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15. Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy

Author

Nassereddine,Samah, Lap,Coen J., and Tabbara,Imad A.

Subjects
OncoTargets and Therapy
Abstract

Samah Nassereddine,1,2 Coen J Lap,2 Imad A Tabbara1,2 1Department of Internal Medicine, The George Washington University School of Medicine, Washington, DC, USA; 2Division of Hematology/Oncology, The George Washington Cancer Center, Washington, DC, USA Abstract: Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the oncometabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years. Keywords: ivosidenib, AML, IDH1, relapsed, refractory

Published
2018

25. An atypical presentation of Sweet’s syndrome in a myelofibrosis patient.

Author

Umera Thebo, Tummala, Sirisha, Nassereddine, Samah, and Haroun, Faysal

Abstract

A 46-year-old man with no significant medical history presented to haematology with symptoms of fatigue, dyspnoea on exertion and weight loss. Physical examination revealed a lesion on the right shin and splenomegaly. Labs were significant for leucocytosis with immature components, thrombocytosis and 3% peripheral blasts on smear. A bone marrow biopsy confirmed a diagnosis of myelofibrosis (MF). Dynamic International Prognosis Scoring system was 2. He was started on ruxolitnib, with decitabine added subsequently prior to definitive therapy with an allogenic haematopoietic stem cell transplant. His course with decitabine was complicated with febrile neutropaenia with multiple tender erythematous plaques unresponsive to antibacterial and antifungal coverage. A skin biopsy showed neutrophilic dermatitis, consistent with a diagnosis of Sweet’s syndrome (SS) and empirical treatment with glucocorticoids was initiated resulting in resolution of symptoms. This report reviews the literature for cases of SS in the setting of MF. [ABSTRACT FROM AUTHOR]

Published
2019
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26. Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy.

Author

Nassereddine, Samah, Lap, Coen J, and Tabbara, Imad A

Subjects
*OLIGODENDROGLIOMAS, *GENETIC disorders, *ACUTE myeloid leukemia, *ISOCITRATE dehydrogenase, *GAIN-of-function mutations, *SMALL molecules
Abstract

Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the oncometabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years. [ABSTRACT FROM AUTHOR]

Published
2019
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37. Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

Author

J. Lap, Coen, Nassereddine, Samah, Liu, Min-Ling, E. Nava, Victor, and Aggarwal, Anita

Abstract

Hematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2+ myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.

Published
2021
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38. Sinusoidal Obstruction Syndrome (Veno-occlusive Disease) Following Hematopoietic Stem Cell Transplant: Insights and Therapeutic Advances.

Author

Nassereddine S, Alsubait S, and Tabbara I

Subjects
Anticoagulants therapeutic use, Biomarkers, Conservative Treatment, Cytokines physiology, Endothelial Cells physiology, Graft vs Host Disease complications, Heparin therapeutic use, Hepatic Veno-Occlusive Disease diagnosis, Hepatic Veno-Occlusive Disease physiopathology, Hepatic Veno-Occlusive Disease therapy, Humans, Polydeoxyribonucleotides therapeutic use, Risk Factors, Ursodeoxycholic Acid therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Hepatic Veno-Occlusive Disease etiology
Abstract

Hepatic sinusoidal obstruction syndrome (SOS) is a rare fatal clinical entity seen following hematopoietic stem cell transplant (HSCT). It is more commonly reported to occur following allogeneic HSCT compared to autologous HSCT. Historically, it is known as hepatitis following HSCT. It is thought that endothelial damage to the hepatic venules leading to occlusion of the terminal hepatic venules and hepatic sinusoids is the trigger for the development of SOS. Several risk factors have been associated with this condition. Some of these risk factors are patient related while others are transplant process related. Given the high mortality of this condition, early identification of high-risk patients with severe disease is of utmost importance. The management of SOS varies depending on the severity of the disease. Mild to moderate disease has a good outcome with supportive measures alone, while severe presentation of the disease requires a more aggressive management. Defibrotide is the only Food and Drug Administration-approved therapy and it is reserved for severe cases of SOS. The role of defibrotide as a prophylactic therapy remains under investigation., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Published
2018
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