Determinants of low health-related quality of life in patients with myelodysplastic syndromes: EUMDS Registry study.

Patients with myelodysplastic syndromes (MDS) frequently experience a significant symptom burden, which reduces health-related quality of life (HRQoL). We aimed to identify determinants of low HRQoL in patients recently diagnosed with MDS, for guiding early intervention strategies. We evaluated longitudinal data in 2205 patients with MDS during their first year after diagnosis. Median values of EQ-5D 3-level (EQ-5D-3L) index (0.78) and visual analog scale (VAS) score (0.70) were used as thresholds for low HRQoL. In addition, the 5 dimensions of EQ-5D-3L were analyzed for impairments (any level vs "no problem" category). After multiple imputation of missing values, we used generalized estimating equations (GEE) to estimate odds ratios (OR) for univariable determinant screening (P < .15), and to subsequently derive multivariable models for low HRQoL with 95% confidence intervals (CI). Multivariable GEE analysis showed the following independent determinants (OR, 95% CI) for low EQ-5D index: increased age (60-75 years: 1.33, 1.01-1.75; >75: 1.84, 1.39-2.45), female sex (1.70, 1.43-2.03), high serum ferritin level (≥1000 vs ≤300 µg/L: 1.41, 1.06-1.87), comorbidity burden (per unit: 1.11, 1.02-1.20), and reduced Karnofsky performance status (KPS, per 10 units: 0.62, 0.58-0.67). For low VAS score, additional determinants were transfusion dependence (1.53, 1.03-2.29), low hemoglobin <10 g/dL (1.34, 1.12-1.61), and high body mass index (≥30 vs 23-29.9 kg/m2: 1.26, 1.02-1.57). Sex, KPS, comorbidity burden, hemoglobin count, and transfusion burden were determinants for all EQ-5D dimensions. Low HRQoL is determined by multiple factors, which should be considered in the management and shared decision making of patients with MDS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Guideline for the first-line management of Classical Hodgkin Lymphoma - A British Society for Haematology guideline.

This guideline was compiled according to the British Society for Haematology (BSH) process at BSH Guidelines Process 2016 (b-s-h.org.uk). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline, PubMed/Medline and Cochrane searches beginning from 2013 up to January 2021. The following search terms were used: [Hodgkin lymphoma OR Hodgkin disease] NOT non-Hodgkin; AND [chemotherapy OR radiotherapy]; AND [elderly]; AND [teenage OR adolescent OR young adult]; AND [pregnancy]. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. References pre-2013 were taken from the previous version of this guideline.1 Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haematology Oncology Taskforce, the BSH Guidelines Committee and the Haematology Oncology sounding board of BSH.

Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival.

Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65 years (n = 244) with PCNSL diagnosed 2012-2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)-based treatment. Patients were categorised based on clinician's treatment choice into 'palliative' (n = 52), 'less intensive: MTX ± rituximab ± alkylators' (n = 74) and 'intensive: MTX/cytarabine combinations' (n = 118) groups. Complete remission (CR) rate, two-year progression-free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment-related mortality (TRM) was 6·8% for MTX-treated patients. Median MTX cumulative dose was 8·8 g/m2 (range 1·5-21) over a median of three cycles. Higher relative dose intensity of MTX (MTX-RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two-year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n = 36) were 65% and 70% respectively. Older patients completing MTX-based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX-RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.

Combined linkage and association analysis of classical Hodgkin lymphoma.

The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL.

Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy.

Pregnant women should be managed by a multidisciplinary team that includes haematologists, obstetricians, neonatologists and anaesthetists (Grade 1C) As for non-pregnant patients, acute myeloid leukaemia (AML) should be diagnosed using the World Health Organization (WHO) classification (Grade 1A) Women diagnosed with AML in pregnancy should be treated without delay (Grade 1B) When the diagnosis of AML is made in the first trimester, a successful pregnancy outcome is unlikely and spontaneous pregnancy loss in this situation carries considerable risks for the mother. The reasons for and against elective termination should be discussed with the patient (Grade 2C) In the case of presentation beyond 32 weeks gestation, it may be reasonable to deliver the foetus prior to commencement of chemotherapy (Grade 2C) Between 24 and 32 weeks, risks of foetal chemotherapy exposure must be balanced against risks of prematurity following elective delivery at that stage of gestation (Grade 1C) The risk-benefit ratio must be carefully considered before using any drugs in pregnancy (Grade 1C) Where AML induction chemotherapy is delivered, a standard daunorubicin, cytarabine 3 + 10 schedule should be used (Grade 1B) Chemotherapy should be dosed according to actual body weight and adjustments made for weight changes during treatment (Grade 1C) Quinolones, tetracyclines and sulphonamide use should be avoided in pregnancy (Grade 1B) Amphotericin B or lipid derivatives are the antifungal of choice in pregnancy (Grade 2C) Cytomegalovirus (CMV)-negative blood products should be administered during pregnancy regardless of CMV serostatus (Grade 1B) A course of corticosteroids should be considered if delivery is anticipated between 24 and 35 weeks gestation, given over a 48-h period during the week prior to delivery (Grade 1A) Use of magnesium sulphate should be considered in the 24 h prior to delivery if this is before 30 weeks gestation (Grade 1A) Where possible, delivery should be planned for a time when the woman is at least 3 weeks post-chemotherapy to minimize risk of neonatal myelosuppression (Grade 1C) Planned delivery is easier to manage than spontaneous labour; induction of labour is usually advised (Grade 2C) Epidural analgesia should be avoided in a woman who is significantly thrombocytopenic (platelet count <80 × 10(9) /l) and/or neutropenic (white blood cell count <1 × 10(9) /l): (Grade 1C) Elective caesarean section should only be recommended for obstetric indications (Grade 2C) Antibiotics should be administered during and after premature rupture of membranes and delivery (Grade 1C).

