Recent studies indicate either nilotinib or dasatinib has a significant, approximately 15 percent, increase in cytogenetic and molecular response and a more rapid response on average when compared to imatinib mesylate. Either of these two drugs has become favored as initial therapy. If a patient has had an excellent molecular response on imatinib mesylate it is reasonable to continue that therapy. It is too early to be absolutely certain that the long-term results will mimic that of imatinib but the probability is sufficiently high to use these second generation agents as initial therapy because of their improved initial effects.
Patients with newly diagnosed CML should be started on a tyrosine kinase inhibitor (TKI). Three choices are approved by the FDA at this time. Dasatinib, 100 mg/day orally, nilotinib, 300 mg every 12 hours, orally, or imatinib mesylate (imatinib) 400 mg/day, orally. In cases with hyperleukocytosis, white cell reduction should precede start of a TKI to lower the risk of tumor lysis syndrome (see above "Hyperleukocytosis")
The efficacy of a TKI is measured by three indicators of response: hematologic, cytogenetic, and molecular (see Table 47–2).
The criteria for assessing the response to a TKI are shown in Table 47–3.
As long as a patient is having continued reduction in the size of the leukemic clone as judged by cytogenetic or molecular measurements, the TKI is continued at the same dose.
If the patient stops responding before a complete cytogenetic or complete molecular remission occurs, the dose may be increased and/or an alternative second generation TKI should be considered (nilotinib or dasatinib).
Imatinib is generally well tolerated. The main side effects are fatigue, edema, nausea, diarrhea, muscle cramps, and rashes. Severe periorbital edema is occasionally observed. Hepatotoxicity occurs in about 3 percent of patients. There are numerous other uncommon side effects. The principal side effects of dasatinib include cytopenias and fluid retention, notably pleural effusion. The side effects of nilotinib include rash, hypergylcemia, increased serum lipase and amylase (pancreatitis), transaminitis, and hypophospatemia.
Neutropenia and thrombocytopenia may occur early in TKI use. Dose reduction for side effects is not recommended. If absolutely necessary, cessation may be required. Often, the mild cytopenias improve with continued therapy.
Guidelines to judge the response to a TKI based on duration of treatment is shown in Table 47–3. Continued response can be quite prolonged, stretching over several years.
TKIs may be teratogenic. Women in the child-bearing age group can (a) use contraception during therapy, (b) use interferon-α until delivery if pregnant when diagnosed and then be placed on a TKI, or (c) if in a complete molecular remission, could have TKI therapy stopped until she conceives and be restarted after delivery.
Leukapheresis may be useful as sole treatment in patients in early pregnancy when it may be necessary to control the white cell count and splenic enlargement without chemotherapy.
In the case of TKI intolerance or resistance, the alternative second generation TKI can be tried: dasatinib, 100 mg/day, or nilotinib, 400 mg twice per day.
Failure of TKI therapy during the course of the disease is often the result of a mutation in the ABL portion of BCR-ABL, which interferes with drug action.
There are several mutations than can induce TKI resistance. Thus, PCR is impractical as a tool to find mutations. It is possible to sequence ABL and, by comparing the results to known mutations, determine the likelihood that a dasatinib-sensitive or nilotinib-sensitive mutation may be present.
If the T315I ABL mutation is found, allogeneic hematopoietic stem cell transplantation should be considered for eligible patients because that mutation is resistant to imatinib, nilotinib, and dasatinib. Third generation TKI inhibitors entering trial may be available for this situation in the future.