Omar Ammari, Mina Shah, Yasmin Elgammal, Ammar Husami, Theodosia A. Kalfa, Jahnavi Gollamudi
<p>Sickle cell trait (SCT) is a heterozygous form of sickle cell disease (SCD) and occurs from a genetic mutation in one of two copies of the beta-globin gene, where valine replaces glutamic acid (HbS) [<span>1</span>]. The prevalence of SCT is around 5% in people of African ancestry in the United States [<span>2</span>]. Most individuals with SCT remain asymptomatic; complications typically occur only under extreme physiological stress, such as high altitude or dehydration [<span>3</span>]. Organ damage is rare, although the presence of SCT has been associated with chronic kidney disease (CKD) and venous thromboembolism (VTE) [<span>3, 4</span>]. Recent literature [<span>2</span>] attributes coinheritance of other red cell disorders as a risk factor for severe organ damage in individuals with SCT [<span>5</span>].</p><p>Hereditary spherocytosis (HS) is a red blood cell (RBC) membranopathy due to a mutation in cytoskeletal proteins, lending RBCs a spherical shape, leading to increased RBC fragility and hemolysis [<span>6</span>]. While individuals with HS and SCT alone have a typically mild clinical course, the coinheritance of these two conditions can result in severe clinical sequalae [<span>7</span>]. Prior literature on HS and SCT coinheritance demonstrates splenic sequestration or infarct as a typical complication in association with stressors, but there are no cases that describe extra-splenic manifestations [<span>7-9</span>]. Herein, we present a case of a 54-year-old female with SCT, HS, and a heterozygous G6PD A-pathogenic variant who presented with avascular necrosis (AVN) and proliferative retinopathy.</p><p>A 54-year-old woman of African ancestry with known SCT presented to our hematology office at the University of Cincinnati Medical Center after X-rays for right knee pain workup indicated medial femoral condyle subchondral lucency with increasing peripheral sclerosis, suggesting AVN. She had thigh and knee pain, fatigue, body aches, and left-sided abdominal pain following air travel and exercise. Labs revealed normal hemoglobin with evidence of chronic hemolysis (see Table 1). A CT scan completed 1 year prior showed normal spleen size. MRI of the right knee confirmed AVN in the lateral and medial femoral condyles.</p><p>The usual causes of AVN were investigated. She denied prolonged steroid exposure, a history of thrombosis, or connective tissue disorders. Serum protein electrophoresis and hypercoagulability workup were negative (see Table 1). She had mildly positive anticardiolipin antibodies which did not meet the Sapporo criteria of antiphospholipid syndrome (APS) [<span>10</span>].</p><p>Hemoglobin electrophoresis and subsequent beta-globin gene testing confirmed SCT [<i>HBB</i> c.20A>T, p.(Glu7Val)]. The incongruence between clinical symptoms and the SCT status led to testing for coinheritance of other RBC disorders. Briefly, hemoglobin-O<sub>2</sub> affinity (p50) and viscosity testing were normal. G6PD level was found to
{"title":"When a Trait Becomes a Disease: A Rare Hematologic Overlap of Sickle Cell Trait and Hereditary Spherocytosis","authors":"Omar Ammari, Mina Shah, Yasmin Elgammal, Ammar Husami, Theodosia A. Kalfa, Jahnavi Gollamudi","doi":"10.1002/ajh.70154","DOIUrl":"10.1002/ajh.70154","url":null,"abstract":"<p>Sickle cell trait (SCT) is a heterozygous form of sickle cell disease (SCD) and occurs from a genetic mutation in one of two copies of the beta-globin gene, where valine replaces glutamic acid (HbS) [<span>1</span>]. The prevalence of SCT is around 5% in people of African ancestry in the United States [<span>2</span>]. Most individuals with SCT remain asymptomatic; complications typically occur only under extreme physiological stress, such as high altitude or dehydration [<span>3</span>]. Organ damage is rare, although the presence of SCT has been associated with chronic kidney disease (CKD) and venous thromboembolism (VTE) [<span>3, 4</span>]. Recent literature [<span>2</span>] attributes coinheritance of other red cell disorders as a risk factor for severe organ damage in individuals with SCT [<span>5</span>].</p><p>Hereditary spherocytosis (HS) is a red blood cell (RBC) membranopathy due to a mutation in cytoskeletal proteins, lending RBCs a spherical shape, leading to increased RBC fragility and hemolysis [<span>6</span>]. While individuals with HS and SCT alone have a typically mild clinical course, the coinheritance of these two conditions can result in severe clinical sequalae [<span>7</span>]. Prior literature on HS and SCT coinheritance demonstrates splenic sequestration or infarct as a typical complication in association with stressors, but there are no cases that describe extra-splenic manifestations [<span>7-9</span>]. Herein, we present a case of a 54-year-old female with SCT, HS, and a heterozygous G6PD A-pathogenic variant who presented with avascular necrosis (AVN) and proliferative retinopathy.