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1. Changes in bone marrow fibrosis during momelotinib or ruxolitinib therapy do not correlate with efficacy outcomes in patients with myelofibrosis

Author

Stephen T. Oh, Srdan Verstovsek, Vikas Gupta, Uwe Platzbecker, Timothy Devos, Jean‐Jacques Kiladjian, Donal P. McLornan, Andrew Perkins, Maria Laura Fox, Mary Frances McMullin, Adam J. Mead, Miklos Egyed, Jiri Mayer, Tomasz Sacha, Jun Kawashima, Mei Huang, Bryan Strouse, and Ruben Mesa

Subjects
bone marrow fibrosis, JAK inhibitor, momelotinib, myelofibrosis, ruxolitinib, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor–naive patients from SIMPLIFY‐1 (NCT01969838), a double‐blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1‐grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.

Published
2024
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2. Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study

Author

Ruben A. Mesa, Claire Harrison, Jeanne M. Palmer, Vikas Gupta, Donal P. McLornan, Mary Frances McMullin, Jean-Jacques Kiladjian, Lynda Foltz, Uwe Platzbecker, Maria Laura Fox, Adam J. Mead, David M. Ross, Stephen T. Oh, Andrew Charles Perkins, Michael F. Leahy, Jun Kawashima, Sunhee Ro, Rafe Donahue, Boris Gorsh, Samineh Deheshi, and Srdan Verstovsek

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients’ quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.

Published
2023
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3. Updated Results from the Momentum Phase 3 Study of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated with a JAK Inhibitor

Author

Aaron T. Gerds, Ruben Mesa, Alessandro M Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal P. McLornan, Andrew Charles Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Rafe Donahue, Jun Kawashima, and Srdan Verstovsek

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

4. The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study

Author

Ruben Mesa, Claire Harrison, Jeanne M. Palmer, Vikas Gupta, Donal P. McLornan, Mary Frances McMullin, Jean-Jacques Kiladjian, Lynda Foltz, Uwe Platzbecker, Maria Laura Fox, Adam J Mead, David M Ross, Stephen T Oh, Andrew Charles Perkins, Michael F. Leahy, Jun Kawashima, Sunhee Ro, Rafe Donahue, Samineh Deheshi, and Srdan Verstovsek

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

5. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Michael H. Albert, Tiarlan Sirait, Dirk-Jan Eikema, Katerina Bakunina, Claudia Wehr, Felipe Suarez, Maria Laura Fox, Nizar Mahlaoui, Andrew R. Gennery, Arjan C. Lankester, Rita Beier, Maria Ester Bernardo, Venetia Bigley, Caroline A. Lindemans, Siobhan O. Burns, Ben Carpenter, Jaroslaw Dybko, Tayfun Güngör, Fabian Hauck, Su Han Lum, Dmitry Balashov, Roland Meisel, Despina Moshous, Ansgar Schulz, Carsten Speckmann, Mary A. Slatter, Brigitte Strahm, Duygu Uckan-Cetinkaya, Isabelle Meyts, Tanja C. Vallée, Robert Wynn, Bénédicte Neven, Emma C. Morris, Alessandro Aiuti, Alexei Maschan, Mahmoud Aljurf, Tobias Gedde-Dahl, Gunhan Gurman, Victoria Bordon, Gergely Kriván, Franco Locatelli, Fulvio Porta, David Valcárcel, Yves Beguin, Maura Faraci, Nicolaus Kröger, Aleksandr Kulagin, Peter J. Shaw, Joan Hendrik Veelken, Cristina Diaz de Heredia, Franca Fagioli, Matthias Felber, Bernd Gruhn, Wolfgang Holter, Claudia Rössig, Petr Sedlacek, Jane Apperley, Mouhab Ayas, Ivana Bodova, Goda Choi, J.J. Cornelissen, Anne Sirvent, Anjum Khan, Alphan Kupesiz, Stig Lenhoff, Hakan Ozdogu, Nicolas von der Weid, Montserrat Rovira, Rik Schots, Donald C. Vinh, Clinical sciences, and Hematology

