American Journal of Hematology最新文献

{"title":"Isolated peripheral nervous system relapse after allogeneic hematopoietic cell transplantation for T-cell acute lymphoblastic leukemia","authors":"Mathijs Willemsen, Pieter Smeets, Aniek de Coninck","doi":"10.1002/ajh.27441","DOIUrl":"10.1002/ajh.27441","url":null,"abstract":"<p>A 23-year-old man was admitted with left peripheral facial nerve palsy and right C7 radiculopathy. Ten weeks prior, he had received an allogeneic hematopoietic stem cell transplant (allo-HSCT) for presumed peripheral nervous system (PNS) and cerebrospinal fluid (CSF) flow cytometry-confirmed central nervous system (CNS) relapse of T-cell acute lymphoblastic leukemia (T-ALL). CNS MRI showed bilateral peripheral facial nerve enhancement without evidence of leptomeningeal or spinal disease (Figure 1A). CSF flow cytometry, viral PCRs, and bacterial cultures were unrevealing on multiple occasions. MRI of the brachial plexus showed diffuse nerve root thickening and edema with pathological enhancement, more pronounced on the right side (Figure 1B,C). Nerve conduction studies showed no evidence of demyelination. A total body PET/CT scan showed bilateral FDG accumulation in the brachial plexus, more pronounced on the right side (Figure 1D). Complete blood count was within normal limits with full donor chimerism. Bone marrow biopsy and flow cytometry excluded medullary relapse. Meanwhile, the patient experienced progressive pain, weakness, and muscle atrophy of the right arm requiring high-dose opioids and also developed right peripheral facial nerve palsy and similar symptomology of the left arm. High-dose intravenous immunoglobulins were ineffective. In an attempt to obtain a definitive diagnosis, the patient underwent surgical brachial plexus C7 biopsy. Hematoxylin and eosin staining showed effacement of normal nerve architecture with diffuse infiltration of blast-like cells (Figure 1E,F). S100 immunohistochemistry revealed sparse preexisting nerve fibers (Figure 1G). Blast-like cells were strongly positive for CD3 (Figure 1H) and TdT (Figure 1I), as well as CD10 and weakly positive for CD4 and CD8. MPO, PAX5 and CD30 were negative. A diagnosis of PNS relapse in the brachial plexus, and potentially facial nerves, was made. Without remaining curative treatment options, the patient received radiotherapy, resulting in substantial pain relief, and dexamethasone and was discharged home with palliative care.</p><p>The infiltration of peripheral nerves by leukemic blasts, termed neuroleukemiosis, is a rare neurological manifestation of leukemia with unknown incidence and no established diagnostic or therapeutic guidelines.<span><sup>1, 2</sup></span> Biopsy-confirmed cases of neuroleukemiosis in T-ALL are only sparsely reported in the literature.<span><sup>3-7</sup></span></p><p>The patient did not have CNS involvement at diagnosis but experienced a combined PNS and CNS relapse after intensive chemotherapy warranting allo-HSCT. Interestingly, relapse post-allo-HSCT was isolated to the PNS with similar symptomology as the pre-allo-HSCT relapse, suggesting that reinduction chemotherapy, myeloablative conditioning, and graft-versus-leukemia effect were more effective in eradicating CNS than PNS disease. Leukemic blasts can persists in the PNS for many years as","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 10","pages":"2023-2025"},"PeriodicalIF":10.1,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27441","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791698","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}

{"title":"Where hematology meets rheumatology—VEXAS syndrome","authors":"Hajer Oun,&nbsp;William Gordon,&nbsp;Mike Leach,&nbsp;Barbara J. Bain","doi":"10.1002/ajh.27446","DOIUrl":"10.1002/ajh.27446","url":null,"abstract":"<p>The bone marrow aspirate was cellular with no abnormal infiltration. The myeloid series was prominent and a proportion of promyelocytes and myelocytes showed prominent cytoplasmic (and some apparently intranuclear) vacuolation (all images ×100 objective). There was maturation to neutrophils, with some showing abnormal nuclear segmentation. The erythroid series showed cytoplasmic vacuolation in the earlier stages (top center, top right), with some cells having giant vacuoles (bottom right). These morphological findings in the context of the clinical presentation raised the suspicion of the VEXAS syndrome. Next-generation molecular sequencing confirmed a p.Met41Thr missense mutation in <i>UBA1</i> (c.122T&gt;C) confirming VEXAS syndrome. A <i>DNMT3A</i> gene splice variant mutation c1429+1G&gt;A was also present. The patient continues on oral prednisolone, and the JAK1/JAK2 inhibitor, barcitinib, and has been referred for consideration for an allogeneic bone marrow transplant.