Review
Biochemistry & Molecular Biology
William Shomali, Jason Gotlib
Summary: Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm driven by the activating KIT D816V mutation. The introduction of KIT inhibitors has improved the prognosis of patients with advanced forms of SM. Different response criteria have been developed to measure mast cell burden and organ damage in advSM, with ongoing challenges in applying these criteria to patients with multiple diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, General & Internal
Aneta Szudy-Szczyrek, Oliwia Bachanek-Mitura, Tomasz Gromek, Karolina Chromik, Andrzej Mital, Michal Szczyrek, Witold Krupski, Justyna Szumilo, Zuzanna Kandula, Grzegorz Helbig, Marek Hus
Summary: Midostaurin has shown to be beneficial for patients with aggressive systemic mastocytosis (ASM), with most patients experiencing clinical improvement and objective response during the treatment course. Some patients also demonstrated a decrease in serum tryptase level and bone marrow infiltration cells during the treatment process.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Oncology
Lina Degenfeld-Schonburg, Susanne Gamperl, Gabriele Stefanzl, Anna-Katharina Schruef, Irina Sadovnik, Karin Bauer, Dubravka Smiljkovic, Gregor Eisenwort, Barbara Peter, Georg Greiner, Emir Hadzijusufovic, Juliana Schwaab, Wolfgang R. Sperr, Gregor Hoermann, Sonja Kopanja, Zsolt Szepfalusi, Konrad Hoetzenecker, Peter Jaksch, Andreas Reiter, Michel Arock, Peter Valent
Summary: Systemic mastocytosis (SM) is a complex hematopoietic neoplasm with clinical symptoms caused by organ infiltration by mast cells (MC) and the release of pro-inflammatory mediators. The growth and survival of MC in SM are triggered by various oncogenic mutant forms of the tyrosine kinase KIT, including the prevalent variant D816V. Two novel drugs, avapritinib and nintedanib, were found to effectively inhibit the growth and survival of neoplastic MC expressing different KIT mutant forms, including D816V, V560G, and K509I, making them potential candidates for the treatment of advanced SM.
AMERICAN JOURNAL OF CANCER RESEARCH
(2023)
Review
Hematology
Cecilia Monaldi, Sara De Santis, Manuela Mancini, Samantha Bruno, Michele Cavo, Simona Soverini
Summary: Significant advances in molecular characterization of systemic mastocytosis have influenced disease diagnosis and management. Evaluating molecular landscape in each patient is crucial for diagnosis, prognosis, treatment, and therapeutic efficacy monitoring. New technologies like digital PCR and NGS play a key role in facilitating this process.
MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES
(2021)
Review
Oncology
Valerie Larouche, Marie-Frederique Pare, Pierre-Olivier Grenier, Anna Wieckowska, Eric Gagne, Rachel Laframboise, Nada Jabado, Isabelle De Bie
Summary: This article reports a case of a 16-year-old girl with an aggressive form of systemic congenital mastocytosis, along with developmental delay, deafness, and multiple anomalies. The study identified a KIT gene alteration and provides clues to the potential etiology of this syndrome.
Article
Biochemistry & Molecular Biology
Nicole Naumann, Johannes Luebke, Sofie Baumann, Juliana Schwaab, Oliver Hoffmann, Sebastian Kreil, Vito Dangelo, Lukas Reiter, Peter Bugert, Thomas Kristensen, Karl Sotlar, Verena Haselmann, Sven Schneider, Georgia Metzgeroth, Christel Weiss, Henning D. Popp, Alice Fabarius, Wolf-Karsten Hofmann, Nicholas C. P. Cross, Andreas Reiter, Mohamad Jawhar
Summary: The KIT D816V mutation in systemic mastocytosis plays a key role in diagnosis and prognosis. Transcriptional activity of KIT D816V can be used to predict disease severity and patient survival.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Medicine, General & Internal
Maura Nicolosi, Andrea Patriarca, Annalisa Andorno, Abdurraouf Mokhtar Mahmoud, Alessandra Gennari, Renzo Boldorini, Gianluca Gaidano, Elena Crisa
Summary: Mastocytosis is a rare hematological neoplasm characterized by abnormal clonal mast cells, with diagnosis based on specific criteria. Over 80% of patients carry a KIT gene mutation, and treatment ranges from symptomatic drugs to kinase inhibitors targeting the mutation.
