The New ELN Recommendations for Treating CML

Abstract

After normal survival has been achieved in most patients with chronic myeloid leukemia (CML), a new goal for treating CML is survival at good quality of life, with treatment discontinuation in sustained deep molecular response (DMR; MR4 or deeper) and treatment-free remission (TFR). Four tyrosine kinase inhibitors (TKIs) have been approved for first-line therapy: imatinib, dasatinib, nilotinib, bosutinib. Unexpectedly, the outcome of long-term randomized trials has shown that faster response as achieved by higher doses of imatinib, imatinib in combination, or second-generation (2G)-TKIs, does not translate into a survival advantage. Serious and frequent, and in part cumulative long-term toxicities, have led to a reevaluation of the role of 2G-TKIs in first-line therapy. Generic imatinib is the current most cost-effective first-line therapy in the chronic phase. A change of treatment is recommended when intolerance cannot be ameliorated or molecular milestones are not reached. Patient comorbidities and contraindications of all TKIs must be considered. Risk profile at diagnosis should be assessed with the EUTOS score for long-term survival (ELTS). Monitoring of response is by polymerase chain reaction (PCR). Cytogenetics is still required in the case of atypical translocations, atypical transcripts, and additional chromosomal aberrations. TKIs are contraindicated during pregnancy. Since the majority of patients are at risk of lifelong exposure to TKIs, amelioration of chronic low-grade side effects is important.

Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia

“…Nilotinib shares a similar target spectrum with imatinib, but has a 30-fold higher potency in vitro against BCR-ABL1 (type 2 inhibition) [35]. It can overcome some imatinib-resistant ABL1 domain-mutated CML cells [13]. Its major molecular response (MMR) and deep molecular response (DMR, defined as 4.0 log reduction of BCR-ABL1 transcript (MR 4.0 ) or deeper) rate in TKInaïve patients with CML CP are 77 and 66% in 5 years, and 82.6% and 73% in 10 years, respectively [6,36].…”

“…Dasatinib binds the activated and open conformation of BCR-ABL1 (type 1 inhibition) [38], and it has more than 300-fold increased potency of kinase inhibition compared to imatinib in vitro [39]. It can overcome P-loop mutations, such as Y255H, E255V/K, as well as the F359V/I/V mutation [13]. As a front-line therapy for CML CP, MMR and MR 4.5 (4.5 log reduction of BCR-ABL1 transcript or deeper) rates of dasatinib therapy in 5 years are 76 and 42%, respectively [7].…”

“…The phase 3 EPIC trial comparing the front-line use of imatinib and ponatinib for CML was terminated early due to concerns of up to 6% serious AOEs in the ponatinib arm. Therefore, the European LeukemiaNet (ELN) 2020 guideline recommends that ponatinib should be confined to a third-line treatment option after failure of two or more TKIs or for the treatment of highly resistant disease carrying the T315I mutation [13]. Close monitoring of cardiac function and adequate management of risk factors, such as hypertension, dyslipidemia, and DM, are required, including smoking cessation.…”

“…Intolerance of TKIs can affect quality of life adversely, and can result in inadequate response and increasing risk of treatment failure. The European LeukemiaNet (ELN) guideline recommends that possible TKI-related toxicities be considered during the TKI drug selection in a comorbid patient [13].…”

Le polynucléaire basophile : du contrôle de l’immunité à celui des leucémies

“…Jusqu'à la fin du 20e siècle, les traitements utilisés étaient peu efficaces et la maladie évoluait rapidement vers la phase d'accélération puis d'acutisation, conduisant à la mort en quelques années. Ces dernières décennies, le développement de traitements ciblés à base d'inhibiteurs de tyrosine kinase (ITK) comme l'imatinib a radicalement changé le pronostic de la LMC qui est devenue une maladie chronique avec un taux de survie à 10 ans de 80 à 90%[78].La majorité des patients sont diagnostiqués pendant la phase chronique, soit fortuitement lors d'une prise de sang pour un bilan de routine, soit du fait de la présence de symptômes tels que fatigue, perte de poids ou splénomégalie. D'autres symptômes (thrombose, arthrite goutteuse et syndrome de leucostase) sont rares lors de la présentation[79].…”