Current and future status of JAK inhibitors McLornan, Donal P; Pope, Janet E; Gotlib, Jason ...
The Lancet (British edition),
08/2021, Letnik:
398, Številka:
10302
Journal Article
Recenzirano
An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing ...applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.
VEXAS (acronym for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a fascinating new entity encompassing a variety of clinical manifestations, spanning from auto-inflammatory symptoms to ...hematologic disorders, including myelodysplastic syndromes and plasma cell dyscrasias. Genetically defined by somatic mutations of the X-linked gene UBA1 in hematopoietic stem and progenitor cells, VEXAS typically manifests in males during the fifth/sixth decade of life. Since its discovery, several groups have documented pleomorphic clinical phenotypes, in addition to a plethora of therapeutic options (e.g., JAK inhibitors, hypomethylating agents, and allogeneic stem cell transplant, allo-HCT) in retrospective case series. However, no treatment guidelines have been validated to date, VEXAS patients are typically steroid-dependent and may manifest life-threatening inflammatory symptoms refractory to multiple lines of therapy. To date, the only curative option appears to be allo-HCT in suitable individuals. Nonetheless, this procedure carries an inherent risk of morbidity and mortality that must be judiciously evaluated against a phenotypically diverse disorder where the optimal therapeutic algorithm remains ill-defined. Herein, we provide an overview of the current VEXAS data/ therapeutic evidence and discuss the curative potential of allo-HCT whilst highlighting the efforts required for generation of robust data able to inform therapeutic decisions.
Synthetic lethality refers to the requirement that two defects be present for cell death to occur. When an agent damages DNA, its effects on the cell can be amplified if the efforts of the cell to ...repair the damage are inhibited. Clinical application of this idea is just beginning.
The development of anticancer treatments that are largely selective for the neoplastic clone has, until recently, remained an elusive goal. However, an expanding cadre of “targeted therapeutics” in clinical use illustrates the enormous potential of this approach. Genetic alterations in cancer in humans may involve gene activation, amplification, or inactivation or allelic haplodeficiency. These signature genetic features that are unique to the malignant clone can be exploited to develop treatments that are inherently tumor-specific.
The concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to . . .
Advances in understanding the pathogenesis and molecular landscape of myelofibrosis have occurred over the last decade. Treating physicians now have access to an ever-evolving armamentarium of novel ...agents to treat patients, although allogeneic hematopoietic stem cell transplantation remains the only curative approach. Improvements in donor selection, conditioning regimens, disease monitoring and supportive care have led to augmented survival after transplantation. Nowadays, there are comprehensive guidelines concerning allogeneic hematopoietic stem cell transplantation for patients with myelofibrosis. However, it commonly remains difficult for both physicians and patients alike to weigh up the risk-benefit ratio of transplantation given the inherent heterogeneity regarding both clinical course and therapeutic response. In this timely review, we provide an up-to-date synopsis of current transplantation recommendations, discuss usage of JAK inhibitors before and after transplantation, examine donor selection and compare conditioning platforms. Moreover, we discuss emerging data concerning the impact of the myelofibrosis mutational landscape on transplantation outcome, peritransplant management of splenomegaly, poor graft function and prevention/management of relapse.
Management approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic advances, outcomes for those patients ...who are not allogeneic haematopoietic cell transplant eligible remain, in general, very poor. Estimated survival rates for such blast phase patients is frequently reported as less than 6 months. No specific immunological, genomic or clinicopathological signature currently exists that accurately predicts the risk and timing of transformation, which frequently induces a high degree of anxiety among patients and clinicians alike. Within this review article, we provide an up-to-date summary of current understanding of the underlying pathogenesis of accelerated and blast phase disease and discuss current therapeutic approaches and realistic outcomes. Finally, we discuss how the horizon may look with the introduction of more novel agents into the clinical arena.
The bone marrow niche is a complex and dynamic structure composed of a multitude of cell types which functionally create an interactive network facilitating hematopoietic stem cell development and ...maintenance. Its specific role in the pathogenesis, response to therapy, and transformation of myeloproliferative neoplasms has only recently been explored. Niche functionality is likely affected not only by the genomic background of the myeloproliferative neoplasm-associated mutated hematopoietic stem cells, but also by disease-associated 'chronic inflammation', and subsequent adaptive and innate immune responses. 'Cross-talk' between mutated hematopoietic stem cells and multiple niche components may contribute to propagating disease progression and mediating drug resistance. In this timely article, we will review current knowledge surrounding the deregulated bone marrow niche in myeloproliferative neoplasms and suggest how this may be targeted, either directly or indirectly, potentially influencing therapeutic choices both now and in the future.
Aplastic anemia (AA) is the prototypical bone marrow failure syndrome. In the current era of readily available 'molecular annotation', application of comprehensive next-generation sequencing panels ...has generated novel insights into underlying pathogenetic mechanisms, potentially leading to improvements in personalized therapeutic approaches. New evidence has emerged as to the role of somatic loss of HLA class I allele expression in 'immune-mediated' AA, associated molecular aberrations, and risk of clonal evolution. A deeper understanding has emerged regarding the role of 'myeloid' gene mutations in this context, translating patho-mechanistic insights derived from wider clinical and translational research within the myeloid disorder arena. Here, we review contemporary 'tools' which aid in confirmation of a diagnosis of AA, with an additional focus on their potential in guiding therapeutic options. A specific emphasis is placed upon interpretation and integration of this detailed diagnostic information and how this may inform optimal transplantation strategies.
Pre-Fibrotic Myelofibrosis is a frequently under-recognised entity that has distinct features separate to those of both Essential Thrombocythaemia and overt Primary Myelofibrosis. Misdiagnosis is ...relatively common due to subtle differences in bone marrow trephine morphology and multidisciplinary approaches are required. The clinical phenotype and disease course is heterogeneous and hence management approaches tend to vary widely. Although patients may initially be asymptomatic, disease-related complications can include troublesome symptom burdens, increased incidence of both arterial and venous thromboses, haemorrhage, anaemia and an inherent risk of disease evolution to either overt myelofibrosis or blastic phase disease. Specific prognostic tools with high discriminatory power are lacking. Within this review we use case-based approaches to review the current literature, highlight challenges in both diagnostics and disease management and suggest contemporary approaches to improve patient outcomes.
Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, ...is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.
In 2021, 47,412 HCT (19,806 (42%) allogeneic and 27,606 (58%) autologous) in 43,109 patients were reported by 694 European centers. 3494 patients received advanced cellular therapies, 2524 of which ...were CAR-T treatments, an additional 3245 received DLI. Changes compared to the previous year were CAR-T treatment (+35%), allogeneic HCT +5.4%, autologous HCT +3.9%, more pronounced in non-malignant disorders. Main indications for allogeneic HCT were myeloid malignancies 10,745 (58%), lymphoid malignancies 5127 (28%) and non-malignant disorders 2501 (13%). Main indications for autologous HCT were lymphoid malignancies 22,129 (90%) and solid tumors 1635 (7%). In allogeneic HCT, use of haploidentical donors decreased by -0.9% while use of unrelated and sibling donors increased by +4.3% and +9%. Cord blood HCT decreased by -5.8%. Pediatric HCT increased overall by +5.6% (+6.9% allogeneic and +1.6% autologous). Increase in the use of CAR-T was mainly restricted to high-income countries. The drop in HCT activity reported in 2020 partially recovered in 2021, the second year of the SARS-CoV-2 pandemic. The transplant community confronted with the pandemic challenge, continued in providing patients access to treatment. This annual EBMT report reflects current activities useful for health care resource planning.
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