Haematologica

The first classification of acute myelogenous leukemia

Marshall A. Lichtman — Sat, 01 Mar 2025 00:00:00 +0000

Is age just a number? Intensive therapy for core-binding factor acute myeloid leukemia in older adults

Benson M. George, Marlise R. Luskin — Thu, 14 Nov 2024 00:00:00 +0000

Infections in sickle cell disease

Lily E.A. Scourfield, Amina Nardo-Marino, Thomas N. Williams, David C. Rees — Thu, 21 Nov 2024 00:00:00 +0000

Sickle cell disease (SCD) is one of the commonest severe inherited disorders in the world. Infection accounts for a significant amount of the morbidity and mortality, particularly in sub-Saharan Africa, but is relatively poorly studied and characterized. Patients with SCD have significant immunodeficiency and are more likely to suffer severe and life-threatening complications of infection, and additionally infections can trigger complications of SCD itself. Those with more severe forms of SCD have functional asplenia from a very early age, which accounts for much of the morbidity in young children, particularly invasive infections from encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae, Salmonella typhi and meningococcal disease. Additionally, there are other defects in immune function in SCD, associated with anemia, tissue infarction and impaired adaptive immunity. Complications of infections in SCD include acute chest syndrome, acute painful episodes, osteomyelitis, meningitis, urinary tract infections, overwhelming sepsis and death. Viral infections cause significant morbidity, particularly severe anemia associated with parvovirus, and to a lesser extent other infections such as influenza and coronavirus disease 2019. The relationship between malaria and SCD is complicated and discussed in this review. Unlike many of the genetic risk factors for poor outcomes in SCD, it is theoretically possible to modify the risks associated with infections with established public health measures. These include the provision of vaccination, prophylactic antibiotics and access to clean water and mosquito avoidance, although current financial restraints and political priorities have made this difficult.

Optimization of T-cell-replete haploidentical hematopoietic stem cell transplantation: the Chinese experience

Xiaodong Mo, Xuying Pei, Xiaojun Huang — Thu, 21 Nov 2024 00:00:00 +0000

Haploidentical-related donor (HID) hematopoietic stem cell transplantation (HSCT) has undergone significant advances in recent decades. Granulocyte colony-stimulating factor- and antithymocyte globulin-based protocols and post-transplantation cyclophosphamide-based regimens represent two of the current T-cell-replete protocols in HID HSCT. Recently, the optimization of several critical transplant techniques has further improved hematopoietic reconstitution, decreased the incidence of relapse and graft-versus-host disease after HID HSCT, and extended the application of HID HSCT to older patients and those with non-malignant hematologic disorders. Combining this approach with novel immunotherapy could further improve the efficacy and safety of HID HSCT. This review focuses on recent progress in the optimization of HID HSCT.

“The End of the Golden Weather”: therapeutic strategies for mantle cell lymphoma relapsed or refractory to covalent BTK inhibitors

Brian T. Grainger, Chan Y. Cheah — Thu, 14 Nov 2024 00:00:00 +0000

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma, often characterized by a pattern of continued relapse after front-line chemoimmunotherapy. Although patients are usually able to regain durable disease control with covalent Bruton’s tyrosine kinase inhibitors (cBTKi) at first relapse, it is now appreciated that such responses are often not sustained and the management of such patients represents a significant area of unmet need. There is an imperative to better understand resistance mechanisms and identify high-risk subsets of patients for whom cBTKi responses may be particularly short. Allogeneic stem cell transplant has an established role in appropriate candidates; however, contemporary consensus is to preferentially offer chimeric antigen receptor (CAR) T-cell therapy. In this Review, we consider the available data on both existing and emerging treatment options, including non-covalent BTK inhibitors, bispecific antibodies, antibody-drug conjugates and Bcl-2 inhibitors, and propose a treatment strategy, prioritizing clinical trials where available.

von Willebrand disease and angiodysplasia: a wider view of pathogenesis in pursuit of therapy

