Blood advances最新文献

Graft-versus-host disease (GVHD), an often-fatal complication of allogeneic hematopoietic stem cell transplantation (HCT), is driven by inflammatory injury that damages target organs of gastrointestinal (GI) tract, skin and liver. Effective therapies must not only suppress GVHD reactivity of donor lymphocytes but permit regeneration of the damaged epithelium, particularly in the GI tract. Systemic corticosteroids are the standard first-line treatment for GVHD due to their powerful immunosuppressive and anti-inflammatory properties but may retard epithelial repair. Ruxolitinib, a selective JAK1/2 inhibitor, is an approved therapy for steroid-refractory GVHD, although its direct effects on epithelial repair are unknown. Intestinal stem cells (ISCs) that are critical for maintaining gut integrity and barrier function are key cellular targets of GVHD. We employed both ileal and colonic organoid cultures to study the direct effects of methylprednisolone and ruxolitinib under conditions that controlled the strength of the GVH reaction. Ruxolitinib prevented inflammatory apoptosis in both human and murine organoids and preserved ISC function and proliferation, while corticosteroids offered no protection and in fact suppressed proliferation. This study highlights the importance of GVHD therapies that facilitate epithelial repair and regeneration, protect target tissues and suppress alloreactivity of donor T cells.

Richter's transformation (RT) to diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma arising from underlying chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL). RT is often chemorefractory, with resultant poor clinical outcomes with standard chemoimmunotherapy. Mosunetuzumab, a bispecific CD20/CD3 T-cell engaging antibody, was investigated in a cohort of 20 patients with relapsed/refractory RT. Cytokine release syndrome (CRS) occurred in 65%, almost exclusively grade 1 (20%) or 2 (40%) and occurring during the first treatment cycle. Other adverse events included infections, neutropenia, thrombocytopenia, tumor flare and low grade neurotoxicity, with no adverse events leading to treatment discontinuation. Mosunetuzumab resulted in an overall response rate (ORR) 40% and complete response rate (CR) 20%. CRs were durable, with 2 patients experiencing CR >20 months without further therapy, and 2 able to proceed to allogeneic stem cell transplant in CR, with no subsequent relapse. Median progression free and overall survival (PFS and OS) was 3.4 and 10.2 months respectively. Given the favorable toxicity profile of mosunetuzumab, and rapid and durable complete responses observed in this cohort, further investigation of mosunetuzumab for the treatment of RT, as monotherapy and in combination with other novel agents or chemotherapy, is warranted. NCT02500407.

Practice variation exists in the management of newly diagnosed pediatric immune thrombocytopenia (ITP) despite availability of evidence-based treatment guidelines. The American Society of Hematology (ASH) ITP guidelines recommend that initial treatment of children should be based on assessment of clinical symptoms rather than the degree of thrombocytopenia and that short courses of corticosteroids should be prescribed to children requiring initial medication treatment. Retrospective review evaluating treatment of newly diagnosed children with ITP has demonstrated that management continues to be based on the platelet count with high use of intravenous immunoglobulin, which results in overuse of medications and high rates of inpatient hospitalizations and medical visits for administration and management of side effects. To improve adherence to ASH guidelines, the ITP Consortium of North America implemented a clinical care pathway as a multicenter quality improvement initiative. Retrospective data (11 centers, n=284) were collected prior to implementation and compared to post-implementation data (12 centers, n=266). With implementation of the clinical pathway, documentation of a bleeding score for children at diagnosis increased from 1% (3/284) to 95% (253/266). At diagnosis, initial treatment with ITP-directed medications decreased in children with no or mild bleeding symptoms (62% (177/284) vs. 31% (83/266), p<0.0001). Intravenous immunoglobulin use reduced from 51% (145/284) to 15% (41/266), p<0.0001. With implementation of the pathway, clinical outcomes were comparable with no increase in inpatient hospitalizations or bleeding events. Implementation of a clinical care pathway for a rare condition increases adherence to evidence-based guidelines and is feasible to implement across multiple centers.

Chronic Graft versus Host Disease (cGVHD) remains a major hurdle to the success of hematopoietic stem cell transplantation (HSCT), directly impacting patient morbidity and mortality. Impaired Treg recovery in patients with cGVHD has led to clinical studies aiming to increase peripheral Treg numbers. We performed Phase I dose escalation clinical trials, testing the feasibility and safety of using freshly isolated donor-derived Treg infusions in steroid-refractory/dependent cGVHD. The Phase I was extended to a preliminary Phase II trial, resulting in a total of 33 treated patients. We report that Treg purification from donor leukapheresis using CliniMACS were feasible and that Treg infusions were safe. Importantly, Treg infusions resulted in improved symptoms, particularly at higher Treg doses. Global responses were observed in 71% of patients, and 52% of patients had at least a 2-point improvement in the cGVHD severity scale. Furthermore, improvement in cGVHD symptoms resulted in reductions in corticosteroids, ruxolitinib and mycophenolate (MMF) in 58%, 83% and 33% of patients, respectively, while calcineurin inhibitors were discontinued in 75% of patients. Exploratory analyses revealed the detection of infused Treg clonotypes up to 12 months post-infusion and suggest increased Treg numbers in circulation. We observed increases in serum levels of IL-7, IFN-g, and decreases in sCD13 and ST2 over time, which were not statistically significant following adjustment for multiple comparisons. Although these studies were not powered to assess efficacy, they suggest potential therapeutic benefits of donor-derived Treg in cGVHD treatment and highlight the need for larger Phase II clinical trials. NCT02385019 NCT03683498 (clinicaltrials.gov).

