American Journal of Hematology最新文献

{"title":"FDA Approval Based on Novel Surrogate Endpoints: Lessons From the Voluntary Withdrawal of Voxelotor in Sickle Cell Disease","authors":"Myung Sun Kim, Vinay Prasad","doi":"10.1002/ajh.27635","DOIUrl":"10.1002/ajh.27635","url":null,"abstract":"<p>On September 25, 2024, Pfizer Inc. announced the voluntary withdrawal of Oxbryta (voxelotor), a hemoglobin S polymerization inhibitor, in all markets where it is approved and the discontinuation of all active clinical trials worldwide [<span>1</span>]. Voxelotor received accelerated US Food and Drug Administration (FDA) approval in 2019 for patients 12 years of age and older with sickle cell disease. The approval was based on the HOPE trial (NCT03036813) [<span>2</span>]. HOPE showed the drug was capable of an increase in hemoglobin from baseline of more than 1.0 g/deciliter at week 24 (1.1 g/dL), which is the primary endpoint. The only clinically relevant endpoint of the study was vaso-occlusive crises, which was reported as a secondary outcome. The drug was developed by Global Blood Therapeutics, a biopharmaceutical company, which was acquired by Pfizer in 2022. In 2024, Pfizer's stated reason for withdrawal was due to an imbalance in vaso-occlusive crises and fatal events, where the overall benefit no longer outweighed the risk of the drug. Further information has not yet been provided.</p><p>A careful review of the regulatory history of voxelotor reveals concerns regarding the product, present since the initial submission. Specifically, how did a 1.0 g/dL rise in hemoglobin come to constitute a surrogate endpoint thought reasonably likely to predict benefit? The case of voxelotor raises lingering questions regarding the FDA's process for soliciting novel, surrogate endpoints from companies, and the timeliness of post-marketing studies to adjudicate benefit.</p><p>Over the last decade, the US FDA has encouraged the development of novel surrogate endpoints by sponsoring companies, and engages with sponsors to provide guidance regarding feasibility and acceptability. Novel biomarker endpoints are often developed for specific diseases—for instance, those lacking good treatment options or for agents with new mechanisms of action. One example is the recent approval of Xolremdi (mavorixafor) for WHIM syndrome, a rare genetic disease, that was based on improvement in absolute neutrophil count as a primary endpoint.</p><p>In the case of voxelotor, the FDA raised concern as early as the initial submission that a small rise in hemoglobin may not be considered a surrogate reasonably likely to predict clinical benefit [<span>3</span>]. The sponsor responded with data from 2 trials, STOP2 (NCT00006182) [<span>4</span>] and SIT (NCT00072761) [<span>5</span>], that studied prophylactic transfusions in preventing stroke and silent cerebral infarction, respectively. The sponsor's argument was that the rise in hemoglobin is a surrogate for the reduction in transcranial doppler (TCD) flow velocity, and TCD velocity is a predictor of stroke and silent infarct risk. The FDA requested further evidence for the chosen cut-off (1 g/dL) and study duration.</p><p>At the time of approval, the logic behind utilizing a 1 g/dL hemoglobin rise was dubious. The American So","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"922-924"},"PeriodicalIF":10.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463044","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":"BTK Inhibitors Versus Venetoclax as First- or Second-Line Therapy in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Real-World Evidence Study","authors":"Lindsey E. Roeker, Yi Han, Anna Teschemaker, Anthony R. Mato, Meghan C. Thompson","doi":"10.1002/ajh.27639","DOIUrl":"10.1002/ajh.27639","url":null,"abstract":"<p>Targeted therapies (e.g., Bruton tyrosine kinase inhibitors [BTKi; ibrutinib, acalabrutinib, zanubrutinib] or B-cell lymphoma-2 inhibitors [BCL-2i; venetoclax]) with or without anti-CD20 monoclonal antibodies (CD20 mAb), have demonstrated consistent survival benefits versus chemoimmunotherapy (CIT) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the front-line (1L) and relapsed/refractory (R/R) settings (summarized in Eichhorst et al. [<span>1</span>]). However, there are currently no prospective data comparing BTKi-based and venetoclax-based therapies directly, and information to guide optimal sequencing strategies for targeted agents is limited [<span>2-4</span>]. An improved understanding of the comparative effectiveness of BTKi and BCL-2i in both 1L and R/R settings, in novel agent–naive and exposed patients, is needed to guide treatment sequencing decisions.</p><p>To better understand the performance of targeted agents, we conducted a retrospective, observational cohort analysis to evaluate clinical outcomes of comparable patients with CLL/SLL who received either BTKi monotherapy or BCL-2i+CD20 mAb in 1L or second-line (2L) settings.