Acalculous cholecystitis is an uncommon but serious complication of myelosuppressive chemotherapy that is most often observed during profound neutropenia and carries a substantially high morbidity and mortality. This case describes the fulminant course of acalculous cholecystitis in a 78-year-old female receiving carboplatin and vinorelbine for non-small cell lung cancer, with rapid progression from initial presentation to septic shock and multiorgan failure. The case highlights the aggressive nature of acalculous cholecystitis in immunocompromised patients and underscores the importance of early clinical suspicion and prompt intervention in preventing progression to catastrophic outcomes.

The multicellular metazoan lineage acquired a novel chaperone in the mitochondrial intermembrane space, the AAA+ disaggregase and refoldase CLPB. Although it is not known how they function together, CLPB and the intrinsically disordered IMS protein HAX1 interact and share disease and cellular phenotypes; loss of function in either gene causes severe congenital neutropenia as well as neuropathology and causes many proteins in the IMS and its bounding membranes to become insoluble. We sought to determine how HAX1 functions with CLPB. Through biochemical reconstitution, we find that HAX1 is a stimulatory cofactor of CLPB. HAX1 promotes oligomerization of CLPB into an active disaggregase and stimulates the ATPase and refoldase activities of the oligomeric complex. A short peptide within HAX1 is necessary for direct interaction with the ankyrin domain of CLPB, but stimulation of CLPB activity requires additional elements of HAX1. Characterization of CLPB and CLPB-HAX1 oligomers indicates that HAX1 shifts the predominant oligomeric state of CLPB from a dodecamer to a hexamer elaborated 1:1 with HAX1, suggesting that this smaller oligomer is important during the cycle of CLPB function with clients.

The TALAPRO-2 trial (NCT03395197) showed that the addition of talazoparib, a potent PARP inhibitor, to enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC. Due to adverse events (AEs), approximately 62% of patients experienced dose interruption and 53% of patients experienced dose reduction of talazoparib in TALAPRO-2 trial. Hematologic AEs such as anemia, thrombocytopenia, and neutropenia were the most common AEs leading to dose interruptions or reductions. We investigated the relationship between talazoparib exposure as well as baseline patients/disease characteristics and Grade ≥ 3 anemia, thrombocytopenia, and neutropenia using graphical examination and Cox proportional hazard models. The results indicated that higher talazoparib exposure, Cavg, t, was associated with a higher risk of Grade ≥ 3 anemia, thrombocytopenia, and neutropenia. Additionally, among the other baseline factors, we observed that higher risk of all tested safety endpoints was associated with lower baseline hemoglobin. In addition, higher risk of anemia was associated with lower baseline body weight and higher baseline lactate dehydrogenase. Higher risk of neutropenia was associated with lower baseline absolute neutrophil count and lower baseline body weight. These findings support the proposed dose modification algorithm as an effective approach for management of AEs.

Iron overload is a significant cause of transfusion-related morbidity and mortality. Deferiprone (DFP) is an established oral iron chelator approved for the treatment of transfusional iron overload in patients with thalassemia, sickle cell disease (SCD), or other anemias. Initially approved as a three times-a-day (TID) formulation, a twice-a-day (BID) formulation was developed to improve patient adherence. Here, we assess the safety of DFP BID in patients with thalassemia, SCD, or other anemias in real-world clinical practice in the United States. Data for patients referred for DFP BID between July 1, 2020 to August 31, 2023 were obtained from the Ferriprox® Total Care Registry. The frequency of adverse events (AEs), serious AEs (SAEs), AEs of special interest and fatal outcomes was assessed. Of the 425 patients referred to the registry, 348 received ≥one DFP shipment and had a primary diagnosis of thalassemia syndromes (N=129), SCD (N=189), or other anemias (N=30) (safety analysis group). Mean (SD) DFP exposure was 343.0 (281.9) days. In total, 1021 AEs and 369 SAEs were reported. As seen with the TID formulation, the most common adverse events with DFP BID were predominantly gastrointestinal or related to underlying disease. Cases of neutropenia and agranulocytosis were rare, reported in 1.7% and 0.6% of patients, respectively and all recovered. None of the 26 fatal outcomes reported were assessed as related to DFP treatment. DFP BID was well-tolerated in real-world clinical practice, and the safety profile was consistent with DFP TID. No new safety concerns were observed.