</p><p>VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory Somatic) syndrome is a recently described auto-inflammatory condition driven by a somatic mutation in <i>UBA1</i> in a hematopoietic progenitor cell.<span>¹</span> Hematological manifestations include cytopenias with clonal evolution, sometimes leading to the development of a myelodysplastic syndrome. There may be macrocytosis and the incidence of venous thromboembolism is increased. The vacuoles are present in both early myeloid and early erythroid precursors in most (but not all) patients with a <i>UBA1</i> mutation, and may also be present in plasma cells and lymphocytes. A threshold of vacuolization of more than 10% of promyelocytes and myelocytes has been proposed as a sensitive and fairly specific indicator of the condition.<span>²</span> Vacuolization of bone marrow progenitors is not, however, exclusive to the VEXAS syndrome, and can be seen in other inflammatory disorders, alcoholism, copper deficiency, and malnutrition. Having been only recently defined, the prevalence of the disease is likely underestimated, but the morphological and molecular features should be sought in male patients presenting with both cytopenias and systemic inflammatory disease.</p><p>The authors declare no conflicts of interest.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 11","pages":"2213-2214"},"PeriodicalIF":10.1,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791699","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}

{"title":"Mitapivat for phosphofructokinase deficiency","authors":"Hanny Al-Samkari","doi":"10.1002/ajh.27442","DOIUrl":"10.1002/ajh.27442","url":null,"abstract":"&lt;p&gt;Pyruvate kinase activation is an emerging therapeutic modality under evaluation to treat congenital hemolytic anemias, including pyruvate kinase deficiency, thalassemia, and sickle cell disease, among others.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The results of a phase 3, randomized, placebo-controlled clinical trial of the pyruvate kinase activator mitapivat to treat the most common glycolytic enzyme defect, pyruvate kinase deficiency, were previously published.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Because mitapivat increases glycolytic flux via allosteric activation of multiple isoforms of pyruvate kinase, it may provide therapeutic benefit in other glycolytic disorders, particularly those resulting in pathologic accumulation of glycolytic intermediates. Phosphofructokinase, another critical glycolytic enzyme, catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Phosphofructokinase deficiency (glycogen storage disease type VII, Tarui disease), an ultrarare enzymopathy occurring in fewer than 1 in 1 000 000 people, causes accumulation of fructose-6-phosphate which is ultimately converted to glycogen that builds up in muscle tissue, resulting in easy fatigability, muscle weakness and pain, myoglobinuria, rhabdomyolysis, and hemolysis.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Phosphofructokinase deficiency has no known effective treatments. The safety and effectiveness of mitapivat in a patient with phosphofructokinase deficiency are described herein.