Christina Crossette-Thambiah, Anna M. Randi, Michael Laffan — Thu, 07 Nov 2024 00:00:00 +0000

Bleeding in the gastrointestinal tract in patients with von Willebrand disease continues to pose a therapeutic challenge for clinicians. It is associated with significant morbidity and mortality and represents the major unmet need in this disease. Defective angiogenesis in the gut is primarily responsible, resulting in angiodysplastic malformations making bleeding notoriously refractory to standard replacement therapy. A substantial body of evidence now shows that von Willebrand factor has a role in the regulation of angiogenesis but the mechanisms responsible for the formation of vascular malformations remain incompletely understood. Data from the wider field of vascular malformations may lend insight and point to novel therapeutic approaches. Here we review evidence linking von Willebrand factor to angiodysplasia, the associated molecular mechanisms and the implications for therapy.

Outcomes of children and young adults with B-cell acute lymphoblastic leukemia given blinatumomab as last consolidation treatment before allogeneic hematopoietic stem cell transplantation

Thu, 31 Oct 2024 00:00:00 +0000

Blinatumomab has remarkable efficacy in patients with relapsed/refractory (r/r) or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated. We conducted a single-center, retrospective analysis of patients given blinatumomab as last treatment before HSCT. Seventy-eight pediatric and YA patients were evaluated. With a median follow- up of 23.23 months, the 2-year disease-free (DFS) and overall survival (OS) probability were 72.2% and 89.2%, respectively, with a 2-year cumulative incidence of non-relapse mortality (NRM) of 2.6%. A trend toward improved 2-year DFS, but not OS, was noted in patients transplanted in first complete remission (CR1) (92.9%) compared to those in second or greater remission (CR2/3) (68.5%; P=0.18) due to a lower cumulative incidence of relapse (0% vs. 29.9%; P=0.05). Among CR2/3 patients, those receiving the sequential combination of inotuzumab and blinatumomab had a significantly lower cumulative incidence of relapse as compared to those who did not receive inotuzumab (9.5% vs. 40.4%; P=0.023). Relapse after HSCT occurred in 16 patients, all exhibiting CD19-positive blasts; ten of them received anti-CD19 chimeric antigen receptor T-cell (CAR T) therapy and two inotuzumab as salvage therapy, leading to a 2-year post-relapse OS of 52.7%. Our results indicate that HSCT following blinatumomab in children and YA with B-ALL is highly effective, being associated with low NRM and not affecting the efficacy of subsequent salvage immunotherapies, including CAR T cells.

Long-term survival can be achieved in a significant fraction of older patients with core-binding factor acute myeloid leukemia treated with intensive chemotherapy

Thu, 10 Oct 2024 00:00:00 +0000

Acute myeloid leukemia (AML) is mainly a disease of the elderly: however, knowledge about the outcomes of treatment of core-binding factor (CBF) AML in an older population is limited. We retrospectively collected data on 229 patients with CBF-AML followed long-term in the last two decades. The 5-year overall survival was 44.2% (95% confidence interval [95% CI]: 39.9-47.5) and the 5-year event-free survival was 32.9% (95% CI: 25.5-40.1). In a subgroup of patients ≥70 years old who completed intensive therapy (induction + ≥3 courses of consolidation including autologous stem cell transplantation: 10 patients) the median event-free survival was 11.8 months (95% CI: 9.4-15.2) and overall survival was 40.0% (95% CI: 36.4- 44.1) at 5 years. In univariate analysis, age ≥70 years (hazard ratio [HR]=1.78, 95% CI: 1.15-2.54, P=0.008), failure to achieve remission following induction (HR=8.96, 95% CI: 5.5-13.8; P<0.0001), no consolidation therapy (HR=0.75, 95% CI: 0.47-1.84, P=0.04) and fewer than three cycles of consolidation (HR=1.48, 95% CI: 0.75-3.2; P=0.0004) predicted poorer event-free survival. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a complete remission seems to be the most important first step and at least three cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.

