Blood advances最新文献

Abstract: Synchronous systemic and de novo secondary central nervous system (CNS) large B-cell lymphoma (LBCL) is an aggressive clinical entity with a historically poor prognosis. Given the rarity of this presentation, prospective studies are limited, and treatment paradigms and outcomes are extrapolated from small, heterogenous retrospective studies. We performed a retrospective study with extended follow-up for 63 consecutive patients with previously untreated synchronous systemic and de novo secondary CNS LBCLs presenting to 2 institutions over 21 years. Most patients had diffuse LBCL (73%) and were treated with an average of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) intercalated with high-dose IV methotrexate (R-CHOP-M). The overall response rate was 84% (75% complete). With a median follow-up of 8.1 years, the median progression-free survival (PFS) was 1.2 years, and the 6-year PFS rate was 37%. The median overall survival (OS) was 7.9 years, and the 6-year OS rate was 52%. Normal lactate dehydrogenase (LDH), low International Prognostic Index (IPI) score, and brain parenchymal-only CNS disease were associated with improved PFS, whereas normal LDH and parenchymal disease were associated with OS. The 25% of patients who underwent consolidation with high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) had superior PFS and OS than patients who did not receive a transplant, with particular benefit in those with IPI score of ≥3. This study demonstrates that a proportion of patients presenting with secondary CNS involvement are cured with upfront chemoimmunotherapy with or without HDC/ASCT and helps identify prognostically favorable subgroups, which can guide counseling of patients with this rare, high-risk clinical presentation.

Abstract: Antiangiogenic agents, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), represent an important class of treatments for a range of solid tumors. However, concerns have arisen over potential associations between antiangiogenic agents and thromboembolic events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared a frequently used VEGFR TKI, cabozantinib, with placebo or usual care. The primary outcome was the risk of any thromboembolism. Secondary outcomes included the risk of venous thromboembolism (VTE), risk of arterial thromboembolism (ATE) and progression-free survival. 14 RCTs were included with a combined total of 4204 patients, of whom 212 (5%) developed thromboembolism. Cabozantinib was associated with a significantly increased risk of any thromboembolism (risk ratio [RR], 2.41; 95% confidence interval [CI], 1.72-3.39) driven by VTE (RR, 3.21; 95% CI, 1.86-5.55) but not ATE (RR, 1.31; 95% CI, 0.76-2.26). To account for between-group differences in time on treatment, progression-free survival-adjusted analyses were conducted, with cabozantinib remaining associated with a significantly increased risk of any thromboembolism (RR, 1.47; 95% CI, 1.02-2.12) and VTE (RR, 1.92; 95% CI, 1.08-3.43) but not ATE (RR, 0.76; 95% CI, 0.41-1.40). In a retrospective single health care system cohort study of 295 patients treated with cabozantinib, a thromboembolism rate of 180 per 1000 patient-years on treatment was observed, with most events occurring in the first 3 months after initiation. Together these data demonstrate that cabozantinib is associated with a significantly increased risk of VTE in patients with cancer.

Abstract: Accurate genomic stratification is essential for guiding therapeutic decisions in myelofibrosis (MF), particularly regarding allogeneic stem cell transplant. Conventional chromosome banding analysis (CBA), however, has limited resolution and provides an informative karyotype in only about half of patients with MF. In a prospective series of 107 patients with primary or secondary MF, we compared optical genome mapping (OGM) plus targeted next-generation sequencing with CBA. OGM generated interpretable cytogenetic data for every sample, whereas CBA succeeded in fewer than half. In addition, OGM revealed structurally complex alterations and copy-neutral loss of heterozygosity that conventional methods missed. Integration of OGM results into contemporary prognostic models, including DIPSS-plus, GIPSS, and MIPSS70-plus version 2.0 (MIPSS70v2), refined risk allocation across the cohort. The greatest impact was observed for the transplant-oriented MIPSS70v2: the proportion of patients assigned to high-risk or very-high-risk categories increased from 19% with CBA alone to 36% after incorporating OGM findings. Incorporation of OGM data enabled full risk stratification of all 57 individuals with nonevaluable CBA karyotypes; 16 were assigned directly to the high-risk or very high MIPSS70v2 risk categories, a reclassification with immediate implications for transplant referral and follow-up intensity. This study represents the largest prospective evaluation of OGM in MF, demonstrating that OGM overcomes the limitations of CBA, uncovers clinically relevant cryptic alterations, and refines prognostic stratification. These findings support integrating OGM with targeted sequencing as a step toward precision medicine in MF.

Abstract: Approximately 20% of patients with Waldenström macroglobulinemia (WM) report family history (FH) of hematologic malignancies. However, the impact of FH on patient outcomes remains unclear. We included 1000 patients with WM to determine the relationship between FH, characteristics, complications, and treatment outcomes. Data collected included clinical features at diagnosis, complications (Bing-Neel syndrome [BNS], aggressive transformation, AL [light chain] amyloidosis, and neuropathy), FH cluster (WM [WM-FH], other B-cell FH [B-FH], non-B-cell FH [NON-B-FH], and sporadic [NO-FH]), and treatment outcomes. Logistic regression models were fitted to estimate the odds of complications. Time-to-event outcomes were assessed using the Kaplan-Meier method, and differences between groups evaluated using the log-rank test. Proportional hazards Cox regression models were fitted to determine the impact of WM-FH on time to first treatment (TTFT), overall survival (OS), and survival after first treatment initiation (SAFTI). The NO-FH group was the reference group for the regression analyses. The median follow-up time from diagnosis was 13 years. There were more women in the WM-FH than in the NO-FH group (50% vs 34%; P< .01). In multivariate logistic regression analysis, WM-FH was associated with higher odds of BNS (odds ratio [OR], 3.90; P = .005) and lower odds of neuropathy (OR, 0.49; P = .03) than NO-FH. The median TTFT was 0.7 years, OS was 23 years, and SAFTI was 20.5 years for all patients. In multivariate Cox regression analyses, WM-FH did not affect TTFT, SAFTI, or OS. Our study suggests higher odds of BNS and lower odds of neuropathy in patients with WM-FH but no impact of WM-FH on TTFT, OS, or SAFTI.