MEDICINA-LITHUANIA
(2021)
Article
Oncology
Catherine Leyh, Ursula Ehmer, Daniel Roessler, Alexander B. Philipp, Florian P. Reiter, Petia Jeliazkova, Leonie S. Jochheim, Matthias Jeschke, Janina Hammig, Johannes M. Ludwig, Jens M. Theysohn, Andreas Geier, Christian M. Lange
Summary: This study compared the sequential systemic therapy after first-line therapy with sorafenib or lenvatinib and discontinuation of therapy in patients with liver cancer. The results showed that liver functional status and patient performance status at the beginning of first-line therapy had an impact on median overall survival (mOS), while the choice of the initial tyrosine kinase inhibitor (TKI) did not affect mOS.
Article
Biochemistry & Molecular Biology
Francesca Crupi, Benedetta Sordi, Fiorenza Vanderwert, Francesca Gesullo, Andrea Amorosi, Francesco Mannelli, Raffaella Santi
Summary: The diagnosis of systemic mastocytosis relies on histological evidence, particularly from bone marrow biopsy. Immunohistochemistry is useful in the diagnosis. Recent evidence from molecular genetics has improved diagnostic capability and provided a foundation for prognostic and therapeutic evaluation. An integrated diagnostic approach is important for SM classification and treatment effectiveness.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
F. Janku, S. Bauer, K. Shoumariyeh, R. L. Jones, A. Spreafico, J. Jennings, C. Psoinos, J. Meade, R. Ruiz-Soto, P. Chi
Summary: This study demonstrates the efficacy and safety of Ripretinib in patients with KIT-altered metastatic melanoma. The drug shows promising results and may play a meaningful role in treating these patients.
Editorial Material
Medicine, General & Internal
Caroline Burgard, Florian Rosar, Fadi Khreish, Samer Ezziddin
Summary: We report a case of a 68-year-old patient with systemic mastocytosis who underwent F-18-Fluorodeoxyglucose ([F-18]FDG) positron-emission tomography/computed tomography (PET/CT) before and after 6 months of midostaurin therapy. The post-therapeutic [F-18]FDG PET/CT showed decreased tracer uptake in the known gastrointestinal lesions, consistent with symptom relief and decreased serum tryptase level. Thus, [F-18]FDG PET/CT may be a potential method for monitoring the outcome of midostaurin therapy in systemic mastocytosis.
Review
Oncology
Samantha Below, Laura C. Michaelis
Summary: Recent research and translational developments have led to promising new options for the management of systemic mastocytosis, including the use of avapritinib (previously known as BLU-285). Phase I and recent Phase II data have demonstrated the safety and efficacy of avapritinib as a monotherapy, even in patients who have failed other targeted therapies. Current studies are focusing on patients with aggressive disease, with new trials also accruing for those with indolent mastocytosis, suggesting a potentially brighter future for these patients.
CURRENT HEMATOLOGIC MALIGNANCY REPORTS
(2021)
Article
Oncology
Julien Rossignol, Sandra Nizard, Anne-Sandrine Blanc, Anne Filipovics, Joannie Lortet-Tieulent, Hassiba Bouktit, Gwendoline Poinsot, Aurelie Schmidt, Fanny Raguideau, Olivier Hermine
Summary: This study describes the characteristics, treatment modalities, outcomes, and serious events requiring hospitalization in patients treated with midostaurin for Advanced Systemic Mastocytosis (Adv-SM). The results show that the patients' characteristics, treatment duration, and survival were consistent with previous studies.
HEMATOLOGICAL ONCOLOGY
(2022)
Editorial Material
Hematology
Jason Gotlib, Andreas Reiter, Daniel J. DeAngelo
Summary: Avapritinib, a highly selective inhibitor of KIT D816V, has been approved for the treatment of advanced systemic mastocytosis (AdvSM). Clinical trials have shown that avapritinib can induce complete and durable responses in patients with AdvSM, including molecular remission of KIT D816V. However, managing the complex mutational landscape of AdvSM, often accompanied by hematologic neoplasms, poses challenges.
Article
Oncology
Anu Gupta, Jarnail Singh, Alfonso Garcia-Valverde, Cesar Serrano, Daniel L. Flynn, Bryan D. Smith
Summary: The majority of GIST patients develop secondary resistance mutations in KIT after treatment with KIT kinase inhibitors. Tumor heterogeneity and reactivation of the MAPK pathway pose challenges to GIST treatment. Combination therapy of ripretinib with MEK inhibitors shows potential for inducing cytocidal responses in GIST and SM cells.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Hematology
Srdan Verstovsek, Naveen Pemmaraju, Nancy L. Reaven, Susan E. Funk, Tracy Woody, Frank Valone, Suneel Gupta
Summary: Polycythemia vera (PV), a type of myeloproliferative neoplasm, has an increased risk of thrombotic events (TE) and mortality. Treatment interventions, such as phlebotomy and cytoreductive medications, aim to maintain hematocrit levels below 45% for better outcomes. A retrospective observational study including 28,306 PV patients found that a majority of both high- and low-risk patients initiated treatment with phlebotomy monotherapy, but hematocrit control was suboptimal in both risk groups. Around 16% of individuals experienced at least 1 TE after treatment initiation, suggesting that current PV treatments may not be fully utilized.
