Evolving treatment strategies in CML - moving from early and deep molecular responses to TKI discontinuation and treatment-free remission: is there a need for longer-term trial outcomes?
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ABSTRACT:
SUBMITTER: Eskazan AE
PROVIDER: S-EPMC6046500 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Publications
Evolving treatment strategies in CML - moving from early and deep molecular responses to TKI discontinuation and treatment-free remission: is there a need for longer-term trial outcomes?
British journal of clinical pharmacology 20180603 8
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Project description:Treatment-free remission (TFR) is a new and significant goal of chronic myeloid leukemia management. TFR should be considered for patients in stable deep molecular response (DMR) after careful discussion in the shared decision-making process. Second-generation tyrosine kinase inhibitors (TKIs) improve the speed of response and the incidence of DMR. Treatment may be changed to a more active TKI to improve the depth of response in selected patients who have not reached DMR. Stem cell persistence is associated with active immune surveillance and activation of BCR-ABL1-independent pathways, eg, STAT3, JAK1/2, and BCL2. Ongoing studies aim to prove the efficacy of maintenance therapies targeting these pathways after TKI discontinuation.
| S-EPMC8791110 | biostudies-literature
Project description:The cost of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) is a substantial economic burden. In Japan, imatinib, dasatinib, and nilotinib are now approved as first-line treatment of CML in chronic phase. Recent "stop TKI" trials have shown that TKIs can be safely discontinued in nearly one-half of patients with sustained deep molecular response (DMR). In this study, we analyzed the cost-effectiveness of a simulated 10 years of CML treatment including stop TKI in both the United States and Japan. We constructed Markov models to compare 4 strategies in which treatment was initiated with imatinib, dasatinib, nilotinib, or any of these TKIs at the physician's discretion. Treatment was switched to another TKI in the case of intolerance or resistance to the initial TKI, and TKIs were discontinued if DMR persisted for 2 years. "Imatinib first" offered 7.34 quality-adjusted life years (QALYs) at the cost of $1 022 148 in the United States (US dollars) and ¥32 526 785 in Japan (Japanese yen). In comparison with imatinib first, the incremental cost-effectiveness ratio per QALY of "dasatinib first" (7.68 QALY, $1 236 052, ¥51 506 254), "nilotinib first" (7.64 QALY, $1 245 667, ¥39 635 598), and "physician's choice" (7.55 QALY, $1 167 818, ¥41 187 740) was $641 324, $696 717, and $666 634 in the United States and ¥54 456 325, ¥23 154 465, and ¥39 635 615 in Japan, respectively. None of the 3 strategies met the willingness-to-pay threshold. The results were robust to univariate and multivariate sensitivity analyses. Imatinib first was shown to be the most cost-effective approach even with the incorporation of stop TKI.
| S-EPMC6855125 | biostudies-literature
Project description:BackgroundUnderstanding the relative risks of maintenance treatment versus discontinuation of antipsychotics following remission in first episode psychosis (FEP) is an important area of practice.MethodA systematic review and meta-analysis. Prospective experimental studies including a parallel control group were identified to compare maintenance antipsychotic treatment with total discontinuation or medication discontinuation strategies following remission in FEP.ResultsSeven studies were included. Relapse rates were higher in the discontinuation group (53%; 95% CIs: 39%, 68%; N = 290) compared with maintenance treatment group (19%; 95% CIs: 0.05%, 37%; N = 230). In subgroup analyses, risk difference of relapse was lower in studies with a longer follow-up period, a targeted discontinuation strategy, a higher relapse threshold, a larger sample size, and samples with patients excluded for drug or alcohol dependency. Insufficient studies included psychosocial functioning outcomes for a meta-analysis.ConclusionsThere is a higher risk of relapse for those who undergo total or targeted discontinuation strategies compared with maintenance antipsychotics in FEP samples. The effect size is moderate and the risk difference is lower in trials of targeted discontinuation strategies.Declaration of interestA.T. has received honoraria and support from Janssen-Cilag and Otsuka Pharmaceuticals for meetings and has been has been an investigator on unrestricted investigator-initiated trials funded by AstraZeneca and Janssen-Cilag. He has also previously held a Pfizer Neurosciences Research Grant. S.M. has received sponsorship from Otsuka and Lundbeck to attend an academic congress and owns shares in GlaxoSmithKline and AstraZeneca. J.H. has attended meetings supported by Sunovion Pharmaceuticals.
| S-EPMC6034451 | biostudies-literature
Project description:Numerous combinations of signaling pathway blockades in association with tyrosine kinase inhibitor (TKI) treatment have been proposed for eradicating leukemic stem cells (LSCs) in chronic myeloid leukemia (CML), but none are currently clinically available. Because targeting protein kinase Cδ (PKCδ) was demonstrated to eliminate cancer stem cells (CSCs) in solid tumors, we evaluated the efficacy of PKCδ inhibition in combination with TKIs for CML cells. We observed that inhibition of PKCδ by a pharmacological inhibitor, by gene silencing, or by using K562 CML cells expressing dominant-negative (DN) or constitutively active (CA) PKCδ isoforms clearly points to PKCδ as a regulator of the expression of the stemness regulator BMI1. As a consequence, inhibition of PKCδ impaired clonogenicity and cell proliferation for leukemic cells. PKCδ targeting in K562 and LAMA-84 CML cell lines clearly enhanced the apoptotic response triggered by any TKI. A strong synergism was observed for apoptosis induction through an increase in caspase-9 and caspase-3 activation and significantly decreased expression of the Bcl-xL Bcl-2 family member. Inhibition of PKCδ did not modify BCR-ABL phosphorylation but acted downstream of the oncogene by downregulating BMI1 expression, decreasing clonogenicity. PKCδ inhibition interfered with the clonogenicity of primary CML CD34+ and BCR-ABL-transduced healthy CD34+ cells as efficiently as any TKI while it did not affect differentiation of healthy CD34+ cells. LTC-IC experiments pinpointed that PKCδ inhibition strongly decreased the progenitors/LSCs frequency. All together, these results demonstrate that targeting of PKCδ in combination with a conventional TKI could be a new therapeutic opportunity to affect for CML cells.
