Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: A randomised trial of the Dutch–Belgian Cooperative Trial for Haemato-Oncology (HOVON)

Thielen, Noortje; Holt, Bronno van der; Cornelissen, Jan J.; Verhoef, Gregor; Gussinklo, Titia; Biemond, Bart J.; Daenen, Simon; Deenik, Wendy; Kooy, Rien van Marwijk; Petersen, Eefke; Smit, Willem M.; Valk, Peter J.M.; Ossenkoppele, Gert J.; Janssen, Jeroen

doi:10.1016/j.ejca.2013.06.018

Cited by 67 publications

(67 citation statements)

References 21 publications

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“…[1][2][3][4][5] Although UMRD with a sensitivity of 4.5-log for at least 2 years is typically required and some factors associated with a higher rate of sustained UMRD after IM discontinuation have been reported, the precise identification of the minimum requirement for a safe and successful TFR and the underlying mechanism of sustained UMRD remain elusive.…”

Section: Introductionmentioning

confidence: 99%

“…Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study Sung-Eun Lee, 1 Soo Young Choi, 1 Hye-Young Song, 1 Soo-Hyun Kim, 1 Mi-Yeon Choi, 1 Joon Seong Park, 2 Hyeoung-Joon Kim, 3 Sung-Hyun Kim, 4 Dae Young Zang, 5 Sukjoong Oh, 6 Hawk Kim, 7 Young Rok Do, 8 Jae-Yong Kwak, 9 Jeong-A Kim, 10 Dae-Young Kim, 11 Yeung-Chul Mun, 12 Won Sik Lee,13 Myung Hee Chang, 14 Jinny Park, 15 Ji Hyun Kwon, 16 and Dong-Wook Kim…”

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confidence: 99%

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Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

et al. 2016

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T he aim of the Korean Imatinib Discontinuation Study was to identify predictors for safe and successful imatinib discontinuation. A total of 90 patients with a follow-up of ≥12 months were analyzed. After a median follow-up of 26.6 months after imatinib discontinuation, 37 patients lost the major molecular response. The probability of sustained major molecular response at 12 months and 24 months was 62.2% and 58.5%, respectively. All 37 patients who lost major molecular response were retreated with imatinib therapy for a median of 16.9 months, and all achieved major molecular response again at a median of 3.9 months after resuming imatinib therapy. We observed newly developed or worsened musculoskeletal pain and pruritus in 27 (30%) patients after imatinib discontinuation. Imatinib withdrawal syndrome was associated with a higher probability of sustained major molecular response (P=0.003) and showed a trend for a longer time to major molecular response loss (P=0.098). Positivity (defined as ≥ 17 positive chambers) of digital polymerase chain reaction at screening and longer imatinib duration before imatinib discontinuation were associated with a higher probability of sustained major molecular response. Our data demonstrated that the occurrence of imatinib withdrawal syndrome after imatinib discontinuation and longer duration of imatinib were associated with a lower rate of molecular relapse. In addition, minimal residual leukemia measured by digital polymerase chain reaction had a trend for a higher molecular relapse.

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confidence: 99%

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Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

et al. 2016

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“…Above mentioned prospective trails had differed in the qualification criteria for TKI discontinuation and there has not been published any consensus yet. Length of TKI treatment duration, level of response, and duration of response were the main criteria used [8,10,11]. At least 3 years of TKI treatment duration was demanded in the STIM and TWISTER study.…”

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confidence: 99%

“…All but one relapsing patient relapsed within 7 months after discontinuation of imatinib. The molecular relapse rate at 12 and 24 months after randomization was 0% and 6% (arm A) and 53% and 67% (arm B) respectively [11].…”

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confidence: 99%

“…Thirty-three patients from the HOVON 51 study with an MR 4.5 for at least 2 years who were still on imatinib treatment were randomized between continuation of imatinib (arm A, n = 18) or discontinuation of imatinib (arm B, n = 15) [11]. After a median follow up of 36 months since randomization, 3 patients (17%) in arm A and 10 patients (67%) in arm B had a molecular relapse.…”

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Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia patients – worldwide battlefield

Dvořák¹,

Lysák²,

Vokurka³

2015

neo

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Advances in understanding the pathogenesis of chronic myeloid leukemia (CML) and implementation of the therapy with tyrosine kinase inhibitors (TKI) could be considered as a prototype of successful fight against cancer. However, for an optimally responding patient it is recommended to follow the TKI therapy indefinitely. The question about the possibility of safe TKI treatment discontinuation in certain clinical situations was raised and is currently under close investigation worldwide. Currently, imatinib discontinuation trails have shown that about 60% of eligible patients experienced molecular recurrence within 6 months of treatment discontinuation, while the remaining 40% remained in defined deep molecular response throughout the duration of mostly two years follow-up. Interestingly, retreatment with the same TKI or another TKI was successful in the vast majority of patients demonstrating molecular recurrence of the disease. These findings support the concept of safe TKI treatment discontinuation and its usefulness for a specific subset of CML patients. However, recent data are not sufficient for TKI discontinuation attempts outside clinical trials yet. Because of the high risk of potentially problematic molecular recurrences of the pathological clones, the key question is to find the right predictive marker of TKI discontinuation success, however it stays unsolved yet. This minireview brings a concise summary of this hot topic with a realistic view from clinical routine.

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Optimization of Interferon–Alpha and Imatinib Combination Therapy for Chronic Myeloid Leukemia: A Modeling Approach

Bunimovich‐Mendrazitsky

Kronik

Vainstein

2018

Advcd Theory and Sims

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Chronic myeloid leukemia (CML) in its chronic phase is treated with imatinib, with an attempt at discontinuation after at least three years of therapy in patients with deep molecular responses. Following the attempted discontinuation, approximately half of the patients regress and need to return to the imatinib treatment. Interferon-alpha monotherapy results in a cure in only a small percentage of patients. The combination of both drugs is simulated to optimize the treatment with respect to duration and schedule. This is achieved through a mathematical model in which three cell types are described: leukemic stem cells, mature leukemic cells, and CML-cytotoxic-lymphocyte (CML-CTL) cells. The model is simulated in silico, under different combination treatment regimens of imatinib and interferon-alpha. It is observed that a low level of CML-CTL cells causes failure of the combination treatment; an intermediate level of CML-CTL produces mixed results for the success of the combination treatment; a high level of CML-CTL cells promotes the successof the combination treatment. According to the model, treatment can lead to low-level persistence of CML stem cells after treatment discontinuation, even in the absence of acquired drug resistance. The model defines conditions under which imatinib-interferon-alpha treatment leads to CML eradication.

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Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: A randomised trial of the Dutch–Belgian Cooperative Trial for Haemato-Oncology (HOVON)

Abstract: Our data suggest that discontinuation of imatinib is safe in patients with durable MR(4.5).

Cited by 67 publications

References 21 publications

Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia patients – worldwide battlefield

Optimization of Interferon–Alpha and Imatinib Combination Therapy for Chronic Myeloid Leukemia: A Modeling Approach

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