Intensive Chemotherapy With or Without Midostaurin in Adults ≥ 60 Years Old With FLT3 ‐Mutated AML : A FILO ‐ DATAML ‐ PETHEMA Real‐World Study

ABSTRACT The addition of midostaurin (MIDO) to intensive chemotherapy (IC) improves survival in younger adults with FLT3 ‐mutated acute myeloid leukemia (AML); however, real‐world data in elderly patients (≥ 60 years) are limited. This large, retrospective, multicenter study from three European registries (PETHEMA, FILO, DATAML) evaluated MIDO+IC ( n  = 194) versus IC alone ( n  = 371) in 565 patients with FLT3 ‐mutated AML aged ≥ 60 years (median age 67.5 years; 35.6% ≥ 70 years). MIDO+IC was associated with lower day‐60 early death (8.2% vs. 21.4%, p  < 0.0001) and higher composite complete remission (CRc) rates (78.9% vs. 63.1%, p  < 0.0001). After a median follow‐up of 46.0 months, median overall survival (OS) was 24.2 months for MIDO+IC versus 8.7 months for IC ( p  < 0.0001), with 5‐year OS rates of 40.6% vs. 12.9%, respectively. Event‐free survival (EFS; median 13.5 vs. 4.6 months; 5‐year EFS: 36.0% vs. 10.1%) and relapse‐free survival (RFS; median 20.2 vs. 8.0 months; 5‐year RFS: 45.4% vs. 15.7%) were also significantly improved (both p  < 0.0001). The 5‐year cumulative incidence of relapse was lower with MIDO+IC (47.8% vs. 67.1%, p  < 0.001). In multivariate analyses, midostaurin was an independent favorable prognostic factor for CRc (aOR 1.97 [95% CI: 1.29–2.98]), OS (aHR 0.46 [95% CI: 0.36–0.58]), EFS (aHR 0.49 [95% CI: 0.39–0.60]), and RFS (aHR 0.47 [CI: 0.36–0.62]) (all p  ≤ 0.002). These benefits were confirmed by propensity score matching. This large real‐world study demonstrates that combining midostaurin with IC significantly improves remission rates and survival outcomes in elderly patients with FLT3 ‐mutated AML, supporting its consideration in this population.

Cryopreservation of Hemopoietic Cells for Allotransplant: Altered Immune Cell Subsets and Clinical Implications

ABSTRACT Cryopreservation of allogeneic peripheral blood stem cells was widely adopted during the SARS‐CoV‐2 pandemic. We evaluated transplant‐related complications and graft product composition in a retrospective ( n = 62) and prospective ( n = 47) series of patients transplanted from an HLA‐identical donor comparing cryopreserved ( n = 50) versus fresh ( n = 59) peripheral blood stem cell grafts. Primary endpoints were hematological reconstitution and cumulative incidence of grade II–IV acute graft versus host disease. Median times to neutrophil and platelet recovery were longer in the cryopreserved group compared with the fresh group: 18 vs. 16 days ( p  < 0.001) and 20 vs. 14 days ( p  < 0.001), respectively. The cumulative incidence of grade II–IV acute graft versus host disease at day 100 and of poor graft function at 1 year was significantly higher in the cryopreserved group: 34% vs. 10.1%, ( p  = 0.0017) and 20% vs. 1.6% ( p  < 0.001), respectively. To characterize immune cell profiles in fresh and cryopreserved samples, a representative subset was analyzed by mass cytometry, revealing a higher number of T‐cell populations known to modulate immune responses and promote graft engraftment in fresh samples. Thus, cryopreservation of allogeneic peripheral blood stem cells is associated with increased incidence of acute graft versus host disease and poor graft function.

