Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

Chen, Yilin; Zou, Jing; Cheng, Fanjun; Li, Weiming

doi:10.3389/fonc.2021.769730

Cited by 12 publications

(17 citation statements)

References 172 publications

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“…However, long‐term TKI use is frequently accompanied by adverse events, impact on quality‐of‐life (QoL), impaired mental health, poor adherence, and high treatment costs 2–4 . In recent years, several clinical trials and real‐world studies have shown that 40%–60% of patients with a sustained, stable deep molecular response (DMR) can successfully discontinue TKI and achieve treatment‐free remission (TFR) 5–7 . Currently, patients with more than 5 years of TKI and 3 years of DMR without prior treatment failure should be considered for withdrawal 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Quality‐of‐life, mental health, and perspective on TKI dose reduction as a prelude to discontinuation in chronic phase chronic myeloid leukemia

Chen

Yang

et al. 2023

Cancer Medicine

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BackgroundTreatment‐free remission (TFR) has become the main target for chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKI) dose optimization is crucial in managing adverse events, and improving adherence in clinical practice. In persons achieving a deep molecular response (DMR), some data suggest TKI dose reduction before discontinuation does not change success rate of achieving TFR, but this is controversial. However, data on quality‐of‐life (QoL) and mental health in CML patients with full‐dose TKI, low‐dose TKI, and TKI discontinuation are limited. Moreover, recent evidence indicating the feasibility of TKI dose reduction and discontinuation after dose reduction, which may change CML patients' perspectives on TKI discontinuation.MethodsWe conducted a cross‐sectional study using online questionnaires to explore the QoL, mental health in patients with diverse TKI dose, and perspective on TKI dose reduction as a prelude to discontinuation.Results1450 responses were included in the analysis. 44.3% of respondents reported a moderate‐to‐severe impact of TKI treatment on their QoL. 17% of respondents had moderate‐to‐severe anxiety. 24.4% of respondents had moderate‐to‐severe depression. In 1326 patients who had not discontinued their medication, 1055 (79.6%) patients reported they would try TKI discontinuation because of concerns over side effects of long‐term medication (67.9%), financial burden (68.7%), poor QoL (77.9%), pregnancy needs (11.6%), anxiety and depression while taking TKI (20.8%), inconvenience of TKI treatment (22.2%). 613 of 817 (75.0%) patients on full‐dose TKI therapy indicated they preferred trying a dose reduction before discontinuing TKI therapy after dose reduction compared with 31 (3.8%) preferring no dose reduction before stopping.ConclusionsTKI dose reduction showed a significant improvement of patients' QoL and mental health, comparable to the effect of TKI discontinuation. Most patients indicated they preferred dose reduction before stopping TKI therapy. In clinical practice, TKI dose reduction can be considered as a bridge from full‐dose treatment to discontinuation.Our results showed that tyrosine kinase inhibitors (TKI) dose reduction showed a significant improvement of patients' quality‐of‐life and mental health, comparable to the effect of TKI discontinuation. Most patients desire to discontinue TKI in the future. TKI discontinuation after dose reduction is more acceptable compared to discontinuing it directly. In clinical practice, TKI dose reduction can be considered as a bridge from full‐dose treatment to discontinuation. Please do not hesitate to contact me in case further clarification is needed with this submission.

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Section: Introductionmentioning

confidence: 99%

Quality‐of‐life, mental health, and perspective on TKI dose reduction as a prelude to discontinuation in chronic phase chronic myeloid leukemia

Chen

Yang

et al. 2023

Cancer Medicine

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“…In some studies, it has been observed that as many as half of the patients can achieve TFR after the discontinuation of a TKI treatment. Moreover, it is observed that molecular recurrence appears within 6 months after discontinuation [ 12 , 13 ]. Factors such as the disease itself or those related to the patient, such as immune status or persistence of CD26+ leukaemic stem cells, may influence the likelihood of achieving and maintaining a TFR.…”

