BACKGROUND: Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer 
driven by the BCR-ABL fusion protein that arises from the translocation of 
chromosomes 9 and 22. The disease begins with an indolent chronic phase (CP) 
that can last for 3 to 5 years. If untreated, it progresses into accelerated 
phase (AP) and within a year, blast phase (BP). Survival at this point is less 
than 1 year. during disease progression, mutations and the Philadelphia 
chromosome (Ph) appear (a process called clonal evolution). The only known 
curative therapy for CML is allogeneic bone marrow transplant (BMT). However, 
toxicity is formidable, with treatment- related mortality reported in the 30% 
range. Thus, effective therapy that maintains the patient with CML in CP with 
minimal toxicity is the goal for treatment of modern therapies. Because the 
preeminent mutation driving CML is BCr-ABL, therapies targeting BCR-ABL are the 
logical choice for disease-specific therapy. BCR-ABL inhibitors, such as 
imatinib, are proof that targeting specific genetic mutations associated with 
cancer yields a high degree of efficacy with minimal toxicity.
OBJECTIVE: This review will outline the evolution of therapy in CML. Preimatinib 
and imatinib-based treatment strategies, clinical efficacy, and the mechanism of 
imatinib resistance will be discussed.
SUMMARY: The discovery of the Ph and, subsequently, the identification of 
BCr-ABL revolutionized the treatment of CML. Cytoreductive chemotherapy, such as 
busulfan and hydroxyurea, was a mainstay of therapy to control white blood cell 
(WBC) counts; however, it did not modify the progression of the disease to AP 
and BP. The overall survival with CML ranges from 45 to 58 months in patients 
treated with cytoreductive therapy only. Treatment was advanced with the 
introduction of interferon (IFn ) immunotherapy in the 1980s. In some studies, 
IFn produced a complete hematologic response (CHR) in more than 50% of patients; 
however, its nonspecific immunostimulatory mechanism also produced severe 
flulike symptoms that limited tolerability. despite the significant toxicity, 
cost, and inconvenience of injecting IFN thrice weekly, median survival ranged 
from 60 to 89 months. Allogeneic BMT is the only known curative therapy for CML; 
however, treatment-related mortality from infection, bleeding, and graft versus 
host disease, age, and the availability of suitable donors limits its widespread 
use. Imatinib functions by competing with adenosine triphosphate (ATP) for 
binding to the BCr-ABL tyrosine kinase. In the absence of ATP, BCR-ABL is not 
able to activate downstream effector tyrosine kinase molecules that drive wBC 
proliferation. The International randomized Interferon versus STI571 clinical 
trial was the first to document the efficacy of imatinib as a first-line therapy 
for patients in CP. More than 90% of these patients had a CHr. Toxicities 
associated with this therapy are low. response in patients with advanced CML is 
less pronounced than in CP and is shorter lived, with less than 30% of patients 
achieving a CHR. For patients with CML in BP, the only viable therapy is to 
attempt a temporary reduction in disease burden with a salvage chemotherapy 
regimen, such as VAC (etoposide, cytarabine, and carboplatin). The goal of this 
induction chemotherapy is to induce a second remission; then the patient may be 
considered for allogeneic BMT. The main toxicities seen with imatinib therapy 
are myelosuppression, edema, and myalgia/arthralgia. In many cases, imatinib 
dosage can be briefly halted or lowered while the toxicity is managed. Imatinib 
resistance may develop at any time and inevitably leads to disease progression. 
resistance is usually caused by mutations within BCr-ABL, decreasing the 
affinity of imatinib binding. next-generation kinase inhibitors are focused on 
the ability to inhibit these mutated forms of BCR-ABL.
CONCLUSION: For the majority of patients with CML in CP, the standard of care is 
to maintain the patient in CP with imatinib therapy. Clinical trials have been 
extraordinarily successful, with 5-year survival rates greater than 90%. 
Allogeneic BMT continues to be an option for those who cannot tolerate imatinib 
or when CML progresses on imatinib therapy.