Subjects
Adult, Adolescent, adolescenti, Trapianto, Immunology, Graft vs Host Disease, Biochemistry, Bronchiectasis/etiology, Humans, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation/adverse effects, Child, Retrospective Studies, cellule staminali ematopoietiche, Hematopoietic Stem Cell Transplantation, Infant, Trapianto, cellule staminali ematopoietiche, adolescenti, Inborn errors of immunity, Cell Biology, Hematology, Middle Aged, Bronchiectasis, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, HSCT, young adult
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published

Published
2022

6. Bone Marrow Fibrosis Changes Do Not Correlate with Efficacy Outcomes in Myelofibrosis: Analysis of More Than 300 JAK Inhibitor-Naïve Patients Treated with Momelotinib or Ruxolitinib

Author

Stephen T Oh, Srdan Verstovsek, Jason Gotlib, Vikas Gupta, Uwe Platzbecker, Heinz Gisslinger, Timothy Devos, Jean-Jacques Kiladjian, Donal P. McLornan, Andrew Charles Perkins, Maria Laura Fox, Mary Frances McMullin, Adam J Mead, Miklos Egyed, Jiri Mayer, Tomasz Sacha, Jun Kawashima, Mei Huang, Bryan Strouse, and Ruben Mesa

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

8. Coexisting Myeloproliferative and Lymphoproliferative Neoplasms: A European Multicenter Retrospective Study

Author

Dolly Viviana Viviana Fiallo Suarez, Ruth Stuckey, Cristina Bilbao, Maria Tapia Torres, Maria Angelina Lemes Castellano, Fernando Fernández-Fuertes, Leonor Pérez-Ortiz, Oscar Borsani, Elisa Rumi, Jean-Christophe Ianotto, Francisca Ferrer Marin, Mercedes Gasior Kabat, Beatriz Cuevas, Krzysztof Lewandowski, Alberto Alvarez-Larran, Marta Anna Sobas, Marco Santoro, María Ángeles Foncillas, Joanna Drozd-Sokolowska, Zuzanna Kandula, Juan Carlos Hernandez Boluda, Anna Angona, Gonzalo Carreño, María Alicia Senin, Maria Isabel Mata Vazquez, Maria Laura Fox, Rafael Del Orbe, Patricia Velez Tenza, Rolando Vallansot, and María Teresa Gómez-Casares

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

9. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM):results from an international, double-blind, randomised, controlled, phase 3 study