| S-EPMC8038300 | biostudies-literature
Project description:BackgroundTypical chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by t(9; 22)(q34; q11) translocation. This chromosomal translocation forms the BCR::ABL1 fusion gene. The tyrosine kinase encoded by the BCR::ABL1 is considered to be the main pathogenic diver. BCR::ABL1 is not only a therapeutic target, but also a monitoring target. Monitoring of BCR::ABL1 reveals the progression of the disease and guides the next treatment. Now for CML, the target of treatment has been focused on treatment-free remission (TFR).MethodsWe conducted a literature review of current developments of treatment-free remission and molecular monitoring methods.ResultsMore effective and sensitive CML monitoring methods such as digital droplet PCR (ddPCR) and next generation sequencing (NGS) have further studied the measurable residual disease (MRD) and clonal heterogeneity, which provides strong support for the exploration of TFR. We discussed some of the factors that may be related to TFR outcomes at the molecular level, along with some monitoring strategies.ConclusionCurrently, predictive indicators for treatment-free remission outcomes and recurrence are lacking in clinical practice. In future, treatment-free remission research should focus on combining the clinical indicators with molecular monitoring and biological markers to personalize patient conditions and guide clinicians to develop individualized treatment plans, so that more patients with CML can achieve safer and stabler treatment-free remission.
| S-EPMC10807643 | biostudies-literature
Project description:The classical natural history of chronic myeloid leukemia (CML) has been drastically modified by the introduction of tyrosine kinase inhibitor (TKI) therapies. TKI discontinuation is currently possible in patients in deep molecular responses, using strict recommendations of molecular follow-up due to risk of molecular relapse, especially during the first 6 months. We report here the case of a patient who voluntarily interrupted her TKI therapy. She remained in deep molecular remission (MR4) for 18 months followed by detection of a molecular relapse at +20 months. Despite this relapse, she declined therapy until the occurrence of the hematological relapse (+ 4 years and 10 months). Retrospective sequential transcriptome experiments and a single-cell transcriptome RNA-seq analysis were performed. They revealed a molecular network focusing on several genes involved in both activation and inhibition of NK-T cell activity. Interestingly, the single-cell transcriptome analysis showed the presence of cells expressing NKG7, a gene involved in granule exocytosis and highly involved in anti-tumor immunity. Single cells expressing as granzyme H, cathepsin-W, and granulysin were also identified. The study of this case suggests that CML was controlled for a long period of time, potentially via an immune surveillance phenomenon. The role of NKG7 expression in the occurrence of treatment-free remissions (TFR) should be evaluated in future studies.
| S-EPMC10062417 | biostudies-literature
Project description:Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.
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Project description:Tyrosine kinase inhibitors (TKIs) to BCR-ABL1 have been successfully used to treat chronic myeloid leukemia (CML), however, multiple TKI-associated adverse events have been reported and become an emerging problem in patients. The mechanisms of TKI-induced toxicity are not fully understood and it remains challenging to predict potential cardiovascular toxicity of a compound. In this study, we established a zebrafish model to evaluate potential in vivo cardiovascular toxicity of TKIs. We treated the endothelium labeled Tg(kdrl:EGFP) transgenic zebrafish embryos with TKIs then performed confocal imaging to evaluate their vascular structure and function. We found that among FDA approved CML TKIs, ponatinib (the only approved TKI that is efficacious to T315I mutation) is the most toxic one. We then evaluated safety profiles of several clinical stage kinase inhibitors that can target T315I and found that HQP1351 treatment leads to vasculopathies similar to those induced by ponatinib while the allosteric ABL inhibitor asciminib does not induce noticeable cardiovascular defects, indicating it could be a promising therapeutic reagent for patients with T315I mutation. We then performed proof-of-principle study to rescue those TKI-induced cardiovascular toxicities and found that, among commonly used anti-hypertensive drugs, angiotensin receptor blockers such as azilsartan and valsartan are able to reduce ponatinib or HQP1351 induced cardiovascular toxicities. Together, this study establishes a zebrafish model that can be useful to evaluate cardiovascular toxicity of TKIs as well as to develop strategies to minimize TKI-induced adverse events.
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Project description:Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is safe under adequate molecular monitoring, but questions remain regarding which factors may be considered predictive for TFR. Argentina Stop Trial (AST) is a multicenter TFR trial showing that 65% of patients sustain molecular remission, and the prior time in deep molecular response (DMR) was associated with successful TFR. Luminex technology was used to characterize cytokines in plasma samples. Using machine learning algorithms, MCP-1 and IL-6 were identified as novel biomarkers and MCP-1low/IL-6low patients showed eightfold higher risk of relapse. These findings support the feasibility of TFR for patients in DMR and MCP-1/IL-6 plasma levels are strong predictive biomarkers.
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