Arsenic trioxide versus Realgar-Indigo naturalis formula in non-high-risk acute promyelocytic leukemia: a multicenter, randomized trial

Thu, 07 Nov 2024 00:00:00 +0000

Realgar-Indigo naturalis formula (RIF) is an oral form of arsenic that is effective against acute promyelocytic leukemia (APL). This multicenter, randomized, controlled trial compared the efficacy of all-trans retinoic acid (ATRA) plus RIF with ATRA plus arsenic trioxide (ATO) in a simplified regimen for non-high-risk APL. Following induction therapy with ATRA and ATO, participants were randomly assigned to receive either ATRA plus ATO or ATRA plus RIF both in a 2-week on 2-week off schedule for consolidation therapy. Once achieving molecular complete remission, the regimen was administered for a total of six cycles. All of 108 eligible patients achieved hematological complete remission after induction therapy. The median follow-up time was 29 months. The primary endpoint of 2-year disease-free survival was 97% in the ATRA-RIF arm and 98% in the ATRA-ATO arm, respectively (the ATRA-RIF arm was found to be non-inferior to the ATRA-ATO arm, [P<0.01], with a percentage difference of -1% [95% confidence interval: -4.8 to 6.9]). No deaths have been observed. Most adverse events were moderate. This study confirms the non-inferiority of RIF to ATO for non-high-risk APL, while also offering a more favorable regimen schedule for post-remission therapy (clinicaltrials gov. identifier: NCT02899169).

Clinical outcomes of three haploidentical transplantation protocols for hematologic malignancies based on data from the Chinese Bone Marrow Transplantation Registry Group

Thu, 03 Oct 2024 00:00:00 +0000

This study aimed to demonstrate the clinical outcomes of granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG), posttransplantation cyclophosphamide (PTCy) and PTCy combined with low-dose ATG (PTCy with ATGlow)-based haploidentical transplantation protocols in patients with hematologic malignancies. The comparisons were conducted via propensity score matching (PSM) analysis to balance the basic characteristics among different groups and were based on the transplantation data reported to the Chinese Bone Marrow Transplantation Registry Group (CBMTRG) from January 2020 to December 2022. For each patient in the PTCy or PTCy with ATGlow group, patients (at a 1:2 ratio) from the G-CSF/ATG group were selected. In total, the PTCy group (N=122) was matched with the G-CSF/ATG group 1 (N=230), and the PTCy+ATGlow group (N=123) was matched with the G-CSF/ATG group 2 (N=226). Compared with those in the PTCy group, the incidences of 28- day neutrophil engraftment (P=0.005), 100-day platelet engraftment (P=0.002), median time to neutrophil engraftment (P<0.001) and platelet engraftment (P=0.011) were significantly greater in the G-CSF/ATG group. No significant differences were observed in acute graft-versus-host disease (aGVHD) incidence or relapse incidence. In addition, patients in the G-CSF/ ATG group had lower non-relapse mortality (NRM; P<0.001), better 3-year overall survival (OS; P<0.001) and leukemia-free survival (P<0.001) rates than those in the PTCy group. Similarly, the G-CSF/ATG group achieved lower NRM (P<0.001) and better 3-year leukemia-free survival (P=0.002) than the PTCy+ATGlow group. In conclusion, G-CSF/ATG-based haplo-HSCT may be a preferential choice for the Chinese population with hematologic malignancies. In the future, a randomized controlled study is needed for further confirmation.

