The Patients & Conditions in Which TKI is Not Good Enough
As stated before, patients are still dying from CML even in the TKI era. Moreover, indefinite treatment with TKIs can be problematic for many reasons including adherence, drug interaction and late side effects. Can we predict or anticipate specific patients and conditions in which the treatment with TKI will eventually not be good enough?
In the chronic phase, the majority of patients will respond to the TKI treatment. Prognostic scores, including Sokal, Euro and even EUTOS, lately developed for patients treated with imatinib-based regimens are limited in their ability to predict true failures. In the late chronic phase and in advanced phases, treatment with TKI will probably not be sufficient, but can we distinguish, in that group of patients, those who will respond with deep and prolonged response to TKIs? Three scenarios will be discussed here, trying to identify the 'role' of HSCT in CML.
Failure of TKIs
In the first published ELN guidelines from 2006, HSCT was suggested as an option for patients failing imatinib treatment or even with a 'suboptimal' response. The option for HSCT was 'pushed' farther away to second and third lines of treatment as years went by, and new TKIs were developed and new data emerged. The recommendations of the European LeukemiaNet for the management of CML are now published online in Blood. Failure in itself is a dynamic definition. In the first years of imatinib, failure to respond to imatinib treatment left patients with no real options except HSCT. How would we define failure nowadays? A large proportion of patients failing imatinib can be treated with second-generation TKIs with about half of the patients achieving CCyR with durable response. There are less data for patients treated with a TKI after failing one of the second-generation TKIs, either after imatinib failure or after first-line treatment with a second-generation TKI. Never-the-less, we can assume that fewer patients are responding, unless the failure is due to intolerability or specific mutation, resistance to one specific TKI but not to others. In the Phase II PACE trial, evaluating ponatinib in TKI-resistant CML, 51% of patients resistant or intolerant to dasatinib or nilotinib achieved major cytogeneic response (MCR). Patients with the T315I mutation had a better result with 70% of patients reaching MCR. Although we do expect a proportion of patients to respond to another trial of a TKI, the rate and depth of response are decreasing as more TKIs are being used. Moreover, due to worse HSCT outcomes in advanced stages of CML, the risk of waiting and postponing the HSCT to later lines of treatment must be considered.
While waiting for more data to emerge with a longer follow-up with the newer drugs, we believe HSCT is indicated after failure of two of the second-generation TKI: nilotinib, dastinib or bosutinib. If a T315I mutation is found, a trial with ponatinib or omacetaxine is a reasonable option before proceeding to HSCT.
Advanced Stage–accelerated Phase & Blast Crisis
Most patients will respond to TKI in the advance stages, but this response is usually partial and temporary. Patients progressing to advanced stages on TKI treatment have an even worse prognosis than those presenting initially with advanced stage. In newly diagnosed accelerated phase patients, treatment with imatinib demonstrated a substantial effectiveness, with complete hematological response, major cytogenetic response and complete cytogenetic response in 87.2, 74 and 60% of patients, respectively. In the same retrospective study, the 24-month OS, progression-free survival and failure-free survival were 87.8, 87.2 and 54.2%, respectively. Second-generation TKIs are proven to be more efficient than imatinib in this scenario as well. Moreover, based on the cytogenetic response after 3 months of treatment, we may be able to identify patients who will have a durable response with a prolonged survival. Even so, HSCT is still considered to be the 'gold standard' in advanced stages. Although some patients with accelerated phase CML may have a long-term response to TKIs, for blast crisis CML, HSCT is unequivocally recommended as a curative option, best offered to patients after they have obtained an initial response to chemotherapy and TKIs. Because of a small number of patients with advanced stages and probably due to other reasons, new data in these scenarios are not expected in the near future.
Very Young Patients & Patients Seeking 'Cure'
Despite the extraordinary effect on the disease, TKI is not considered to be a 'cure' for CML. For now, treatment is indefinite. Discontinuation of imatinib is potentially applicable only in a very small percentage of patients with sustained CMR. Even in those patients, only about 40% will sustain remission after discontinuation of imatinib.[9,52] Although large studies of discontinuation of second-generation TKIs are ongoing, a study on a small cohort of patients evaluating the feasibility of second-generation TKI discontinuation was recently reported. Sixteen of 39 (41%) patients lost their major molecular response, after only a 12-month follow-up from discontinuation of second-generation TKI. Thus, a true 'cure' related to TKIs is not expected in the near future.
Pediatric patients treated with TKIs have safety and efficacy profiles comparing favorably to those in adults.[54,55] Never-the-less, patients diagnosed with CML in a very young age, from childhood to young adulthood, have decades of treatment with TKI, monitoring response and overcoming side effects and possible drug interactions. Importantly, there is increasing evidence that prolonged treatment with imatinib may cause growth failure in children. This growth failure is probably due to disturbance in growth hormone: insulin-like growth factor-1 axis. Growth impairment is seen predominantly in children who started imatinib at a prepubertal age. Those patients should probably be offered HSCT as an alternative to a lifelong TKI treatment. A subgroup of patients, at any age, will probably feel the need to find a true cure for their leukemia. For this reason, HSCT should still be discussed with all patients, potential candidates for HSCT, even if it is usually not clinically indicated.
Expert Rev Hematol. 2013;6(6):759-765. © 2013 Expert Reviews Ltd.