ANNALS OF HEMATOLOGY
(2023)
Review
Oncology
Helen T. Chifotides, Lucia Masarova, Srdan Verstovsek
Summary: The development of MF therapeutics has achieved remarkable progress, with JAK2 inhibitors playing a transformative role in MPN treatment. In addition to these inhibitors, there are numerous novel monotherapies and rational combinations being developed to address different aspects of the disease. These advancements have the potential to improve patient outcomes and lead to a golden era in MF treatment.
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Review
Hematology
Nicola Polverelli, Juan Carlos Hernandez-Boluda, Tomasz Czerw, Tiziano Barbui, Mariella D'Adda, Hans Joachim Deeg, Markus Ditschkowski, Claire Harrison, Nicolaus Martin Kroger, Ruben Mesa, Francesco Passamonti, Francesca Palandri, Naveen Pemmaraju, Uday Popat, Damiano Rondelli, Alessandro Maria Vannucchi, Srdan Verstovsek, Marie Robin, Antonio Colecchia, Luigi Grazioli, Enrico Damiani, Domenico Russo, Jessica Brady, David Patch, Slawomir Blamek, Gandhi Laurent Damaj, Patrick Hayden, Donal P. McLornan, Ibrahim Yakoub-Agha
Summary: Splenomegaly is a common complication in myelofibrosis patients and can negatively impact outcomes of allogeneic hematopoietic cell transplantation (HCT). This Position Paper provides a shared position statement on the management of splenomegaly before HCT. The assessment, prevalence, and clinical significance of splenomegaly are discussed, along with the need for therapeutic intervention. Specific scenarios, such as splanchnic vein thrombosis and COVID-19, are also addressed.
LANCET HAEMATOLOGY
(2023)
Review
Hematology
Srdan Verstovsek
Summary: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by mutations (most frequently in JAK2, CALR, or MPL), burdensome symptoms, splenomegaly, cytopenia, and shortened life expectancy. In addition to other clinical manifestations, patients with MF often develop anemia, which can either be directly related to MF pathogenesis or a result of MF treatment with Janus kinase (JAK) inhibitors, such as ruxolitinib and fedratinib. This review provides detailed treatment and patient management approaches for both types of anemia presentations in MF and offers recommendations for the treatment of MF in the presence of anemia.
ANNALS OF HEMATOLOGY
(2023)
Article
Oncology
Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Naval G. Daver, Koji Sasaki, Helen T. Chifotides, Lingsha Zhou, Hagop M. Kantarjian, Zeev Estrov, Srdan Verstovsek
Summary: This retrospective study evaluated the impact of different therapies on the survival of patients with myelofibrosis. The results showed that treatment with the JAK inhibitor ruxolitinib improved patient outcomes. Approximately 61% of patients initiated MF-directed therapy, with ruxolitinib being the most common choice. About 32% of patients required second-line therapy.
Article
Oncology
Srdan Verstovsek, Jean-Jacques Kiladjian, Alessandro M. M. Vannucchi, Ruben A. A. Mesa, Peg Squier, J. E. Hamer-Maansson, Claire Harrison
Summary: This study analyzed the impact of the timing of ruxolitinib treatment on clinical outcomes in patients with intermediate-2 and high-risk myelofibrosis. The results showed that patients who initiated treatment earlier had better outcomes in terms of thrombocytopenia and anemia, higher spleen volume response, and longer overall survival.