Immune reconstitution dynamics after unrelated allogeneic transplantation with post-transplant cyclophosphamide compared to classical immunosuppression with anti-thymocyte globulin: a prospective cohort study

Thu, 12 Sep 2024 00:00:00 +0000

Post-transplant cyclophosphamide (PTCy) has contributed to the success of haploidentical hematopoietic stem cell transplantation (HSCT) and is also used in transplantation from matched donors. However, limited data on the immune reconstitution after this type of immunosuppression is available. We aimed to evaluate immune reconstitution after HSCT from unrelated donors, comparing anti-thymocyte globulin (ATG) and PTCy. Consecutive patients undergoing HSCT from unrelated donors and receiving either ATG or PTCy were prospectively included. Immune reconstitution analyses were performed by flow cytometry pre-transplant and on days 30, 60, 90, and 180 post-transplant. We included 36 patients, 20 in the ATG group and 16 in the PTCy group. In the early post-transplant period (day [d]+30), the ATG group showed a higher number of total lymphocytes, T, B, and natural killer (NK) cells compared to the PTCy group. However, at d+180, the PTCy group exhibited a higher number of B cells. On d+60 and d+90, the ATG group displayed higher number of NK cells CD56dim compared to the PTCy group, while on d+180, the PTCy group showed higher number of CD56-, CD16+, and, NKG2D+ NK cells. Naive CD4+, transition CD4+, and naive CD8+ T cells on d+60 were identified as risk factors for acute graft-versus-host disease grade 2-4, and a higher count of CD4+ memory cells on d+180 was identified as a risk factor for chronic graft-versus-host disease. In the context of unrelated allogeneic transplantation, immunosuppression with PTCy was associated with later B-, T- and NK-cell reconstitution compared to ATG.

Predictors and implications of renal injury after CD19 chimeric antigen receptor T-cell therapy

Thu, 21 Nov 2024 00:00:00 +0000

Chimeric antigen receptor (CAR) T cells targeting CD19 induce durable remissions in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), but many patients experience treatment-related toxicity. Cytokine release syndrome and immune effector cell-associated neurologic syndrome are extensively characterized. However, limited data exist on the burden, predictors, and implications of acute kidney injury (AKI) after CAR T-cell therapy. On initial screening of the Food and Drug Administration adverse event reporting system, we identified a disproportionately high rate of renal adverse events among nearly 6,000 CAR T adverse event reports, suggesting it is clinically important in this patient population. In a subsequent single-center analysis of 399 NHL patients treated with CD19 CAR T cells, we found a substantial burden of AKI after CAR T infusion (10% and 5% of any grade and grade ≥2 AKI) with pre-renal causes being predominant (72%). Evolution to chronic kidney disease was rare, however, three patients required hemodialysis. Importantly, patients experiencing cytokine release syndrome and/or neurotoxicity as well as those with low serum albumin and high inflammatory cytokines, including IL-6 and TNF-α, were more likely to develop AKI. While pre-CAR T renal dysfunction was not associated with adverse outcomes, patients developing post-CAR T AKI had lower overall survival compared to their counterparts. Our findings indicate that renal dysfunction is a common toxicity of CAR T-cell therapy with meaningful prognostic impact. Notably, the link between systemic inflammation and renal dysfunction, suggests that readily available biomarkers may inform on renal injury risk after CAR T-cell therapy.

Ultrasound-mediated catheter delivery of tissue plasminogen activator promotes thrombolysis by altering fibrin fiber thickness and clot permeability

Robert A.S. Ariëns, Andrew S.P. Sharp, Cédric Duval — Thu, 21 Nov 2024 00:00:00 +0000

It has been proposed that low power, high frequency ultrasound can augment the ability of thrombolytic agents to dissolve clot in patients with venous thromboembolism. We created a bench model to examine what role and mechanism ultrasound may have in this process. Fibrin polymerization was analyzed through modified light-scattering experiments with the inclusion of catheter-mediated ultrasound application. We studied fibrin fiber diameters through scanning electron microscopy of ultrasound treated fibrin clots. Clot porosity was investigated using permeation tests, while fibrinolysis was analyzed through light-scattering experiments, and by changes in porosity of lysing clots under flow. Whilst application of ultrasound did not change initial fibrin polymerization, it did induce a reversible change in maximal turbidity of already formed fibrin clots. This change in turbidity was caused by a reduction in fibrin fiber diameter and was associated with an increase in clot porosity. These reversible structural changes were associated with a linear increase in fibrinolysis rates under static conditions, while an exponential increase in rates was observed under flow. The use of ultrasound augmentation of thrombolysis enhances clot dissolution through greater and more rapid fibrin degradation. This is due to conformational change created by the ultrasound in clot structure, a reversible phenomenon that may increase binding sites for lytic agent, and could potentially allow the use of lower doses and shorter infusion times of ultrasound-assisted thrombolytic to treat venous thromboembolism in vivo.

