Planned Pregnancy in Female Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitor Therapy.
The aim of this study was to explore outcomes of planned pregnancy in female patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors (TKIs).
Data of female patients proceeding with a planned pregnancy were retrospectively reviewed.
A total of 17 patients with CML who achieved at least a major molecular response (MMR) during imatinib (n = 13) or nilotinib (n = 4) therapy prior to a planned pregnancy were enrolled. At the time of TKI interruption, six were in MMR, two in molecular response 4 (MR4), and nine in molecular response 4.5 (MR4.5). TKI therapy was discontinued 6 weeks (range, 2-15 weeks) before conception in 4 patients and at gestational age of 4 weeks (range, 2-5 weeks) after determination of pregnancy in 13 patients. Apart from 1 patient who suffered a spontaneous abortion, 16 patients delivered uneventfully. A total of 10 patients lost MMR after stopping TKIs; 8 lost molecular response 2, and 3 lost complete hematological response. Log-rank analyses showed achieving MR4 (p = .030) or MR4.5 (p = .031), complete cytogenetic response duration ≥3.5 years (p = .049), and MMR duration ≥3.5 years (p = .040) were significantly associated with longer MMR-failure-free survival during TKI interruption.
Planned pregnancy might be pragmatic in female patients with CML on TKIs. Achieving deep molecular response and, importantly, MMR duration ≥3.5 years were significantly associated with maintaining MMR during pregnancy.
Female patients with chronic myeloid leukemia on tyrosine kinase inhibitors (TKIs) wishing to conceive are currently advised to discontinue TKIs before conception. However, the ideal degree and duration of response before stopping TKI, in addition to whether there will be any adverse effect caused by a short exposure of TKI, is unknown. Data of 17 female patients, who achieved at least a major molecular response (MMR) before TKI interruption, was revised, and it was found that achieving deep molecular response and MMR duration ≥3.5 years was significantly associated with maintaining MMR during pregnancy. This provides direct evidence for a planned pregnancy strategy, and stopping TKI immediately after determination of pregnancy in female patients might be pragmatic.
Dou X
，Qin Y
，Huang X
，Jiang Q
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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.
Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.
In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114.
Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported.
Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure.
ELN Foundation and France National Cancer Institute.
Saussele S
，Richter J
，Guilhot J
，Gruber FX
，Hjorth-Hansen H
，Almeida A
，Janssen JJWM
，Mayer J
，Koskenvesa P
，Panayiotidis P
，Olsson-Strömberg U
，Martinez-Lopez J
，Rousselot P
，Vestergaard H
，Ehrencrona H
，Kairisto V
，Machová Poláková K
，Müller MC
，Mustjoki S
，Berger MG
，Fabarius A
，Hofmann WK
，Hochhaus A
，Pfirrmann M
，Mahon FX
，EURO-SKI investigators
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Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials.
Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP.
In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression.
Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR(4·5) response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason.
Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy.
MD Anderson Cancer Center, National Cancer Institute.
Jain P
，Kantarjian H
，Alattar ML
，Jabbour E
，Sasaki K
，Nogueras Gonzalez G
，Dellasala S
，Pierce S
，Verstovsek S
，Wierda W
，Borthakur G
，Ravandi F
，O'Brien S
，Cortes J
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《Lancet Haematology》
ResearchGate
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