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However, patients from more deprived areas had inferior overall survival and access to post-CAR T therapies, underscoring healthcare inequalities in these patients. B Background: b CAR T-cell therapy has revolutionised treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL), but it is unclear whether access and clinical benefit is equal for ethnic minorities and deprived communities. CAR T treatment access and outcomes in patients with large B-cell lymphoma according to ethnicity and socioeconomic deprivation. [Extracted from the article]

Background and Purpose: Adenophostin A (AdA) is a potent agonist of inositol 1,4,5-trisphosphate receptors (IP(3) R). AdA shares with IP(3) the essential features of all IP(3) R agonists, namely structures equivalent to the 4,5-bisphosphate and 6-hydroxyl of IP(3) , but the basis of its increased affinity is unclear. Hitherto, the 2'-phosphate of AdA has been thought to provide a supra-optimal mimic of the 1-phosphate of IP(3) .Experimental Approach: We examined the structural determinants of AdA binding to type 1 IP(3) R (IP(3) R1). Chemical synthesis and mutational analysis of IP(3) R1 were combined with (3) H-IP(3) binding to full-length IP(3) R1 and its N-terminal fragments, and Ca(2+) release assays from recombinant IP(3) R1 expressed in DT40 cells.Key Results: Adenophostin A is at least 12-fold more potent than IP(3) in functional assays, and the IP(3) -binding core (IBC, residues 224-604 of IP(3) R1) is sufficient for this high-affinity binding of AdA. Removal of the 2'-phosphate from AdA (to give 2'-dephospho-AdA) had significantly lesser effects on its affinity for the IBC than did removal of the 1-phosphate from IP(3) (to give inositol 4,5-bisphosphate). Mutation of the only residue (R568) that interacts directly with the 1-phosphate of IP(3) decreased similarly (by ~30-fold) the affinity for IP(3) and AdA, but mutating R504, which has been proposed to form a cation-π interaction with the adenine of AdA, more profoundly reduced the affinity of IP(3) R for AdA (353-fold) than for IP(3) (13-fold).Conclusions and Implications: The 2'-phosphate of AdA is not a major determinant of its high affinity. R504 in the receptor, most likely via a cation-π interaction, contributes specifically to AdA binding. [ABSTRACT FROM AUTHOR]

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Multiple myeloma (MM) accounts for 10% of haematological malignancies. Overall survival (OS) has improved in recent years due to increased use of autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed MM and the advent of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. To assess trends in ASCT including patient selection, choice of induction regimen, depth of response and survival, we performed a retrospective analysis of all patients undergoing first ASCT for MM in European Society for Blood and Marrow Transplantation centres between 1995 and 2019. A total of 117 711 patients across 575 centres were included. The number of transplants performed increased sevenfold across the study period. The median age increased from 55 to 61 years, and the percentage of patients aged >65 years rose from 7% to 30%. Use of chemotherapy-based induction fell significantly, being largely replaced by bortezomib-based regimens. The two-year complete response rate increased from 22% to 42%. The five-year progression-free survival and OS rates increased from 28% to 31% and from 52% to 69%, respectively. Transplant mortality fell from 5.9% to 1.5%. Ongoing advances in MM treatment may challenge the future role of ASCT. However, at the current time, ASCT remains central to the MM treatment paradigm., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Myeloproliferative Neoplasm (MPN), unclassifiable (MPN-U) is a heterogeneous disease with regards to both clinical phenotype and disease course. Patients may initially be asymptomatic or present with leucocytosis or thrombocytosis, anaemia, progressive splenomegaly, constitutional symptom, thromboses or accelerated/blastic phase disease. Treatment strategies are variable and there are no widely accepted consensus management guidelines for MNU-U. Allogeneic Haematopoietic Cell Transplantation (allo-HCT) remains the only curative strategy yet outcomes, to date, are not well defined. We hereby report on the largest retrospective study of patients with MPN-U undergoing allo-HCT, highlighting the potentially curative role and providing clinicians with robust engraftment, GvHD and outcome data to facilitate patient discussion., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

We assessed the susceptibility of secondary acute myeloid leukaemia (sAML) to graft-versus-leukaemia effects. Data from 2414 sAML patients in first (n = 2194) or second (n = 220) complete remission were included. They were given grafts from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD (P < 0·001). Limited (hazard ratio [HR] = 0·66, P < 0·001) and extensive (HR = 0·52, P < 0·001) chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute (HR = 7·04, P < 0·001) as well as limited (HR = 1·42, P = 0·03) and extensive (HR = 3·97, P < 0·001) chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS; HR = 0·61, P < 0·001) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS (HR = 3·16, P < 0·001 and HR = 1·21, P = 0·03, respectively). Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse (HR = 0·82, P = 0·03) but higher NRM (HR = 1·38, P = 0·004). In conclusion, these data demonstrate that sAML is susceptible to graft-versus-leukaemia effects., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)-identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3-year progression-free (PFS) and overall survival (OS) for the entire group was 36% (34-37%) and 41% (40-43%), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) was 37% (35-39%) and 27% (26-29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo-HSCT., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

From February 1975 to February 1977, 880 patients with acute lymphoblastic leukaemia were enrolled on Children's Cancer Study Group protocol 141 designed to evaluate prognostic factors and more intensive therapy for patients with poor prognosis. 765 diagnostic bone marrow aspirates from 23 institutions were available for classification using the French-American-British system. 60 of 615 patients with L1 morphology had vacuolated lymphoblasts. Patients with vacuolated lymphoblasts had a better disease-free survival (P = 0.14) and a significantly better survival (P = 0.03) but the presence of vacuoles was associated with a low initial WBC and an age range associated with improved prognosis for disease-free and over-all survival.