Impact of CSF3R Mutations on Leukemic Transformation in Severe Congenital Neutropenia: A Retrospective Analysis From the Italian Neutropenia Registry

Encouraging Outcomes in Pediatric Malignancy‐Associated Hemophagocytic Lymphohistiocytosis: Results From the Italian HLH Registry

Venetoclax or Pirtobrutinib in Relapsed/Refractory Waldenström Macroglobulinemia: Clinical and Molecular Predictors and Sequencing Implications

ABSTRACT Venetoclax and pirtobrutinib have emerged as two chemotherapy‐free options for relapsed or refractory Waldenström macroglobulinemia (WM). However, evidence to guide treatment sequencing or identify molecular subsets most likely to benefit from each agent remains limited. We retrospectively evaluated consecutive WM patients treated with venetoclax or pirtobrutinib. Major response rate (MRR) and progression‐free survival (PFS) were assessed for each agent, with predictors of response and PFS analyzed using logistic and Cox regression. Comparative efficacy was examined in unmatched analyses and in a 1:1 matched cohort. Among 91 treatment exposures (64 venetoclax and 27 pirtobrutinib) across 80 unique patients, treatment discontinuation due to adverse effects occurred in 12 of 64 patients (19%) treated with venetoclax and in none treated with pirtobrutinib. In the venetoclax cohort, TP53 alterations were associated with shorter PFS (10.0 vs. 35.6 months; p  < 0.001). In the pirtobrutinib cohort, CXCR4 mutations predicted lower MRR (40% vs. 91%; p  = 0.01) and shorter PFS (8.3 months vs. not reached; p  = 0.02). When transitioning from a cBTKi, IgM rebound occurred in 62% (8/13) of patients initiating venetoclax without overlap, whereas no rebound was observed with cBTKi‐venetoclax overlap (0/5) or with pirtobrutinib initiation (0/15). In the matched cohort ( n  = 42), venetoclax and pirtobrutinib demonstrated comparable outcomes for MRR ( p  = 0.91) and PFS ( p  = 0.83). Despite the retrospective design and limited sample size, these findings indicate comparable efficacy between venetoclax and pirtobrutinib with distinct molecular vulnerabilities and support consideration of pirtobrutinib sequencing when transitioning from a cBTKi, as well as further exploration of combination strategies that may exploit complementary vulnerabilities.

Genetic Ancestry Reveals Historical Diversity of Formation Across Three Brazilian Communities of African Descent ( Quilombos ) in Central Brazil

ABSTRACT Introduction Characterized as relatively isolated communities, many Brazilian quilombos were formed during the period of slavery in Brazil when enslaved persons (most of African descent) ran away or were abandoned by their enslavers. Quilombos in Central Brazil, whose settlement was more recent due to the relative isolation of the region, remain understudied. To address this gap, this study estimated the genetic ancestry of three quilombo communities in Central Brazil. Methods A cross‐sectional study was performed among three Central Brazilian quilombos , Cocalinho ( N  = 54) and Pé do Morro ( N  = 58) located in the Brazilian state of Tocantins, and Kalunga ( N  = 132) located in the state of Goiás. Genetic ancestry was estimated from 61 Ancestry‐informative INDEL biallelic markers collected from blood samples and analyzed using STRUCTURE v 2.3. Statistical analyses were performed using SAS statistical software, v. 9.4. Results The population demonstrated heterogeneous genetic admixture by quilombo . Average African admixture estimates were 36.75%, 29.82%, and 63.17% in Cocalinho (semirural), Pé do Morro (urban), and Kalunga (rural) communities, respectively. Indigenous and European ancestry contributions also varied by quilombo , with participants from the more recently populated quilombos and those living closest to urban areas having higher European and Indigenous genetic ancestry contributions. Conclusions This study demonstrates that quilombos comprise rich population histories shaped by culture, historical events, and sociodemographic and environmental interactions. By unraveling the genetic tapestry of Central Brazil's quilombos , this study contributes to a deeper understanding of Brazil's intricate social and historical landscape.

Sacroiliac Joint Involvement: An Underreported Complication of NF1

ABSTRACT NF1‐related bone dysplasia in children and young adults with neurofibromatosis type 1 (NF1) involving the sacroiliac joint has been rarely described. We report four participants who underwent whole‐body magnetic resonance imaging (WB‐MRI) as part of a longitudinal imaging and plexiform neurofibroma (PN) biomarker study (NCT05238909) at Ann & Robert H. Lurie Children's Hospital of Chicago in collaboration with the National Institutes of Health. The four participants were aged 12, 17, 32, and 34 at the time of WB‐MRI; three out of four were female. In cases 1 through 3, there was an underlying internal PN on the side of sacroiliac dysplasia. All cases were unilateral and intraarticular, and two involved subcutaneous tissue. The PNs were too small to measure in two cases. Among the measurable lesions, one was localized, and one was diffuse with extension into the lower extremity. The localized PN showed a 20% increase in size over a one‐year follow‐up period. In cases 1 through 3, no sequelae such as pain or fractures were observed during the follow‐up period. Case 4 was referred for surgical evaluation due to persistent pain. Our findings highlight a potentially underreported developmental abnormality of the sacroiliac joint in individuals with NF1.

