Midostaurin: A New Oral Agent Targeting FMS ‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 yrs), and treatment options, especially in the elderly population, are limited. Induction chemotherapy with 7 + 3, the combination of continuous‐infusion cytarabine and intermittent dosing of an anthracycline administered over 7 and 3 days, respectively, has remained the standard of care since its introduction in 1973 in the United States. Midostaurin is a first‐generation FMS‐like tyrosine kinase 3 (FLT3) inhibitor (TKI) that was approved by the U.S. Food and Drug Administration in April 2017 for the treatment of FLT3‐mutant AML. We performed a search of the PubMed database (January 1990–January 2017) to review pertinent clinical trials of midostaurin. Phase I, II, and III trials reported in English evaluating the safety and efficacy of midostaurin in patients with AML or myelodysplastic syndrome were included. The ClinicalTrials.gov database was also searched for ongoing trials. In the only phase III trial that has been conducted to date, midostaurin demonstrated significant improvement compared with placebo in overall and event‐free survival in patients aged 18–59 years with newly diagnosed FLT3‐mutant AML treated with standard induction chemotherapy. The median overall survival for patients randomized to the midostaurin group was 74.7 months versus 25.6 months in the placebo group...
Source: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy - Category: Drugs & Pharmacology Authors: Tags: Review of Therapeutics Source Type: research

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CONCLUSIONS: We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life. PMID: 30080246 [PubMed - as supplied by publisher]
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
Publication date: Available online 9 November 2017Source: Seminars in Cancer BiologyAuthor(s): Christian Flotho, Sebastian Sommer, Michael LübbertAbstractMyelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular resp...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Allogeneic stem cell transplantation (alloSCT) is a potentially curative therapeutic option for patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Disease relapse occurs in 35-45% of patients following alloSCT, and is the most frequent cause of treatment failure and mortality [1-4]. Moreover, relapse after alloSCT is associated with poor prognosis despite salvage chemotherapy, donor lymphocyte infusions, and/or second transplants [4].
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells that mainly affect the elderly and are characterized by ineffective hematopoiesis, leading to cytopenia, infections, and a significant reduction in the quality of life [1,2]. Intensive chemotherapy combined with hematopoietic stem cell transplantation (HSCT) is the only curative treatment for this disease. However, its applicability in elderly patients is limited by comorbidities and poor performance status. Azacytidine (AZA) significantly reduces transfusion dependence, decreases the risk of transformation to acute myeloid leukemia (AML), and...
Source: Experimental Hematology - Category: Hematology Authors: Tags: Brief Communication Source Type: research
Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells that mainly affect the elderly, characterized by ineffective hematopoiesis, leading to cytopenia, infections, and a significant reduction in the quality of life [1,2]. Intensive chemotherapy combined with hematopoietic stem cell transplantation (HSCT) is the only curative treatment for this disease. However, it's applicability in elderly patients is limited by comorbidities and poor performance status. Azacytidine (AZA) significantly reduces transfusion dependence, decreases the risk of transformation to acute myeloid leukemia (AML), and impro...
Source: Experimental Hematology - Category: Hematology Authors: Tags: Brief Communication Source Type: research
We report here indiscriminate killing of CD123+ normal and acute myeloid leukemia / myelodysplastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123- lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 significantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
ConclusionDe novo myeloid sarcoma mostly presented isolated. Lesions were often localized at skin and lymph nodes. Genetic aberrations frequently involved core‐binding factor rearrangements in de novo cases and a complex karyotype in secondary cases.This article is protected by copyright. All rights reserved.
Source: European Journal of Haematology - Category: Hematology Authors: Tags: Original Article Source Type: research
DISCUSSION: Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML. ABBREVIATIONS: AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; DFS, disease-free survival; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HR, hazard ratio; MDS, myelodysplastic syndrome; OR, odds ratio; OS, overall survival; RCTs, randomized control trials; RR, relative risk. PMID: 29516766 [PubMed - as supplied by publisher]
Source: Hematology - Category: Hematology Tags: Hematology Source Type: research
AbstractImmunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. ...
Source: Annals of Hematology - Category: Hematology Source Type: research
Abstract Disease overviewThe myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. DiagnosisDiagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is usually complementary and may help refine diagnosis. Ri...
Source: American Journal of Hematology - Category: Hematology Authors: Tags: ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES Source Type: research
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