CD20 and CD40 mediated mitogenic responses in B-lineage acute lymphoblastic leukaemia

Activation of CD20, a cross-membrane ion channel, induces cell cycle progression from G0 to G1 in B lymphocytes. Subsequent activation of CD40, a membrane receptor of the nerve growth factor receptor superfamily, transits the B cells to the S phase. CD40 may also act synergistically in combination with IL-4 (B lymphocytes) or IL-3/IL-7 (B-cell precursors). We investigated the proliferative responses of B-lineage acute lymphoblastic leukaemia (ALL) cells to CD20/CD40 activation. In 18/56 ALL cases, CD20 activation resulted in significant increases in DNA synthesis. Similar, although more moderate, effects were seen of activation of CD40 in 10/44 cases. Responses to CD20 or CD40 activation were independent of co-stimulation with IL-3, IL-4 or IL-7, and various cocktails of the different growth stimuli did not act synergistically

Hoping for a normal life:Decision-making on hematopoietic stem cell transplantation by patients with a hemoglobinopathy and their caregivers

Background: To provide insight into the perspectives of children and young adults with transfusion-dependent thalassemia and sickle cell disease and their caregivers regarding the decision for hematopoietic stem cell transplantation (HSCT). Procedure: A qualitative longitudinal multicenter study. Data collection consisted of 40 audio-recorded conversations between physicians and families and 77 interviews with patients and/or caregivers related to 27 unique cases, collected at different time points throughout the decision-making process. Results: Conversations and interviews revealed “hoping for a normal life” as an overarching theme, consisting of four main topics: (i) “Building a frame of reference” refers to a process where patients or families try to obtain comprehensive information on HSCT and translate this to their situation to decide. (ii) “Balancing between loss and benefit” reports the process of considering the advantages and disadvantages of continuing with supportive care to treat their disease versus choosing HSCT. (iii) “Experiencing the impact of HSCT” describes the impactfull experience of the HSCT period by those who chose HSCT. (iv) “Balancing again” refers to reflecting on the decision made. Conclusions: The hope for a normal life guided the decision-making process, described as a constant balance between the impact of the disease and HSCT. A structured approach to explore patients’ and caregivers’ perspectives on HSCT decision-making is needed, where specifically discussing the impact of the disease and hope for a normal life need to be integrated in the process.</p

Hoping for a normal life:Decision-making on hematopoietic stem cell transplantation by patients with a hemoglobinopathy and their caregivers

Background: To provide insight into the perspectives of children and young adults with transfusion-dependent thalassemia and sickle cell disease and their caregivers regarding the decision for hematopoietic stem cell transplantation (HSCT). Procedure: A qualitative longitudinal multicenter study. Data collection consisted of 40 audio-recorded conversations between physicians and families and 77 interviews with patients and/or caregivers related to 27 unique cases, collected at different time points throughout the decision-making process. Results: Conversations and interviews revealed “hoping for a normal life” as an overarching theme, consisting of four main topics: (i) “Building a frame of reference” refers to a process where patients or families try to obtain comprehensive information on HSCT and translate this to their situation to decide. (ii) “Balancing between loss and benefit” reports the process of considering the advantages and disadvantages of continuing with supportive care to treat their disease versus choosing HSCT. (iii) “Experiencing the impact of HSCT” describes the impactfull experience of the HSCT period by those who chose HSCT. (iv) “Balancing again” refers to reflecting on the decision made. Conclusions: The hope for a normal life guided the decision-making process, described as a constant balance between the impact of the disease and HSCT. A structured approach to explore patients’ and caregivers’ perspectives on HSCT decision-making is needed, where specifically discussing the impact of the disease and hope for a normal life need to be integrated in the process.</p

Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management

Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options

High Treosulfan Exposure is Associated with Early Toxicity in Pediatric Hematopoietic Stem Cell Transplantation: A Prospective Multicenter Study

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Predictors of outcomes in hematopoietic cell transplantation for Fanconi anemia

Allogeneic hematopoietic cell transplantation (HCT) remains the only cure for the hematologic manifestations of Fanconi anemia (FA). We performed retrospective predictor analyses for HCT outcomes in FA for pediatric and young adult patients transplanted between 2007 and 2020 across three large referral institutions. Eighty-nine patients, 70 with bone marrow failure +/- cytogenetic abnormalities, 19 with MDS/AML, were included. Five-year overall survival (OS) was 83.2% and event-free survival (EFS) was 74%. Age ≥19, HLA mismatch and year of HCT were multivariable predictors (MVPs) for OS, EFS and treatment-related mortality (TRM). In the pediatric group, TCD was a borderline MVP (P = 0.059) with 5-year OS of 73.0% in TCD vs. 100% for T-replete HCT. The cumulative incidence of day 100 grade II-IV aGvHD and 5-year cGvHD were 5.6% and 4.6%, respectively. Relapse in the MDS/AML subgroup occurred in 4 patients (16%). Graft failure was seen in 9 patients (TCD 6/37 [16%]; T-replete 3/52 [5.7%]). Six patients developed malignancy after HCT. Survival chances after HCT for FA are excellent and associated with high engrafted survival and low toxicity. Age ≥19, HLA mismatch, year of transplant and 'TCD in the <19 years group' (although borderline) were found to be negative predictors for survival

ADAMTS-13 and bleeding phenotype in von Willebrand disease

Background: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS-13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS-13 is in individuals with VWD. Objectives: We therefore studied how ADAMTS-13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD. Methods: We measured ADAMTS-13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross-sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score. Results: ADAMTS-13 activity was similar in individuals with VWD (109% ± 20.6%) and controls (110% ± 19.7%). ADAMTS-13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%-20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%-25.1%). ADAMTS-13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS-13 increase, 95% CI, −0.2 to 0.3). Furthermore, ADAMTS-13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, −2.1% to 4.9%). Conclusion: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD

Stem cell transplantation for congenital dyserythropoietic anemia : an analysis from the European Society for Blood and Marrow Transplantation

Non peer reviewe