A retrospective study of autologous stem cell mobilization to guide an immediate salvage protocol using plerixafor for patients who mobilize stem cells poorly.

The addition of plerixafor to G-CSF decreases the risk of failed stem cell collection, but at considerable extra cost. Using a logistic regression model based on 354 autologous mobilizations, we have identified a local minimum peripheral blood CD34 count at which the probability of a successful collection is 50%. This seems an appropriate CD34 count at which to add immediate salvage plerixafor.

Acute myeloid leukemia presenting in a mother and daughter pair with the identical acquired karyotypic abnormality consisting of inversion 3q21q26 and monosomy 7: a review of possible mechanisms.

The 3q21q26 inversion is associated with both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), often in association with monosomy 7. In this report, we present a young woman and her mother, both diagnosed with AML, exhibiting similar morphological and identical cytogenetic features. AML with abnormalities of chromosome 3q is often characterized by abnormal megakaryopoeisis and diabetes insipidus, and both were seen in these cases. To our knowledge, this is the first report of familial aggregation of AML displaying an inversion of chromosome 3q and monosomy 7. We discuss possible mechanisms for the development of familial AML with identical karyotypic abnormalities and the link between 3q aberrations and monosomy 7.

Being underweight may reduce your ability to mobilise peripheral blood stem cells.

Being underweight is associated with a poorer outcome after haematopoietic stem cell transplantation (HSCT). We investigated whether nutritional status affects a patient's ability to mobilise stem cells. Weights, heights, peripheral blood CD34 counts and total collected stem cells were collected on 305 patients. Those patients who were underweight had a lower median peripheral blood CD34 count than those who were not underweight (36.0 vs. 53.0 × 10(6)/L (p = 0.0047)). However, the proportion of patients achieving a collection containing the minimum number of CD34 cells required to define a successful stem cell collection was similar in those who were underweight and those who were not. Therefore being underweight may reduce a patient's ability to mobilise peripheral blood stem cells and, if confirmed, improving nutritional status may reduce the number of patients who fail to mobilise.

Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma.

Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMCs) and involved tissues from 30 patients. CD25(+)FoxP3(+)CD127(low)CD4(+) Treg cells were increased markedly in PBMCs (median = 20.4% CD4 T cells, n = 20) versus healthy controls (median = 3.2%, n = 13, P < .001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (R(s) = 0.79, P < .001). T-cell hyporesponsiveness was reversed by depleting CD25(+) cells, or by adding anti-CTLA-4, supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median = 38.8% CD4 T cells, n = 15) versus reactive nodes (median = 11.6%, n = 2, P = .02). When autologous CD25(-) PBMC fractions were incubated with tumor cells from patients (n = 6) in vitro, there was consistent strong induction and then expansion of cells with the CD4(+)CD25(+)FoxP3(+) phenotype of classic "natural" Treg cells. This population was confirmed to be suppressive in function. Direct cell-cell interaction of tumor cells with CD25(-) PBMCs was important in Treg induction, although there was heterogeneity in the mechanisms responsible. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.

A high rate of CLL phenotype lymphocytes in autoimmune hemolytic anemia and immune thrombocytopenic purpura.

Minor CLL-like clones are found in approximately 3% of healthy individuals. AIHA and ITP are common in CLL and may be causally linked. We investigated the presence of CLL phenotype lymphocytes in 11 cases of primary AIHA, 18 of ITP and 2 of Evans' Syndrome, compared with 26 age-matched healthy controls. A population of 'CLL phenotype' was seen in 6/31 patients compared to 1/26 healthy controls (chi(2)=3.9; p=0.05). Such clones may be important in the pathogenesis of autoimmune blood disorders.