&lt;/p&gt;&lt;p&gt;A 29-year-old man with classic phosphofructokinase deficiency presenting with lifelong easy fatigability, muscle weakness and pain, and hemolysis (without anemia) resulting in severe physical activity limitation and poor health-related quality of life was treated with oral mitapivat with close monitoring for safety and effectiveness. The patient's diagnosis was confirmed via genetic testing demonstrating two known pathogenic mutations in the M isoform of phosphofructokinase (&lt;i&gt;PFKM&lt;/i&gt; c.2003delC [p.Pro668Glnfs*17] and &lt;i&gt;PFKM&lt;/i&gt; c.237+1G&gt;A [splice donor variant]). At baseline, the patient scored poorly across all eight domains of the well-validated Short Form-36 Health Survey (SF-36), but dose-dependent and ultimately marked improvements across all eight domains were observed with mitapivat treatment (Figure 1). Mitapivat was well-tolerated with no adverse events except mild transient erythrocytosis (hematocrit 61%, up from pretreatment baseline of 46%) after initial dose escalation to 20 mg twice daily; this resolved with a temporary dose decrease to 20 mg once daily and did not recur following resumption of 20 mg twice daily or dose escalation to 50 mg once daily. While the maximum approved mitapivat dose for pyruvate kinase deficiency is 50 mg twice daily, the decision was made to stay at 50 mg daily and not dose escalate to 50 mg twice daily because the patient felt markedly improved on 50 mg once daily and there was a desire to avoid potential recurrence of erythrocytosis.&lt;/p&gt;&lt;p&gt;Consistent wi","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 10","pages":"2045-2046"},"PeriodicalIF":10.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747161","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}

{"title":"Network meta-analysis of upfront fixed-duration therapies in chronic lymphocytic leukemia","authors":"Stefano Molica,&nbsp;David Allsup,&nbsp;Diana Giannarelli","doi":"10.1002/ajh.27437","DOIUrl":"10.1002/ajh.27437","url":null,"abstract":"&lt;p&gt;The emergence of Bruton's tyrosine kinase (BTK) inhibitors marked a significant advancement in chronic lymphocytic leukemia (CLL) management, especially for high-risk patients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Ibrutinib, the pioneering BTK inhibitor, has undergone extensive study. The final analysis of the RESONATE-2 study confirms its sustained survival benefit for first-line CLL treatment with up to 10 years of follow-up.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Despite its efficacy, prolonged administration of BTK inhibitors can lead to cardiovascular toxicities and emergence of therapy resistance mutations.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Time-limited CLL-directed therapies, inspired by venetoclax's unique attributes in inducing deep therapeutic responses, aim to address continuous therapy limitations.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Venetoclax combined with anti-CD20 monoclonal antibodies in fixed-duration (FD) regimens, showcased in relapsed/refractory CLL with MURANO and in frontline with CLL14 and CLL13 trials, sustain responses with manageable toxicity across CLL patient profiles.&lt;span&gt;&lt;sup&gt;6-9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;By harnessing the synergistic potential of venetoclax and ibrutinib (VI), which combines agents with distinct mechanisms of action and non-overlapping toxicities, researchers aim to attain deeper and persistent treatment responses without associated therapy resistance.&lt;span&gt;&lt;sup&gt;10-14&lt;/sup&gt;&lt;/span&gt; This combination has recently received approval from the European Medicines Agency (EMA) for frontline treatment of CLL.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; This approval is based on pivotal findings from the Phase 3 GLOW study, which demonstrated superior PFS in patients treated with VI compared with those treated with chlorambucil-obinutuzumab, and from the FD cohort of the Phase 2 CAPTIVATE study.&lt;span&gt;&lt;sup&gt;10, 11&lt;/sup&gt;&lt;/span&gt; However, the choice between FD therapies remains challenging due to the lack of head-to-head comparative data. Results from the ongoing CLL17 trial (NCT04608318), which is comparing continuous BTK inhibitor therapy with FD regimens, including VI and venetoclax-obinutuzumab (VO), are eagerly anticipated.&lt;/p&gt;&lt;p&gt;To provisionally support evidence-based decision-making, we performed a network meta-analysis (NMA) comparing all approved FD therapies in the setting of treatment-naïve (TN) CLL patients.&lt;/p&gt;&lt;p&gt;Relevant randomized clinical trials were identified through a systematic review of the literature in MEDLINE. To be included, studies had to meet the following criteria: (1) to be randomized controlled trials (RCTs) focusing on FD therapy in TN CLL patients; (2) to investigate the effectiveness of FD therapy with venetoclax as its core component; and (3) to provide data on both progression-free survival (PFS) and overall survival (OS). Reporting of the systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt; Two reviewers (S.M. and D.G.) independently assessed ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 10","pages":"2041-2044"},"PeriodicalIF":10.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747162","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}