Abstract: HLA class I-immunized patients can experience a serious complication known as platelet transfusion refractoriness (PTR). This issue becomes especially relevant in onco-hematology departments where platelet transfusions are at the heart of patient care. Although transfusion failure is evidenced by a rapid elimination of allogeneic platelets from the recipient's bloodstream, the mechanisms behind it remain poorly characterized. The aim of this study was to better define these mechanisms to improve therapy for PTR. Using a murine model of major histocompatibility complex class I incompatibility to mimic PTR, we first established that antibodies, but not natural killer or CD8 cells, mediated platelet clearance. However, blocking Fcγ receptors with intravenous immunoglobulin or a monoclonal antibody or complement depletion did not correct refractoriness in alloimmune mice. Therefore, we investigated other alternatives beyond antibody-dependent mechanisms. Flow cytometric and microscopic analysis showed that Kupffer cells in the liver and red pulp macrophages in the spleen phagocytose allogeneic platelets during PTR. Moreover, intravital microscopy revealed allogeneic platelets retained in close interaction with macrophages in the red pulp only in alloimmune animals. Splenectomy or Kupffer cell depletion with clodronate in alloimmune mice suggested the existence of compensatory elimination mechanisms in the liver and spleen. Therefore, the simultaneous removal of both macrophage populations was an effective strategy to abrogate PTR. Our study provides an insight into the mechanisms of platelet clearance in alloimmune pathologies and opens up new perspectives for therapeutic targets.

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potential curative therapy for myelodysplastic syndrome (MDS), recommended in higher risk disease according to the International Prognostic Scoring System (IPSS). We conducted a phase 2 multicenter trial (MDS-ALLO-RISK) investigating whether allogeneic HSCT improves overall survival (OS) in patients with lower-risk MDS who exhibit additional high-risk features (intermediate or higher revised-IPSS risk, thrombocytopenia with <20 × 109/L, neutropenia <0.5 × 109/L, or failure to 2 lines of therapy). A total of 77 patients (median age, 62.5 years) with low or intermediate-1 IPSS scores were enrolled and stratified based on the presence of a matched HLA donor, 62 patients in the donor arm and 15 without a donor. Despite high remission rates in patients who had received a transplant (67.8% vs 21.4%), the 3-year OS did not significantly differ between arms (57.6% in the donor arm vs 64.3% in the no-donor arm; hazard ratio, 0.75; P = .53). The adjusted analysis using inverse probability of treatment weighting confirmed the lack of survival benefit with HSCT. Transplantation was associated with higher rates of chronic graft-versus-host disease, severe infections, and nonrelapse mortality (24.7%). Although quality of life improved slightly over time in patients who had received a transplant, the difference was not statistically significant. The trial was stopped early due to slow enrollment and futility. The findings highlight the need for improving posttransplant outcomes to justify HSCT in patients with lower-risk MDS with poor prognostic features. This trial was registered at www.clinicaltrials.gov as #NCT02757989.

Abstract: Hydroxyurea provides effective disease-modifying treatment for people with sickle cell anemia (SCA), especially when escalated to maximum tolerated dose (MTD), which has wide interpatient dosing variability due to pharmacokinetic (PK) differences. Whether hydroxyurea PK parameters differ among children with SCA in different global regions is unknown. We compared hydroxyurea PK parameters among children with SCA from 5 clinical trials: HUSTLE (United States), TREAT (United States), NOHARM (Uganda), REACH (Uganda and Kenya), and EXTEND (Jamaica). Key hydroxyurea PK parameters were determined using HdxSim, a validated hydroxyurea PK software program. The results were compared across regions by analysis of variance. PK profiles from 451 children with SCA (146 from the United States, 265 from Africa, and 40 from the Caribbean) were included. Children from Africa had slightly lower volumes of distribution, but absorption rate and clearance were similar across regions. The PK-recommended doses to achieve MTD were statistically different but clinically similar across the United States (26.6 ± 5.9 mg/kg per day), Africa (27.6 ± 6.5 mg/kg per day), and the Caribbean (25.2 ± 4.7 mg/kg per day) (P = .04). In multivariable regression, younger age and increased reticulocyte counts were associated with higher PK-recommended doses. Hydroxyurea PK parameters in children with SCA differ minimally across global populations, predicting clinically similar doses to achieve MTD. Individualized hydroxyurea dosing based on a PK-population model derived from US children with SCA can be used broadly to maximize the benefits of this critical medication in other global populations. These trials were registered at www.ClinicalTrials.gov as #NCT00305175 (HUSTLE), #NCT02286154 (TREAT), #NCT01976416 (NOHARM), #NCT01966731 (REACH), and #NCT02556099 (EXTEND).