Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients

Abstract

Over half of chronic myeloid leukemia (CML) patients in deep molecular response do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in clinical trials, but its applicability in the real-life setting remains unsettled. We describe the outcomes after TKI discontinuation in a nationwide series of 236 CML patients. Median follow-up from treatment discontinuation was 21.5 months and 5 patients died from CML-unrelated causes. TKI therapy was reinitiated due to MMR loss (n = 52), increase ≥ 1 log in BCR-ABL transcript level without losing MMR (n = 12), patient preference (n = 2), and withdrawal syndrome (n = 1). Treatment-free remission rate at 4 years was 64% (95% confidence interval, CI: 55%–72%). Cumulative incidence of molecular recurrence at 3 years was 33% (95% CI: 26%–38%). TKI treatment for < 5 years and MR4.5 duration shorter than 4 years were both associated with higher incidence of molecular recurrence. No patient had disease progression. Response status at last control was: MR4.5 (n = 196), MR4 (n = 15), MMR (n = 14), complete cytogenetic response (n = 10), and other (n = 1). A significant increase in Hb and cholesterol levels was observed after imatinib withdrawal. Our results demonstrate that TKI treatment discontinuation is feasible in real-life clinical practice.

Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta‐analysis of studies over the last ten years

“…The type of transcript was not always reported (half of the studies). Despite that, in most cases, the type corresponds to Major e13a2 and e14a2 transcripts, some studies included a few patients with atypical transcripts such as e13a3, e14a3 and e1a2 (Hernández‐Boluda et al , ; Chamoun et al , ).…”

“…Treatment at first and second attempt in the different studies is presented in Tables respectively. Median duration of TKI treatment varied between 43·5 months (Ross et al , ) and 123·5 months (Hernández‐Boluda et al , ). Median duration of DMR before the first attempt of TKI discontinuation varied between 22·4 months (Takahashi et al , ) and 75 months (Chamoun et al , ) (Table ).…”

“…Eight studies reported additional reasons for TKI discontinuation. The main additional reasons were adverse events (Takahashi et al , ; Lee et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Chamoun et al , ; Fava et al , ; Iino et al , ), concomitant disease [10, 14, 16, 18, 19], planned pregnancy (Takahashi et al , ; Lee et al , ; Hernández‐Boluda et al , ; Chamoun et al , ; Fava et al , ; Iino et al , ), inconvenience of daily doses (Lee et al , ), medical cost (Takahashi et al , ; Lee et al , ; Chamoun et al , ; Iino et al , ) or recommendations by physician/patient request (Lee et al , ; Rea et al , ; Cerveira et al , ; Fava et al , ; Iino et al , ). When specified, adverse events were facial oedema, skin rash (Takahashi et al , ), pleural effusion and/or pulmonary hypertension (Cerveira et al , ; Iino et al , ), acute renal failure (Cerveira et al , ) or chronic kidney disease (Iino et al , ), diarrhoea, hyperkalaemia, anaemia, and ischaemic heart disease (Iino et al , ).…”

“…Since the first pilot study (Rousselot et al , ), two pioneers studies confirmed that treatment discontinuation is feasible and safe (Mahon et al , ; Ross et al , ) and numerous clinical trials and observational studies have been published thereafter to refine the criteria for stopping and molecular recurrence (MolRec), not only after imatinib treatment (Rousselot et al , ; Mori et al , ; Lee et al , ; Ferrero et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Saussele et al , ; Takahashi et al , , ; Chamoun et al , ; Fava et al , ; Fujisawa et al , ; Iino et al , ; Nicolini et al , ) but also after second‐generation TKIs whether used in first or second line (Rea et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Kumagai et al , ; Mahon et al , ; Okada et al , ; Saussele et al , ; Ross et al , ; Takahashi et al , ; Iino et al , ).…”

“…Recently, second attempts to discontinue TKI in patients who relapsed have been reported (Legros et al , , ; Rea et al , ; Ross et al , ). Although the predictors of MolRec are not fully identified, criteria such as duration of treatment or duration of molecular response before discontinuation or initial response to TKI have been found to be associated with MolRec in several studies (Takahashi et al , ; Imagawa et al , ; Etienne et al , ; Legros et al , ; Rea et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Okada et al , ; Saussele et al , ; Chamoun et al , ; Fava et al , ; Fujisawa et al , ; Iino et al , ; Nicolini et al , ). Recommendations on the selection of patients with a higher probability of successfully attempting to discontinue TKI have been proposed by Australian and French experts (Hughes & Ross, ; Rea et al , ).…”