Author

Srdan Verstovsek, Aaron T Gerds, Alessandro M Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew T Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela C Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Nikki Granacher, Sung-Eun Lee, Luminita Ocroteala, Francesco Passamonti, Claire N Harrison, Barbara J Klencke, Sunhee Ro, Rafe Donahue, Jun Kawashima, Ruben Mesa, Adi Shacham Abulafia, Bjorn Andreasson, Anna Angona, Rosa Ayala, Soo-Mee Bang, Bruce Bank, Fiorenza Barraco, Eloise Beggiato, Fleur Samantha Benghiat, MassimiliaNo Bonifacio, Claire Bories, Gabriela Borsaru, Mette Brabrand, Andrei Braester, Andes Broliden, Veronika Buxhofer-Ausch, Nathalie Cambier, Marianna Caramella, Benjamin Carpentier, Nicola Cascavilla, Maria Giraldo Castellano, Hung Chang, Chih-Cheng Chen, June-Won Cheong, Yunsuk Choi, Philip Choi, Maria Teresa Corsetti, Isabel Montero Cuadrado, Julia Cunningham, Gandhi Laurent Damaj, Valerio De Stefano, Robert Delage, Regina Garcĺa Delgado, Jose Miguel Torregrosa Diaz, Péter Dombi, Viviane Dubruille, Miklós Egyed, Daniel El Fassi, Anna Elinder-Camburn, Elena Maria Elli, Martin Ellis, Carmen Fava, Salman Fazal, Angela Fleischman, Lynda Foltz, Laura Fox, Nashat Gabrail, Jose Valentĺn Garcĺa-Gutiérrez, Aaron Gerds, Stephane Girault, Heinz Gisslinger, Alexandru Gluvacov, Joachim Göthert, Evgeni (Evgueniy) Hadjiev (Hadzhiev), Kaoutar Hafraoui, Aryan Hamed, Claire Harrison, Hans Hasselbalch, Hanns Hauser, Mark Heaney, Holger Hebart, Jesus Maria Hernandez Rivas, Victor Higuero Saavedra, Christopher Hillis, Hsin-An Hou, Jonathan How, Daniel Huang, Marek Hus, Arpad Illés, Alessandro Isidori, Vadim Ivanov, Peter Johansson, Chul Won Jung, Ilya Kirgner, Maya Koren-Michowitz, Steffen Koschmieder, Szabolcs Ors Kosztolanyi, Natalia Kreiniz, Andrew Kuykendall, Jonathan Lambert, Kamel Laribi, Axelle Lascaux, Noa Lavie, Mihaela Lazaroiu, Michael Leahy, Ewa Lech-Maranda, Won Sik Lee, Ollivier Legrand, Roberto Lemoli, James Liang, Sung-Nam Lim, Michael Loschi, Alessandro Lucchesi, Ioan Macarie, Jean-Pierre Marolleau, Maurizio Martelli, Jiri Mayer, James McCloskey, Christopher McDermott, Brandon McMahon, Priyanka Mehta, Gábor Mikala, Dragana Milojkovic, Philippe Mineur, Elena Mishchenko, Joon Ho Moon, Zsolt Nagy, Srinivasan Narayanan, Casey O'Connell, Stephen Oh, Mario Ojeda-Uribe, Kiat Hoe Ong, Folashade Otegbeye, Jeanne Palmer, Fabrizio Pane, Andrea Patriarca, Giuseppe Pietrantuono, Mark Plander, Uwe Platzbecker, Ritam Prasad, Witold Prejzner, Tobias Rachow, Atanas Radinoff, László Rejtő, Ciro Rinaldi, Tadeusz Robak, Maria Angeles Fernandez Rodriguez, Aaron Ronson, David Ross, Tomasz Sacha, Parvis Sadjadian, Antonio Salar, Guillermo Sanz Santillana, Christof Scheid, Aline Schmidt, Marianne Tang Severinsen, Vera Stoeva, Paweł Szwedyk, Mario Tiribelli, Karolin Trautmann-Grill, Amy Trottier, Nikolay Tzvetkov, Janusz van Droogenbroeck, Alessandro Vannucchi, Nicola Vianelli, Nikolas von Bubnoff, Dominik Wolf, Dariusz Woszczyk, Tomasz Woźny, Tomasz Wróbel, Blanca Xicoy, and Su-Peng Yeh

Subjects
Anemia/drug therapy, Treatment Outcome, Double-Blind Method, Janus Kinase Inhibitors/therapeutic use, Danazol/adverse effects, Humans, Primary Myelofibrosis/complications, General Medicine
Abstract

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.FUNDING: Sierra Oncology.

Published
2023

10. Determinants of early triage for hospitalization in myeloproliferative neoplasm (MPN) patients with COVID-19

Author

Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Alessandra Iurlo, Marta Anna Sobas, Elena Maria Elli, Elisa Rumi, Valerio De Stefano, Francesca Lunghi, Monia Marchetti, Rosa Daffini, Mercedes Gasior Kabat, Beatriz Cuevas, Maria Laura Fox, Marcio Miguel Andrade‐Campos, Francesca Palandri, Paola Guglielmelli, Giulia Benevolo, Claire Harrison, Maria‐Angeles Foncillas, Massimiliano Bonifacio, Alberto Alvarez‐Larran, Jean‐Jacques Kiladjian, Estefanía Bolaños Calderón, Andrea Patriarca, Keina Quiroz Cervantes, Martin Griesshammer, Valentin Garcia‐Gutierrez, Alberto Marin Sanchez, Elena Magro Mazo, Giuseppe Carli, Juan Carlos Hernandez‐Boluda, Santiago Osorio, Gonzalo Carreno‐Tarragona, Miguel Sagues Serrano, Rajko Kusec, Begona Navas Elorza, Anna Angona, Blanca Xicoy Cirici, Emma Lopez Abadia, Steffen Koschmieder, Daniele Cattaneo, Cristina Bucelli, Edyta Cichocka, Anna Kulikowska de Nałęcz, Fabrizio Cavalca, Oscar Borsani, Silvia Betti, Marta Bellini, Natalia Curto‐Garcia, Alessandro Rambaldi, and Alessandro Maria Vannucchi

Subjects
Hospitalization, Myeloproliferative Disorders, Myeloproliferative Disorders / complications, Humans, COVID-19, Hematology, Myeloproliferative Disorders / therapy, Triage, Bone Marrow Neoplasms
Published
2022