</p><p>This study used Flatiron Health electronic health record-derived de-identified data from August 1, 2014 to February 28, 2022. Adult patients (≥ 18 years) with CLL/SLL were included if they received BTKi monotherapy (acalabrutinib or ibrutinib) or BCL-2i (venetoclax) in combination with a CD20 mAb in the 1L or 2L setting and had 2 or more clinical encounters during the study period. The study compared time-to-next-treatment-or-death (TTNTD; defined as time from initiation of the current treatment to the starting time of a new line of therapy or death) for patients treated with BTKi monotherapy versus BCL-2i+obinutuzumab (1L), or BTKi monotherapy versus BCL-2i+CD20 mAb (ofatumumab, rituximab, or obinutuzumab) (2L).</p><p>Kaplan–Meier analysis was used to obtain unadjusted TTNTD curves for each of the cohorts. TTNTD was descriptively compared between cohorts using a Cox proportional-hazards model to estimate adjusted hazard ratios (HR). Propensity score matching (PSM) was used to improve the comparability between cohorts and reduce the effects of confounding. Each patient treated with BCL-2i+obinutuzumab (1L) or BCL-2i+CD20 mAb (2L) was matched with two patients treated with BTKi monotherapy in each setting. PSM balanced key demographic and disease characteristics: age, gender, race, Rai stage, time from diagnosis to index date, del(17p), del(11q), and immunoglobulin heavy chain variable region (IGHV) mutational status, Eastern Cooperative Oncology Group performance status, total number of therapy lines received during the study period, and prior novel agent exposure. Inverse probability of treatment weighting (IPTW) was used as an alternative to PSM to control for potential confounding and reduce noncomparability between cohorts (Supporting Information Methods).</p><p","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"720-723"},"PeriodicalIF":10.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427261","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":"Steady-State Ratio of von Willebrand Factor Antigen to ADAMTS13 Activity Predicts Low Platelet Count at Hospitalization for Sickle Cell Disease Vaso-Occlusive Episodes","authors":"Xu Zhang, Binal N. Shah, Jin Han, José A. López, Dominic W. Chung, Junmei Chen, Santosh L. Saraf, Victor R. Gordeuk","doi":"10.1002/ajh.27636","DOIUrl":"10.1002/ajh.27636","url":null,"abstract":"<p>A vaso-occlusive episode (VOE) is the most common reason for emergency room visits and hospitalizations in patients with sickle cell disease (SCD). During a VOE, sickled red blood cells occlude the microvasculature causing ischemic injury and potential organ damage. We previously reported that in 130 adult patients, a > 20% decline in platelet count from steady state to presentation to the emergency room (ED) predicted an increased risk of severe complications during the VOE admission, defined as an acute pulmonary event, acute kidney or liver injury, stroke, venous thromboembolism, death, requirement for exchange blood transfusion, or transfer to the intensive care unit [<span>1</span>]. In other studies, a 33% increase of active von Willebrand Factor (VWF) in VOE relative to steady state coincided with a low platelet count and the development of acute chest syndrome in 24 patients [<span>2</span>], and a decline in platelet count of over 300 × 10<sup>3</sup>/μL in less than 15 h preceded adherence of large VWF aggregates to the pulmonary vascular endothelium in 3 out of 10 patients who died from acute chest syndrome [<span>3</span>]. VWF is synthesized in endothelial cells and released as large glycoprotein multimers that mediate adhesion of platelets to sites of vascular damage [<span>4</span>]. Newly secreted VWF multimers undergo limited cleavage by the metalloproteinase, ADAMTS13, on the endothelial surface [<span>4</span>].</p><p>Here we investigated plasma VWF antigen level and ADAMTS13 activity at steady state as predictors of platelet count decline and severe complications in VOE admissions. VWF antigen and ADAMTS13 activity were measured [<span>4</span>] at outpatient visits when the patient was not experiencing a VOE (i.e., steady state). VWF antigen was expressed as fold increase or decrease from the concentration of 12.2 μg/mL in normal pooled plasma (Precision BioLogic Inc., Canada), which equals 122 IU/dL and is within the normal 50–200 IU/dL range; ADAMTS13 activity was expressed as the fold change of the value from normal pooled plasma, which was considered to have 100% activity. Electronic records of VOE admissions to the inpatient sickle cell disease service from 7/1/2017 to 6/30/2018, all occurring > 21 days after the steady-state evaluation, were reviewed. Ninety-seven admissions involving 55 patients were selected based on inclusion/exclusion criteria [<span>1</span>]. Platelet counts were collected at steady state and at presentation to the ER leading to the admissions under study. Severe complications during admission were defined as (1) acute pulmonary events including acute chest syndrome, new infiltrate on chest X-ray, or use of a ventilator; (2) acute kidney injury; (3) acute liver injury; (4) thrombotic or hemorrhagic stroke; (5) thromboembolism including deep vein thrombosis, pulmonary embolism, or arterial thrombosis; (6) need for transfer to the intensive care unit; (7) need for exchange blood transfusion","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"913-916"},"PeriodicalIF":10.