</p><p>A 54-year-old woman of African ancestry with known SCT presented to our hematology office at the University of Cincinnati Medical Center after X-rays for right knee pain workup indicated medial femoral condyle subchondral lucency with increasing peripheral sclerosis, suggesting AVN. She had thigh and knee pain, fatigue, body aches, and left-sided abdominal pain following air travel and exercise. Labs revealed normal hemoglobin with evidence of chronic hemolysis (see Table 1). A CT scan completed 1 year prior showed normal spleen size. MRI of the right knee confirmed AVN in the lateral and medial femoral condyles.</p><p>The usual causes of AVN were investigated. She denied prolonged steroid exposure, a history of thrombosis, or connective tissue disorders. Serum protein electrophoresis and hypercoagulability workup were negative (see Table 1). She had mildly positive anticardiolipin antibodies which did not meet the Sapporo criteria of antiphospholipid syndrome (APS) [<span>10</span>].</p><p>Hemoglobin electrophoresis and subsequent beta-globin gene testing confirmed SCT [<i>HBB</i> c.20A>T, p.(Glu7Val)]. The incongruence between clinical symptoms and the SCT status led to testing for coinheritance of other RBC disorders. Briefly, hemoglobin-O<sub>2</sub> affinity (p50) and viscosity testing were normal. G6PD level was found to ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"601-605"},"PeriodicalIF":9.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Niccolò Bartalucci, Danilo Tarantino, Giuseppe G. Loscocco, Alessio Enderti, Daniele Colazzo, Raffaella Santi, Daniela Parrini, Manjola Balliu, Valentina Boldrini, Yasmine Abbassi, Elisabetta Pelo, Monia Marchetti, Paola Guglielmelli, Alessandro M. Vannucchi
In our study, we identified a novel, ruxolitinib-sensitive, CCDC6::JAK2 fusion gene as a driver of atypical JAK2-unmutated MPN with a polycythemic phenotype. The CCDC6::JAK2 chimeric protein retains the CCDC6 coiled-coil domain and the JAK2 kinase domain. Dimerization of chimeric proteins through coiled-coil domains promotes JAK2 autophosphorylation leading to constitutive activation of the JAK/STAT signaling pathway.
{"title":"A Novel, Ruxolitinib-Sensitive, CCDC6::JAK2 Fusion Gene in a Patient With Atypical, JAK2 Unmutated, Polycythemia Vera-Like, Myeloproliferative Neoplasm","authors":"Niccolò Bartalucci, Danilo Tarantino, Giuseppe G. Loscocco, Alessio Enderti, Daniele Colazzo, Raffaella Santi, Daniela Parrini, Manjola Balliu, Valentina Boldrini, Yasmine Abbassi, Elisabetta Pelo, Monia Marchetti, Paola Guglielmelli, Alessandro M. Vannucchi","doi":"10.1002/ajh.70156","DOIUrl":"10.1002/ajh.70156","url":null,"abstract":"<p>In our study, we identified a novel, ruxolitinib-sensitive, <i>CCDC6</i>::J<i>AK2</i> fusion gene as a driver of atypical <i>JAK2</i>-unmutated MPN with a polycythemic phenotype. The CCDC6::JAK2 chimeric protein retains the CCDC6 coiled-coil domain and the JAK2 kinase domain. Dimerization of chimeric proteins through coiled-coil domains promotes JAK2 autophosphorylation leading to constitutive activation of the JAK/STAT signaling pathway.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"379-383"},"PeriodicalIF":9.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pablo Bartolucci, Étienne Audureau, Vincent Audard, Frédéric Galactéros, Guillaume Lettre, Charmaine Anthony, Olufolake Egbujo, Jin Han, Maria Armila Ruiz, James P. Lash, Victor R. Gordeuk, Xu Zhang, Santosh L. Saraf
Chronic kidney disease (CKD) is common and a major contributor to increased morbidity and early mortality in people with sickle cell anemia (SCA). Urine albumin-to-creatinine ratio (uACR) is recommended to identify patients with SCA-related CKD but its utility in predicting long-term kidney dysfunction remains unclear in this patient population. In two independent, longitudinal cohorts of patients with hemoglobin SS or Sβ0-thalassemia (USA: n = 268, median follow-up 6 years; France: n = 310, median follow-up 8.2 years) we investigated the utility of uACR, as well as other clinical and modifiable risk factors, for predicting a decline in kidney function as determined by the rate of estimated glomerular filtration rate (eGFR) decline. Using linear mixed-effects models, a higher baseline uACR independently predicted a faster rate of eGFR decline as well as a more rapid annual eGFR decline, defined as ≥ 3 mL/min/1.73m2 (p ≤ 0.009). Furthermore, baseline uACR of ≥ 100 mg/g creatinine was independently associated with the rate of eGFR decline and rapid annual eGFR decline in both cohorts. Tobacco smoking was also associated with a faster rate of eGFR decline and was congruous between the two cohorts. In conclusion, we demonstrate that uACR is an important clinical tool that predicts a more rapid decline in kidney function and should be routinely monitored in people with SCA. Our data also support preventative care to reduce tobacco smoking for mitigating the risk of CKD progression in this high-risk population.
