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Patients with myeloma often face significant diagnostic delay, with up to one-third of UK patients diagnosed after an emergency presentation (EP). Compared with other routes, patients presenting as an emergency have more advanced disease, increased complications, and poorer prognosis.

Introduction

Background

Introduction

Background

Summary Local and generalized changes in coagulation may be important in the genesis of vegetations and embolism in infective endocarditis. To characterize such alterations, serial hematological investigations were performed on nine consecutive patients who satisfied the inclusion criteria. Platelet survival was measured by Indium111 labeling. Acute and convalescent samples were analyzed for fibrinogen, factor VIIIc, antithrombin III (AT III), fibrin/fibrinogen degradation products (FDPs), and platelet aggregation. The results suggest that in the active stage of the disease: (1) hypercoagulability may be caused by a rise in acute phase reactants, (2) an acceleration of coagulation and fibrinolysis may supervene, and (3) in some cases there is a reduction in platelet aggregation, possibly as a result of continued circulation of previously activated “exhausted” platelets.

Background

Ramasamy: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nador:Amgen: Research Funding. Kishore:Celgene: Honoraria; Takeda: Honoraria, Other: travel support. Rabin:Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support , Speakers Bureau; Celgene: Speakers Bureau. Yong:Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria. Ashcroft:Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amaris Medical: Consultancy, Honoraria. Bowcock:Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Takeda: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Drayson: Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Bowcock: Celgene: Other: Educational support; Amgen: Honoraria; Takeda: Other: educational support. Yong: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Introduction

Introduction and methods:Myeloma is a cancer with one of the longest pathways to diagnosis. This may be due to the non-specific nature of presenting symptoms and its' relative rarity. Early diagnosis initiatives have focused on the role of the primary physician. Despite concern that patients referred to non-haematology specialists may experience long diagnostic intervals, data remain sparse on pathways within hospital care. The TEAMM trial is a double-blind, placebo controlled multicentre UK trial of supportive care, investigating levofloxacin prophylaxis for 12 weeks from diagnosis to reduce infection, versus the risk of healthcare associated infection. Data were collected from patients within 14 days of starting anti-myeloma treatment, including symptoms attributable to myeloma, visits to their primary physician, first hospital department visited for these symptoms, and first visit to a haematologist, with corresponding dates. The relationship between diagnostic time intervals and the number of CRAB (hyperCalcaemia, Renal disease, Anaemia, Bone disease) features and ISS (International Staging System) were analysed by pathway into hospital care using the chi-square test for categorical variables or Wilcoxon/Kruskal-Wallis test for continuous variables as appropriate.