Challenges associated with access to recently developed hemophilia treatments in routine care: perspectives of healthcare professionals

Thu, 14 Nov 2024 00:00:00 +0000

The treatment landscape for hemophilia continues to rapidly develop, and expectations for future treatment success are high. There is limited information on the challenges of accessing new and innovative therapies. The aim of this study was to explore challenges of accessing hemophilia treatment from the perspective of healthcare professionals (HCP). A cross-sectional study design was used. A pilot-tested, online survey was distributed to hemophilia treatment centers in Australia, Canada, France, Italy, New Zealand, Republic of Ireland, Turkey, USA and UK. The questionnaire covered questions on product access, economic considerations, health technology assessment requirements, and patient organization involvement. The results were analyzed descriptively using SPSS. A total of 154 HCP completed the questionnaire. There was heterogeneity across countries, regions, and centers regarding HCP knowledge of access to novel recently developed treatments. Notable limitations to access were reported such as differences in access based on age of patient and type of product, economic considerations, and the growing influence of health technology assessment bodies. Many countries have a hemophilia patient organization that does not have a vote at the decision-making table. There is a need to empower HCP to better understand national healthcare structures and decisions that lead to access limitations. Requirements from health technology assessment bodies must be understood to optimally design clinical studies and value generation of treatment options. This may strengthen the hemophilia treatment center’s voice to collectively mandate for exchange with key involved individuals, such as the payers and politicians for the provision of optimal therapy.

Loncastuximab tesirine in Chinese patients with relapsed or refractory diffuse large B-cell lymphoma: a multicenter, open-label, single-arm, phase II trial

Thu, 05 Sep 2024 00:00:00 +0000

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase II LOTIS-2 study. In the China bridging pivotal phase II OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥2 lines of systemic therapies were enrolled and treated every 3 weeks with 150 μg/kg Lonca for two cycles; then 75 μg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by an independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data cutoff, 64 patients received Lonca (median 4.0 cycles; range, 1-17). The median number of prior lines of therapies was 3.0 (range, 2-12). The ORR was 51.6% (95% confidence interval [CI]: 38.7-64.2), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) grade ≥3 treatment-emergent adverse events (TEAE), in which increased γ-glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAE were reported in 35 of 64 patients with four fatal TEAE. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

Comparative efficacy of lisocabtagene maraleucel in the PILOT study versus second-line chemotherapy regimens in the real world

Thu, 31 Oct 2024 00:00:00 +0000

This study assessed the comparative efficacy of lisocabtagene maraleucel (liso-cel) in the open-label, phase II PILOT study (clinicaltrials.gov NCT 03483103) versus conventional second-line (2L) chemotherapy regimens in the real world administered to patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) who were not intended for hematopoietic stem cell transplantation (HSCT). The liso-cel–treated cohort (N=61) was based on patients who received liso-cel in the PILOT study. The conventional chemotherapy cohort included patients who met PILOT eligibility criteria and received conventional 2L chemotherapy in the real-world clinical setting (N=273). After using the trimmed stabilized inverse probability of treatment weighting method to balance cohorts according to baseline characteristics, there were statistically significant differences in all tested measures of efficacy. Compared with real-world conventional chemotherapy regimens, liso-cel demonstrated higher overall response rates (79.6% with liso-cel vs. 50.5% with conventional chemotherapy; relative risk [RR]: 1.6; P<0.0001) and complete response rates (53.1% vs. 24.0%; RR: 2.2; P<0.0001), longer median duration of response (12.1 vs. 4.3 months; hazard ratio [HR: 0.40; P=0.0001), longer median event-free survival (7.0 vs. 2.8 months; HR: 0.43; P<0.0001), longer median progression-free survival (7.0 vs. 2.9 months; HR: 0.46; P<0.0001), and longer median overall survival (not reached vs. 12.6 months; HR: 0.58; P=0.0256). Results from analyses applying various additional statistical approaches consistently favored outcomes with liso-cel over real-world conventional chemotherapy regimens. These results reinforce the efficacy of liso-cel as 2L therapy for patients with R/R LBCL who are not intended for HSCT.

