CML guidelines highlight need for TKI switch timing, choice

By Lynda Williams, Senior medwireNews Reporter

A review of the European LeukemiaNet (ELN) guidelines on the care of patients with chronic myeloid leukaemia (CML) highlights the need for research into the timing and use of second-line and third-line tyrosine kinase inhibitors (TKIs).

The ELN guidelines, most recently published in 2013, are created by an international expert panel and revised every 3 years, explain Gianantonio Rosti and co-authors, from the University of Bologna in Italy, in the review published in the Annals of Hematology.

They note that the guidelines define accelerated phase (AP) and blast phase (BP) CML at a lower blast cell percentage than the World Health Organization definitions, at 15% to 29% versus 15% to 19%, and 30% to 49% versus 20% or above, respectively.

Patients who present with AP should be given TKIs, with allogeneic stem cell transplantation (SCT) for those with a suboptimal response, whereas patients in BP at presentation are at high risk of relapse and are eligible for SCT, the researchers explain. Patients who progress from chronic phase (CP) should be given TKIs, but are also eligible for SCT.

The team notes that three scores for prediction of a poor response to TKIs have been validated and these can be used alongside clonal chromosomal abnormalities in Philadelphia (Ph)-positive cells to identify patients who should be monitored or may be eligible for investigational treatment.

ELN recommends monitoring during TKI therapy should include cytogenetic testing at 3, 6 and 12 months until a complete response is detected. Molecular monitoring using real-time quantitative polymerase chain reaction should also be performed every 3 months until at least a major molecular response has been achieved. Molecular monitoring should continue monthly for the first year after treatment discontinuation and at 3-month intervals thereafter.

The researchers explain that treatment response to TKI is defined as “optimal” (continue treatment in expectation of “almost normal” survival), “failure” (primary or secondary) and “warning” (response could be better but no clear guidance on whether treatment should be changed).

Moreover, Rosti et al note that while the definitions of response to first-line TKI are based on “solid data”, to the definitions of response to second-line treatment are “provisional” and those for third-line treatment are “completely insufficient”.

The current recommendation for first-line treatment is imatinib, nilotinib or dasatinib, with some suggestion that AP or BP patients may benefit more from the second-generation TKI option, write the authors.

Second-line treatment following first-line toxicity can consist of any alternative TKI. Following resistance to imatinib, patients should switch to another TKI, such as dasatinib, nilotinib, bosutinib or ponatinib. From nilotinib, patients should switch to dasatinib, bosutinib or ponatinib, whereas patients with dasatinib resistance should be given nilotinib, bosutinib or ponatinib.

In the absence of data, “the choice of the second-line TKI is guided by some patient characteristics, mainly age and comorbidities, by the type of side effects with the first TKI, and by the presence of BCR-ABL1 kinase domain point mutations, and also by drug availability and cost, and by doctor experience”, write Rosti and co-authors.

They add that there are no “evidence-based, reliable, specific recommendations” for patients after two or three TKIs, noting that treatment failure may be associated with poor compliance, side effects or true cell resistance.

“In these cases, a study of cell karyotype, a study of BCR-ABL1 kinase domain point mutations, a bone marrow biopsy, and a stringent monitoring are necessary, in preparation of SCT”, the reviewers add.

Finally, the authors observe that CML treatment aims are moving from patient survival to disease cure and then treatment discontinuation, with the final goal of treatment-free remission (TFR), with a rapid decrease in BCR–ABL1 transcripts a useful surrogate marker for this outcome.

“It is not yet known how many patients will achieve that condition, and it is not yet clear which drugs and which treatment policies will be more successful”, they conclude.

“It is likely that an extended use of second-generation TKIs that are more potent and induce faster and deeper molecular remissions will bring more patients into TFR, and it is likely that the earlier and the deeper the early molecular response, the higher will be the number of patients in TFR.”

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