Patients (pts) of older age, poor performance status (PS) and advanced stage with aggressive B cell lymphomas are regarded as poor prognosis and may receive no treatment, or palliative rather than curative chemotherapy. Studies suggest these pts may be undertreated and poor outcome may be partly related to undertreatment. Our unit has had a policy of offering treatment with curative intent to all pts presenting with aggressive B cell lymphomas, whatever their age or PS providing comorbidities allow. We reviewed the outcome of this policy.All pts age≥70 years with diffuse large B cell lymphoma (DLBCL) or Burkitts lymphoma (BL) between 2000–2010 incl. were found from histology, chemotherapy and registry records. Poor PS pts were selected by including all who were inpatients during their 1st chemotherapy cycle, or if untreated, at diagnosis. If ECOG PS had not been prospectively recorded, ≥2 staff (from the 6 who were present throughout the 10 years) independently attributed status from memory and hospital notes. Only confirmed bedbound pts were designated PS4. Percentage chemotherapy doses delivered were calculated against the projected full dose and categorised into ≥85% Full, 60–85% RD, 30–60% HD. Pts receiving CHOP±R or CODOX-M/IVAC were called intensive (Int) and pts receiving low dose regimens called non-intensive (NI).61 pts were found and 37 were inpatients. Of the 37 inpatients, 30 received chemotherapy, 29 for DLBCL and 1 for BL. Of the 30 treated pts (table 1) where parameters were assessable, LDH raised 92%, R-IPI ≥3 97%, PS 3/4 in 93%, stage3/4 86%, albumin <35g/l 70%. Of the 30 patients treated with chemotherapy, 18 achieved a CR with a median OS of 39 months(m) (range 8–123). There were 23 Int pts (9 were PS4, 7 of these being moribund), and 16 achieved CR median OS 48 m (range 12–99), 6 of them being PS4 and 4 were moribund. All pts achieving CR remained so except 1 late relapse (96m). Comorbidities were supported but did not influence treatment decisions except poor ejection fraction or dementia. (7 patients received no chemotherapy; declined ×3, cancer ×1, dementia ×1, not referred ×2)Our data show that very poor PS elderly pts can achieve CR (70%) with good OS with current intensive chemotherapy (CHOP±R, CODOX-M/IVAC±R). Further discussion refers to these pts (Int). CRs not only occurred in the PS2/3 pts, but also in 6/9 PS4 pts. The survivors could not be predicted and included 4 moribund pts. Toxicities were acceptable. Three of 4 moribund pts who survived received HD chemotherapy which was staggered due to emergency presentation. The 2nd cycle was given as soon as possible if improvement occurred (all responders did) with escalation of chemotherapy doses. This aggressive chemotherapeutic approach may have contributed to the good response rate. Our data show that putative toxicity is not a barrier to treatment with judicious dose reduction in the 1st cycle. Retrospective PS attribution was a weakness of the study. But objective parameters eg LDH, IPI, albumin and chemotherapy dose delivered concurred with the scores supporting their validity. PS4 criteria were objective. These data are important because they represent pts mostly excluded from trials. Recent data suggest that comorbidities may not influence survival. Our data support this. We suggest that elderly very poor PS pts can tolerate curative chemotherapy with encouraging remission rates and OS. Previous poor results may be due partly to undertreatment and most pts should be offered proper curative chemotherapy. A positive medical team attitude may be important.No relevant conflicts of interest to declare.

tMDS/tAML are recognised late complications of chemotherapy and increased risk associated with advancing age. The rate of development of tMDS/tAML following fludarabine therapy has been reported to range between 4% - 20% with combination treatments particularly anthracyclines and cyclophosphamide, usually after second and subsequent lines of therapy. To date, none of the large first line trials using PA with cyclophosphamide have reported increased incidence of tMDS. We analysed the incidence of tMDS/tAML in patients treated with PA, predominantly fludarabine for LPD in two centres.All patients treated with PA for LPD between 1993 and 2004 (Sidcup) and 2006 to 2008 (Maidstone) were analysed. If significant cytopenias (Hb<8g/dL, neutrophils<1×109/L, platelets<50×109/L) occurring >10weeks after chemotherapy were not due to recent chemotherapy or disease infiltration, bone marrows were independently reviewed by 2 haematologists. Cytogenetics were performed for most.93 patient records were studied; median age 74 years (53-89). 43 patients received fludarabine for treatment of Chronic lymphocytic leukaemia, 33 patients for follicular lymphoma, 12 patients for lymphoplasmacytic lymphoma (one received additional Cladribine), 3 for mantle cell lymphoma and 2 for marginal zone lymphoma. After exclusion of patients who had immediate allogeneic bone marrow transplantation (AlloBMT) and those who survived less than 12 months post completion of therapy, 68 patients were included in the study. 13/68 (19%) patients developed tMDS/tAML at median times of 19 months. Around 50% had poor/complex cytogenetic abnormalities. Of these 13 patients, 9 (69%, 13.2% of total) have died, 2 are on a waiting list for alloBMT, 1 is on 5-Azacytidine therapy for monosomy 7 and 1 on regular transfusion programme. Of the 9 patients who have died, 7 died from tMDS/tAML, 1 post alloBMT complications, and 1 from pancreatic carcinoma. Median age of patients who developed tMDS/tAML was 72 years (57-82). All patients who developed tMDS/tAML and 46/55 of the others had received previous chemotherapy with alkylating agents. All 13 patients had received fludarabine in combination with cyclophosphamide and there appears to be a dose threshold. None of those who received PA monotherapy developed tMDS.In our unselected series 19 % of patients who received PA combined with cyclophosphamide developed tMDS/tAML. All have previously received alkylator therapy and there appears to be a dose threshold. Complex/poor cytogenetics were seen in those with positive results and the prognosis is exceptionally poor with a mortality rate of 70% of those affected in our series. Our higher incidence than other reports may be due to the older age of our patients, previous alkylator therapy and use of PA in combination with cyclophosphamide. None of those who received Fludarabine monotherapy developed tMDS. We urge close follow up and dose monitoring of patients receiving PA and alkylators following previous therapy with alkylating agents. We suggest that where PA are effective, they are used first line.Rassam: Johnson and Johnson: Research Funding.