Loncastuximab in high-risk and heavily pretreated relapsed/refractory diffuse large B-cell lymphoma: a realworld analysis from 21 US centers

Thu, 14 Nov 2024 00:00:00 +0000

Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab- teserine (Lonca) is an antibody-drug conjugate which was approved by the Food and Drug Administration for the treatment of patients with R/R DLBCL who have received at least two prior lines of therapy, based on the results of the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting. This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis comprises 187 patients with notably higher-risk baseline features compared to those of the LOTIS-2 population, including a higher proportion of patients with bulky disease (17% vs. 0%), high-grade B-cell histology (22% vs. 8%), and increased number of prior lines of therapy (median 4 vs. 3). The complete response rate was 14% and overall response rate was 32%. The median event-free survival and overall survival were 2.1 and 4.6 months, respectively. Those with bulky disease and high-grade B-cell histology had significantly worse outcomes, and those with non-germinal center cell of origin and a complete response to the most recent line of therapy demonstrated superior outcomes. In summary, in this largest retrospective cohort study of Lonca in the real-world setting, the response rates, event-free survival and overall survival were lower than those reported in LOTIS-2, which is likely reflective of its use in higher risk and more heavily pre-treated patients in the real world compared to the patients enrolled on a clinical study.

Safety and efficacy of acalabrutinib plus bendamustine and rituximab in patients with treatment-naïve or relapsed/refractory mantle cell lymphoma: phase Ib trial

Thu, 05 Sep 2024 00:00:00 +0000

This multicenter, open-label, phase Ib study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naïve (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN cohort and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AE) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3-4 AE, most commonly neutropenia (TN: 38.9%; R/R: 50.0%). AE leading to death were pneumonitis (N=1, TN cohort), COVID-19, and cerebrospinal meningitis (N=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL.

Targeting P-selectin and interleukin-1β in mice with sickle cell disease: effects on vaso-occlusion, liver injury and organ iron deposition

Thu, 21 Nov 2024 00:00:00 +0000

Continuous vaso-occlusive and inflammatory processes cause extensive end-organ damage in adults with sickle cell disease (SCD), and there is little evidence that long-term hydroxyurea therapy prevents this. In initial trials, P-selectin blockade with crizanlizumab reduced SCD vaso-occlusive crisis frequency, and interleukin (IL)-1β inhibition in SCD patients, using canakinumab, lowered inflammatory markers. We used murine SCD models to examine the effects of acute and chronic blockade of P-selectin and of IL-1β on vaso-occlusive events, their inflammatory profile and organ health. Both approaches improved impaired cutaneous microvascular perfusion in SCD mice by reducing TNF-α-induced vaso-occlusion. Acute P-selectin blockade markedly reduced TNF-α-induced neutrophil-platelet aggregate formation in SCD mice, and decreased leukocyte- rolling movements in the microvasculature, while acute IL-1β inhibition attenuated microvascular leukocyte adhesion. Six weeks of IL-1β-blocking immunotherapy improved the inflammatory profile of SCD mice, considerably reduced hepatic fibrosis and provided some relief from lung injury. In contrast, although P-selectin blockade reduced glomerular congestion, no significant benefit to overall organ pathology was observed. Unexpectedly, while combining the two immunotherapies reduced microvascular occlusion, their prolonged use caused acute liver injury. Notably, inhibition of IL-1β, but not of P-selectin, remarkably decreased hemosiderosis, in association with reduced tissue macrophage infiltration and the correction of biomarkers of dysregulated iron turnover. Our findings suggest that the attenuation of inflammation, as well as of vaso- occlusive processes, may be crucial for mitigating organ damage in SCD. Future trials should explore the ability of cytokine blockade to prevent multi-organ damage in patients with SCD, beyond evaluating vaso-occlusive crisis frequency.

