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Mao, Xuehan; Yan, Wenqiang; Mery, David; Liu, Jiahui; Fan, Huishou; Xu, Jingyu; Xu, Yan; Sui, Weiwei; Deng, Shuhui; Zou, Dehui; Du, Chenxing; Yi, Shuhua; Rhee, Frits; Barlogie, Bart; Shaughnessy, John D.; Anderson, Kenneth C.; Zhan, Fenghuang; Qiu, Lugui; An, Gang
doi: 10.1002/ajh.27207pmid: 38247315
Current standard predictive models of disease risk do not adequately account for the heterogeneity of survival outcomes in patients with new‐diagnosed multiple myeloma (NDMM). In this retrospective, multicohort study, we collected clinical and genetic data from 1792 NDMM patients and identified the prognostic impact of all features. Using the top‐ranked predictive features, a weighted Myeloma Prognostic Score System (MPSS) risk model was formulated and validated to predict overall survival (OS). In the training cohort, elevated lactate dehydrogenase level (LDH), International Staging System (ISS) Stage III, thrombocytopenia, and cumulative high‐risk cytogenetic aberration (HRA) numbers were found to have independent prognostic significance. Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one HRA 1, and ≥2 HRA 2, points). Patients were further stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2–3 points), and IV (21.3%, 4–7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (p < .001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R‐ISS, R2‐ISS, and MASS). Utilization of the MPSS model in clinical practice could improve risk estimation in NDMM patients, thus prompting individualized treatment strategies.
Fioredda, F.; Beccaria, A.; Casartelli, P.; Turrini, E.; Contratto, C.; Giarratana, M. C.; Bagnasco, F.; Saettini, F.; Pillon, M.; Marzollo, A.; Zanardi, S.; Civino, A.; Onofrillo, D.; Lanciotti, M.; Ceccherini, I.; Grossi, A.; Coviello, D.; Terranova, P.; Lupia, M.; Del Borrello, G.; Uva, P.; Cangelosi, D.; Cavalca, G.; Miano, M.; Dufour, C.
doi: 10.1002/ajh.27221pmid: 38282561
This study identifies a new chronic form of immune neutropenia in the young with or without detectable indirect anti‐neutrophil antibodies, characterized by mild/moderate neutropenia low risk of severe infection (14%), tendency to develop autoimmune phenomena over the course of the disease (cumulative incidence of 58.6% after 20 years of disease duration), leukopenia, progressive reduction of absolute lymphocyte count and a T‐ and B‐cell profile similar to autoimmune disorders like Sjogren syndrome, rheumatoid arthritis, and systemic lupus erythematosus (increased HLADR+ and CD3 + TCRγδ cells, reduced T regulatory cells, increased double‐negative B and a tendency to reduced B memory cells). In a minority of patients, P/LP variants related to primary immuno‐regulatory disorders were found. This new form may fit the group of “Likely acquired neutropenia,” a provisional category included in the recent International Guidelines on Diagnosis and Management of Neutropenia of EHA and EUNET INNOCHRON ACTION 18233. The early recognition of this form of neutropenia would help clinicians to delineate better specific monitoring plans, genetic counseling, and potentially targeted therapies.
Zurawska, Gabriela; Jończy, Aneta; Niklewicz, Marta; Sas, Zuzanna; Rumieńczyk, Izabela; Kulecka, Maria; Piwocka, Katarzyna; Rygiel, Tomasz P.; Mikula, Michal; Mleczko‐Sanecka, Katarzyna
doi: 10.1002/ajh.27223pmid: 38293789
BMP6 is an iron‐sensing cytokine whose transcription in liver sinusoidal endothelial cells (LSECs) is enhanced by high iron levels, a step that precedes the induction of the iron‐regulatory hormone hepcidin. While several reports suggested a cell‐autonomous induction of Bmp6 by iron‐triggered signals, likely via sensing of oxidative stress by the transcription factor NRF2, other studies proposed the dominant role of a paracrine yet unidentified signal released by iron‐loaded hepatocytes. To further explore the mechanisms of Bmp6 transcriptional regulation, we used female mice aged 10–11 months, which are characterized by hepatocytic but not LSEC iron accumulation, and no evidence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 mRNA levels as compared to young controls, but do not show a transcriptional signature characteristic of activated NFR2‐mediated signaling in FACS‐sorted LSECs. We further observed that primary murine LSECs derived from both wild‐type and NRF2 knock‐out mice induce Bmp6 expression in response to iron exposure. By analyzing transcriptomic data of FACS‐sorted LSECs from aged versus young mice, as well as early after iron citrate injections, we identified ETS1 as a candidate transcription factor involved in Bmp6 transcriptional regulation. By performing siRNA‐mediated knockdown, small‐molecule treatments, and chromatin immunoprecipitation in primary LSECs, we show that Bmp6 transcription is regulated by iron via ETS1 and p38/JNK MAP kinase‐mediated signaling, at least in part independently of NRF2. Thereby, these findings identify the new components of LSEC iron sensing machinery broadly associated with cellular stress responses.