{"title":"Advances in sickle cell retinopathy screening techniques, tests, and practices: A systematic review","authors":"Olivia W. Cummings,&nbsp;Sara Rahman,&nbsp;Lauren Fletcher,&nbsp;Adrienne W. Scott","doi":"10.1002/ajh.27439","DOIUrl":"10.1002/ajh.27439","url":null,"abstract":"<p>Sickle cell retinopathy (SCR) is a progressive, sight-threatening ophthalmic complication of sickle cell disease (SCD). Current SCR screening focuses on the detection of pathologic sea fan neovascularization, the first sign of proliferative sickle cell retinopathy (PSR). If untreated, PSR can lead to severe visual impairment and blindness through progression to vitreous hemorrhage and/or retinal detachment. SCR screening with dilated fundus examination (DFE) is recommended every 1–2 years starting at age 10, but data underlying this recommendation are of poor quality and based upon expert consensus. We performed a systematic review to characterize imaging techniques, laboratory-based tests, and clinical practices for SCR screening. This PROSPERO-registered systematic review included relevant texts identified through predetermined searches in online databases. Collected test accuracy data facilitated the calculation of likelihood ratios. Forty-four studies evaluating 4928 patients were included. DFE demonstrated moderate test accuracy (LR+ of 8.0, LR- of 0.3). Ultra-widefield-fundus photography demonstrated superior accuracy (LR+ 32.5, LR- 0.03). Optical coherence tomography angiography applications were highly accurate for PSR identification (machine learning LR+ 32.5, LR- 0.03; human grader LR+ 2.8–213.1, LR- 0.1-0.2). Most techniques and tests were more accurate at detecting PSR than staging SCR or detecting lower-grade SCR. Our findings support the integration of advanced image-based approaches, such as computer-based image analysis and ultra-wide-field fundus imaging, for SCR screening in SCD patients given the superior accuracy in PSR detection compared with the current standard of care. Rigorous SCR screening implementation studies are needed to support evidence-based SCR screening recommendations.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 11","pages":"2152-2163"},"PeriodicalIF":10.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747160","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}

{"title":"Disease burden, management strategies, and unmet needs in α-thalassemia due to hemoglobin H disease","authors":"Ashutosh Lal,&nbsp;Vip Viprakasit,&nbsp;Elliott Vichinsky,&nbsp;Yongrong Lai,&nbsp;Meng-Yao Lu,&nbsp;Antonis Kattamis","doi":"10.1002/ajh.27440","DOIUrl":"10.1002/ajh.27440","url":null,"abstract":"<p>Alpha-thalassemia is an inherited blood disorder caused by impaired α-globin chain production, leading to anemia and other complications. Hemoglobin H (HbH) disease is caused by a combination of mutations generally affecting the expression of three of four α-globin alleles; disease severity is highly heterogeneous, largely driven by genotype. Notably, non-deletional mutations cause a greater degree of ineffective erythropoiesis and hemolysis, higher transfusion burden, and increased complication risks versus deletional mutations. There are limited treatment options for HbH disease, and effective therapies are needed. This review discusses the pathophysiology of HbH disease, current management strategies, unmet needs, and emerging treatment options.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 11","pages":"2164-2177"},"PeriodicalIF":10.1,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27440","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733337","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}

