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Evidence-Based Oncology January/February

Literature Review: Chronic Myeloid Leukemia



Trying to Calculate the Economic Value of Dasatinib or Nilotinib for Imatinib-Resistant CML

Although it is now standard practice to utilize the second-generation tyrosine-kinase inhibitors dasatinib or nilotinib in patients whose chronic myeloid leukemia has recurred while taking imatinib treatment, published support for the economic value of this approach is lacking. Investigators from the University of Exeter, United Kingdom, conducted a review of the literature and produced an economic model to help fill this information gap.

They evaluated contributions to key databases (MEDLINE [including MEDLINE In-Process and Other Non-Indexed Citations], EMBASE [ISI Web of Science], Conference Proceedings Citation Index, as well as 4 other sites). Their research led to 15 relevant studies, the most recent from June 2009.

Two separate decision-analysis economic models for chronic myeloid leukemia (CML) were utilized, in which patients in chronic-phase CML either showed the potential to become or did become resistant to a normal dose of imatinib (imatinib resistant), or due to adverse events had to cease imatinib treatment (imatinib intolerant). Another was used to evaluate patients with CML that had progressed to blast crisis.

Although the number of studies regarding the effectiveness of dasatinib and nilotinib for treating chronic-phase CML patients (who were either imatinib resistant or imatinib intolerant) was limited, the investigators found ample evidence for the clinical effectiveness of these agents, based on positive cytogenetic and hematological responses.

However, it was very difficult, they stated, to come to any conclusions regarding cost-effectiveness with either dasatinib or nilotinib treatment of patients in those with imatinib-resistant CML. Serious data flaws were noted, in one way or another, for all the economic models produced.

All available data regarding accelerated and blast crisis came from observational observational single-arm trials. Unfortunately, meaningful comparisons between the treatments was greatly undercut because of various and possible baseline characteristic variations.

Accelerated phase and blast crisis de novo models could not be expanded because the available clinical data were deficient. In addition, there was sparse evidence regarding the effectiveness of second-generation tyrosine-kinase inhibitors (TKIs) compared with high-dose treatment with imatinib, which severely weakened the economic evaluations done by the manufacturers.

Interestingly, a separate review of the studies on the value of high-dose imatinib in patients with chronic-phase CML resistant to standard-dose imatinib revealed that up to one-third experienced a complete cytogenetic response (up to four-fifths experienced a complete hematologic response), with grade 3 or 4 adverse events occurring in 40% of patients (up to one-fifth discontinued because of these adverse effects). In an economic analysis, nilotinib appeared to have greater cost-effectiveness than high-dose imatinib, followed by dasatinib, in these resistant patients. However, they caution that the study was not based on direct comparisons with identical outcomes measures.

Although the second-generation TKIs appear to add clinical value to the armamentarium against CML, the clinicians acknowledge that a meaningful costeffectiveness conclusion is not possible. Until a randomized, 3-way, double-blind clinical study involving dasatinib, nilotinib, and high-dose imatinib is conducted, they added, the true economic value of the second-generation TKIs cannot be revealed.

Sources: Rogers G, Hoyle M, Thompson Coon J, et al. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(22):1-410.

Loveman E, Cooper K, Bryant J, et al. Dasatinib, high-dose imatinib, and nilotinib for the treatment of imatinibresistant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(23): iii-xiii, 1-137.

Chronic Myeloid Leukemia Treatment Practices in the United States

The multinational, prospective WORLD CML registry was established in order to measure how patients with CML are managed by evaluating global clinical practice patterns. This registry, with sites around the world, recently examined results for patients with CML at locations in the United States and assessed how practice patterns correspond with National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.

The care of 377 patients (median age, 53 years; range, 18-91 years) with a confirmed CML diagnosis enrolled in the United States from February 2008 to December 31, 2010, was analyzed by American researchers. Of these participants, 363 (96%) received a chronic phase diagnosis.

First-line therapy of imatinib was prescribed for 73% of patients with chronic phase CML, compared with hydroxyurea (6%), nilotinib (3%), and dasatinib (1%). (The clinicians noted that patients may have received more than 1 medication.) The median treatment period lasted 7.6 months (range, 0.1-33.5 months). The dose of imatinib treatment was increased in 29 of the 363 patients with chronic phase CML (8%) primarily as a result of physician request and lack of efficacy. In 32 patients (9%), the imatinib dose was reduced, primarily because of adverse events and physician request. Lack of efficacy and adverse events led to the treatment regimen being changed from imatinib to nilotinib in 21 patients (6%) and to dasatinib in 20 patients (6%).

