Management of chronic myeloid leukemia in 2023 – common ground and common sense

Abstract

With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

Real-world experience with ponatinib therapy in chronic phase chronic myeloid leukemia: impact of depth of response on survival and prior exposure to nilotinib on arterial occlusive events

“…7 The latter observation is practically relevant considering the consensus rst-line drug of choice being imatinib, which might not necessarily be the most effective in rapidly inducing MMR/DMR, 8-10 and yet arguably the safest and least expensive, among the currently FDA-approved TKIs for CML, 11 the others being dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. 9,[12][13][14][15][16][17][18][19][20][21] However, a substantial minority of patients with CML-CP are either intolerant or fail to achieve the desired response milestone with imatinib and, therefore, require treatment with an alternative TKI. 22 In this regard, our current preference as second-line drug of choice is dasatinib, based on its proven e cacy, even at a lower dose schedule, 23 and the nature of associated side effects seen with the other TKIs, especially in terms of nilotinib-associated vacular complications, including arterial occlusive events (AOEs).…”

The Mozart effect in chronic myeloid leukaemia

“…As a child prodigy, the treatment principle humiliated even well‐documented curative therapy even before any formal scientific evidence had been published 3,4 . The inhibitors revolutionized the therapy of CML, changed the prognosis profoundly 5 and introduced entirely new concepts like molecular remission, provisional cure and treatment‐free remission 2,6 . The timely advent of novel technology, the automated real‐time quantitative PCR, paved the way for the development of disease monitoring and therapeutic decisions, 7,8 and the light of a new molecular genetic era shone over the leukaemias and oncology in general.…”

“…However, the disadvantage of being a child prodigy is that the spell of the genius not necessarily transmits to new members of the family. Whereas a number of changes in the molecules, leading to second and third generations of drugs, took care of specific resistance problems caused by target mutations, it remains uncertain whether the new generations of BCR‐ABL 1 kinase inhibitors in general add value to such an extent that they should be used as first‐line therapy 6,9 . It is ironical and amusing that Alcazar et al.…”