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435662","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":"Frontline Therapy of AML in the Fit and Younger Population—Incorporating Molecularly Targeted Agents","authors":"Keith W. Pratz,&nbsp;Harry P. Erba","doi":"10.1002/ajh.27585","DOIUrl":"https://doi.org/10.1002/ajh.27585","url":null,"abstract":"<p>Backbone therapy for acute myeloid leukemia for younger adults has for 50 years been based on a combination of cytarabine and anthracycline. Over the past 10 years the addition of several targeted agents has been found to improve the outcomes of subsets of AML with particular molecular changes. In this review we will examine the data generated to date on the addition of agents targeting CD33, FLT3, IDH, and BCL2 to standard high intensity therapies. We will also review the potential for future studies evaluating the application of highly active lower intensity therapies developed in older adults to patients considered “fit for high intensity induction.” Lastly, we review the data around the role of stem cell transplant in the modern targeted era.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 S2","pages":"16-22"},"PeriodicalIF":10.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424068","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":"Maintenance Therapy in AML: What Is the Future Potential?","authors":"Hannah Goulart,&nbsp;Andrew H. Wei,&nbsp;Tapan M. Kadia","doi":"10.1002/ajh.27583","DOIUrl":"https://doi.org/10.1002/ajh.27583","url":null,"abstract":"<p>Over the last decade, there have been significant advancements in the treatment for patients with acute myeloid leukemia (AML) including the addition of novel, targeted agents to intensive or nonintensive chemotherapy regimens. However, despite this, the majority of patients will still ultimately relapse and long-term survival remains poor. While the use of maintenance therapy has emerged as a potential strategy to maintain more durable remissions and improve overall survival, the optimal use of these therapies has not yet been clearly defined. In this review, we provide a comprehensive overview of the evolution of maintenance strategies in AML and present a commentary on the future of maintenance therapy, including the pressing, unmet needs in this field.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 S2","pages":"38-49"},"PeriodicalIF":10.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27583","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424069","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":"Therapeutic Advances and Future of Therapy in Acute Myeloid Leukemia","authors":"Farhad Ravandi","doi":"10.1002/ajh.27617","DOIUrl":"https://doi.org/10.1002/ajh.27617","url":null,"abstract":"&lt;p&gt;Significant progress in the characterization of molecular pathogenic events in acute myeloid leukemia (AML) has led to better characterization of prognosis and identification of subsets that are more likely to benefit from currently available strategies. Furthermore, deciphering these molecular pathogenic events has led to the development of a number of effective molecularly targeted agents that have significantly improved our armamentarium in managing patients with AML. This has certainly provided us with opportunities for improving outcomes but at the same time has created new challenges for satisfactory patient management.&lt;/p&gt;&lt;p&gt;Better characterization of cytogenetic and molecular subsets serves to provide long-term prognostic information but also necessitates rapid identification of subsets that may be amenable to specific therapeutic interventions. Furthermore, gaining deeper insights into the biology of disease may increase the emphasis on these pathogenic biologic events rather than morphology for disease characterization. For example, blurring the boundaries of AML and myelodysplastic syndrome (MDS), and relying more on molecular rather than morphological features for disease characterization.