{"title":"Albuminuria Predicts a Rapid Decline in Kidney Function in 2 International, Longitudinal Cohorts of Adults With Sickle Cell Anemia","authors":"Pablo Bartolucci, Étienne Audureau, Vincent Audard, Frédéric Galactéros, Guillaume Lettre, Charmaine Anthony, Olufolake Egbujo, Jin Han, Maria Armila Ruiz, James P. Lash, Victor R. Gordeuk, Xu Zhang, Santosh L. Saraf","doi":"10.1002/ajh.70155","DOIUrl":"10.1002/ajh.70155","url":null,"abstract":"<p>Chronic kidney disease (CKD) is common and a major contributor to increased morbidity and early mortality in people with sickle cell anemia (SCA). Urine albumin-to-creatinine ratio (uACR) is recommended to identify patients with SCA-related CKD but its utility in predicting long-term kidney dysfunction remains unclear in this patient population. In two independent, longitudinal cohorts of patients with hemoglobin SS or Sβ<sup>0</sup>-thalassemia (USA: <i>n</i> = 268, median follow-up 6 years; France: <i>n</i> = 310, median follow-up 8.2 years) we investigated the utility of uACR, as well as other clinical and modifiable risk factors, for predicting a decline in kidney function as determined by the rate of estimated glomerular filtration rate (eGFR) decline. Using linear mixed-effects models, a higher baseline uACR independently predicted a faster rate of eGFR decline as well as a more rapid annual eGFR decline, defined as ≥ 3 mL/min/1.73m<sup>2</sup> (<i>p</i> ≤ 0.009). Furthermore, baseline uACR of ≥ 100 mg/g creatinine was independently associated with the rate of eGFR decline and rapid annual eGFR decline in both cohorts. Tobacco smoking was also associated with a faster rate of eGFR decline and was congruous between the two cohorts. In conclusion, we demonstrate that uACR is an important clinical tool that predicts a more rapid decline in kidney function and should be routinely monitored in people with SCA. Our data also support preventative care to reduce tobacco smoking for mitigating the risk of CKD progression in this high-risk population.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"304-310"},"PeriodicalIF":9.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alicja Sadowska-Klasa, Fang Yun Lim, Hu Xie, Danniel Zamora, Terry Stevens-Ayers, Wendy M. Leisenring, Bradley C. Edmison, Stephen C. De Rosa, Marco Mielcarek, Michael Boeckh
Polyfunctional cytomegalovirus (CMV)-specific T cells are critical for antiviral immunity in allogeneic hematopoietic cell transplantation (HCT) recipients. However, gaps remain in managing refractory CMV and optimizing virus-specific cellular therapy (VST). We conducted a comparative analysis of how timing and dosing of immunosuppressive agents, including post-transplant cyclophosphamide (PT-Cy), corticosteroids, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs), shape CMV-specific T-cell polyfunctionality. CD4+ and CD8+ T-cell responses (IFN-γ plus ≥ 1 functional marker) were assessed following pp65 stimulation within 100 days post-HCT in the pre- and post-letermovir era. Among 243 patients, 31% exhibited polyfunctional CD4+ and CD8+ responses. PT-Cy did not significantly impair T-cell functionality. Cyclosporine was associated with higher frequencies of polyfunctional T cells compared to tacrolimus, even at concentrations above the therapeutic range. Intermediate (≥ 0.5 mg/kg) and high-dose (≥ 1 mg/kg) corticosteroids, especially within 2–4 weeks before testing, significantly suppressed T-cell responses, though rapid tapering preserved function. Prolonged administration of MMF (≥ 2000 mg) diminished T-cell polyfunctionality. These findings provide novel insights into the importance of timing and dosing of the immunosuppressive effects of PT-Cy, corticosteroids, MMF and CNIs on CMV-specific immunity. Adjusting immunosuppression in specific time windows may improve the management of refractory CMV infections and optimize VST in HCT recipients.