{"title":"Risk of myeloproliferative neoplasms among U.S. Veterans from Korean, Vietnam, and Persian Gulf War eras","authors":"Andrew Tiu,&nbsp;Zoe McKinnell,&nbsp;Shanshan Liu,&nbsp;Puneet Gill,&nbsp;Martha Antonio,&nbsp;Zoe Shancer,&nbsp;Nandan Srinivasa,&nbsp;Guoqing Diao,&nbsp;Ramesh Subrahmanyam,&nbsp;Craig M. Kessler,&nbsp;Maneesh Jain","doi":"10.1002/ajh.27438","DOIUrl":"10.1002/ajh.27438","url":null,"abstract":"<p>The Promise to Address Comprehensive Toxics (PACT) Act expanded U.S. Veterans' health care and benefits for conditions linked to service-connected exposures (e.g., Burn Pits, Agent Orange). However, myeloproliferative neoplasms (MPN) are not recognized as presumptive conditions for Veterans exposed to these toxic substances. This study evaluated the development of MPN among U.S. Veterans from the Korean, Vietnam, and Persian Gulf War eras. This retrospective cohort study included 65 425 Korean War era Veterans; 211 927 Vietnam War era Veterans; and 214 007 Persian Gulf War era Veterans from January 1, 2006, to January 26, 2023. Veterans with MPN, thrombosis, bleeding, and cardiovascular risk factors were identified through ICD-9 and -10 codes. Veterans from the Persian Gulf War era had the highest risk of developing MPN compared with Veterans from the Korean and Vietnam War eras, hazard ratio (HR) 4.92, 95% confidence interval (CI) 4.20–5.75 and HR 2.49, 95% CI 2.20–2.82, both <i>p</i> &lt; .0001, respectively. Vietnam War era Veterans also had a higher risk of MPN development compared with Korean War era Veterans, HR 1.97, 95% CI 1.77–2.21, <i>p</i> &lt; .0001. Persian Gulf War era Veterans were diagnosed with MPN at an earlier age, had higher risks of thrombosis and bleeding, and had lower survival rates compared with Korean War and Vietnam War era Veterans. This study reinforces evidence that environmental and occupational hazards increase the risk of clonal myeloid disorders and related complications, impacting overall survival with MPN. Limitations include the inability to confirm clonality and fully verify deployment and exposure status.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 10","pages":"1969-1978"},"PeriodicalIF":10.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27438","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632454","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}

{"title":"A growing panoply of options for patients with paroxysmal nocturnal hemoglobinuria","authors":"David J. Young","doi":"10.1002/ajh.27426","DOIUrl":"10.1002/ajh.27426","url":null,"abstract":"&lt;p&gt;In this issue, the COMMODORE 1&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and COMMODORE 2&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; trials of crovalimab for previously treated and treatment-naïve paroxysmal nocturnal hemoglobinuria, respectively, are presented, demonstrating efficacy and safety for both patient populations in comparison with the benchmark, eculizumab.&lt;/p&gt;&lt;p&gt;Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia characterized by sometimes painful intravascular hemolysis (IVH), pancytopenia with increased infections, and significant risk of potentially fatal venous thrombosis especially of the sagittal sinuses and hepatoportal system. Instead of autoantibodies, PNH is a clonal disorder driven by the acquisition of somatic mutations in &lt;i&gt;PIGA&lt;/i&gt;. These mutations, as well as rarer mutations in related genes, lead to loss of the glycosylphosphatidylinositol (GPI) anchor required for presenting an array of cell-surface proteins. Loss of GPI anchorage has wide ranging consequences, key among them is loss of CD55 and CD59, proteins essential for regulating cell surface-aspects of complement (Figure 1). Without CD55 and CD59, complement complexes cannot be removed from the cell surface, leading to C5 activation, membrane attack complex (MAC) formation, and cell lysis. This causes erythrocyte destruction, thrombosis through inappropriate platelet activation, and infections secondary to leukopenia. As the &lt;i&gt;PIGA&lt;/i&gt;-deficient clone or clones expand—patients often acquire multiple, separate mutations—the risk and severity of these complications increase. The causes and mechanisms underlying this expansion are complex and beyond the scope of this commentary.