&lt;/p&gt;&lt;p&gt;Although cytotoxic chemotherapy such as cytarabine and anthracyclines remain the mainstay of therapeutic regimens in AML particularly in the younger and fitter patients who are able to tolerate them, the introduction of venetoclax-based regimens has revolutionized the management of older patients with AML who constitute the vast majority of the patients. This has improved the outcomes of less fit, older patients significantly, but long-term follow-up has demonstrated that such benefit has not been universal and is also very much dependent on the molecular characteristics of the disease. Further incorporation of targeted agents in such backbones has been attempted in several subsets of AML such as &lt;i&gt;FLT3&lt;/i&gt; mutated, &lt;i&gt;IDH&lt;/i&gt; mutated and &lt;i&gt;KMT2A&lt;/i&gt; rearranged AML with significant success, yet generating the debate about whether a concomitant or sequential administration of these agents is the best strategy. Conventional wisdom that led to the development of multiagent regimens in cancer therapy suggests that the former rather than the latter would be the more effective strategy that would prevent the development of resistance and thereby would provide a more sustained response translating to longer survival and potential cure. Of course, the challenge will remain how to best develop such combinations so that the benefits are not offset by any potential toxicities. The recent development and availability of oral formulations of hypomethylating agents has allowed the development of fully oral regimens that clearly can improve the convenience of administration and adherence to therapy. Such oral regimens are not without their challenges and toxicities and their general applicability will require further assessment in ongoing clinical trial","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 S2","pages":"3-4"},"PeriodicalIF":10.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27617","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424075","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":"Treatment of Relapsed/Refractory AML—Novel Treatment Options Including Immunotherapy","authors":"Catherine Gutierrez Moore,&nbsp;Anthony Stein,&nbsp;Amir T. Fathi,&nbsp;Vinod Pullarkat","doi":"10.1002/ajh.27584","DOIUrl":"https://doi.org/10.1002/ajh.27584","url":null,"abstract":"<p>Acute myeloid leukemia is a molecularly heterogenous disease caused by the rapid expansion and impaired differentiation of malignant myeloid progenitors. Overall, outcomes remain poor, and more than half of patients develop relapsed or refractory disease after front-line therapy. Allogeneic hematopoietic stem cell transplant (HCT) remains the best chance for cure for eligible patients, and the development of novel therapies including BCL2, FLT3, IDH1/2 and menin inhibitors, which are efficacious yet generally more tolerable, have enabled better bridging to prompt HCT. Despite the early success of targeted therapies, more generalized and efficacious therapeutic approaches remain in need, and numerous targeted immunotherapeutic agents (including CAR-T, bispecific and trispecific antibody therapies) are currently under investigation.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 S2","pages":"23-37"},"PeriodicalIF":10.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27584","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424070","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":"Moving the Therapeutic Needle in Immunoglobulin Light Chain and TTR Cardiac Amyloidosis","authors":"Morie A. Gertz","doi":"10.1002/ajh.27642","DOIUrl":"10.1002/ajh.27642","url":null,"abstract":"<p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"900-902"},"PeriodicalIF":10.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27642","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417440","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":"Impairment of Innate Immunity and Depletion of Vaccine-Induced Memory B and T Cells in the Absence of the Spleen","authors":"Veronica Bordoni,&nbsp;Bianca Laura Cinicola,&nbsp;Eva Piano Mortari,&nbsp;Concetta Castilletti,&nbsp;Federica Guarracino,&nbsp;Christian Albano,&nbsp;Silvia Accordini,&nbsp;Anwar Baban,&nbsp;Antonio Di Sabatino,&nbsp;Carlo Maria Rossi,&nbsp;Marco Vincenzo Lenti,&nbsp;Anna Maria Zicari,&nbsp;Riccardo Cirelli,&nbsp;Marco Spada,&nbsp;Gian Luca Forni,&nbsp;Isabella Quinti,&nbsp;Mattia Algeri,&nbsp;Maddalena Casale,&nbsp;Silverio Perrotta,&nbsp;Franco Locatelli,&nbsp;Chiara Agrati,&nbsp;Rita Carsetti","doi":"10.1002/ajh.27634","DOIUrl":"10.1002/ajh.27634","url":null,"abstract":"<p>Splenectomy or congenital asplenia is associated with severe reduction of memory B cells and increased risk of fulminant sepsis by encapsulated bacteria. Current guidelines recommend vaccinations against these pathogens before or after splenectomy, but the longevity of immunity acquired after splenectomy has not been determined. The impact of splenectomy on innate immune cells is unknown. We analyzed frequency, differentiation stage, and function of innate and adaptive immunity in the peripheral blood of adult (<i>n</i> = 41) and pediatric (<i>n</i> = 14) patients splenectomized or born asplenic and in spleens of solid organ donors. The absence of the spleen impacts the B-cell compartment, causing a significant increase of circulating immature transitional and depletion of memory B cells. Using SARS-CoV-2 vaccination as a model, we show that 1 year after