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Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT)., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for chronic phase (CP) chronic myeloid leukemia (CML) has dramatically decreased. Imatinib was the first TKI introduced to the clinical arena, predominantly utilized in the first line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with either a second or third generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2, or 3 TKI prior to allo-HCT for CP CML in 904 patients. A total of 323-, 371-, and 210 patients had 1, 2, or 3 TKI prior to transplant, respectively; imatinib (n = 778), dasatinib (n = 508), nilotinib (n = 353), bosutinib (n = 12), and ponatinib (n = 44). The majority had imatinib as first TKI (n = 747, 96%). Transplants were performed in CP1, n = 549, CP2, n = 306, and CP3, n = 49. With a median follow-up of 52 months, 5-year OS for the entire population was 64.4% (95% CI 60.9-67.9%), PFS 50% (95% CI 46.3-53.7%), RI 28.7% (95% CI 25.4-32.0%), and NRM 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI, or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI (p = ns). Significant factors influencing OS and PFS were > CP1 versus CP1 and Karnofsky performance (KPS) score > 80 versus ≤80, highlighting CP1 patients undergoing allo-HCT have improved survival compared to >CP1 and the importance of careful allo-HCT candidate selection., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group., (© 2019 The Authors. British Journal of Haematology published by 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.)

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m 2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival., (© 2017 John Wiley & Sons Ltd.)

A growing population of long-term survivors of myeloma is now accumulating the 'late effects' not only of myeloma itself, but also of several lines of treatment given throughout the course of the disease. It is thus important to recognise the cumulative burden of the disease and treatment-related toxicity in both the stable and active phases of myeloma, some of which is unlikely to be detected by routine monitoring. We summarise here the evidence for the key late effects in long-term survivors of myeloma, including physical and psychosocial consequences (in Parts 1 and 2 respectively), and recommend the use of late-effects screening protocols in detection and intervention. The early recognition of late effects and effective management strategies should lead to an improvement in the management of myeloma patients, although evidence in this area is currently limited and further research is warranted., (© 2017 John Wiley & Sons Ltd.)

Allogeneic haemopoietic stem cell transplantation offers a potentially curative treatment option for a wide range of life-threatening malignant and non-malignant disorders of the bone marrow and immune system in patients of all ages. With rapidly emerging advances in the use of alternative donors, such as mismatched unrelated, cord blood and haploidentical donors, it is now possible to find a potential donor for almost all patients in whom an allograft is indicated. Therefore, for any specific patient, the transplant physician may be faced with a myriad of potential choices, including decisions concerning which donor to prioritize where there is more than one, the optimal selection of specific umbilical cord blood units and which conditioning and graft-versus-host disease prophylactic schedule to use. Donor choice may be further complicated by other important factors, such as urgency of transplant, the presence of alloantibodies, the disease status (homozygosity or heterozygosity) of sibling donors affected by inherited disorders and the cytomegalovirus serostatus of patient and donor. We report UK consensus guidelines on the selection of umbilical cord blood units, the hierarchy of donor selection and the preferred conditioning regimens for umbilical cord blood transplantation, with a summary of rationale supporting these recommendations., (© 2015 John Wiley & Sons Ltd.)

Analysis of short tandem repeats (STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme., (© 2014 John Wiley & Sons Ltd.)

The British Society of Blood and Marrow Transplantation Data Registry was used to analyse outcomes of haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases (SADs) from 1997 to 2009. 55 autologous and 15 allogeneic HSCT were registered (0·22% of overall UK HSCT activity). Sustained responses were observed following HSCT, although toxicity was significant. This is the first reported national analysis of long-term outcomes of HSCT in SADs, and should be viewed in the context of translational and developmental phases of HSCT in poor prognosis and refractory SADs. Treatment of poor-risk but reversible SADs with adequate fitness for HSCT in accordance with current guidelines is warranted., (© 2012 Blackwell Publishing Ltd.)

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011., (© 2011 Blackwell Publishing Ltd.)

Thalidomide maintenance has unresolved issues regarding dosage and toxicity. We evaluated this in five dose cohorts in 100 patients. At a median follow-up of 32.3 months, 23 patients had stopped thalidomide for disease progression, 54 for side effects. 3-year overall and progression-free survival was 76% and 41% respectively. Dosage did not influence disease outcome but greatly affected toxicity. Fifteen patients converted from partial remission to complete remission on thalidomide at a median of 13.5 months. Maintenance doses >200 mg were largely unachievable and peripheral neuropathy was the main toxicity. Lower doses enabled more patients to stay on the drug for a useful period of time.

