Molecular and Cytogenetic Assessments Infrequently Performed in Patients with CML Receiving First-Line Imatinib

February 2013 Vol 6, No 1, Special Issue - Leukemia

Many patients with chronic myeloid leukemia (CML) in the United States are being treated with imatinib (Gleevec) as first-line therapy without molecular or cytogenetic assessments being performed by their physicians, according to the US findings from an international registry.

The routine monitoring of newly diagnosed patients with CML receiving a tyrosine kinase inhibitor as primary treatment is recommended by the National Comprehensive Cancer Network (NCCN).

Robert C. Hermann, MD, FACP, from Northwest Georgia Oncology Centers, Marietta, and colleagues evaluated the alignment of registry patients enrolled at US sites with current NCCN guidelines. Approximately 377 patients (median age, 53 years) who were diagnosed with any-phase Philadelphia chromosome–positive (Ph+) or BCR-ABL–confirmed CML within 6 months of entry into the registry were enrolled in the analysis.

“Physicians treating patients with CML should be made aware of key recent updates to the NCCN guidelines, such as the importance of assessing early molecular response by polymerase chain reaction at 3 months,” Dr Hermann said.

Patient Population
Nearly all of the patients (96.3%) in the main analysis were in chronic phase; 2.7% were in acute phase, and 1.1% were in blast crisis. Evaluations used to establish the CML diagnosis were hematologic (85%), bone marrow (84%), cytogenetic (82%), and molecular (polymerase chain reaction; 52%). Most patients (91.0%) had no prognostic risk score assigned at baseline.

Imatinib was used as first-line therapy in 73% of patients in chronic phase, 80% in acute phase, and 75% of patients in blast phase. The median duration of imatinib treatment in chronic-phase patients was 7.6 months. Nilotinib (Tasigna) was used in 2.8% of patients in chronic phase, 10% in acute phase, and 25% of patients in blast phase. Dasatinib (Sprycel) was used in 1.1% of patients in chronic phase.

Of the patients with chronic-phase CML who were treated with first-line imatinib, 10.9% had their dose increased, with the primary reasons being physician request and lack of efficacy. Of the patients, 12.1% had their imatinib dose decreased, mainly as a result of adverse events (AEs) and physician request, and 3.8% had treatment interrupted, primarily as a result of AEs.

Imatinib was switched to nilotinib in 7.9% of patients and to dasatinib in 7.5% of patients, with the primary reasons being lack of efficacy and AEs.

Molecular Assessment
Disease burden during the time the patients were receiving imatinib was most frequently assessed using blood counts. Only 15.5% of patients had a molecular assessment at 3 months. Molecular assessments were most frequently (in 46.7%-64.1% of patients) performed between 12 months and 36 months.

Cytogenetic assessment was even rarer, and was performed in 12.5% of patients at 3 months since the start of imatinib, 34.3% at 6 months, 32.1% at 12 months, 25.2% at 18 months, 28.3% at 24 months, and 33.3% at 36 months.

“Approximately one fourth of patients with chronic-phase CML receiving first-line imatinib achieved a complete cytogenetic response by 12 and 18 months,” said Dr Hermann. The rates are lower than those that were historically reported in clinical trials of imatinib, he noted, with the difference potentially being a result of a lower percentage of cytogenetic assessments being performed.

Of the 141 patients who were treated with first-line imatinib and were assessed at 12 months for cytogenetic response, 66 had a complete cytogenetic response (CCyR). At 18 months, 71 of the 144 patients who were assessed for cytogenetic response had a CCyR.

Approximately 25% of patients with chronic-phase CML who were receiving imatinib as first-line treatment achieved a major molecular response (MMR). Of the 152 patients who were assessed for molecular response at 12 months, 66 had an MMR, and of the 157 who were assessed at 18 months, 78 had an MMR. Again, these rates are lower than those historically reported in clinical trials.

The estimated 3-year overall survival (OS) was 88.4% among the US patients with chronic-phase CML who were treated with first-line imatinib; the estimated event-free survival at 3 years for this group was 77.8%.

The estimated 3-year OS was higher in patients who received imatinib on at least 85% of days compared with those who received it on <85% of days (95.8% vs 67.3%, respectively).

Adverse Events
The AEs that were reported in ≥1% of all patients included nausea (3%), fatigue (2%), rash (2%), diarrhea (2%), headache (2%), thrombocytopenia (2%), neutropenia (1%), and dyspnea (1%). Of the 17 deaths, 5 were related to CML progression, 1 was suspected to be related to CML treatment (necrotizing pneumonia), 7 were unrelated to CML treatment, and 4 had unknown causes.

The findings may reflect the lack of readily available molecular testing during part of the period evaluated by the registry (February 2008-December 31, 2010), Dr Hermann noted.

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