Allali, Slimane; Galactéros, Frédéric; Oevermann, Lena; Cannas, Giovanna; Joseph, Laure; Loko, Gylna; Elenga, Narcisse; Benkerrou, Malika; Etienne‐Julan, Maryse; Castex, Marie‐Pierre; Brousse, Valentine; Montalembert, Mariane
doi: 10.1002/ajh.27214pmid: 38247384
Acute splenic sequestration crisis (ASSC) is a potentially life‐threatening complication of sickle cell disease (SCD), typically occurring in young patients under 5 years of age, with a median age at first episode of less than 2 years. Because a beneficial effect of hydroxyurea (HU) on spleen perfusion and splenic function has been suspected, we hypothesized that HU treatment might be associated with later onset of ASSC in patients with SCD. To investigate this hypothesis, we analyzed data from the ESCORT‐HU study on a large cohort of patients with SCD receiving HU, enrolled between January 2009 and June 2017 with a follow‐up of 7309 patient‐years of observation. The median age at ASSC of the 14 patients who experienced a first episode of ASSC during the study period was 8.0 [IQR: 5.0–24.1] years. The median age at HU initiation was significantly lower in these 14 patients (4.8 [IQR: 3.3–18.7] years) compared to the 1664 patients without ASSC (19.9 [8.8–33.4] years, p = .0008). These findings suggest that ASSC may occur at an unusually late age in patients receiving HU, possibly reflecting longer preservation of spleen perfusion and function secondary to early initiation of HU. Further studies are needed to better characterize the effects of HU on spleen perfusion/function and on the occurrence of ASSC in patients with SCD (ClinicalTrials.gov identifier: NCT02516579; European registry ENCEPP/SDPP/10565).
Ahmed, Sairah; Bashir, Qaiser; Bassett, Roland L.; Ullah, Fauzia; Aung, Fleur; Valdez, Benigno C.; Alousi, Amin M.; Hosing, Chitra; Kebriaei, Partow; Khouri, Issa; Marin, David; Nieto, Yago; Olson, Amanda; Oran, Betul; Qazilbash, Muzaffar H.; Rezvani, Katayoun; Mehta, Rohtesh; Shpall, Elizabeth J.; Ciurea, Stefan; Andersson, Borje S.; Champlin, Richard E.; Popat, Uday R.
doi: 10.1002/ajh.27233pmid: 38314663
Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) with bone marrow graft and post‐transplant cyclophosphamide (PCy)‐based graft‐versus‐host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post‐haplo‐HSCT. The prospective study included patients ≥18 years of age who received haplo‐HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/μL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy‐three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/μL platelet count by Day 60 (p = .043). No eltrombopag‐related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/μL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%–100%) with eltrombopag versus 67.5% (95% CI: 57%–78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression‐free survival, GVHD rate, relapse rate, and non‐relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo‐HSCT with bone marrow graft and PCy.
Ito, Satoko; Pandya, Ankur; Hauser, Ronald G.; Krishnamurti, Lakshmanan; Stites, Edward; Tormey, Chris; Krumholz, Harlan M.; Hendrickson, Jeanne E.; Goshua, George
doi: 10.1002/ajh.27211pmid: 38279581
Red blood cell alloimmunization and consequent delayed hemolytic transfusion reaction (DHTR) incidence and mortality in patients with sickle cell disease (SCD) are high. A shared transfusion resource has decreased both in other countries, while in the United States cost concerns persist. We conducted a Markov cohort simulation of a birth cohort of alloimmunized patients with SCD to estimate lifetime DHTR incidence, DHTR‐specific mortality, quality‐adjusted life expectancy (QALE), and costs with the implementation of a shared transfusion resource to identify antibody history versus without (i.e., status quo). We conducted our analysis using a lifetime analytic time horizon and from a United States health system perspective. Implementation of shared transfusion resource projects to decrease cumulative DHTR‐specific mortality by 26% for alloimmunized patients with SCD in the United States, relative to the status quo. For an average patient population of 32 000, this intervention would generate a discounted increment of 4000 QALYs at an incremental discounted cost of $0.3 billion, resulting in an incremental cost‐effectiveness ratio of $75 600/QALY [95% credible interval $70 200–81 400/QALY]. The results are most sensitive to the baseline lifetime medical expenditure of patients with SCD. Alloantibody data exchange is cost‐effective in 100% of 10 000 Monte Carlo simulations. The resource would theoretically need a minimum patient population of 1819 patients or cost no more than $5.29 million annually to be cost‐effective. By reducing DHTR‐specific mortality, a shared transfusion resource in the United States projects to be a life‐saving and cost‐effective intervention for patients with SCD in the United States.
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