{"title":"New Insights Into Factors Shaping CMV-Specific T-Cell Polyfunctionality After Hematopoietic Cell Transplantation","authors":"Alicja Sadowska-Klasa, Fang Yun Lim, Hu Xie, Danniel Zamora, Terry Stevens-Ayers, Wendy M. Leisenring, Bradley C. Edmison, Stephen C. De Rosa, Marco Mielcarek, Michael Boeckh","doi":"10.1002/ajh.70152","DOIUrl":"10.1002/ajh.70152","url":null,"abstract":"<p>Polyfunctional cytomegalovirus (CMV)-specific T cells are critical for antiviral immunity in allogeneic hematopoietic cell transplantation (HCT) recipients. However, gaps remain in managing refractory CMV and optimizing virus-specific cellular therapy (VST). We conducted a comparative analysis of how timing and dosing of immunosuppressive agents, including post-transplant cyclophosphamide (PT-Cy), corticosteroids, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs), shape CMV-specific T-cell polyfunctionality. CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses (IFN-γ plus ≥ 1 functional marker) were assessed following pp65 stimulation within 100 days post-HCT in the pre- and post-letermovir era. Among 243 patients, 31% exhibited polyfunctional CD4<sup>+</sup> and CD8<sup>+</sup> responses. PT-Cy did not significantly impair T-cell functionality. Cyclosporine was associated with higher frequencies of polyfunctional T cells compared to tacrolimus, even at concentrations above the therapeutic range. Intermediate (≥ 0.5 mg/kg) and high-dose (≥ 1 mg/kg) corticosteroids, especially within 2–4 weeks before testing, significantly suppressed T-cell responses, though rapid tapering preserved function. Prolonged administration of MMF (≥ 2000 mg) diminished T-cell polyfunctionality. These findings provide novel insights into the importance of timing and dosing of the immunosuppressive effects of PT-Cy, corticosteroids, MMF and CNIs on CMV-specific immunity. Adjusting immunosuppression in specific time windows may improve the management of refractory CMV infections and optimize VST in HCT recipients.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"255-268"},"PeriodicalIF":9.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Malagola, L. Castagna, D. Matranga, et al., “Outcome of Patients With Acute Myeloid Leukemias or Myelodysplastic Syndromes After Relapsing From Allogeneic Stem Cell Transplantation: The GITMO AML/MDS-Relapse Registry Study.” American Journal of Hematology 100, no. 10 (2025): 1902–1905. https://doi.org/10.1002/ajh.70030.
In this article, the authorsʼ names were incorrect. The correct list is below:
DuJiang Yang, Jiexiang Yang, Shuang Wang, GuoYou Wang
{"title":"Determinants of Ultra‐Long‐Term Survival in Multiple Myeloma: A Critical Appraisal of Foundational Assumptions and a Call for Biologically Driven Inquiry","authors":"DuJiang Yang, Jiexiang Yang, Shuang Wang, GuoYou Wang","doi":"10.1002/ajh.70153","DOIUrl":"https://doi.org/10.1002/ajh.70153","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"200 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicola Polverelli, Caterina Zerbi, Maria Grazia Benevento, Mattia Algeri, Alessandra Algarotti, Emanuele Angelucci, Adriana Cristina Balduzzi, Marco Basiricò, Simona Bassi, Giorgia Battipaglia, Edoardo Benedetti, Alessandra Biffi, Francesca Bonifazi, Carlo Borghero, Stefania Bramanti, Lucia Brunello, Paola Bresciani, Alessandro Busca, Roberto Cairoli, Paola Carluccio, Francesca Carobolante, Angelo Michele Carella, Irene Maria Cavattoni, Raffaella Cerretti, Annalisa Chiappella, Patrizia Chiusolo, Michele Cimminiello, Paolo Corradini, Alessandra Crescimanno, Angela Cuoghi, Nicola Di Renzo, Franca Fagioli, Renato Fanin, Maura Faraci, Vincenzo Federico, Antonella Geromin, Luisa Giaccone, Alice Giacomazzi, Anna Grassi, Giovanni Grillo, Annalisa Imovilli, Claudia Ingrosso, Anna Paola Iori, Giorgio La Nasa, Salvatore Leotta, Maria Teresa Lupo Stanghellini, Giorgia Mancini, Jacopo Mariotti, Anna Mele, Mariacristina Menconi, Francesco Merli, Nicola Mordini, Maurizio Musso, Chiara Nozzoli, Fabrizio Pane, Matteo Parma, Rocco Pastano, Domenico Pastore, Francesca Patriarca, Alessandra Picardi, Simona Piemontese, Antonio Pierini, Eugenia Piras, Fulvio Porta, Gaetana Porto, Arcangelo Prete, Lucia Prezioso, Anna Proia, Annamaria Raiola, Roberto Ricci, Marcello Roberto, Chiara Rosignoli, Domenico Russo, Dalila Salvatore, Stella Santarone, Giorgia Saporiti, Francesco Saraceni, Carmine Selleri, Bianca Serio, Cristina Skert, Simona Sica, Alessandro Spina, Francesco Paolo Tambaro, Cristina Tecchio, Elisabetta Terruzzi, Manuela Tumino, Daniele Vallisa, Francesco Zallio, Marco Zecca, Alessia Taurino, Antonio Bianchessi, Irene Defrancesco, Giulia Losi, Eliana Degrandi, Michele Malagola, Luca Castagna, Massimo Martino
Compared to historical reports, both aGVHD and cGVHD appeared to have decreased in the recent transplant era, possibly due to the extension of T-cell depletion, the availability of effective second-line approaches in SR/D GVHD and improved anti-infectious prophylaxis and treatments.