Review
Pharmacology & Pharmacy
Pankit Vachhani, Srdan Verstovsek, Prithviraj Bose
Summary: Cytopenic myelofibrosis is a subtype of myelofibrosis characterized by low blood counts, lower driver mutation allele burden, increased likelihood of occurring de novo, greater genomic complexity, worse survival, and higher rates of leukemic transformation. Several JAK inhibitors are available for clinical use, including pacritinib and momelotinib, which show promise in improving cytopenias. These newer JAK inhibitors may become the foundation for future combination therapies.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Article
Oncology
John Mascarenhas, Marina Kremyanskaya, Andrea Patriarca, Francesca Palandri, Timothy Devos, Francesco Passamonti, Raajit K. Rampal, Adam J. Mead, Gabriella Hobbs, Joseph M. Scandura, Moshe Talpaz, Nikki Granacher, Tim C. P. Somervaille, Ronald Hoffman, Marielle J. Wondergem, Mohamed E. Salama, Gozde Colak, Jike Cui, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Srdan Verstovsek, Natalia Curto-Garcia, Claire Harrison, Vikas Gupta
Summary: In patients with myelofibrosis who are naive to JAKi treatment, the rational combination of the BET inhibitor pelabresib and ruxolitinib showed good tolerability and durable improvements in spleen and symptom burden.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Oncology
Naveen Pemmaraju, Prithviraj Bose, Raajit Rampal, Aaron T. Gerds, Angela Fleischman, Srdan Verstovsek
Summary: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, abnormal cytokine expression, cytopenias, and progressive bone marrow fibrosis. Ruxolitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor, was the first approved agent for MF and has revolutionized the treatment approach. The understanding of MF has improved significantly due to targeted JAK1/JAK2 inhibition and extensive literature on ruxolitinib, leading to better management strategies and discussion on future treatment options.
LEUKEMIA & LYMPHOMA
(2023)
Article
Hematology
Ivan Krecak, Marko Skelin, Srdan Verstovsek
Summary: Interferons (IFNs) have been used for decades to treat polycythemia vera (PV). Single-arm clinical trials have shown high hematological and molecular response rates with IFNs, indicating potential disease-modifying activity. However, discontinuation rates of IFNs have been rather high due to frequent treatment-related side-effects.
EXPERT REVIEW OF HEMATOLOGY
(2023)
Review
Hematology
Ivan Krecak, Srdan Verstovsek, Marko Lucijanic
Summary: The exact prognostic role of cardiovascular risk factors in BCR-ABL1 negative MPN patients is unknown. Current treatment of CV risk factors in MPNs is not guided by the presence of these risk factors. Target levels for different metabolic deflections in MPNs have not been defined. This review discusses the important aspects of individual CV risk factors in MPNs, summarizes recent advances, and proposes future directions and research areas.
ANNALS OF HEMATOLOGY
(2023)
Review
Oncology
Srdan Verstovsek, Ruben A. Mesa, Robert A. Livingston, Wilson Hu, John Mascarenhas
Summary: Myelofibrosis is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been approved for the treatment of intermediate or high-risk MF patients. It remains the standard of care for higher-risk MF, and dose optimization and management are crucial for maximizing its benefits.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Srdan Verstovsek, Ivan Krecak, Florian H. Heidel, Valerio De Stefano, Kenneth Bryan, Mike W. Zuurman, Michael Zaiac, Mara Morelli, Aoife Smyth, Santiago Redondo, Erwan Bigan, Michael Ruhl, Christoph Meier, Magali Beffy, Jean-Jacques Kiladjian
Summary: The PV-AIM study used machine learning to identify markers of thromboembolic events (TE) in patients with polycythemia vera (PV). The study found that lymphocyte percentage (LYP), neutrophil percentage (NEP), and red cell distribution width (RDW) are closely associated with TE risk, and can be used to identify high-risk patients.
Article
Hematology
Vikas Gupta, John Mascarenhas, Marina Kremyanskaya, Raajit K. Rampal, Moshe Talpaz, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Srdan Verstovsek, Gozde Colak, Debarshi Dey, Claire Harrison
Summary: A study suggests that pelabresib in combination with ruxolitinib may have higher efficacy in treating JAKi treatment-naive MF patients compared to JAKi monotherapy, with significant improvements in spleen volume reduction and total symptom scores.
Article
Hematology
Srdan Verstovsek, Ruben Mesa, Vikas Gupta, David Lavie, Viviane Dubruille, Nathalie Cambier, Uwe Platzbecker, Marek Hus, Blanca Xicoy, Stephen T. Oh, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Aaron Gerds, Miklos Egyed, Jiri Mayer, Tomasz Sacha, Jun Kawashima, Marc Morris, Mei Huang, Claire Harrison
Summary: Momelotinib is a first-in-class inhibitor of Janus kinases 1 and 2, as well as activin A receptor type 1, and has shown efficacy in addressing the symptoms of myelofibrosis, such as splenomegaly, constitutional symptoms, and anemia. This long-term analysis of pooled data from three phase 3 studies demonstrated the safety and tolerability of momelotinib, with no evidence of long-term or cumulative toxicity. The most common adverse events were diarrhea and hematologic abnormalities, but they were generally manageable. This analysis provides valuable evidence supporting the use of momelotinib in the treatment of myelofibrosis.