11. Post thawing viable CD34+ Cells dose is a better predictor of clinical outcome in lymphoma patients undergoing autologous stem cell transplantation

Author

Jesus Fernandez-Sojo, Joan Cid, Carmen Azqueta, Elena Valdivia, Lluis Martorell, Margarita Codinach, Julia Marsal, Alberto Mussetti, Albert Esquirol, Maria Trabazo, Maria Isabel Benitez, Christelle Ferra, Maria Laura Fox, Mónica Linares, Eva Alonso, Enric García-Rey, Nadia García-Muñoz, Laura Medina, Nerea Castillo-Flores, Ferran Vall-Llovera, Antoni Garcia, Asuncion Pinacho, Carme Talarn, Jose Garcia Arroba, Rosa Coll, Mireia Santos, Oliver Valero, Enric Carreras, Miquel Lozano, and Sergio Querol

Subjects
Peripheral Blood Stem Cell Transplantation, Transplantation, Lymphoma, Hematopoietic Stem Cell Transplantation, Humans, Antigens, CD34, Hematology, Transplantation, Autologous
Published
2022

12. Second versus first wave of COVID-19 in patients with MPN

Author

Tiziano Barbui, Alessandra Iurlo, Arianna Masciulli, Alessandra Carobbio, Arianna Ghirardi, Greta Carioli, Marta Anna Sobas, Elena Maria Elli, Elisa Rumi, Valerio De Stefano, Francesca Lunghi, Monia Marchetti, Rosa Daffini, Mercedes Gasior Kabat, Beatriz Cuevas, Maria Laura Fox, Marcio Miguel Andrade-Campos, Francesca Palandri, Paola Guglielmelli, Giulia Benevolo, Claire Harrison, Maria Angeles Foncillas, Massimiliano Bonifacio, Alberto Alvarez-Larran, Jean-Jacques Kiladjian, Estefanía Bolaños Calderón, Andrea Patriarca, Keina Quiroz Cervantes, Martin Griessammer, Valentin Garcia-Gutierrez, Alberto Marin Sanchez, Elena Magro Mazo, Marco Ruggeri, Juan Carlos Hernandez-Boluda, Santiago Osorio, Gonzalo Carreno-Tarragona, Miguel Sagues Serrano, Rajko Kusec, Begona Navas Elorza, Anna Angona, Blanca Xicoy Cirici, Emma Lopez Abadia, Steffen Koschmieder, Daniele Cattaneo, Cristina Bucelli, Edyta Cichocka, Anna Masternak Kulikowska de Nałęcz, Fabrizio Cavalca, Oscar Borsani, Silvia Betti, Lina Benajiba, Marta Bellini, Natalia Curto-Garcia, Alessandro Rambaldi, and Alessandro Maria Vannucchi

Subjects
Cancer Research, COVID-19 / virology, Myeloproliferative Disorders, SARS-CoV-2, COVID-19, Hematology, SARS-CoV-2 / isolation & purification, Survival Analysis, Myeloproliferative disease, COVID-19 / mortality, Oncology, Risk Factors, Myeloproliferative Disorders / complications, Correspondence, Humans, Infectious diseases, COVID-19 / complications
Published
2021

13. Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies

Author

Marta Crespo, Eva Catalá, Isabel Ruiz-Camps, Maria Laura Fox, Guillermo Villacampa, Mónica Martínez-Gallo, Gemma Pujadas, Pau Abrisqueta, Candela Fernández-Naval, Soraya Peralta-Garzón, David Valcárcel, Tomás Pumarola, Moraima Jiménez, Magda Campins, Daniel Medina-Gil, Pere Barba, Alba Cabirta, Cristina Hernández, M. Hernández, Alberto Orfao, Francesc Bosch, Ana Marín-Niebla, Guillermo Ortí, Mercedes Valentín, Marcos González, Juliana Esperalba, Elisa Roldán, Mercedes Gironella, Carlota Pagès Geli, Generalitat de Catalunya, Institut Català de la Salut, [Jiménez M, Roldán E, Gironella M, Fox L, Orti G, Barba P, Valcárcel D, Bosch F, Abrisqueta P] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Fernández-Naval C, Pumarola T, Esperalba J] Servei de Microbiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Villacampa G] Oncology Data Science (ODysSey) Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Martinez-Gallo M, Hernández M] Servei d’Immunologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Medina-Gil D, Peralta-Garzón S, Pujadas G, Hernández C, Pagès C, Crespo M] Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Cabirta A, Catalá E, Valentín M, Marín-Niebla A] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Orfao A] Department of Medicine and Cytometry General ServiceNucleus, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), Salamanca, Spain. [González M] Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), CIBERONC–CB16/12/00233 and Center for Cancer Research–IBMCC (USAL-CSIC), Salamanca, Spain. [Campins M] Servei de Medicina Preventiva i Epidemiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ruiz-Camps I] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
COVID-19 Vaccines, Immunobiology and Immunotherapy, Clinical Trials and Observations, T cell, Antibodies, Viral, Hypogammaglobulinemia, Immunogenicity, Vaccine, medicine, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Humans, RNA, Messenger, Immune System Phenomena::Antibody Formation::Immunogenicity, Vaccine [PHENOMENA AND PROCESSES], neoplasias::neoplasias por localización::neoplasias hematológicas [ENFERMEDADES], BNT162 Vaccine, Aged, Response rate (survey), Messenger RNA, business.industry, SARS-CoV-2, Immunogenicity, Antibody titer, COVID-19, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Regular Article, Hematology, Aplasia, Neoplasms::Neoplasms by Site::Hematologic Neoplasms [DISEASES], medicine.disease, Antibodies, Neutralizing, medicine.anatomical_structure, Hematologic Neoplasms, Immunology, Humoral immunity, Sang - Malalties, fenómenos del sistema inmunitario::formación de anticuerpos::inmunogenicidad vacunal [FENÓMENOS Y PROCESOS], business, Immunoglobulines, COVID-19 (Malaltia) - Vacunació, 2019-nCoV Vaccine mRNA-1273
Abstract

Recent studies have shown a suboptimal humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients diagnosed with hematologic malignancies; however, data about cellular immunogenicity are scarce. The aim of this study was to evaluate both the humoral and cellular immunogenicity 1 month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by using the Elecsys and LIAISON anti–SARS-CoV-2 S assays, and T-cell response was assessed by using interferon-γ release immunoassay technology. Overall, 76.3% (184 of 241) of patients developed humoral immunity, and the cellular response rate was 79% (184 of 233). Hypogammaglobulinemia, lymphopenia, active hematologic treatment, and anti-CD20 therapy during the previous 6 months were associated with an inferior humoral response. Conversely, age >65 years, active disease, lymphopenia, and immunosuppressive treatment of graft-versus-host disease (GVHD) were associated with an impaired cellular response. A significant dissociation between the humoral and cellular responses was observed in patients treated with anti-CD20 therapy (the humoral response was 17.5%, whereas the cellular response was 71.1%). In these patients, B-cell aplasia was confirmed while T-cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients undergoing immunosuppressive treatment of GVHD, whereas only 52.4% had a cellular response. The cellular and humoral responses to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematologic malignancies are highly influenced by the presence of treatments such as anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients., The authors also thank the Cellex Foundation for providing research facilities and equipment and the CERCA Programme/Generalitat de Catalunya for institutional support.

Published
2021

14. Poster: MPN-483 Thrombocytopenic Myelofibrosis (MF) Patients Previously Treated With a JAK Inhibitor in a Phase 3 Randomized Study of Momelotinib (MMB) versus Danazol (DAN) [MOMENTUM]

Author

Aaron Gerds, Srdan Verstovsek, Alessandro Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Rafe Donahue, Jun Kawashima, and Ruben Mesa

Subjects
Cancer Research, Oncology, Hematology
Published
2022

15. MPN-483 Thrombocytopenic Myelofibrosis (MF) Patients Previously Treated With a JAK Inhibitor in a Phase 3 Randomized Study of Momelotinib (MMB) versus Danazol (DAN) [MOMENTUM]

Author

Aaron, Gerds, Srdan, Verstovsek, Alessandro, Vannucchi, Haifa Kathrin, Al-Ali, David, Lavie, Andrew, Kuykendall, Sebastian, Grosicki, Alessandra, Iurlo, Yeow Tee, Goh, Mihaela, Lazaroiu, Miklos, Egyed, Maria Laura, Fox, Donal, McLornan, Andrew, Perkins, Sung-Soo, Yoon, Vikas, Gupta, Jean-Jacques, Kiladjian, Rafe, Donahue, Jun, Kawashima, and Ruben, Mesa