CD4(+) T-cell responses to Epstein-Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV-associated non-Hodgkin lymphoma: Th1 in active disease but Tr1 in remission.

Primary infection with Epstein-Barr virus (EBV) in childhood is usually asymptomatic, whereas infection in adolescence may result in infectious mononucleosis (IM) often followed by a fatigue syndrome. EBV latent membrane protein 1 (LMP1) is expressed in latency and in many EBV-associated tumours, including non-Hodgkin lymphoma (NHL). Given the regulatory nature of the CD4(+) T-cell response against LMP1 previously reported in healthy donors, we investigated whether patients with active EBV-driven disease can nevertheless mount effector [T-helper cell, type 1 (Th1)] anti-LMP1 responses. We therefore performed a longitudinal study of the nature of CD4(+) T-cell responses to LMP1 in four patients with IM, and five patients with NHL. In both groups, responses changed with time. During symptomatic infection or active tumour growth, responses were dominated by a Th1 effector phenotype, but switched to a regulatory interleukin-10 response upon recovery. In addition, the fine specificities of the T cells driving these responses evolved. This study showed the dynamic nature of CD4(+) T-cell responses to LMP1, and demonstrated that, although patients can mount Th1 effector responses, recovery from IM and NHL is associated with regulatory responses.

The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma.

OBJECTIVE: Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is expressed by the malignant cells of about 30% of cases of Hodgkin's lymphoma (HL) and is therefore a potential target for immune attack. Given the predominantly immunosuppressive nature of HL infiltrating lymphocytes (HLILs) and the ability of LMP1 to stimulate regulatory T (Treg) responses in healthy donors, we hypothesized that LMP1 was important in the generation of Treg responses in HL. METHODS: We compared T helper (Th) 1, Th2, and Treg responses to LMP1 by peripheral blood mononuclear cells (PBMCs) and HLILs from EBV-positive and -negative HL patients. The number of Treg cells in patients' PBMCs and HLILs was determined by flow cytometry ex vivo. Proliferation ((3)H-thymidine incorporation) and cytokine (interleukin [IL]-10, IL-4 and gamma-interferon) secretion by LMP1-stimulated PBMCs and HLILs was also measured. RESULTS: Ex vivo EBV-positive HL patients had increased numbers of IL-10-secreting/cytotoxic T-lymphocyte-associated antigen-4-expressing cells compared with EBV-negative HL patients. PBMC/HLIL responses to LMP1 from most patients were characterized by IL-10 secretion, although isolated HL patients mounted Th1-like responses. Several responses to LMP1 peptides were made by HLILs, which were otherwise unresponsive to control stimuli. CONCLUSIONS: These results suggest that LMP1 epitopes can induce HLIL Treg cells. However, there was no clear evidence of a greater bias toward regulation in EBV-positive HL cases over EBV-negative cases, and thus there are likely to be other mechanisms of Treg cell induction in EBV-negative HL patients. Manipulating the balance of T-helper response to LMP1 might be exploited in immunotherapy of these lymphomas.

Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma.

Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4+ T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)-secreting T-regulatory 1 (Tr1) and CD4+CD25+ regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells.

Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma.

Anti-resorptive bisphosphonates, such as pamidronate, are an effective treatment for osteolytic disease and hypercalcaemia in patients with multiple myeloma, but have also been shown to cause apoptosis of myeloma cell lines in vitro. In this study, we found that a single infusion of pamidronate, in 16 newly diagnosed patients with multiple myeloma, caused a marked increase in apoptosis of plasma cells in vivo in 10 patients and a minimal increase in four patients (P < 0.05). The nitrogen-containing bisphosphonates pamidronate and zoledronic acid also induced apoptosis of authentic, human bone marrow-derived plasma cells in vitro. Apoptosis of plasma cells in vitro was probably caused by inhibition of the mevalonate pathway and loss of prenylated small GTPases, as even low concentrations (>or= 1 micro mol/l) of zoledronic acid caused accumulation of unprenylated Rap1A in cultures of bone marrow mononuclear cells in vitro. GGTI-298, a specific inhibitor of geranylgeranyl transferase I, also induced apoptosis in human plasma cells in vitro, suggesting that geranylgeranylated proteins play a role in signalling pathways that prevent plasma cell death. Our results suggest that pamidronate may have direct and/or indirect anti-tumour effects in patients with multiple myeloma, which has important implications for the further development of the more potent nitrogen-containing bisphosphonates, such as zoledronic acid, in the treatment of myeloma.