Objectives: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML). Methods: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017. Results: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response. Conclusion: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.
Background: Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) indicated for adult patients with chronic, accelerated or blast phase CML resistant or intolerant to nilotinib or dasatinib or with Ph+ALL resistant or intolerant to dasatinib or for patients with the T315I mutation. Real-world data on ponatinib treatment are limited but are important to evaluate the effectiveness and safety of ponatinib and optimize its use in daily practice. Aims: To report 5-year-Belgian registry data on ponatinib use in CML and Ph+ALL patients in routine clinical practice. Methods: This ongoing prospective multi-center registry (NCT03678454) includes ≥18-year-old patients with CML or Ph+ALL eligible for ponatinib treatment per product label. Data on demographics, effectiveness (major molecular response [MMR] rate) and safety were collected for patients enrolled from 01-March-2016 onwards and are presented here up to 17-May-2021. Results: In this interim analysis, 77 patients from 21 hospitals were enrolled (50 CML, 27 Ph+ALL). Of the 28 patients (39%; 14 CML, 14 Ph+ALL) with mutations in the BCR-ABL1 kinase domain, 17 (8 CML, 9 Ph+ALL) had the T315I mutation at entry. Median age at ponatinib start was 61 years for CML and 56 years for Ph+ALL patients. 88% of CML and 96% of Ph+ALL patients had received ≥2 prior TKIs. Potential pre-existing risk factors for TKI cardiovascular toxicity were observed: history of cardiovascular disease (27 patients), hypertension (23), smoking (15), diabetes (13), hypercholesterolemia (8), hyperlipidemia (6). The most frequently reported risk factor was history of cardiovascular disease (36% CML, 33% Ph+ALL). Median follow-up was 545 (14-3190) days for CML and 210 (26-2933) days for Ph+ALL patients. Reasons for starting ponatinib therapy were intolerance to previous TKIs (26 CML, 11 Ph+ALL), relapse on/refractoriness to previous TKIs (11 CML, 8 Ph+ALL), T315I mutation (6 CML, 6 Ph+ALL) and disease progression (7 CML, 2 Ph+ALL). Ponatinib starting doses were: 45 mg/day (66%), 30 mg/day (10%), 15 mg/day (22%) in CML patients (1 patient started with 15 mg every 2 days) and 45 mg/day (67%), 30 mg/day (15%), 15 mg/day (19%) in Ph+ALL patients. MMR was achieved in 58% of CML and 52% of Ph+ALL patients. The median time-to-MMR was 170 days in CML and 86 days in Ph+ALL patients. Of the 37 patients who started ponatinib due to intolerance to previous TKIs, 59% (15 CML, 7 Ph+ALL) achieved MMR. Adverse reactions (ARs) were reported in 63 patients (82%); the most common were rash (23% of all), constipation (18% of CML) and headache (11% of Ph+ALL patients). Seventeen patients developed 26 serious AR. Serious cardiovascular ARs were reported in 7 patients (coeliac artery stenosis [in 2 patients], ischemic stroke [1], worsening hypertension [1], hypertension [1], deep venous thrombosis [1], possible transient ischemic attack [1]). Eight deaths were recorded, none related to ponatinib treatment. 56% of CML and 24% of Ph+ALL patients discontinued ponatinib treatment due to an AR. Summary/Conclusion: This real-world Belgian registry over 5 years supports the use of ponatinib in CML and Ph+ALL patients resistant or intolerant to previous TKIs or carrying the T315I mutation. Results obtained in routine clinical practice are in concordance with clinical trials, including PACE, in which CML patients had durable and clinically meaningful responses to ponatinib. Funding: Incyte Biosciences Benelux BV Acknowledgements: Medical writing support was provided by Adina Truta (Modis)
For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.
Abstract Regulatory T cells (Tregs) are central for maintaining immune balance and their dysfunction drives the expansion of critical immunologic disorders. During the past decade, microRNAs (miRNAs) have emerged as potent regulators of gene expression among which immune‐related genes and their immunomodulatory properties have been associated with different immune‐based diseases. The miRNA signature of human peripheral blood (PB) CD8 + CD25 + CD127 low Tregs has not been described yet. We thus identified, using TaqMan low‐density array (TLDA) technique followed by individual quantitative real‐time polymerase chain reaction (qRT‐PCR) confirmation, 14 miRNAs, among which 12 were downregulated whereas two were upregulated in CD8 + CD25 + CD127 low Tregs in comparison to CD8 + CD25 − T cells. In the next step, microRNA Data Integration Portal (mirDIP) was used to identify potential miRNA target sites in the 3′‐untranslated region (3′‐UTR) of key Treg cell‐immunomodulatory genes with a special focus on interleukin 10 (IL‐10) and transforming growth factor β (TGF‐β). Having identified potential miR target sites in the 3′‐UTR of IL‐10 (miR‐27b‐3p and miR‐340‐5p) and TGF‐β (miR‐330‐3p), we showed through transfection and transduction assays that the overexpression of two underexpressed miRNAs, miR‐27b‐3p and miR‐340‐5p, downregulated IL‐10 expression upon targeting its 3′‐UTR. Similarly, overexpression of miR‐330‐3p negatively regulated TGF‐β expression. These results highlighted an important impact of the CD8 + Treg mirnome on the expression of genes with significant implication on immunosuppression. These observations could help in better understanding the mechanism(s) orchestrating Treg immunosuppressive function toward unraveling new targets for treating autoimmune pathologies and cancer.
Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro , MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.