Matteo Molica, Gema Miralles, Richard Dillon, Mario Annunziata, Faisal Basheer, Juan M. Bergua, Ferran Vall-Llovera Calmet, Victoria Campbell, Denis Cetin, Gaetano Cimino, Giulia Ciotti, Andrea Corbingi, Laura De Fazio, Hasim Atakan Erol, Vincenzo Federico, Cristina Gil, Yasa Gul Mutlu, Amaia Balerdi Malcorra, Sabrina Mariani, Carla Mazzone, Antonino Mulè, Gerardo Musuraca, Anjum Khan, Mariana Norata, Jenny O'Nions, Fanny Erika Palumbo, Cristina Papayannidis, Anna Lina Piccioni, Maria Teresa Olave Rubio, Jackeline Sanchez-Tovar, Istemi Serin, Alessandra Serrao, Omur Gokmen Sevindik, Giuseppe Sucato, Marina Aurora Urbano, Calogero Vetro, Susana Vives, Marco Rossi, Maria Paola Martelli, Pau Montesinos, Jad Othman, Salvatore Perrone
Gilteritinib is a selective FLT3 inhibitor approved for the treatment of relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) following ≥ 1 prior line of therapy. However, data on its effectiveness in later-line settings is limited. We conducted a multicenter, retrospective study including 171 adult patients with R/R FLT3-mutated AML who received gilteritinib as third-line or beyond between August 2017 and March 2024 across centers in Italy, Spain, the United Kingdom, and Turkey. The primary endpoint was overall survival (OS). Secondary endpoints included overall response rate (ORR), composite complete remission (cCR), duration of response. Among the 171 patients, 84% carried FLT3-ITD mutations and 26% had received ≥ 3 prior lines of therapy. The cCR rate was 28%, and ORR was 47%. Patients who were younger and presented with relapsed (vs. refractory) disease had better outcomes. Prior exposure to venetoclax or allogeneic hematopoietic stem cell transplantation (HSCT) was associated with inferior response. Gilteritinib enabled HSCT in 12% of patients. Median OS was 7.1 months (95% CI, 5.9–10.1), and in Cox-regression analysis was significantly improved among responders and those who underwent HSCT (median OS: 21.5 months; 95% CI, 12.8–NR). Prior venetoclax exposure was associated with shorter survival (5.7 months; 95% CI, 5.1–8.8). On multivariate analysis, previous exposure to venetoclax and FLT3 inhibitors was the strongest predictor of reduced response rates. Despite heavy pretreatment, gilteritinib retained clinically relevant activity in later-line R/R FLT3-mutated AML. Its use beyond second-line may serve as a bridge to HSCT in selected patients. Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.
{"title":"Effectiveness of Gilteritinib Beyond Second-Line Therapy in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Real-World Multicenter Study of 171 Patients","authors":"Matteo Molica, Gema Miralles, Richard Dillon, Mario Annunziata, Faisal Basheer, Juan M. Bergua, Ferran Vall-Llovera Calmet, Victoria Campbell, Denis Cetin, Gaetano Cimino, Giulia Ciotti, Andrea Corbingi, Laura De Fazio, Hasim Atakan Erol, Vincenzo Federico, Cristina Gil, Yasa Gul Mutlu, Amaia Balerdi Malcorra, Sabrina Mariani, Carla Mazzone, Antonino Mulè, Gerardo Musuraca, Anjum Khan, Mariana Norata, Jenny O'Nions, Fanny Erika Palumbo, Cristina Papayannidis, Anna Lina Piccioni, Maria Teresa Olave Rubio, Jackeline Sanchez-Tovar, Istemi Serin, Alessandra Serrao, Omur Gokmen Sevindik, Giuseppe Sucato, Marina Aurora Urbano, Calogero Vetro, Susana Vives, Marco Rossi, Maria Paola Martelli, Pau Montesinos, Jad Othman, Salvatore Perrone","doi":"10.1002/ajh.70142","DOIUrl":"10.1002/ajh.70142","url":null,"abstract":"<p>Gilteritinib is a selective FLT3 inhibitor approved for the treatment of relapsed or refractory (R/R) <i>FLT3</i>-mutated acute myeloid leukemia (AML) following ≥ 1 prior line of therapy. However, data on its effectiveness in later-line settings is limited. We conducted a multicenter, retrospective study including 171 adult patients with R/R <i>FLT3</i>-mutated AML who received gilteritinib as third-line or beyond between August 2017 and March 2024 across centers in Italy, Spain, the United Kingdom, and Turkey. The primary endpoint was overall survival (OS). Secondary endpoints included overall response rate (ORR), composite complete remission (cCR), duration of response. Among the 171 patients, 84% carried <i>FLT3</i>-ITD mutations and 26% had received ≥ 3 prior lines of therapy. The cCR rate was 28%, and ORR was 47%. Patients who were younger and presented with relapsed (vs. refractory) disease had better outcomes. Prior exposure to venetoclax or allogeneic hematopoietic stem cell transplantation (HSCT) was associated with inferior response. Gilteritinib enabled HSCT in 12% of patients. Median OS was 7.1 months (95% CI, 5.9–10.1), and in Cox-regression analysis was significantly improved among responders and those who underwent HSCT (median OS: 21.5 months; 95% CI, 12.8–NR). Prior venetoclax exposure was associated with shorter survival (5.7 months; 95% CI, 5.1–8.8). On multivariate analysis, previous exposure to venetoclax and FLT3 inhibitors was the strongest predictor of reduced response rates. Despite heavy pretreatment, gilteritinib retained clinically relevant activity in later-line R/R <i>FLT3</i>-mutated AML. Its use beyond second-line may serve as a bridge to HSCT in selected patients. Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 1","pages":"89-96"},"PeriodicalIF":9.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parsa Riazi Esfahani, Tri Brian Nguyen, Akshay Reddy, Aidan Yong, Jason Ward, Nathaniel Tak, Victoria Farasat, Kimia Rezaei, Ekjyot Gill, Jayanth Sridhar
<p>Anemia, characterized by decreased hemoglobin concentration and reduced red blood cell count, affects more than one-third of the global population and contributes substantially to illness and death among young children and pregnant women [<span>1</span>]. Conventional laboratory-based screening is resource-intensive and often inaccessible in low-resource settings [<span>2</span>]. Clinical assessment of conjunctival pallor offers a rapid, noninvasive alternative; however, its accuracy varies with observer experience and lighting conditions [<span>3</span>].</p><p>Deep convolutional neural networks can learn useful image features directly from data, improving the detection of subtle signs. Initial image-processing and thresholding methods achieved about 80%–84% accuracy in detecting conjunctival pallor [<span>2, 3</span>]. More recent studies using ensemble learning and CNNs on augmented data reported nearly 90% accuracy and added hemoglobin level prediction in pediatric groups [<span>4-6</span>]. However, previous studies have varied in algorithmic approach and dataset scope: Tamir et al. applied SVM thresholding to the anterior conjunctiva with 78.9% accuracy, Noor et al. compared decision trees, SVM, and KNN reaching up to 82.6% accuracy, Dimauro et al. mapped noninvasive devices, Appiahene CP-AnemiC yielded 80.6% accuracy, Appiahene's smartphone application reached 92.5% accuracy, Asare et al. reported 98.5% accuracy on pediatric conjunctiva, and Sehar et al. evaluated ensembles and CNNs achieving 89.5% accuracy (see Table S1 for the complete list of studies) [<span>2-8</span>]. A systematic review of these studies was conducted in accordance with PRISMA guidelines (see Figure S1). The question of whether training on comprehensive full-eye images rather than isolated palpebral views yields better generalization has not been directly addressed.</p><p>We used 218 conjunctival photographs (126 healthy and 92 anemic) from the Eyes-Defy-Anemia dataset, which provides both full-eye photographs and corresponding isolated palpebral images [<span>9</span>]. Images were divided into training (<i>n</i> = 174; 80%), validation (<i>n</i> = 22; 10%), and test (<i>n</i> = 22; 10%) sets by stratified sampling (Figure S2). Labels were based on WHO hemoglobin thresholds (< 12 g/dL for nonpregnant females and < 13 g/dL for males) and incorporated biological sex. Gender, age, and Hb levels were provided, and the anemic labels followed WHO definitions [<span>10-12</span>].</p><p>Images were split using stratified sampling into training (<i>n</i> = 174), validation (<i>n</i> = 22), and test (<i>n</i> = 22) sets, with a fixed random seed (Figure S2). This mitigated the impact of random split variation and allowed consistent evaluation across models. Four AutoML image classification models were trained using Google Vertex AI (single-label, default settings), which performs transfer learning on a modern CNN backbone with automated hyperparameter tuning. We co
{"title":"Advancing Anemia Detection With Deep Neural Networks: A Comparative Analysis of Training Strategies Using Conjunctival Images","authors":"Parsa Riazi Esfahani, Tri Brian Nguyen, Akshay Reddy, Aidan Yong, Jason Ward, Nathaniel Tak, Victoria Farasat, Kimia Rezaei, Ekjyot Gill, Jayanth Sridhar","doi":"10.1002/ajh.70143","DOIUrl":"10.1002/ajh.70143","url":null,"abstract":"<p>Anemia, characterized by decreased hemoglobin concentration and reduced red blood cell count, affects more than one-third of the global population and contributes substantially to illness and death among young children and pregnant women [<span>1</span>]. Conventional laboratory-based screening is resource-intensive and often inaccessible in low-resource settings [<span>2</span>]. Clinical assessment of conjunctival pallor offers a rapid, noninvasive alternative; however, its accuracy varies with observer experience and lighting conditions [<span>3</span>].