Impact of route and adequacy of nutritional intake on outcomes of allogeneic haematopoietic cell transplantation for haematologic malignancies.

BACKGROUND: Allogeneic haematopoietic cell transplantation (HCT) is often associated with poor oral intake due to painful mucositis and gastrointestinal sequalae that occur following a preparative regimen of intensive chemotherapy and/or total body radiation. Although attractive to assume that optimal nutrition improves HCT outcomes, there are limited data to support this. It is also unclear whether artificial nutrition support should be provided as enteral tube feeding or parenteral nutrition (PN). METHODS: We analysed day-100 non-relapse mortality (NRM), incidence of acute graft-versus-host disease (GvHD), acute gastrointestinal GvHD, 5-year survival and GvHD-free/relapse-free survival (GRFS) according to both route and adequacy of nutritional intake prior to neutrophil engraftment, together with other known prognostic factors, in a retrospective cohort of 484 patients who underwent allogeneic HCT for haematologic malignancy between 2000 and 2014. RESULTS: Multivariate analyses showed increased NRM with inadequate nutrition (hazard ratio (HR) 4.1; 95% confidence interval (CI) 2.2-7.2) and adequate PN (HR 2.9; 95% CI 1.6-5.4) compared to adequate enteral nutrition (EN) both P < .001. There were increased incidences of gastrointestinal GvHD of any stage and all GvHD ≥ grade 2 in patients who received PN (odds ratio (OR) 2.0; 95% CI 1.2-3.3; P = .006, and OR 1.8; 95% CI 1.1-3.0; P = .018, respectively), compared to adequate EN. Patients who received adequate PN and inadequate nutrition also had reduced probabilities of survival and GRFS at 5 years. CONCLUSION: Adequate EN during the early transplantation course is associated with reduced NRM, improved survival and GRFS at 5 years. Furthermore, adequate EN is associated with lower incidence of overall and gut acute GvHD than PN, perhaps because of its ability to maintain mucosal integrity, modulate the immune response to intensive chemo/radiotherapy and support the gastrointestinal tract environment, including gut microflora.

Salvage autologous stem cell transplantation for multiple myeloma relapsing or progressing after up-front autologous transplantation.

Progression or relapse occurs in the vast majority of patients with multiple myeloma (MM) who undergo up-front autologous hematopoietic cell transplantation (AHCT1), which remains a cornerstone of treatment in the era of novel agents. Limited data are available regarding the value of salvage therapy with a second AHCT (AHCT2) in patients who relapse/progress after AHCT1. We analyzed the outcome of 83 patients who underwent salvage AHCT2 between 1994 and 2011. Most patients (77%) had received treatment with novel agents between AHCT1 and AHCT2, and 28% of patients were from ethnic minority groups. Median overall survival (OS) from AHCT2 was 31.5 months (95% confidence interval [CI]: 22-41), and median progression-free survival (PFS) was 15.5 months (95% CI: 11-20). In multivariate analysis, only disease status (≥ PR) at AHCT2 was associated with better OS. The 3-year OS rates for patients receiving AHCT2 in > PR and PR were 85.9% (95% CI: 61-96) and 51.3% (95% CI: 34-68), respectively. Disease status at AHCT2 and time to progression/relapse after AHCT1 were associated with PFS in multivariate analysis. In summary, salvage AHCT2 is an effective treatment option in patients with chemosensitive relapse/progression and prolonged remission after a prior autograft.

Cellular (FLICE) like inhibitory protein (cFLIP) expression in diffuse large B-cell lymphoma identifies a poor prognostic subset, but fails to predict the molecular subtype.

Immunohistochemistry can sub-classify diffuse large B-cell lymphoma (DLBCL) into germinal centre B-cell like (GCB) and non-GCB subtypes. The latter consists predominately of the activated B-cell like subgroup in which nuclear factor kappa-B activation is its characteristic. Expression of cellular caspase 8 (FLICE)-like inhibitory protein (cFLIP), a caspase 8 homologue, is regulated by nuclear factor kappa-B signalling, and it is the main inhibitor of Fas ligand activated apoptosis. To determine if cFLIP expression was confined to non-GCB subtype, we studied 66 cases of DLBCL. cFLIP expression showed no significant correlation to DLBCL subtypes (GCB or non-GCB) but was associated with a worse clinical outcome. For cFLIP positive and negative patients, the five-year event free survival was 20 and 31%, respectively (p = 0.049), and the five-year overall survival was 20 and 57%, respectively (p = 0.041).

The two faces of myeloproliferative neoplasms: Molecular events underlying lymphoid transformation.