The potential of haemopoietic stem cell transplantation (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serendipitous remissions of autoimmune disease observed in patients undergoing transplantation for haematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases. Phase III clinical trials are in progress for some diseases. This review provides a comprehensive update on the efficacy and toxicity of HSCT in severe autoimmune disease. Future directions in the context of other evolving therapies are discussed.

Objective: Based on animal studies and anecdotal case reports, high-dose therapy and autologous blood stem cell rescue have been proposed as an experimental treatment for severe, refractory rheumatoid arthritis (RA). This study aimed to establish the toxicity of this treatment and obtain preliminary efficacy data upon which to base future clinical trials., Methods: Two cohorts of 4 patients who fulfilled criteria for severe, active, treatment-resistant RA were recruited into a dose-escalation study of cyclophosphamide (CYC) (100 mg/kg or 200 mg/kg) followed by unmanipulated peripheral blood stem cell rescue. Patient treatment was managed according to a standard supportive care protocol. Disease-modifying drugs were discontinued before treatment, but corticosteroids were maintained and later tapered where possible. Patients' conditions were assessed using World Health Organization toxicity criteria and standard parameters for rheumatic disease., Results: Dose-dependent differences in hematologic toxicity were observed between cohorts 1 and 2, although toxicity was similar for other systems and was most significant in the gastrointestinal system. Patients in cohort 1 had only transient responses to therapy, lasting 2-3 months. Substantial improvements were sustained beyond 17-19 months in cohort 2, including steroid-independent disease remission for 1 patient, although the procedure did not completely abolish disease activity., Conclusion: High-dose CYC and unmanipulated autologous blood stem cell rescue has acceptable dose-dependent toxicity in severe, treatment-resistant RA, and 200 mg/kg of CYC induces substantial clinical responses. Refinement of this intensive approach might include further intensification of the preparation regimen, graft manipulation, and posttransplant immunomodulation.

High-dose chemotherapy with autologous stem cell rescue has been proposed as an intensive therapy for severe rheumatoid arthritis (RA). In view of previous observations of abnormal haemopoiesis in RA patients, the composition and function of peripheral blood stem cell harvests (PBSCH) was investigated. Compared with PBSCH from healthy allogeneic donors mobilized with the same dose of G-CSF (filgrastim; 10 microg/kg/d, n = 14), RA PBSCH (n = 9) contained significantly fewer mononuclear cells (375 v 569 x 10(6)/kg, P = 0.03) and CD34+ cells (2.7 v 5.8 x 10(6)/kg, P = 0.003). However, there were increased proportions of CD14+ cells (P = 0.006) and CD14+ CD15+ cells (the phenotype of previously described 'abnormal' myeloid cells, P = 0.002) in the RA PBSCH which translated into 3.5- and 7-fold increases respectively on a per CD34+ cell basis. There were no differences in T-cell activation status as judged by proportions of CD4+ and CD8+ expressing CD45RA, CD45RO, HLA-DR and CD28 (RA PBSCH, n = 7, donor PBSCH, n = 5, P = 0.2-0.7). Phytohaemagglutinin responses determined fluorocytometrically with induction of CD69 expression were reduced in CD4+ and CD8+ cells following filgrastim administration in 3/3 RA patients tested. Compared with bone marrow as a potential source of CD34+ cells, PBSCH contained 11-fold more T cells (P < 0.0005), 8-fold more B cells (P < 0.0005) and 4-fold more monocytes (P = 0.02). In short-term methylcellulose culture there were no differences in colony counts (CFU-GM, CFU-GEMM, BFU-E) per CD34+ cell from PBSCH from RA patients (n = 11) and healthy donors (n = 10). Long-term culture initiator cells were cultured successfully from cryopreserved PBSCH from RA patients (n = 9). In conclusion, PBSCH from RA patients differed significantly in composition from normal individuals, but in vitro studies support normal stem and progenitor cell function. Changes in T-cell function occur during mobilization in RA patients. This work provides reassurance for the use of PBSCH as haematological rescue and baseline data for clinical trials of graft manipulation strategies in patients with RA.