</p><p>Deep convolutional neural networks can learn useful image features directly from data, improving the detection of subtle signs. Initial image-processing and thresholding methods achieved about 80%–84% accuracy in detecting conjunctival pallor [<span>2, 3</span>]. More recent studies using ensemble learning and CNNs on augmented data reported nearly 90% accuracy and added hemoglobin level prediction in pediatric groups [<span>4-6</span>]. However, previous studies have varied in algorithmic approach and dataset scope: Tamir et al. applied SVM thresholding to the anterior conjunctiva with 78.9% accuracy, Noor et al. compared decision trees, SVM, and KNN reaching up to 82.6% accuracy, Dimauro et al. mapped noninvasive devices, Appiahene CP-AnemiC yielded 80.6% accuracy, Appiahene's smartphone application reached 92.5% accuracy, Asare et al. reported 98.5% accuracy on pediatric conjunctiva, and Sehar et al. evaluated ensembles and CNNs achieving 89.5% accuracy (see Table S1 for the complete list of studies) [<span>2-8</span>]. A systematic review of these studies was conducted in accordance with PRISMA guidelines (see Figure S1). The question of whether training on comprehensive full-eye images rather than isolated palpebral views yields better generalization has not been directly addressed.</p><p>We used 218 conjunctival photographs (126 healthy and 92 anemic) from the Eyes-Defy-Anemia dataset, which provides both full-eye photographs and corresponding isolated palpebral images [<span>9</span>]. Images were divided into training (<i>n</i> = 174; 80%), validation (<i>n</i> = 22; 10%), and test (<i>n</i> = 22; 10%) sets by stratified sampling (Figure S2). Labels were based on WHO hemoglobin thresholds (< 12 g/dL for nonpregnant females and < 13 g/dL for males) and incorporated biological sex. Gender, age, and Hb levels were provided, and the anemic labels followed WHO definitions [<span>10-12</span>].</p><p>Images were split using stratified sampling into training (<i>n</i> = 174), validation (<i>n</i> = 22), and test (<i>n</i> = 22) sets, with a fixed random seed (Figure S2). This mitigated the impact of random split variation and allowed consistent evaluation across models. Four AutoML image classification models were trained using Google Vertex AI (single-label, default settings), which performs transfer learning on a modern CNN backbone with automated hyperparameter tuning. We co","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"361-364"},"PeriodicalIF":9.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yu Hu, Hui Chen, Zhifa Wang, Jingyao Ma, Shuyue Dong, Xi Lin, Xiaoling Cheng, James B. Bussel, Zhenping Chen, Runhui Wu
<p>Immune thrombocytopenia (ITP), an acquired autoimmune thrombocytopenic disorder, results from increased platelet destruction by the mononuclear phagocyte system and inadequate platelet production [<span>1</span>]. Patients not responding to first-line treatments (intravenous immunoglobulin, IVIG and steroids), or second-line rescue therapies (immunosuppressive agents, thrombopoietin receptor agonists (TPO-RAs), or splenectomy), and requiring long-term treatment, have refractory primary immune thrombocytopenia (RITP) [<span>2</span>]. Chronic RITP (CRITP) is associated with significant worsening of QoL and difficult clinical management, which can lead to life-threatening bleeding with high morbidity and mortality [<span>3</span>]. There remains a need for novel therapeutics in CRITP beyond TPO-RA. Daratumumab (Dara), a humanized anti-CD38 antibody widely used for treating multiple myeloma [<span>4</span>], has a favorable safety profile and is a promising candidate for treating antibody-mediated autoimmune diseases, including ITP [<span>5-7</span>].</p><p>We report 11 CRITP patients treated with anti-CD38 monoclonal antibody (Dara) from April 2023 to August 2024. Patients were eligible if aged 1–18 years and diagnosed with ITP according to the International Working Group (IWG) guidelines [<span>8</span>]. Additional key eligibility criteria were: (1) mean platelet count on two separate occasions at least 7 days apart less than 30 × 10<sup>9</sup>/L; (2) patients had failed to respond to both Rituximab and a TPO-RA; (3) minimum interval of ≥ 6 months since last Rituximab.