Discontinuation of tyrosine kinase inhibitors in CML patients in real-world clinical practice at a single institution

Abstract

BackgroundMost patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) will relapse if treatment is withdrawn, but various trials have recently demonstrated that a significant proportion of patients who achieved a stable and deep molecular response (DMR) can stop therapy without relapsing. However, most information on treatment cessation was obtained from clinical trials with strict recruiting criteria.MethodsWe evaluated the outcome of 25 patients with CML that discontinued TKI therapy in our institute in real-world clinical practice.ResultsOf the 25 patients, 76% discontinued therapy in sustained deep molecular response (SDMR) and 24% were in unsustained DMR (UDMR). Discontinuation of therapy due to adverse effects was observed in 5 and 50% of the patients in the SDMR and UDMR groups, respectively. After TKI discontinuation, patients were followed for a median of 24 months. At the time of this analysis, 56% patients had a molecular relapse after a median of 4 months. SDMR and longer treatment duration were associated with lower probability of molecular relapse: 25% in SDMR patients with TKI treatment > 96 months and 85% in UDMR patients with TKI treatment ≤96 months. All relapsed patients promptly resumed TKI therapy and regained at least major molecular response (MMR).ConclusionsOur results suggest that TKI discontinuation is safe outside clinical trials and particularly effective in CML patients who are in SDMR with longer TKI treatment duration.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5167-y) contains supplementary material, which is available to authorized users.

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 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 , ). Concomitant diseases reported were pulmonary tuberculosis (Cerveira et al , ), asthma, dementia (Iino et al , ) or a second cancer (Chamoun et al , ; Fava 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 , ). Concomitant diseases reported were pulmonary tuberculosis (Cerveira et al , ), asthma, dementia (Iino et al , ) or a second cancer (Chamoun et al , ; Fava 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 , ).…”

Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia

“…TFR rates of 40-60% in eligible patients have been corroborated by numerous, subsequent, randomised clinical trials (in which the eligibility criteria of TKI, time on TKI, and length and depth of molecular response have varied) and have been recently reviewed [4,5]. Outside of clinical trials, similar TFR rates are also achievable in the "real-world" setting [6][7][8]. Importantly, in all these studies where patients relapse after discontinuation (nearly always within the first six months of stopping), reintroduction of a TKI results in attainment of a favourable molecular response in the vast majority of patients [9].…”