We report five cases of clonal lymphocytosis with striking monocytoid features, immunophenotype and clinical features distinct from chronic lymphocytic leukaemia (CLL), splenic marginal zone lymphoma (MZL) also known as splenic lymphoma with villous lymphocytes (SLVL) and mantle cell lymphoma (MCL). We believe these cases to represent a unique leukaemic variant of monocytoid MZL. All cases presented with marked peripheral blood lymphocytosis, no smear cells and monocytoid morphology with voluminous sometimes vacuolated cytoplasm. Immunophenotyping confirmed clonal lymphocytosis with strong light chain restriction, positivity for CD19 and CD20, absent or weak expression of CD10, CD22, CD23 and FMC7 and variable but weak CD5 expression. Bone marrow trephine biopsies revealed marked hypercellularity with a non-nodular diffuse lymphoid infiltrate. Cytogenetic analysis in cases 1 and 5 was normal, and fluorescent in-situ hybridisation (FISH) for abnormalities associated with CLL (11q23, trisomy 12, 13q14 and 17p13) and MCL (t11,14) were negative. Case 1: A 70 year old male presented with symptoms of anaemia, generalised lymphadenopathy, splenomegaly and leucocytosis. He progressed through chlorambucil and prednisolone but responded to oral fludarabine. He has been successfully retreated with fludarabine on relapse and remains alive, more than six years post diagnosis. Case 2: A 79 year old female was admitted with abdominal pain and vomiting. Investigation revealed marked leucocytosis with grossly abnormal liver function tests. This patient’s condition deteriorated rapidly and she died before intervention was possible, ten days post presentation. Case 3: An 87 year old female presented with an incidental finding of lymphocytosis and isolated splenomegaly. Six months following her presentation she developed anaemia, thrombocytopenia and progressive lymphocytosis. Her disease progressed through chlorambucil and cyclophosphamide but responded to fludarabine. She unfortunately died of a cerebrovascular accident, eighteen months after diagnosis. Case 4: A 72 year old female presented with B symptoms, axillary lymphadenopathy and massive splenomegaly. She developed progressive B symptoms and rapid doubling of her white cell count, necessitating initiation of treatment. Despite an initial partial response to chlorambucil and prednisolone, her disease continued to progress and was refractory to multiple lines of chemotherapy. She died six years after her initial presentation. Case 5: An 84 year old presented with mild anaemia and leucocytosis and had clinical splenomegaly. He was managed with supportive therapy only and died of unrelated causes. Summary: The clinical presentation of these cases mimics that of CLL. The morphology of the peripheral blood lymphocytes is, however, markedly different. Patients are typically elderly with a high white cell count, marked splenomegaly and heavy marrow infiltration. Marker analysis is distinct from typical CLL and extranodal features at presentation are atypical of SLVL and nodal MZL. FISH results in two cases were also atypical for CLL. The clinical behaviour is distinct with resistance to alkylating agents but sensitivity to purine analogues. We believe that these unique cases represent an as yet undescribed leukaemic variant of monocytoid MZL probably currently classed and treated as atypical CLL.