Subjects
Cancer Research, Pyrimidines, Oncology, Primary Myelofibrosis, Danazol, Benzamides, Humans, Janus Kinase Inhibitors, Pyrazoles, Anemia, Hematology, Thrombocytopenia
Abstract

MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, was evaluated (vs DAN) in a pivotal phase 3 study of MF patients previously treated with a JAK inhibitor (JAKi). This subgroup analysis evaluated MOMENTUM patients with baseline platelet counts ≤150 × 10Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; total symptom score (TSS) ≥10; hemoglobin10 g/dL; prior JAKi ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 weeks or Grade 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm; platelets ≥25 × 10TSS response (≥50% reduction from baseline) rate at week 24. Secondary endpoints at week 24: transfusion independence (TI) rate, splenic response rate (SRR; ≥25% volume reduction from baseline), TSS change from baseline, SRR (≥35% reduction), and rate of zero transfusions since baseline.Mean baseline TSS: 29 MMB, 26 DAN, hemoglobin: 8.1 MMB, 7.8 DAN g/dL, and platelets: 74 × 10In symptomatic, anemic, and thrombocytopenic MF patients, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF patients. NCT04173494.

Published
2022

16. Poster: MPN-478 MOMENTUM: Phase 3 Randomized Study of Momelotinib (MMB) versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated With a JAK Inhibitor

Author

Ruben Mesa, Aaron Gerds, Alessandro Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Rafe Donahue, Jun Kawashima, and Srdan Verstovsek

Subjects
Cancer Research, Oncology, Hematology
Published
2022

17. Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5

Author

Marc E. Rothenberg, Florence Roufosse, Stanislas Faguer, Gerald J. Gleich, Jonathan Steinfeld, Steven W. Yancey, Eleni Mavropoulou, Namhee Kwon, Gabriel Ricardo García, Adriana Sosso, Luis Wehbe, Anahí Yañez, Daniël Blockmans, Martti Anton Antila, Daniela Blanco, Sergio Grava, Marina Andrade Lima, Andreia Luisa Francisco Pez, Mohamed A. Hamidou, Jean-Emmanuel Kahn, Guillaume Lefévre, Knut Brockow, Peter M. Kern, Andreas J. Reiter, Bastian Walz, Tobias Welte, Fabrizio Pane, Alessandro M. Vannucchi, Ruth Cerino-Javier, Alfredo Gazca-Aguilar, Dante D. Hernández-Colín, Héctor Glenn Valdéz-López, Izabela R. Kupryś-Lipińska, Jacek Musial, Witold Prejzner, Eniko Mihaly, Viola Popov, Mihnea Tudor Zdrenghea, Sergey V. Gritsaev, Vladimir Ivanov, Nikolay Tsyba, Aránzazu Alonso, Maria Cinta Cid Xutgla, Maria Laura Fox, Regina Garcia Delgado, Jesús María Hernández Rivas, Guillermo Sanz Santillana, Ana Isabel González, Andrew J. Wardlaw, Praveen Akuthota, Joseph H. Butterfield, Geoffrey L. Chupp, John B. Cox, and Devi Jhaveri

Subjects
Immunology and Allergy
Published
2022

18. Navitoclax plus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis: Preliminary safety and efficacy in a multicenter, open-label phase 2 study

Author

Francesco Passamonti, James M. Foran, Anand Tandra, Valerio De Stefano, Maria Laura Fox, Ahmad Hatem Mattour, Mary Frances McMullin, Andrew Perkins, Gabriela Rodriguez-Macias, Hassan Sibai, Qin Q. Qin, Jalaja Potluri, and Jonathan B. How