</p><p>Dara was initiated at 16 mg/kg weekly for 2–8 cycles, with treatment duration determined through shared decision-making between clinicians and patients' parents based on therapeutic response monitoring and availability of treatment. Retreatment was considered in responders who relapsed when patients developed two consecutive weekly platelet counts below 30 × 10<sup>9</sup>/L, occurring at least 4 weeks after initial response to Dara. Prophylaxis against hypersensitivity reactions included concomitant administration of methylprednisolone (1–2 mg/kg IV) prior to each infusion. To mitigate secondary hypogammaglobulinemia, all patients received low-dose IVIG 200 mg/kg monthly for six cycles. Patients receiving TPO-RAs had to maintain fixed doses during the final 4 weeks preceding Dara initiation.</p><p>Primary outcome measures were initial response (IR) and sustained response (SR). Secondary outcomes included number of Dara doses, platelet count changes, bleeding scores and adverse events. The bleeding assessment was conducted using the 2019 ICR bleeding score [<span>8</span>].</p><p>Eleven pediatric patients received 2–8 weeks of weekly Dara. At baseline, they exhibited a median disease duration of 36 months (range: 13–121), a median platelet count of 4 × 10<sup>9</sup>/L (range: 2–9), and a median bleeding score of 2 (range: 1–3). All patients had failed first-line and seco
{"title":"Daratumumab in Pediatric Chronic Refractory Primary Immune Thrombocytopenia (ITP): Rapid Platelet Recovery, Sustained Response, and Immune Reconstitution Dynamics","authors":"Yu Hu, Hui Chen, Zhifa Wang, Jingyao Ma, Shuyue Dong, Xi Lin, Xiaoling Cheng, James B. Bussel, Zhenping Chen, Runhui Wu","doi":"10.1002/ajh.70148","DOIUrl":"10.1002/ajh.70148","url":null,"abstract":"<p>Immune thrombocytopenia (ITP), an acquired autoimmune thrombocytopenic disorder, results from increased platelet destruction by the mononuclear phagocyte system and inadequate platelet production [<span>1</span>]. Patients not responding to first-line treatments (intravenous immunoglobulin, IVIG and steroids), or second-line rescue therapies (immunosuppressive agents, thrombopoietin receptor agonists (TPO-RAs), or splenectomy), and requiring long-term treatment, have refractory primary immune thrombocytopenia (RITP) [<span>2</span>]. Chronic RITP (CRITP) is associated with significant worsening of QoL and difficult clinical management, which can lead to life-threatening bleeding with high morbidity and mortality [<span>3</span>]. There remains a need for novel therapeutics in CRITP beyond TPO-RA. Daratumumab (Dara), a humanized anti-CD38 antibody widely used for treating multiple myeloma [<span>4</span>], has a favorable safety profile and is a promising candidate for treating antibody-mediated autoimmune diseases, including ITP [<span>5-7</span>].</p><p>We report 11 CRITP patients treated with anti-CD38 monoclonal antibody (Dara) from April 2023 to August 2024. Patients were eligible if aged 1–18 years and diagnosed with ITP according to the International Working Group (IWG) guidelines [<span>8</span>]. Additional key eligibility criteria were: (1) mean platelet count on two separate occasions at least 7 days apart less than 30 × 10<sup>9</sup>/L; (2) patients had failed to respond to both Rituximab and a TPO-RA; (3) minimum interval of ≥ 6 months since last Rituximab.</p><p>Dara was initiated at 16 mg/kg weekly for 2–8 cycles, with treatment duration determined through shared decision-making between clinicians and patients' parents based on therapeutic response monitoring and availability of treatment. Retreatment was considered in responders who relapsed when patients developed two consecutive weekly platelet counts below 30 × 10<sup>9</sup>/L, occurring at least 4 weeks after initial response to Dara. Prophylaxis against hypersensitivity reactions included concomitant administration of methylprednisolone (1–2 mg/kg IV) prior to each infusion. To mitigate secondary hypogammaglobulinemia, all patients received low-dose IVIG 200 mg/kg monthly for six cycles. Patients receiving TPO-RAs had to maintain fixed doses during the final 4 weeks preceding Dara initiation.</p><p>Primary outcome measures were initial response (IR) and sustained response (SR). Secondary outcomes included number of Dara doses, platelet count changes, bleeding scores and adverse events. The bleeding assessment was conducted using the 2019 ICR bleeding score [<span>8</span>].</p><p>Eleven pediatric patients received 2–8 weeks of weekly Dara. At baseline, they exhibited a median disease duration of 36 months (range: 13–121), a median platelet count of 4 × 10<sup>9</sup>/L (range: 2–9), and a median bleeding score of 2 (range: 1–3). All patients had failed first-line and seco","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"384-387"},"PeriodicalIF":9.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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