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Annals of Hematology Oct 2023The addition of midostaurin to standard chemotherapy has improved survival in patients with FLT3-mutated AML. However, the impact of midostaurin and other FLT3... (Review)
Review
Treatment with midostaurin and other FLT3 targeting inhibitors is associated with an increased risk of cardiovascular adverse events in patients who underwent allogeneic hematopoietic stem cell transplantation with FLT3-mutated AML.
The addition of midostaurin to standard chemotherapy has improved survival in patients with FLT3-mutated AML. However, the impact of midostaurin and other FLT3 inhibitors (FLT3i) on cardiovascular adverse events (CAEs) has not been studied in patients who underwent allogeneic hematopoietic stem cell transplantation in a real-world setting. We reviewed 132 patients with AML who were treated with intensive induction therapy and consecutive allogeneic stem cell transplantation at our institution (42 FLT3-mutated AML and 90 with FLT3 wildtype). We identified treatment with midostaurin and/or FLT3i as an independent risk factor for CAEs not resulting in higher non-relapse mortality (NRM) or impaired overall survival (OS). Hence, close monitoring for CAEs is warranted for these patients.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; Staurosporine; Protein Kinase Inhibitors; Hematopoietic Stem Cell Transplantation; fms-Like Tyrosine Kinase 3
PubMed: 37552323
DOI: 10.1007/s00277-023-05396-y -
Nature Communications Oct 2023Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial...
Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
Topics: Humans; Lung Neoplasms; Drug Repositioning; Proto-Oncogene Proteins p21(ras); Drug Combinations; Protein Kinase Inhibitors; Mutation; Cell Line, Tumor
PubMed: 37816716
DOI: 10.1038/s41467-023-41828-z -
Blood Advances May 2023Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological...
Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.
Topics: Humans; Middle Aged; Aged; Aged, 80 and over; Leukemia, Lymphocytic, Chronic, B-Cell; Nivolumab; Programmed Cell Death 1 Receptor; B-Lymphocytes; Lymphoma, Large B-Cell, Diffuse
PubMed: 36287248
DOI: 10.1182/bloodadvances.2022008790 -
Journal of Clinical Medicine May 2023The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 () mutations has been mitigated by the recent... (Review)
Review
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 () mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 -mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review.
PubMed: 37297842
DOI: 10.3390/jcm12113647 -
Mediterranean Journal of Hematology and... 2022Management of Indolent and Smoldering SM is focused on preventing anaphylactic reactions and identifying and avoiding symptom triggers. Skin and gastrointestinal... (Review)
Review
Management of Indolent and Smoldering SM is focused on preventing anaphylactic reactions and identifying and avoiding symptom triggers. Skin and gastrointestinal symptoms are managed with H1- and H2-antihistamines. When skin symptoms are not adequately controlled, leukotriene antagonists and oral psoralen combined with ultraviolet therapy may be added. Proton pump inhibitors, sodium cromolyn, and oral corticosteroids may be added for gastrointestinal symptoms. Patients should be prescribed self-injectable epinephrine and trained to treat recurrent cardiovascular symptoms or anaphylaxis. Depression and cognitive impairment require a psychiatric evaluation for tailored treatment. Bone involvement is managed with bisphosphonates and eventually interferon. Omalizumab is effective on all vasomotor symptoms, including anaphylaxis, but not on respiratory, musculoskeletal, and neuropsychiatric symptoms. A cytoreductive treatment is not recommended unless anti-mediator therapy has failed. Venom immunotherapy is mandatory for patients with Hymenoptera venom allergy. There is no curative option for patients with advanced SM. The available therapeutic options include tyrosine-kinase inhibitors and cladribine, with variable duration and extent of response. Imatinib mesylate was the first drug approved for SM lacking the cKIT D816V mutation; dasatinib and nilotinib are ineffective. Midostaurin is active on both wild-type and mutant cKIT D816V, while Avapritinib is a selective cKIT D816V inhibitor: they are approved for the treatment of advanced SM. Cladribine is a purine analog with significant activity against monocytes that were thought to have a common progenitor with mast cells. Allogeneic stem cell transplantation is usually performed in younger selected patients.
PubMed: 35615325
DOI: 10.4084/MJHID.2022.040 -
Clinical and Translational Science Oct 2023Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes...
Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (C ) was greater than three times higher than reported; moreover, midostaurin C , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.