De Novo Truncating Variants in ZNF865 Cause a Novel Neurodevelopmental Disorder

ABSTRACT Despite significant knowledge advances in recent decades, the role of most protein‐coding genes in human disease remains incompletely understood. Exome sequencing continues to improve our understanding by elucidating novel genotype–phenotype associations. Across multiple healthcare centers, either exome or genome sequencing was performed in 18 patients with shared features of global developmental delay, hypotonia, and dysmorphisms. De novo, truncating variants in ZNF865 were identified in all 18 patients, with all but one clustered toward the C‐terminus. Four variants were seen more than once in unrelated patients. No disease‐causing variants were identified in other genes that would explain the patients' phenotypes. Little is known of the function of ZNF865, which belongs to the poly‐zinc finger family of proteins that contain a large array of tandem C2H2 zinc finger DNA binding domains. Our findings suggest that protein‐truncating variants in this gene lead to intellectual disability with a recognizable phenotypic pattern.

Efficacy and Safety of Olipudase Alfa for the Treatment of Acid Sphingomyelinase Deficiency ( ASMD ): A Systematic Review and Meta‐Analysis

ABSTRACT Acid sphingomyelinase deficiency (ASMD), or Niemann–Pick disease types A, B, and A/B, is a rare lysosomal storage disorder caused by SMPD1 mutations. Clinical forms range from severe neurovisceral (type A) to chronic visceral (type B), mainly affecting the liver, spleen, and lungs. Until 2022, treatment was limited to supportive care. The approval of olipudase alfa for the non‐central nervous system (CNS) manifestations of ASMD marked a major advance, with trials showing improvements in organ volumes and lung function. This meta‐analysis evaluates the broader clinical impact of olipudase alfa in ASMD. A systematic search of Cochrane, PubMed, and Embase identified RCTs and cohort studies on olipudase alfa in patients with ASMD. Primary outcomes included mean change in %DLco, %Liver volume, and %Spleen volume; other secondary outcomes were also assessed. Study selection followed PRISMA guidelines, and statistical analyses were conducted using R software. The study was registered in PROSPERO CRD420251032281. Three studies (One RCT) encompassing 46 patients were included. Follow‐up duration ranged from 1 to 6.5 years. All patients received olipudase alfa; only one study included a placebo group. Pooled results showed a mean DLco increase of 34.63% (95% CI: 26.09–43.18), a liver volume reduction of −37.76% (95% CI: −49.78 to −25.75), and a spleen volume reduction of −49.46% (95% CI: −57.39 to −41.53) after 2 years. The olipudase alfa demonstrates substantial clinical benefits in ASMD, significantly improving lung function and reducing organomegaly. Further studies are needed to confirm long‐term safety and efficacy.

Nance‐Horan Syndrome: Further Delineation of the Affected Male and the Female Carrier Phenotypes

ABSTRACT Nance‐Horan syndrome (NHS; OMIM 302350) is a rare, X‐linked syndrome characterized by bilateral congenital cataracts leading to profound vision loss, specific dental anomalies including characteristic screwdriver blade‐shaped incisors, facial anomalies, and intellectual disability. It is caused by deleterious loss of function variants or deletions involving the NHS gene at Xp22.13. Heterozygous females often present with similar, but less severe features than affected males. We describe a relatively large cohort of eight new patients with NHS, including two patients with microdeletions including NHS who had classical presentations, and provide detailed descriptions of the clinical findings for both affected males and females. The spectrum of clinical features in NHS is variable and can be mild, in particular for females, and the condition can remain undiagnosed. This report contributes to the delineation of the phenotypic and genotypic findings associated with this condition.