Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial

Saußele, Susanne; Richter, Johan; Guilhot, Joëlle; Gruber, Franz; Hjorth‐Hansen, Henrik; Almeida, António; Janssen, Jeroen; Mayer, Jiřı́; Koskenvesa, Perttu; Panayiotidis, Panayiotis; Olsson‐Strömberg, Ulla; Martínez‐López, Joaquín; Rousselot, Philippe; Vestergaard, Hanne; Ehrencrona, Hans; Kairisto, Veli; Poláková, Kateřina Machová; Müller, Martin C.; Mustjoki, Satu; Berger, Marc; Fabarius, Alice; Hofmann, Wolf‐Karsten; Hochhaus, Andreas; Pfirrmann, Markus; Mahon, François‐Xavier; Ossenkoppele, Gert J.; Pagoni, Maria; Söderlund, Stina; Escoffre‐Barbe, Martine; Étienne, Gabriel; Dengler, Jolanta; Huguet, Françoise; Bubnoff, Nikolas von; Klamová, Hana; Faber, Edgar; Guilhot, François; Lotfi, Kourosh; Réa, Delphine; Brümmendorf, Tim H.; Greef, Gorgine E. de; Stenke, Leif; Nicolini, Franck E.; Legros, Laurence; Burchert, Andreas; Voglová, J; Charbonnier, Aude; Gyan, Emmanuel; Kunzmann, Volker; Westerweel, Peter E.

doi:10.1016/s1470-2045(18)30192-x

Cited by 490 publications

(696 citation statements)

References 29 publications

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“…In our cohort of patients, the TFR rate was higher than the one currently reported in the IM and second‐generation TKI discontinuation studies but, as expected, the loss of MR occurred in 24/111 (22%) cases early after TKIs discontinuation (3 months). This highly positive selection could be explained, as above reported, by the prolonged treatment and the DMR duration . Furthermore, the major part of the patients (75%) who underwent TKIs discontinuation was characterized by the presence of the transcript b3a2.…”

Section: Discussionmentioning

confidence: 99%

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

et al. 2019

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Treatment‐free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real‐time quantitative PCR (RT‐qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT‐qPCR for BCR‐ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR‐ABL1 transcripts in the RT‐qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR 4.0 and MR 4.5 ( P = 0.0104) or MR 5.0 ( P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR 4.0 vs MR 4.5‐5.0 ) were superimposable. Conversely, patients with dPCR values <0.468 BCR‐ABL1 copies/µL (as we previously described) showed a longer DMR duration ( P = 0.0220) and mainly belonged to MR 4.5‐5.0 ( P = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR 3.0 or MR 4.0 . RT‐qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation ( P = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR‐ABL1 values ≥0.468 and 12/86 (14%) patients with BCR‐ABL1 values <0.468 lost DMR in this cohort, respectively ( P = 0.0003). Treatment‐free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% P = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation.

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Section: Discussionmentioning

confidence: 99%

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

et al. 2019

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“…Briefly, the STIM2 trial allowed imatinib therapy to be discontinued in CML patients after at least 3 years of treatment and with undetectable residual disease and BCR‐ABL1 level close to 4·5 log for at least 2 years. The EURO‐SKI trial evaluated TKI discontinuation (imatinib or second‐generation TKI in the case of intolerance) in patients with CML treated for at least 3 years and with residual disease ≤MR4 for at least 1 year (Saussele et al , ). Adverse events (AEs) were collected prospectively in the electronic case report form (e‐CRF) of these patients as part of the pharmacovigilance follow‐up for both trials.…”

Section: Methodsmentioning

confidence: 99%

“…In this context, new priorities have emerged, such as the identification of predictive factors of TFR and of the risk of relapse, and the consequences of TKI withdrawal on the patients’ quality of life. Indeed, the Nordic group of the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial (Saussele et al , ) reported the appearance or worsening of musculoskeletal pain in some patients after stopping imatinib, suggesting a withdrawal syndrome (WS) (Richter et al , ). A few cases were also observed after imatinib discontinuation in France (Rousselot et al , ) and South Korea (Park et al , ).…”

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confidence: 99%

Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome

Berger

Pereira²,

Rousselot

et al. 2019

Br J Haematol

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Summary The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO‐SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02–2·74)] with a 93‐month cut‐off time, and history of osteoarticular symptoms [RR = 1·84 (1·04–3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre‐existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.

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“…While MRD can serve as a tool to identify patients at risk of disease progression or relapse, MRD negativity may also be used in the future as a tool to de‐escalate or discontinue treatment in the right clinical scenario. This concept has also gained momentum in other haematological malignancies, such as ALL, where MRD‐negative patients may be spared an allogeneic transplant in the right clinical context (Dhedin et al , ), and in CML, where treatment discontinuation is being studied in patients with extended deep responses with TKIs (Mahon et al , ; Saussele et al , ).…”

Section: Opportunitiesmentioning

confidence: 99%

Challenges and opportunities in the assessment of measurable residual disease in multiple myeloma

et al. 2019

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Summary Treatment response assessment in multiple myeloma (MM) relies on the detection of paraprotein in serum and/or urine, bone marrow morphology and immunohistochemistry. With remarkable advances in therapy, particularly in the newly diagnosed setting, achievement of complete remission became frequent, creating the need to identify smaller amounts of residual disease and understand their prognostic and therapeutic implications. Measurable residual disease (MRD) can be assessed primarily by flow cytometry and next generation sequencing and state‐of‐the‐art assays have sensitivity approaching 1 in 106 cells. This review discusses the existing challenges in utilizing MRD to inform management of MM and highlights open research questions and opportunities as MRD is more routinely incorporated into clinical practice for patients with MM.

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Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial

Abstract: ELN Foundation and France National Cancer Institute.

Cited by 490 publications

References 29 publications

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome

Challenges and opportunities in the assessment of measurable residual disease in multiple myeloma

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