Multipotent haematopoietic stem cells pass through stages of differentiation with the progressive loss of developmental options leading to the production of terminally differentiated mature blood cells. This process is regulated by soluble cytokines binding to a ligand specific cell surface receptor on a precursor cell. Key to signal transduction are tyrosine kinase proteins which can be divided into two sub families, the receptor protein tyrosine kinases which are transmembrane receptors and retain an intact catalytic kinase domain and the cytoplasmic tyrosine kinases which bind to cytokine receptors. Abnormalities of tyrosine kinase proteins are well recognised in myeloid malignancies, mutation in the cytoplasmic tyrosine kinase JAK2 (V617F) is key in the pathogenesis of myeloproliferative neoplasms, and translocations involving ABL key in the development of chronic myeloid leukaemia. However tyrosine kinase mutations are increasingly recognised to play a role in the pathogenesis of a wider range of haematological cancers. This review focuses on the role of deregulated tyrosine kinase genes either as part of novel fusion proteins involving FGFR1, PDGFRα, PDGFRß, JAK2 and ABL, or as a consequence of point mutation in JAK1 or JAK2 in the development of precursor T and B lymphoid malignancies or mixed myeloid/lymphoid disorders. We also set out some of the postulated mechanisms which underlie the association of tyrosine kinase mutations with the development of lymphoid malignancy.

LACE-conditioned autologous stem cell transplantation for relapsed or refractory diffuse large B-cell lymphoma: treatment outcome and risk factor analysis from a single centre.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed diffuse large B-cell lymphoma. We have analysed 51 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n = 34, 67%) or primary refractory (n = 17, 33%) diffuse large B-cell lymphoma. With a median follow-up of 60 months (range 2-216) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 47 and 42%, respectively. The cumulative treatment-related mortality was 10% (n = 5). Probabilities for OS and PFS at 5 years were 56 and 50% for patients with chemosensitive and 29 and 27% for patients with chemorefractory disease. In multivariate analysis abnormal pre-ASCT levels of C-reactive protein (>5 mg/L) were identified as a risk factor for worse OS, whereas abnormal pre-ASCT levels of C-reactive protein and chemoresistance predicted inferior PFS. LACE followed by ASCT is an effective treatment for approximately half of patients with chemosensitive relapsed diffuse large B-cell lymphoma, and a proportion of chemorefractory patients also benefit.

The Hammersmith Hospital hematopathology case of the month: paraspinal B lymphoblastic lymphoma – problems in diagnosis and initial indolent behavior.

We describe a young man who presented with neurological signs and symptoms, and with a paraspinal soft tissue mass involving the vertebral body at T4. The patient was treated with dexamethasone prior to neurosurgical decompression and debulking. Biopsy showed features of a small B-cell lymphoma possibly of follicle center cell origin. The patient achieved complete remission with radiotherapy. However, he experienced relapse 10 months later with a soft tissue mass close to and involving the posteroinferior aspect of the sternum. Biopsy of the recurrent lesion showed features of B lymphoblastic leukemia/lymphoma. The first biopsy was revisited to demonstrate the lymphoblastic immunophenotype of the lesional cells. The 'indolent' appearance of the cells in the first biopsy was attributable to treatment with dexamethasone prior to the biopsy.

Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase.

Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.

Specific patterns of chromosomal gains and losses associate with t(3;14), t(8;14), and t(14;18) in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. Certain chromosomal translocations are associated with clinical outcome, but it is likely that there are both tumor suppressor genes and oncogenes that cooperate with the primary translocations. We have used the Mitelman database to compare chromosomal losses and gains of DLBCL possessing t(14;18), t(8;14), or t(3;14) with DLBCL lacking any of these translocations. The data we obtained are low resolution, but results for t(3;14) validate the methodology. In accord with the literature, loss of 6q was associated with t(3;14). Chromosomes 11, 13, and X were gained significantly in t(3;14), whereas 8p23 was lost. Cases with t(14;18) were associated with gains of chromosomes 7 and 12; cases with t(8;14) were associated with gains of chromosomes 1 and 4.

Management of paraproteinaemia.

A paraprotein is a monoclonal immunoglobulin or light chain present in the blood or urine; it is produced by a clonal population of mature B cells, most commonly plasma cells. In individuals aged >50 years the incidence of a paraprotein is 3.2%. Plasma cell disorders can be considered as a spectrum of conditions ranging from monoclonal gammopathy of undetermined significance (MGUS), through asymptomatic, to symptomatic myeloma. MGUS is defined by a low level of paraprotein <30 g/l, bone marrow plasma cells <10% and the absence of myeloma related organ or tissue damage (predominantly renal, skeletal or bone marrow impairment.) MGUS requires no therapy and the overall risk of progression to myeloma is 1% per year. Myeloma remains incurable with a median survival of 3-4 years; autologous stem cell transplant can prolong survival, if appropriate. Thalidomide in combination with dexamethasone has an emerging role in the treatment of myeloma.

A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloid leukaemia.

The RUNX1 (AML1, CBFA2) gene is a member of the runt transcription factor family, responsible for DNA binding and heterodimerization of other non-DNA binding transcription factors. RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and lymphoblastic leukaemia. Germline mutations of RUNX1 have also recently been described and are dominantly associated with inherited leukaemic conditions. We have identified a unique point mutation of the RUNX1 gene (A107P) in members of a family with autosomal dominant inheritance of thrombocytopenia. One member has developed acute myeloid leukaemia (AML).