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Historically, non-transplant management of PNH consisted of anticoagulation—typically anti-vitamin K—and supportive care. However, lifelong anticoagulation has obvious hemorrhagic risks and does not address ongoing hemolysis. Recognition that the clinical manifestations of PNH arise from inappropriate complement-mediated cell membrane attack led to the development of the terminal complement inhibitor eculizumab. By targeting C5, the key enzyme downstream of all complement pathways, eculizumab prevents the final step in cell lysis: membrane disruption by MAC (Figure 1). Provided as fortnightly intravenous infusions, eculizumab has proven revolutionary in the treatment of PNH, eliminating anemia and transfusion requirements for 49% of subjects in the TRIUMPH study&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; (increasing to 88% in long-term follow-up&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;) and reducing the risks of thrombosis and its recurrence by 85%.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; It received FDA approval as the first PNH-specific treatment in 2007. As such, it has become the gold standard against which novel treatments are assessed.&lt;/p&gt;&lt;p&gt;Crovalimab is a humanized anti-C5 monoclonal antibody engineered to be recycled instead of cleared following Fcγ receptor binding, leading to a prolonged half-life and the ability","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 9","pages":"1667-1669"},"PeriodicalIF":10.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27426","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632453","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}

{"title":"Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia","authors":"Sanam Loghavi,&nbsp;Qing Wei,&nbsp;Farhad Ravandi,&nbsp;Andres E. Quesada,&nbsp;Mark J. Routbort,&nbsp;Shimin Hu,&nbsp;Gokce A. Toruner,&nbsp;Sa A. Wang,&nbsp;Wei Wang,&nbsp;Roberto N. Miranda,&nbsp;Shaoying Li,&nbsp;Jie Xu,&nbsp;Courtney D. DiNardo,&nbsp;Naval Daver,&nbsp;Tapan M. Kadia,&nbsp;Ghayas C. Issa,&nbsp;Hagop M. Kantarjian,&nbsp;L. Jeffrey Medeiros,&nbsp;Guilin Tang","doi":"10.1002/ajh.27435","DOIUrl":"10.1002/ajh.27435","url":null,"abstract":"<p>Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision-making. We examined the clinical utility of optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed and 56 refractory/relapsed), all of whom also underwent chromosomal banding analysis (CBA), fluorescence in situ hybridization, and targeted next-generation sequencing. OGM detected nearly all clinically relevant cytogenetic abnormalities that SCG identified with &gt;99% sensitivity, provided the clonal burden was above 20%. OGM identified additional cytogenomic aberrations and/or provided information on fusion genes in 77 (48%) patients, including eight patients with normal karyotypes and four with failed karyotyping. The most common additional alterations identified by OGM included chromoanagenesis (<i>n</i> = 23), <i>KMT2A</i> partial tandem duplication (<i>n</i> = 11), rearrangements involving <i>MECOM</i> (<i>n</i> = 7), <i>NUP98</i> (<i>n</i> = 2), <i>KMT2A</i> (<i>n</i> = 2), <i>JAK2</i> (<i>n</i> = 2), and other gene fusions in 17 patients, with 10 showing novel fusion gene partners. OGM also pinpointed fusion genes in 17 (11%) patients where chromosomal rearrangements were concurrently detected by OGM and CBA. Overall, 24 (15%) aberrations were identified exclusively by OGM and had the potential to alter AML classification, risk stratification, and/or clinical trial eligibility. OGM emerges as a powerful tool for identifying fusion genes and detecting subtle or cryptic cytogenomic aberrations that may otherwise remain undetectable by CBA.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 10","pages":"1959-1968"},"PeriodicalIF":10.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625724","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}

{"title":"Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?","authors":"Jennifer Marvin-Peek,&nbsp;Jason S. Gilbert,&nbsp;Daniel A. Pollyea,&nbsp;Courtney D. DiNardo","doi":"10.1002/ajh.27434","DOIUrl":"10.1002/ajh.27434","url":null,"abstract":"<p>The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 9","pages":"1790-1801"},"PeriodicalIF":10.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625723","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}