TREATMENT AND RESPONSE
In the treatment of Ph+ CML, it is important to evaluatethe response to therapy, particularly cytogenetic response,hematologic response, and molecular response. Responseto therapy may vary with each patient.1 The NCCN criteriafor determining cytogenetic, hematologic, and molecularresponse when assessing patients with Ph+ CML are summarizedin Table 1.
While CML may be cured by invasive procedures,(ie, bone marrow transplantation), significant progress hasbeen made, both in understanding the disease and in thedevelopment of multiple, non-invasive treatment options.1 Among the available treatment options are the class of oralTKIs.
Imatinib, one of the success stories of molecular medicine,was the first therapy designed to target the bcr-abl oncogenethat causes CML.10 Previously, treatment options for patientswith Ph+ CML in chronic phase included interferon-alphaplus daily low-dose cytarabine.16 After its approval in 2001for the advanced stages of CML and in 2002 for newlydiagnosed Ph+ CML,17 imatinib clinically demonstrated itsefficacy in a large number of patients10 by inducing hematologicand cytogenetic remissions in all phases of CML.2,7
Evidence of imatinib’s potential was noted in theInternational Randomized Study of Interferon and STI571[imatinib] (IRIS) clinical trial, published in 2003.4 IRISevaluated imatinib for cytogenetic response rates and thedevelopment of accelerated-phase or blast-phase CMLversus the existing standard of care, interferon-alpha plusdaily low-dose cytarabine.4
Overall study results showed that imatinib was significantlysuperior to the standard, combination therapy withinterferon-alpha plus daily low-dose cytarabine in theresults of major cytogenetic response rates (Figure 2),complete cytogenetic response, and progression-freesurvival at 18 months (P<0.001).4
FIGURE 2. Kaplan–Meier Estimates of Time to Major Cytogenetic Response Rates
Progression was defined by any of the following events, whichever came first: death,accelerated-phase or blast-crisis CML, loss of response, or an increasing white cell count.The P value is for the difference between treatment groups within each risk group.
Source: O’Brien 2003.4
Ultimately, imatinib became the standard frontline therapyfor patients with Ph+ CML in chronic phase. Long-termoutcomes with imatinib have documented an 8-yearevent-free survival rate of 81% and an estimated overallsurvival of 85%.18 However, >30% of patients treated withimatinib do not achieve a complete cytogenetic responseat 12 months.7
Suboptimal responses with imatinib may be the result ofresistant mechanisms that develop over time. Patients withCML who become resistant to imatinib may have eitherprimary or secondary resistance.1,19 Primary resistance isdefined by lack of efficacy at treatment onset, as identifiedby the NCCN as a failure to reach complete hematologicremission to imatinib within 3 to 6 months; failure toachieve any cytogenetic response at 6 months; major cytogeneticresponse at 12 months; or complete cytogeneticresponse at 18 months.1,19 After an initial response to treatmentwith imatinib, a patient may develop secondary, oracquired, resistance (relapse). Acquired resistance is definedas a loss of previously achieved hematologic or cytogeneticresponse or progression of CML while on imatinibtreatment.19 An example of acquired resistance was clearlyseen in the IRIS trial, where, after 5 years, 17% of thosewho initially responded to treatment with imatinib subsequentlyrelapsed and 7% progressed to accelerated-phaseor blast-phase CML.7
The incidence of primary and acquired resistance alsoincreases with the progression of CML.20 Among patientswith advanced disease (accelerated phase or blast phase)versus those in chronic phase, response rates are lower. Forthat reason, patients who are receiving treatment withimatinib should be monitored continuously, to improvedetection of secondary resistance as early as possible.7,21
Resistance mechanisms have also been uncovered overrecent years and may explain why some patients have onlya partial response when treated with TKIs. The most commonmechanisms of imatinib resistance are bcr-abl kinasedomain mutations. At least 30 point mutations that codefor different single amino-acid substitutions in this domainhave been detected in CML patients who are imatinibresistant.19 The 3 main regions of the domain where mutationshave been detected are: 1) the amino-terminal ATPphosphate-binding (P-loop); 2) the catalytic domain andintervening sequences containing amino acids that contactimatinib; and 3) the carboxyl-terminal activation loop,which is involved in the control of catalytic activity.19
Studies have shown that P-loop mutations are associatedwith a less favorable prognosis compared to non–P-loopmutations.22 While some mutations may be managed byinterrupting or stopping imatinib therapy (ie, P-loop mutationsE255K and Y253F), or by using combination therapy,others require the use of alternative therapies; an exampleof this is seen with imatinib-resistant mutations F359C/Vand F317L, which are sensitive to dasatinib and nilotinib,respectively.1,21 Currently, there is one mutation that maybe resistant to all available agents, as is the case with theT315I mutation, which confers resistance to imatinib,nilotinib, and dasatinib.19 Research is ongoing to determinewhether this mutation can be overcome with alternativedrug treatment.3
In patients treated with imatinib, nurses may also detectadverse events such as edema, nausea and vomiting, rash,fatigue, and cytopenia. The most common adverse eventsreported by newly diagnosed patients taking imatinib wereedema, nausea and vomiting, muscle cramps, musculoskeletalpain, diarrhea, and rash; the frequency of adverse events innewly diagnosed CML patients are noted in Table 2.17
Management of these adverse events includes treatmentof symptoms or discontinuation of therapy until symptomsresolve, followed by treatment at the same dose (for grade1 adverse events); discontinuation of therapy until symptomsresolve, followed by treatment at a reduced dose (for grade2 or 3 adverse events); or drug discontinuation (grade 4adverse events).21 When resistance to imatinib is detected—whether primary or acquired—treatment should be changedpromptly to ensure the best opportunity for a positivetreatment outcome.21