Objective: To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism., Methods: Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases., Results: In 2 of the RA patients, the RA remained in remission without treatment, with nonprogressive disease, 11 and 13 years after BMT. The third patient with RA had a relapse 2 years after BMT, although the previously aggressive disease subsequently ran an attenuated course with treatment-free remission for the last 11 years. Comparison with other cases of RA suggests that graft-versus-host disease may influence the long-term outcome, perhaps through ongoing inhibition of the immune system. In the patient with psoriasis, BMT was followed by remission, but the psoriatic rash recurred and arthropathy developed 12 months later. The psoriasis and arthropathy remained active 4.5 years post-BMT, although the CML remained in remission. Molecular studies in the 2 patients whose RA remained in continued remission and in the patient with psoriasis that relapsed confirmed complete donor hemopoietic reconstitution., Conclusion: Long-term followup of autoimmune disease after allogeneic transplantation confirmed cure of the autoimmune disease in some, but eventual relapse in others. The occurrence of relapse despite complete donor hemopoietic reconstitution is evidence for the development of de novo, as opposed to persistent, disease, and is possibly related to intrinsic susceptibility of the transplanted stem cells or to host factors. There may be a relationship between remission of autoimmune disease and graft-versus-host reaction. These findings have relevance for the evolving application of stem cell transplantation as a therapy for autoimmune diseases.

Based on successful results in animal models, it has been proposed that high-dose myeloablative therapy followed by autologous bone marrow or stem cell transplantation (ABMT/ASCT) may cure autoimmune disease. The coexistence of autoimmune disease and hematologic malignancy provides an opportunity to examine the response of autoimmune disease to ABMT or ASCT. We describe 4 patients with autoimmune disease (3 with psoriasis and 1 with rheumatoid arthritis) and hematologic malignancy. In each patient, the autoimmune disease remitted posttransplantation, but, in 4 patients with long-term followup, it recurred at 8-24 months. The earliest relapse occurred in a patient treated with interferon-alpha. Our experience suggests that a single autograft with unpurged stem cells is unlikely to cure autoimmune disease, but that other strategies building on this approach are worthy of investigation.

The prognostic significance of cytogenetic abnormalities was determined in 106 patients with well-characterized idiopathic myelofibrosis who were successfully karyotyped at diagnosis. 35% of the cases exhibited a clonal abnormality (37/106), whereas 65% (69/106) had a normal karyotype. Three characteristic defects, namely del(13q) (nine cases), del(20q) (eight cases) and partial trisomy 1q (seven cases), were present in 64.8% (24/37) of patients with clonal abnormalities. Kaplan-Meier plots and log rank analysis demonstrated an abnormal karyotype to be an adverse prognostic variable (P<0.001). Of the eight additional clinical and haematological parameters recorded at diagnosis, age (P<0.01), anaemia (haemoglobin < or = 10 g/dl: P<0.001), platelet (< or = 100 x 10(9)/l, P<0.0001) and leucocyte count (> 10.3 x 10(9)/l; P=0.06) were also associated with a shorter survival. In contrast, sex, spleen and liver size, and percentage blast cells were not found to be significant. Multivariate analysis, using Cox's regression, revealed karyotype, haemoglobin concentration, platelet and leucocyte counts to retain their unfavourable prognostic significance. A simple and useful schema for predicting survival in idiopathic myelofibrosis has been produced by combining age, haemoglobin concentration and karyotype with median survival times varying from 180 months (good-risk group) to 16 months (poor-risk group).

We report the sudden and dramatic reversal of maturity onset diabetes in a 57-year-old woman in association with relapse of IgA myeloma diagnosed 3 years earlier. Prior to the relapse of the myeloma, twice daily insulin had been administered at a dose which had been stable for 3 years. However, the same dose produced hypoglycaemic coma at the time of relapse and, subsequently, blood glucose was controlled by diet alone. There had been no significant change in weight or renal function prior to the hypoglycaemic episode. Investigations showed a suppressed fasting serum insulin level in association with an inappropriately high serum level of IGF-II compared with IGF-I and a 'big' IGF-II concentration at the upper end of the normal range. Pituitary, adrenal and liver disease, as well as the autoimmune insulin syndrome, were excluded. The findings are consistent with the hypothesis that the plasma cell tumour was associated with excessive production of insulin-like peptides with consequent reduction in the blood glucose level.