Section: Discussionmentioning

confidence: 99%

“…They were not excluded from the analysis if they stopped having a response before 6 months. This period of follow-up was determined on the basis of several studies that showed that the incidence of molecular recurrence is highest in the first 6 months [ 12 , 13 ]. As the literature regarding their effectiveness on low-dose patients is more limited, all patients on low-dose TKIs were included, regardless of the duration of the dose.…”

Section: Methodsmentioning

confidence: 99%

A Real-World Evidence-Based Study of Long-Term Tyrosine Kinase Inhibitors Dose Reduction or Discontinuation in Patients with Chronic Myeloid Leukaemia

et al. 2023

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The therapeutic approach to chronic myeloid leukaemia (CML) has changed in recent years. As a result, a high percentage of current patients in the chronic phase of the disease almost have an average life expectancy. Treatment also aims to achieve a stable deep molecular response (DMR) that might allow dose reduction or even treatment discontinuation. These strategies are often used in authentic practices to reduce adverse events, yet their impact on treatment-free remission (TFR) is a controversial debate. In some studies, it has been observed that as many as half of patients can achieve TFR after the discontinuation of TKI treatment. If TFR was more widespread and globally achievable, the perspective on toxicity could be changed. We retrospectively analysed 80 CML patients treated with tyrosine kinase inhibitor (TKI) at a tertiary hospital between 2002 and 2022. From them, 71 patients were treated with low doses of TKI, and 25 were eventually discontinued, 9 of them being discontinued without a previous dose reduction. Regarding patients treated with low doses, only 11 of them had molecular recurrence (15.4%), and the average molecular recurrence free survival (MRFS) was 24.6 months. The MRFS outcome was not affected by any of the variables examined, including gender, Sokal risk scores, prior treatment with interferon or hydroxycarbamide, age at the time of CML diagnosis, the initiation of low-dose therapy and the mean duration of TKI therapy. After TKI discontinuation, all but four patients maintained MMR, with a median follow-up of 29.2 months. In our study, TFR was estimated at 38.9 months (95% CI 4.1–73.9). This study indicates that low-dose treatment and/or TKI discontinuation is a salient, safe alternative to be considered for patients who may suffer adverse events (AEs), which hinder the adherence of TKI and/or deteriorate their life quality. Together with the published literature, it shows that it appears safe to administer reduced doses to patients with CML in the chronic phase. The discontinuation of TKI therapy once a DMR has been reached is one of the goals for these patients. The patient should be assessed globally, and the most appropriate strategy for management should be considered. Future studies are needed to ensure that this approach is included in clinical practice because of the benefits for certain patients and the increased efficiency for the healthcare system.

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“…The action of HIF-1 inhibitors associated with TKIs has been shown to reduce the survival and growth of cells in CML in murine models. The HIF-1 deletion has also been tested in in vivo and in vitro models and has been shown to inhibit CML proliferation, both without serious effects on HSCs (120)(121)(122).…”

Section: Treatment Perspectivesmentioning

confidence: 99%

“…Despite the large number of tests involving TKIs, medications and methodologies have also been developing as the case of Bortezomibe. Its function is based on decreasing the expression of CDK6, an important agent in the proliferation of LSCs (120,125,126).…”

Section: Treatment Perspectivesmentioning

confidence: 99%

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

Barreto

Pessoa²,

Machado³

et al. 2022

Front. Oncol.

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Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

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Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

Cited by 12 publications

References 172 publications

Quality‐of‐life, mental health, and perspective on TKI dose reduction as a prelude to discontinuation in chronic phase chronic myeloid leukemia

Quality‐of‐life, mental health, and perspective on TKI dose reduction as a prelude to discontinuation in chronic phase chronic myeloid leukemia

A Real-World Evidence-Based Study of Long-Term Tyrosine Kinase Inhibitors Dose Reduction or Discontinuation in Patients with Chronic Myeloid Leukaemia

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

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