Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase

Mahon, François Xavier; Boquimpani, Carla; Kim, Dong Wook; Benyamini, Noam; Clementino, Nelma Cristina D.; Shuvaev, Vasily; Ailawadhi, Sikander; Lipton, Jeffrey H.; Turkina, Anna; Paz, Raquel de; Moiraghi, Beatriz; Nicolini, Franck E.; Dengler, Jolanta; Sacha, Tomasz; Takahashi, Naoto; Fellague-Chebra, Rafik; Acharya, Sandip; Wong, Stephane; Jin, Yu; Hughes, Timothy P.

doi:10.7326/m17-1094

Cited by 119 publications

(142 citation statements)

References 25 publications

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“…An increase in the numbers of patients with MS pain was reported in patients treated with frontline nilotinib in the ENEST freedom trial (Hochhaus et al , ; Ross et al , ). However, this study was not designed to describe the painful syndromes that could be considered as WS, and the collection of cases over a 48‐week period remains questionable (Mahon et al , ).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The GFR estimating equation was based on the creatinine filtration marker and developed by the Modification of Diet in Renal Disease study group [18, 19]. For T2DM subjects, albumin creatinine ratio (ACR), serum creatinine, cholesterol profile and HbA1c were obtained at the time of initial visit or within the previous 6–12 months from subject medical records.…”

Section: Methodsmentioning

confidence: 99%

Uromodulin mRNA from Urinary Extracellular Vesicles Correlate to Kidney Function Decline in Type 2 Diabetes Mellitus

Yamamoto¹,

Murakami²,

Oakes³

et al. 2018

Am J Nephrol

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Background: Extracellular vesicles (EVs) enclose mRNA derived from their cell of origin and are considered a source of potential biomarkers. We examined urinary EV mRNA from individuals with diabetic kidney disease (DKD), chronic kidney disease, type 2 diabetes (T2DM), and obese and healthy controls to determine if such biomarkers had the potential to classify kidney disease and predict patients at higher risk of renal function decline. Methods: A total of 242 participants enrolled in this study. Urinary EV mRNA from all subjects were isolated by a filter-based platform, and the expression of 8 target genes were determined by quantitative polymerase chain reaction (qPCR). Changes in estimated glomerular filtration rate (eGFR) in 161 T2DM patients were evaluated for 2 consecutive years and compared with EV RNA profiles at baseline. Results: We observe that mild and severe DKD groups show a significant 3.2- and 4.4-fold increase in UMOD compared to healthy controls and expression increases linearly from healthy, diabetic, and DKD subjects. UMOD expression is significantly correlated to albumin creatinine ratio (ACR), eGFR, and HbA1c. Using linear discriminant analyses with mRNA from severe DKD and T2DM as training data, a multi-gene signature classified DKD and non-DKD with a sensitivity of 93% and specificity of 73% with area under the receiver operating characteristic (ROC) curve (AUC) = 0.90. Although 6% of T2DM were determined to have a > 80% posterior probability of developing DKD based on this mRNA profile, eGFR changes observed within the 2-year follow-up did not reveal a decline in kidney function. Conclusion: Urinary EV UMOD mRNA levels are progressively elevated from T2DM to DKD groups and correlate with widely used eGFR and ACR diagnostic criteria. An EV mRNA signature could identify DKD with greater than 90% sensitivity and 70% specificity.

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“…Eighteen patients achieved a second DMR after a median interval of 2.5 months (range, 1-18 months), and 6 patients are currently in MMR after having resumed a TKI for a median of 3 months. [2][3][4][5][6][7][8][9][10] One patient died of pancreatic cancer during follow-up while in DMR.…”

Section: Treatment-free Remission By Transcript Typementioning

confidence: 99%

“…Recently, the pivotal study STIM1 (Stop Imatinib) demonstrated that patients with CML who had a sustained DMR (sDMR) could safely stop TKI treatment, and approximately 40% of them did not develop recurrent CML or a molecular relapse and did not need to restart TKI, remaining in so‐called “treatment‐free remission” (TFR) after long‐term follow‐up . Several studies have confirmed the possibility of maintaining a TFR either at the DMR level or, more recently, at the MMR level after TKI discontinuation in a proportion of patients ranging from 40% to 60% . Hence, the possibility of permanently stopping CML treatment has become a realistic and, for many patients, highly desirable objective …”

Section: Introductionmentioning

confidence: 99%

“…5 Several studies have confirmed the possibility of maintaining a TFR either at the DMR level or, more recently, at the MMR level after TKI discontinuation in a proportion of patients ranging from 40% to 60%. [6][7][8][9][10] Hence, the possibility of permanently stopping CML treatment has become a realistic and, for many patients, highly desirable objective. 11,12 Maintaining an sDMR on a TKI for at least 2 years before treatment suspension is considered mandatory to allow safe TKI discontinuation.…”

Section: Introductionmentioning

confidence: 99%

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The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

D’Adda

Farina

Schieppati

et al. 2019

Cancer

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Background Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment‐free remission (TFR). Methods The potential predictive role of BCR‐ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors’ center. Results Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second‐generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second‐generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. Conclusions The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.

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Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase

Abstract: Novartis Pharmaceuticals Corporation.

Cited by 119 publications

References 25 publications

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

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

Uromodulin mRNA from Urinary Extracellular Vesicles Correlate to Kidney Function Decline in Type 2 Diabetes Mellitus

The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

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