Temporal changes in erythroid progenitors in critically ill patients: a prospective cohort study

Thu, 03 Oct 2024 00:00:00 +0000

Cumulative review of hypertension in patients with chronic lymphocytic leukemia treated with acalabrutinib

Thu, 07 Nov 2024 00:00:00 +0000

Posterior cerebral circulation in children with sickle cell anemia: an uncharted territory

Thu, 24 Oct 2024 00:00:00 +0000

Belantamab mafodotin monotherapy for relapsed or refractory multiple myeloma: a real-world observational study in the United States

Thu, 17 Oct 2024 00:00:00 +0000

Ixazomib, pomalidomide and dexamethasone in relapsed or refractory multiple myeloma characterized with highrisk cytogenetics: the IFM 2014-01 study

Thu, 14 Nov 2024 00:00:00 +0000

Comparison of EasyM, a clonotypic mass spectrometry assay, and EuroFlow minimal residual disease assessment in multiple myeloma

Thu, 07 Nov 2024 00:00:00 +0000

Frequency of secondary T-cell lymphoma in chimeric antigen receptor T-cell naïve B-cell lymphoid-lineage cancers is higher than that reported on chimeric antigen receptor T-cell therapy

Christian Brieghel, Søren L. Petersen, Peter de N. Brown, Carsten U. Niemann — Thu, 17 Oct 2024 00:00:00 +0000

Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients

Thu, 10 Oct 2024 00:00:00 +0000

Eleven cases of laryngeal edema after tisagenlecleucel infusion: a 3-year single center retrospective study of CD19-directed chimeric antigen receptor T-cell therapy for relapsed and refractory B-cell lymphomas

Thu, 17 Oct 2024 00:00:00 +0000

HDAC6 inhibitors sensitize resistant t(11;14) multiple myeloma cells to a combination of bortezomib and BH3 mimetics

Thu, 10 Oct 2024 00:00:00 +0000

Impact of daratumumab/bortezomib/thalidomide and dexamethasone induction therapy on chemo-free stem cell mobilization in transplant-eligible newly diagnosed multiple myeloma: a multicenter real-world experience

Thu, 31 Oct 2024 00:00:00 +0000

Early death and intracranial hemorrhage prediction in acute promyelocytic leukemia: validation of a risk score in a cohort from an international consortium treated with chemotherapy plus all-trans retinoic acid

Thu, 31 Oct 2024 00:00:00 +0000

Survival outcomes in diffuse large B-cell lymphoma patients with and without HIV in the United States from 2001 to 2016: a population-based analysis

Thu, 31 Oct 2024 00:00:00 +0000

Severe acute cutaneous-only graft-versus-host disease after late relapse of chronic myeloid leukemia and ultraviolet B phototherapy

Thu, 17 Oct 2024 00:00:00 +0000

Chimeric antigen receptor T-cell therapy remains effective after exposure to bispecific antibodies. Comment to “Sequencing of cellular therapy and bispecific antibodies for the management of diffuse large B-cell lymphoma”

Gilles Crochet, Roch Houot — Thu, 19 Sep 2024 00:00:00 +0000

List of the reviewers who in 2024 generously made an essential contribution to the high scientific quality of Haematologica

Haematologica, Editorial Office — Sat, 01 Mar 2025 00:00:00 +0000