapies have to date not achieved the
expectations set by imatinib in CML. Therefore, we believe a
review of the CML experience is required to potentially
apply the lessons learned to solid tumors.
Lessons from the CML Experience
In hindsight, the positive results of imatinib therapy in
CML seem now preordained. However, at the start of the
imatinib trials, a common prediction shared by some CML
experts was that 1) CML is a heterogeneous disease with
multiple molecular abnormalities with increasing prevalence
in advanced CML; 2) although early trials appeared
favorable, CML cells will ultimately develop resistance and
eventual late disease transformation even with early Bcr-
From the Department of Leukemia; Department of Lymphoma and Myeloma; Department
of Investigational Cancer Therapeutics, University of Texas M. D. Anderson Cancer Center,
Houston, TX.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Razelle Kurzrock, MD, M. D. Anderson Cancer Center, 1400
Holcombe Blvd., Houston, TX 77030; email: rkurzro@mdanderson.org.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10
179