Topics: Humans; Antifungal Agents; Micafungin; Prospective Studies; Leukemia, Myeloid, Acute; Neutropenia; fms-Like Tyrosine Kinase 3
PubMed: 37515369
DOI: 10.1111/cts.13595 -
Diagnostics (Basel, Switzerland) Dec 2023Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in... (Review)
Review
Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in organ dysfunction and reduced life expectancy. The subtypes include aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). The gain of function D816V mutation is present in most cases. The availability of tyrosine kinase inhibitors (TKIs) has revolutionised the treatment landscape for patients with this life-limiting disease. Patients are now able to achieve molecular remission, improved quality of life and improved overall survival. This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease.
PubMed: 38201389
DOI: 10.3390/diagnostics14010080 -
Hematology. American Society of... Dec 2022The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes... (Review)
Review
The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes with the discovery of druggable targets. The multikinase/KIT inhibitor midostaurin and the highly selective KIT D816V inhibitor avapritinib can elicit marked improvements in measures of mast cell (MC) burden as well as reversion of MC-mediated organ damage (C-findings) and disease symptoms. With avapritinib, the achievement of molecular remission of KIT D816V and improved survival compared with historical therapy suggests a potential to affect disease natural history. BLU-263 and bezuclastinib are KIT D816V inhibitors currently being tested in trials of AdvSM. In the new World Health Organization and International Consensus Classifications, the category of "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions" is inclusive of rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1. While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the "poster children" of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhibitor pemigatinib, approved in August 2022, is a promising therapy in aggressive FGFR1-driven diseases and highlights the role of such agents in bridging patients to allogeneic transplantation. This review summarizes the data for these approved and investigational agents and discusses open questions and future priorities regarding the management of these rare diseases.
Topics: Child; Humans; Mastocytosis, Systemic; Protein Kinase Inhibitors; Myeloproliferative Disorders; Imatinib Mesylate; Eosinophilia; Proto-Oncogene Proteins c-kit; Mastocytosis
PubMed: 36485158
DOI: 10.1182/hematology.2022000368 -
Endocrinology, Diabetes & Metabolism... May 2023We report the case of a 69-year-old female with systemic mastocytosis, diagnosed based on widespread pigmented papules and macules, elevated serum tryptase levels and...
SUMMARY
We report the case of a 69-year-old female with systemic mastocytosis, diagnosed based on widespread pigmented papules and macules, elevated serum tryptase levels and confirmatory skin and bone marrow biopsy, on a background of osteoporosis. A CT demonstrated multiple sclerotic lesions within lumbar vertebral bodies, sacrum and ileum, with surrounding osteolysis but no obvious compression fractures. She was treated with the RANK-L inhibitor denosumab, resulting in significant bone mineral density gain over the following 5 years. However, her serum tryptase levels gradually increased during this period despite treatment with the multikinase inhibitor, midostaurin. It is thus conceivable that her rapid increase in bone mineral density may be partly contributed by a predominance of pro-osteoblastic mediators released by abnormal mast cells, suggestive of more advanced disease. This case highlights the complexities of systemic mastocytosis-related bone disease and the interplay of numerous mediators contributing to a phenotype of both increased bone resorption and formation.
LEARNING POINTS
Systemic mastocytosis is a neoplastic disease of mast cells characterized by abnormal proliferation and accumulation in the skin and other organs. It is most frequently associated with the somatic gain-of-function KIT D816V mutation. Systemic mastocytosis should be suspected in patients presenting with not only cutaneous symptoms suggestive of mast cell degranulation such as anaphylaxis, flushing or urticaria but also unexplained osteoporosis and gastrointestinal and constitutional symptoms. The prevalence of osteoporosis in systemic mastocytosis is high. Mast cell activation leads to the secretion of numerous chemical mediators which either promote or inhibit osteoclastic and/or osteoblastic activity, with the balance usually in favour of increased bone resorption. However, in advanced diseases with high mast cell burden, mast-cell-derived cytokines and mediators may promote osteoblastic activity, leading to osteosclerosis and apparent increases in bone mineral density. Treatment of osteoporosis in systemic mastocytosis involves antiresorptive therapy with bisphosphonates and more recently, denosumab. There are limited data on the role of osteoanabolic agents.
PubMed: 37166908
DOI: 10.1530/EDM-22-0408 -
Cancer Drug Resistance (Alhambra,... 2023FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected... (Review)
Review
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1 and 2 generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
PubMed: 37457126
DOI: 10.20517/cdr.2022.130