Clinicians most commonly used hematology assessments to evaluate CML treatment progress (Table 1). After 3 months of imatinib treatment, a molecular assessment was sought for only 16% of patients, although up to 64% of patients underwent molecular disease testing by 2 years of therapy. The least common assessment, cytogenetics, was performed in only 13% of patients after 3 months and up to 34% after 6 months of treatment.

The investigators concluded that many patients being treated with firstline imatinib for chronic phase CML did not routinely undergo cytogenetic or molecular assessments. According to NCCN guidelines, such testing should be conducted more frequently (Table 2). They indicate that access to molecular testing may have been an issue during the study period, and that these findings therefore should be updated to reflect more current availability of cytogenetic and molecular testing.

Source: Hermann R, Miller CB, Catchatorian R, et al. Understanding US treatment practices for the management of chronic myeloid leukemia (CML) in clinical practice: a US subgroup analysis of the WORLD CML Registry. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.

Unfavorable Results of Imatinib Treatment in Patients With High BCR-ABL Levels

With several TKIs available today to treat patients whose CML has recurred despite standard imatinib therapy, it may be beneficial to predetermine in some way those patients who may be optimally treated with alternative agents. This points to the need for a better understanding of the relevant biomarkers to predict who will not respond sufficiently to imatinib treatment.

Recent reports have suggested that after 3 months of treatment with imatinib, patients with CML may experience inferior outcomes (in terms of both progression- free survival and overall survival [OS]) when they experience BCR-ABL/ ABLIS levels above 10%, or more than 1% after 6 months of imatinib therapy. Italian and German researchers have attempted to extend this finding by 1 step: to determine whether high levels of BCR-ABL transcripts found at the time of diagnosis would also be connected with an inadequate reaction to imatinib treatment.

The researchers analyzed BCR-ABL levels of 230 patients with newly diagnosed CML who were to receive imatinib /day. Either ABL or glucuronidasebeta (GUS) was used as reference genes for all molecular verifications.

The median follow-up time in the study population was 42 months. Cumulative incidences estimated at 5 years for complete hematologic responses, complete cytogenetic response (CCyR), and major molecular response were 98%, 89%, and 65%, respectively. Overall survival rate using 5-year probabilities was 93.8%, while a transformation-free survival rate, defined as survival without disease transformation to the accelerated phase or blast crisis, and failurefree survival (survival without imatinib failure as indicated in the 2009 European Leukemia Net recommendations) were 98% and 76%, respectively.

When GUS was used instead of ABL as a reference gene at diagnosis, connections between high BCR-ABL transcripts and the differential in inadequate IM responses were much greater. Both elevated BCR-ABL/GUSIS (P <.0001) and elevated BCR-ABL/ABLIS (P <.0001) levels were associated with a lower probability of optimal response. The investigators also indicated that after 12 months of imatinib therapy, a link existed between lower rates of cytogenetic response and higher BCR-ABL/ GUSIS measurements (P <.0001) but not higher BCR-ABL/ABLIS values (P = .18).

They noted that overall survival could not be predicted by levels of BCR-ABL/GUSIS or BCR-ABL/ABLIS at diagnosis. However, a more accurate connection between high levels of BCR-ABL/GUSIS and lower probabilities of failure-free survival (P <.0001) and transformationfree survival (P = .01) was found when compared with high levels of BCR-ABL/ABLIS (P = .02 and P = .36, respectively).

After subdividing the patient cohort into optimal responders, suboptimal responders, and subjects failing first-line therapy, based on the 2009 European 16% of patients, although up to 64% of patients underwent molecular disease testing by 2 years of therapy. The least common assessment, cytogenetics, was performed in only 13% of patients after 3 months and up to 34% after 6 months of treatment.

The investigators concluded that many patients being treated with firstline imatinib for chronic phase CML did not routinely undergo cytogenetic or molecular assessments. According to NCCN guidelines, such testing should be conducted more frequently (Table 2). They indicate that access to molecular testing may have been an issue during the study period, and that these findings therefore should be updated to reflect more current availability of cytogenetic and molecular testing.

Source: Hermann R, Miller CB, Catchatorian R, et al. Understanding US treatment practices for the management of chronic myeloid leukemia (CML) in clinical practice: a US subgroup analysis of the WORLD CML Registry. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.

Unfavorable Results of Imatinib Treatment in Patients With High BCR-ABL Levels

With several TKIs available today to treat patients whose CML has recurred despite standard imatinib therapy, it may be beneficial to predetermine in some way those patients who may be optimally treated with alternative agents. This points to the need for a better understanding of the relevant biomarkers to predict who will not respond sufficiently to imatinib treatment.

 
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