We hypothesized that a time-limited frontline treatment strategy with abbreviated chemoimmunotherapy followed by targeted consolidation could achieve durable disease control with manageable toxicity in CLL. We evaluated the safety and efficacy of short-course bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation. In a multicenter, single-arm Phase 2 trial (NCT03609593), previously untreated CLL/SLL needing therapy received BR for three 28-day cycles followed by venetoclax ramp-up to 400 mg daily plus rituximab every 28 days for six cycles; venetoclax continued to 12 cycles (total treatment, 15 months). The primary endpoint was overall response rate (ORR); key secondary endpoints included uMRD, PFS/OS, and safety per CTCAE v4. Forty-two patients were enrolled (median age 61.5 years; 64% unmutated IGHV; 29% complex karyotype; 10% TP53 aberrancy); 93% completed all planned therapy. At end of treatment, ITT ORR was 86% (CR/CRi 64%, PR 21%); among efficacy-evaluable patients, ORR was 100% (CR/CRi 75%). End-of-therapy uMRD was achieved by 83% in bone marrow and 84% in blood among efficacy-evaluable patients. Three-year PFS and OS were 87.5% and 92.7%. TLS risk was downstaged after BR, and no TLS events occurred. Febrile neutropenia occurred in 12% of patients. Two on-study deaths due to COVID-19 occurred; no Richter transformation occurred. Time-limited BR-VR achieved high uMRD rates and durable remissions with a manageable safety profile. While the treatment landscape in CLL has largely shifted toward chemotherapy-free regimens, these data demonstrate the biological proof-of-concept that limited induction chemotherapy can effectively mitigate TLS risk and facilitate safe outpatient ramp-up of venetoclax.

IntroductionRabbit anti-thymocyte globulin (rATG) induction ideal dosing strategies in kidney transplant recipients have not been fully elucidated.Project AimsThis study compares the impact of ideal body weight-based versus actual body weight-based rATG dosing on drug purchasing costs and kidney transplant outcomes.DesignRetrospective, single-center chart review of kidney transplant recipients receiving rATG induction using (1) actual body weight-based dosing between May 17, 2019, and Mar 13, 2020, versus (2) ideal body weight-based dosing between May 17, 2022, and Mar 13, 2023. The primary endpoint is the rATG drug cost/kidney transplant recipient [measured by average wholesale price] compared between cohorts. Secondary endpoints are rates of biopsy-proven acute rejection, readmissions secondary to infection, myelosuppression (leukopenia or neutropenia), and viremia (Epstein-Barr virus, cytomegalovirus, and BK virus) measured for 6 months. Study design adhered to EQUATOR STROBE guidelines for reporting cohort studies.ResultsOverall, rATG ideal body weight-based dosing resulted in a median $3838 saved per kidney transplant recipients, based on average wholesale price, and a statistically significant reduction in cost versus actual body weight-based dosing (P = .02). Secondary outcomes were generally similar between groups, with a difference in Epstein-Barr viremia (P = .017) not translating to a significant difference in readmissions for infection (P = .226).ConclusionOur institution conducts around 250 kidney transplants annually, and considering the majority will receive rATG induction, this dosing protocol estimates average wholesale price drug purchasing cost-savings of about $900 000/year without compromising early clinical outcomes.

Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has emerged as a potential therapy for recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation; however, data on subcutaneous administration and its use in de novo disease are limited. We report 3 kidney transplant recipients with recurrent (n = 1) and de novo (n = 2) FSGS who were plasma exchange-dependent and/or rituximab-resistant and treated with subcutaneous daratumumab. All patients achieved remission, with sustained reductions in albuminuria and stable graft function at follow-up. Treatment was well tolerated, with no injection-related reactions; 1 patient developed transient neutropenia and oral ulcers. Subcutaneous daratumumab may represent a feasible and effective option for recurrent and de novo FSGS after kidney transplantation, including refractory cases, in conjunction with anti-CD20 therapy. Prospective studies are needed to define its role as monotherapy and the durability of response.

Background In resource-limited settings, febrile neutropenia (FN) is one of the common cause of morbidity and mortality among immunocompromised individuals particularly those undergoing chemotherapy for malignancies. The clinical diagnosis and management of disease is challenging, due to the diverse range of causative pathogens and overreliance on the traditional diagnostic techniques. TaqMan array card (TAC), a microfluidics-based technique that allows simultaneous and rapid detection of multiple pathogens with high sensitivity, addressing these diagnostic needs. Objective The aim of this study was to determine the role of TAC in improving pathogen identification in hospitalized patients with FN. Methods This cross-sectional study enrolled 156 FN patients admitted to Aga Khan University and Hospital, Karachi, Pakistan. To enhance pathogen detection, blood culture broths were used for microbial enrichment, improving sensitivity and reliability. Both blood cultures and TAC assays were performed on the collected broths. Enrichment strategies were employed to reduce the impact of PCR inhibitors and increase microbial biomass, thereby enhancing the diagnostic sensitivity of TAC. Results TAC identified a diverse range of pathogens compared with traditional blood culture. Of 156 study participants, 61 (39.1%) were culture-positive and at least one pathogen was detected in 50 of the 146 samples by TAC assay. The common pathogen detected by TAC was K. pneumonia followed by E. coli and S. aureus , and Candida species along with two viruses (Parvovirus B19 and HHV6). Kappa values of 0.319 for E. coli and 0.644 for K. pneumoniae , TAC demonstrated a moderate association with blood culture results. Moreover, K. pneumoniae , E. coli , and P. aeruginosa and Candida species were significantly associated with increased mortality among FN patients. Conclusion The findings of this study suggest that TAC improves pathogen detection with high sensitivity in FN patients. Incorporating TAC into clinical settings may facilitate early pathogen identification leading to better clinical outcomes. Multicenter studies are needed to validate these results and assess the effectiveness of TAC in broader clinical settings.