Newly diagnosed mantle cell lymphoma (MCL) is commonly treated with rituximab (R) combined with anthracycline-based chemotherapy, with or without autologous stem-cell transplantation (ASCT). While rituximab maintenance (RM) in clinical trials has been shown to prolong overall survival (OS), its impact at population level remains largely unknown. This study evaluates the effect of RM on outcome of patients with MCL. Patients aged ≥18 years diagnosed with MCL between 1989-2020 were identified using the Netherlands Cancer Registry, and categorized into periods reflecting R and RM implementation (1989-2000, 2001-2014, 2015-2020). Treatment strategies were categorized as R-CHOP, R-CHOP followed by high-dose cytarabine (intensive) and ASCT, and other. The primary endpoint was 5-year OS. Multivariable analysis (MVA) was performed using Cox regression. Among 4,751 patients, 5-year relative survival (RS) improved from 38% (1989-2000) to 47% (2001-2014) and 60% (2015-2020) (p<0.01), irrespective of age (≤65 years: 32% and >65 years: 20% increase over time. Patients with progression (POD) within 12 months had 2-year OS of 25%. Since 2014, RM implementation reached 80% in younger and 50% in older patients. RM was associated with improved OS especially for patients in partial remission (PR), after induction treatment with R-CHOP. In MVA patients with R-CHOP, RM was independently associated with reduced mortality (hazard ratio 0.69; 95% CI, 0.53 - 0.90). Relative survival in MCL improved by more than 20% over the past 30 years. Early disease progression remains associated with poor outcome. RM was associated with improved survival, especially for patients achieving PR following R-CHOP.

Since the introduction of allogeneic bone marrow transplantation (BMT) for aplastic anemia, major advances have included refinements in conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, high-resolution human leukocyte antigen (HLA) typing, pre-transplant transfusion practices, and general supportive care. We present a comprehensive retrospective single-center cohort study of 607 children and adults who underwent allogeneic transplantation for aplastic anemia over six decades at a single BMT center. We highlight key temporal changes in conditioning for related donor transplants, GVHD prophylaxis, and HLA matching that correspond with improved non-relapse mortality, reduced GVHD rates, and better overall survival among HLA-matched related and unrelated donor transplants. This work provides a historical perspective on the evolution of BMT for aplastic anemia for HLA-matched related and unrelated donor recipients and identifies persistent barriers to curative therapy, including patient age and donor availability. Further studies are needed to clarify the role of anti-thymocyte globulin in conditioning regimens, improve GVHD prevention and management, and expand use of alternative donors.

Background: In patients with immune thrombocytopenia (ITP), a critical bleed such as intracranial hemorrhage or bleeding causing hemodynamic instability, requires urgent treatment to rapidly raise the platelet count and restore hemostasis. There is no standardized approach to this hematological emergency.

Objective: The McMaster ITP Emergency Management Guideline Group developed evidence-informed recommendations for the management of a critical bleed in adults and children with ITP.

Methods: The guideline panel included 5 clinical experts in adult ITP, 3 clinical experts in pediatric ITP, 2 emergency department physicians, 1 emergency department nurse, 2 methodologists, and 4 patient partners. To inform recommendations, the guideline team conducted a multicentre retrospective cohort study and systematic reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence and GRADE's evidence-to-decision framework to formulate recommendations.

Results: Given the life-threatening nature or significant morbidity associated with the condition, despite low or very low certainty evidence, the panel made strong recommendations for the combined use of high-dose corticosteroids, high-dose intravenous immunoglobulin (IVIG), platelet transfusions, tranexamic acid, and thrombopoietin receptor agonists (TPO-RAs) for the treatment of adults or children with a critical ITP bleed. The panel made a conditional recommendation for urgent splenectomy when other treatments have failed and, due to the risk of thrombosis, a conditional recommendation against the use of recombinant factor VIIa.

Conclusions: Motivated by the life-threatening nature of the condition, the panel made strong recommendations for the combined use of high-dose corticosteroids, high-dose IVIG, platelet transfusions, tranexamic acid, and TPO-RAs for the emergency management of adults and children with a critical ITP bleed.

Patients with large B-cell lymphoma (LBCL) are at increased risk of heart failure (HF) potentially due to anthracycline-based chemotherapy. However, associations with LBCL treatment intensity, HF subtype, and outcome remain under-characterized. We conducted a nationwide cohort study of 8,453 Swedish patients diagnosed with LBCL (median age 70 years) between 2007-2022 and 71,506 matched population comparators without a history of HF. The 5-year cumulative incidence of new-onset HF among patients was 8.1% overall, corresponding to a two-fold increased rate, driven mainly by non-ischemic HF (hazard ratio [HR]non-ischemic 2.33, 95% confidence interval [CI] 2.16-2.50), and less by ischemic HF (HRischemic 1.30, 95% CI 1.04-1.62). An increased rate of new-onset non-ischemic HF remained after 2 years of follow-up (HR 1.78, 95% CI 1.60-1.94). Few patients had reduced-intensity treatment (4 R-CHOP, n=84) of whom none developed HF. Patients selected for intensive treatment (e.g., R-CHOEP/R-DA-EPOCH) were not at higher risk of HF compared with standard R-CHOP (HR 0.73, 95% CI 0.58-0.92), although unmeasured differences in baseline fitness or frailty may have influenced treatment selection. After HF onset, LBCL patients had consistently higher all-cause (but not cardiovascular) mortality than comparators. Our findings indicate that LBCL patients face a sustained long-term risk of non-ischemic HF, highlighting the importance of survivorship care and vigilant HF symptom screening.