Treatment is usually not emergent even with white blood counts over 200,000/mcL (200 × 109/L), since the majority of circulating cells are mature myeloid cells that are smaller and more deformable than primitive leukemic blasts. In the rare instances in which symptoms result from extreme hyperleukocytosis (priapism, respiratory distress, visual blurring, altered mental status), emergent leukapheresis is performed in conjunction with myelosuppressive therapy.
In chronic-phase CML, the goal of therapy is normalization of the hematologic abnormalities and suppression of the malignant bcr/abl-expressing clone. The treatment of choice consists of a tyrosine kinase inhibitor (eg, imatinib, nilotinib, dasatinib) targeting the aberrantly active abl kinase. It is expected that a hematologic complete remission, with normalization of blood counts and splenomegaly will occur within 3 months of treatment initiation. Second, a major cytogenetic response should be achieved, ideally within 3 months but certainly within 6 months. A major cytogenetic response is identified when less than 35% of metaphases contain the Philadelphia chromosome. Lastly, a major molecular response is desired within 12 months and is defined as a 3-log reduction of the bcr/abl transcript as measured by quantitative PCR. This roughly corresponds to a bcr/abl ratio (compared to abl) of less than 0.01. Patients who achieve this level of molecular response have an excellent prognosis, with 100% of them remaining progression-free at 8 years. On the other hand, patients have a worse prognosis if these targets are not achieved, cytogenetic or molecular response is subsequently lost, or new mutations or cytogenetic abnormalities develop.
Imatinib mesylate was the first tyrosine kinase inhibitor to be approved and it results in nearly universal (98%) hematologic control of chronic-phase disease at a dose of 400 mg/day. The rate of a major molecular response with imatinib in chronic-phase disease is ∼30% at 1 year. The second-generation tyrosine kinase inhibitors, nilotinib and dasatinib, are also used as front-line therapy and can significantly increase the rate of a major molecular response compared to imatinib (71% for nilotinib at 300–400 mg twice daily by 2 years, 64% for dasatinib at 100 mg/day by 2 years) and result in a lower rate of progression to advanced-stage disease. However, these agents can also salvage 90% of patients who do not respond to treatment with imatinib and may therefore be reserved for use in that setting. A dual bcr/abl tyrosine kinase inhibitor, bosutinib, is used for patients who are resistant or intolerant to the other tyrosine kinase inhibitors. The complete cytogenetic response rate to bosutinib is 25%, but it is not active against the T315I mutation.
Patients taking tyrosine kinase inhibitors should be monitored with a quantitative PCR assay. Those with a consistent increase in bcr/abl transcript or those with a suboptimal molecular response as defined above should undergo abl mutation testing and then be switched to an alternative tyrosine kinase inhibitor. The T315I mutation in abl is specifically resistant to therapy with imatinib, dasatinib, nilotinib, and bosutinib but appears to be sensitive to the third-generation agent ponatinib. However, ponatinib is associated with a high rate of vascular thrombotic complications. For patients with the T315I mutation as well as patients who have not responded to multiple tyrosine kinase inhibitors, including ponatinib, the novel allosteric inhibitor asciminib can be tried. It has shown a 54% complete hematologic response rate and a 48% sustained major molecular response in heavily pretreated patients. Dose-limiting toxic effects include asymptomatic elevations in the lipase level and clinical pancreatitis. Lastly, omacetaxine—a non–tyrosine kinase inhibitor therapy approved for patients with CML who are resistant to at least two tyrosine kinase inhibitors—can produce major cytogenetic responses in 18% of patients. Patients in whom a good molecular response to any of these agents cannot be achieved or in whom disease progresses despite therapy should be considered for allogeneic stem cell transplantation.
Patients with advanced-stage disease (accelerated phase or myeloid/lymphoid blast crisis) should be treated with a tyrosine kinase inhibitor alone or in combination with myelosuppressive chemotherapy. The doses of tyrosine kinase inhibitors in that setting are usually higher than those appropriate for chronic-phase disease. Since the duration of response to tyrosine kinase inhibitors in this setting is limited, patients who have accelerated or blast- phase disease should ultimately be considered for allogeneic stem cell transplantation.