Subjects
Cancer Research, Oncology
Abstract

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-XL and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 109/L or >150 × 109/L, respectively. RUX was given BID with starting dose based on BL platelet count per local label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow (BM) fibrosis reduction, and anemia response. Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 pts received NAV+RUX. Median duration of f/u was 6.1 (range, 1.9 ─ 18.6) mos. 28 (88%) pts received NAV 200 mg and 4 (13%) received 100 mg OD. Median age was 69 (44 ─ 83) yrs, and median spleen volume was 1889.08 cm3 (645.6 ─ 7339.6). Median NAV and RUX exposures were 24.1 (5.1 ─ 80.9) and 20.1 (0.1 ─ 80.1) wks, respectively. 31 (97%) pts reported ≥1 AE (Grade ≥3 AEs, 25 [78%]; serious AEs, 6 [19%]). Most common Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). 3 (9%) and 2 (6%) pts reported an AE leading to NAV and RUX discontinuation, respectively, and 2 (6%; 1 PD, 1 cardiac disorder unrelated to NAV) AEs led to death ≤30 days after last NAV dose. SVR35 was achieved by 52% of evaluable pts at wk 24 (SVR35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR35 was 12.1 (11 ─ 47) wks. Conclusions: The combination of NAV+RUX was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in pts without prior JAK-2 inhibitor exposure. SVR35, TSS50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]

Published
2022

19. Thrombocytopenic myelofibrosis (MF) patients previously treated with a JAK inhibitor in a phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) [MOMENTUM]

Author

Aaron Thomas Gerds, Srdan Verstovsek, Alessandro Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew T. Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Cornelia Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal P. McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Rafe Donahue, Jun Kawashima, and Ruben A. Mesa

Subjects
Cancer Research, Oncology
Abstract

7061 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials, including in MF patients (pts) with thrombocytopenia. MOMENTUM is a pivotal phase 3 study of symptomatic and anemic MF pts previously treated with a JAK inhibitor (JAKi) testing MMB vs DAN. This analysis evaluated MOMENTUM pts with baseline (BL) platelet counts (PLT) ≤150 x 109/L. Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb 9/L. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks. Primary endpoint: TSS response (≥50% reduction from BL) rate at wk 24. Key secondary endpoints, assessed sequentially at wk 24: RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 60 (74%) of 81 MMB pts and 25 (58%) of 43 DAN pts with BL PLT ≤150 x 109/L completed the 24-week randomized treatment (RT) phase. Median BL TSS were 29 (MMB) and 24 (DAN), Hgb were 7.9 (MMB) and 8.0 (DAN) g/dL, and PLT were 67 x 109/L (MMB) and 64 x 109/L (DAN). Prior JAKi was ruxolitinib in 124 pts (100%) and fedratinib in 6 pts (5%). Efficacy results are in Table. These results are consistent with the overall ITT analysis set (N=195). Most common Gr ≥3 TEAEs in the RT phase were thrombocytopenia (MMB, 31%; DAN, 16%) and anemia (MMB, 7%; DAN, 14%); Gr ≥3 bleeding events occurred in 9% of MMB and 5% of DAN pts. TEAEs led to study drug discontinuation in 15% of MMB and 19% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN [HR (95% CI)=0.490 (0.195, 1.235)]. Additional analyses of pts with BL PLT 9/L (N=100) and BL PLT 9/L (N=31) show similar treatment effects of MMB vs DAN. Conclusions: In thrombocytopenic MF pts who were symptomatic and anemic, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses and showed comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF pts. Clinical trial information: NCT04173494. [Table: see text]

Published
2022

20. MOMENTUM: Phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor

Author

Ruben A. Mesa, Aaron Thomas Gerds, Alessandro Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew T. Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Cornelia Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal P. McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Rafe Donahue, Jun Kawashima, and Srdan Verstovsek

Subjects
Cancer Research, Oncology
Abstract

7002 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials. This pivotal phase 3 study of MF patients (pts) previously treated with a JAK inhibitor (JAKi) tested MMB vs DAN on key symptom, anemia, and spleen volume endpoints at 24 weeks (wks). Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb 9/L. BL TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%). All primary and key secondary endpoints were met (Table). Most common Gr ≥3 TEAEs in the RT phase of the study were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). Gr ≥3 infections occurred in 15% of MMB and 17% of DAN pts. Peripheral neuropathy occurred in 5 (4%) of MMB (all Gr ≤2) and 1 (2%) of DAN (Gr ≤2) pts in the RT phase, and none discontinued study drug. Overall, TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN (HR=0.506, p=0.0719). Conclusions: In symptomatic and anemic MF pts, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF pts with anemia. Clinical trial information: NCT04173494. [Table: see text]

Published
2022

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