the last immunization, despite normal levels of neutralizing antibodies, memory B and T cells were significantly reduced. Analysis of post-pandemic spleens shows that spike-specific memory B and T cells homed to the spleen. We also show a previously unrecognized role of the spleen in the homeostasis of innate NK and Vδ2 T cells. These populations showed altered phenotype and impaired function in the adults, but not in children, suggesting that other tissues may support innate cell development during early life. The reduced function of innate lymphocytes must be considered as an additional immune impairment and risk factor. These findings emphasize the spleen's irreplaceable role in maintaining immune memory across all ages and suggest that its absence contributes to dysfunctions of innate and adaptive immunity in adults.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"770-784"},"PeriodicalIF":10.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27634","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417441","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":"Isolated Cerebral Myeloid Sarcoma in an Allogeneic Stem Cell Transplant Recipient","authors":"Gabriele Magliano,&nbsp;Silvia Zanon,&nbsp;Rachele de Domenico,&nbsp;Marco Galli,&nbsp;Enrico Morello,&nbsp;Luisa Lorenzi,&nbsp;Gaetano Paolino,&nbsp;Marco Fontanella,&nbsp;Luciano Buttolo,&nbsp;Diego Bertoli,&nbsp;Giorgio Biasiotto,&nbsp;Michele Malagola,&nbsp;Riccardo Marnoni,&nbsp;Mirko Farina,&nbsp;Vera Radici,&nbsp;Simona Bernardi,&nbsp;Alessandro Leoni,&nbsp;Domenico Russo,&nbsp;Daniele Avenoso","doi":"10.1002/ajh.27640","DOIUrl":"10.1002/ajh.27640","url":null,"abstract":"&lt;p&gt;Late relapse of acute myeloid leukemia (AML) is the main reason for treatment failure after a successful allogeneic hematopoietic stem cell transplant (allo-HSCT). A rare manifestation of disease reoccurrence is isolated myeloid sarcoma. A 67-year-old gentleman underwent allo-HSCT in 2020 after achieving second complete remission, following salvage treatment for relapsed AML originally diagnosed in 2018. At the onset, the cytogenetic assay on bone marrow was remarkable for translocation (16;17)(p11;p13); retrospective next-generation sequencing revealed an acquired mutation in RUNX1, ASXL1, SRSF2, and DNMT3A.&lt;/p&gt;&lt;p&gt;In October 2024, the patient attended our clinic for the onset of a nuchal headache and mild visual disturbances, prompting extensive diagnostic investigations. Magnetic resonance imaging of the central nervous system (CNS) showed the presence of an intra-axial expansive lesion in the right parietal–temporal lobe (maximum orthogonal diameters were 3.4 × 3.1 cm in T2W—Figure 1A and in T1W sequence—Figure 1B). Histopathological analysis revealed the presence of immature cells (Figure 1C) with partial expression of CD34, MPO, CD117, CD4, and CD163, along with negative staining for CD3, CD20, CD19, and CD1a. Nuclear NPM expression was normal. These findings led to the diagnosis of isolated cerebral myeloid sarcoma. Molecular evaluation of the brain biopsy showed the presence of RUNX1, ASXL1, SRSF2, previously detected at the diagnosis. This finding allowed us to rule out a donor-derived myeloid neoplasia. Furthermore, the NGS evaluation was negative for any targetable lesion such as FLT3-ITD, IDH1, or IDH2 but remarkable for new mutations such as STAG2, BCOR, and NRAS, suggesting a clonal evolution of the original disease. Notably, bone marrow biopsy and aspirate confirmed the absence of systemic disease, and chimerism analysis showed 100% donor origin within the CD34+ and CD3 fractions, suggesting that an effective immunological pressure for 4 years was likely the reason for a relapse within a sanctuary organ. Intravenous chemotherapy with cytosine arabinoside (3 g/m&lt;sup&gt;2&lt;/sup&gt;) was administered with minimal clinical response. The patient rapidly developed pancytopenia and faced a septic shock due to multi-susceptible \u0000 &lt;i&gt;Pseudomonas aeruginosa&lt;/i&gt;\u0000 (which prevented an association with radiotherapy). He died after 5 days because of multi-organ failure.&lt;/p&gt;&lt;p&gt;This case underscores the critical importance of a multidisciplinary approach in allo-HSCT recipients, considering the complex interaction between donor immune cells and recipient leukemia cells. It also highlights the necessity of invasive diagnostic procedures for precise disease characterization, which is pivotal for guiding therapeutic strategies and determining prognosis.&lt;/p&gt;&lt;p&gt;Patient provided written consent to collect data for publication. The manuscript was approved by the internal board of the institution.&lt;/p&gt;&lt;p&gt;The authors declare no conflicts of","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"695-696"},"PeriodicalIF":10.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27640","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417439","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}