Lenalidomide monotherapy and in combination with cytarabine, daunorubicin and etoposide for high-risk myelodysplasia and acute myeloid leukaemia with chromosome 5 abnormalities.

Patients with high risk myelodysplasia (HR-MDS) and acute myeloid leukaemia (AML) with chromosomal changes involving deletion of the long arm of chromosome 5 (del5q), especially with complex karyotype, rarely have a durable response to combination chemotherapy. In the subgroup with monosomal karyotype there are no long term survivors (Fang et al., 2011) [1]. Recent experience indicates that the incidence of del5q in AML is ~20-30%, with only 20-25% of patients achieving complete remission (CR) (Farag et al., 2006) [2]. Additionally, therapy has significant toxicity, with induction death rates ~20% even in younger patients (Juliusson et al., 2009) [3]. This lack of efficacy provides the clinical rationale for combination/sequential therapy with Lenalidomide and combination chemotherapy. Dose dependent haematological toxicity is the major safety concern with such a combination protocol. Therefore we conducted a phase 2 study, AML Len5 (ISRCTN58492795), to assess safety, tolerability and efficacy of lenalidomide monotherapy, followed by lenalidomide with intensive chemotherapy in patients with primary/relapsed/refractory high risk MDS or AML with abnormalities of chromosome 5.

Factors affecting decision making about fertility preservation after cancer diagnosis: a qualitative study.

OBJECTIVE: To increase our understanding of factors underlying the decision to store gametes after the diagnosis of cancer. DESIGN: Qualitative interview study. SETTING: Andrology, Haematology, and Oncology Departments of a Scottish teaching hospital, and patients' own homes. POPULATION: Sixteen men and 18 women aged 17-49 years recently diagnosed with cancer; 15 health professionals concerned in cancer care. METHODS: Audio-recorded semi-structured interviews were transcribed verbatim and analysed thematically. Topics included perceptions of diagnosis; prognosis; future reproductive choices; priorities; quality of information received; communication and decisions made about future reproductive choices; and the role of partners, family, friends and healthcare professionals. Professional interviews examined their role in decision making and that of protocols and guidelines, together with information emerging from patient interview analysis. MAIN OUTCOME MEASURE: Themes identified following analysis of interview transcripts. RESULTS: The primary barriers to pursuing fertility preservation were the way in which information was provided and the 'urgent need for treatment' conveyed by staff. Survival was always viewed as paramount, with future fertility secondary. Sperm banking was viewed as 'part and parcel' of oncology care, and the majority of men quickly stored sperm as 'insurance' against future infertility. Few women were afforded the opportunity to discuss their options, reflecting clinicians' reservations about the experimental nature of egg and ovarian tissue cryopreservation, and the need for partner involvement in embryo storage. CONCLUSIONS: Significant gaps in the information provided to young women diagnosed with cancer suggest the need for an early appointment with a fertility expert.

Systematic review and meta-analyses of studies of glutamine supplementation in haematopoietic stem cell transplantation.

It is unclear whether supplemental glutamine is of benefit in haematopoietic stem cell transplantation (HSCT). We performed a systematic review and meta-analyses using Cochrane methodology. Seventeen randomized controlled trials (RCTs) were found. There was considerable heterogeneity between studies in terms of patient demographics and glutamine administration schedule. Many of the studies were small and scored poorly on methodological quality. Oral glutamine may reduce mucositis (average mucositis score: standard mean difference -0.38, 95% confidence interval (CI) -0.59 to -0.16) and days of opioids (mean difference -1.95 days, 95% CI -3.66 to -0.25) and GVHD (relative risk 0.42, 95% CI 0.21-0.85). Glutamine (i.v.) may reduce clinical infections (relative risk 0.75, 95% CI 0.58 to 0.97) and positive cultures (relative risk 0.72, 95% CI 0.57-0.91) but may also increase the risk of relapse (relative risk 2.91, 95% CI 1.34-6.29) but this is based on only two small studies. There was no effect of oral or i.v. glutamine on overall transplant-related mortality at day +100. In conclusion, there may be beneficial effects of glutamine in HSCT but larger, well-designed studies are required to confirm the beneficial effects and investigate possible adverse effects.

Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin.

Immunosuppressive therapy has been shown to induce sustained hematological responses in a subset of patients with myelodysplastic syndromes (MDS). In particular, antithymocyte globulin (ATG), a polyclonal immunoglobulin induces hematological responses in up to 60% of MDS patients. We report herein on the results of a retrospective multicenter study on the use of ATG in the treatment of 96 patients with MDS. Patients were evaluated for duration of response to ATG, as well as survival after administration of ATG. The median age of the cohort was 54.7 years (range: 19-75 years), with a median follow-up of 33.8 months (range: 0.8-133 months). A total of 40 patients (42%) achieved a hematological response, of which 30 patients (75%) had a durable hematological response lasting a median duration of 31.5 months (range: 6-92 months). On multivariate analysis, both low International Prognostic Scoring System (IPSS) and bone marrow (BM) hypocellularity were independent predictive factors for improved response to ATG (IPSS Int-2/high: odds ratio (OR) 0.08, P=0.018 and BM normo/hypercellularity: OR 0.49, P=0.012). In addition, IPSS was the sole predictor of overall survival, with Int-2/high risk patients having a significantly poorer survival outcome (OR 0.08, P<0.01). In conclusion, this study identifies BM hypocellularity and a low IPSS as important factors predicting response to ATG.

A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab.

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.

Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of ISIS 3521, an antisense phosphorothioate oligonucleotide to protein kinase C alpha in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Twenty-six patients received ISIS 3521 (2 mg/kg/day) as a continuous infusion over 21 days of each 28-day cycle. RESULTS: The median age of the patients was 53 years (range 37-77). Histological subtypes were low-grade follicular lymphoma (n = 22) and B-cell small lymphocytic lymphoma (n = 4). Twenty-one (81%) had stage III/IV disease. The median number of previous lines of chemotherapy was two (range one to six). A total of 87 cycles of ISIS 3521 were administered. Twenty-three patients were assessable for response. Three patients achieved a partial response. No complete responses were observed. Ten patients had stable disease. Grade 3-4 toxicity was as follows: neutropenia (3.8%) and thrombocytopenia (26.9%). CONCLUSIONS: ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low-grade lymphoma, and further trials are warranted.

Transfusion-associated graft-versus-host disease in a patient with Waldenstrom's macroglobulinaemia.

BACKGROUND AND OBJECTIVES: Routine irradiation of cellular blood products is not presently recommended for patients with non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: We report the case of a 72-year-old-man with Waldenstrom's macroglobulinaemia who developed transfusion-associated graft-versus-host disease (TA-GvHD) 13 days following a non-irradiated red cell transfusion. RESULTS: The patient had not previously received purine analogues and none of the donors was homozygous for a human leucocyte antigen (HLA) haplotype that was shared by the recipient. Therefore, his only apparent risk factor was lymphoplasmacytoid NHL. CONCLUSIONS: This case further strengthens the argument that NHL per se is a risk factor for TA-GvHD and supports the proposal that the guidelines for prophylactic irradiation of cellular blood products be extended to include all cases of NHL.

Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young.

Conditions which result in hypercoagulable blood or venous stasis may predispose to the development of deep vein thrombosis (DVT). Most of the recently described risk factors for DVT induce a hypercoagulable state. Over a 3-year period we have observed anomaly of the inferior vena cava (IVC) in four young patients presenting with spontaneous unprovoked DVT. This is a greater than expected rate (5% observed versus 0.5% expected). Further, bilateral DVT, which constitutes less than 10% of cases in most series, was present in three of the four cases. Anomaly of the IVC is a rare example of a prevalent congenital condition that predisposes to DVT, presumably by favouring venous stasis. This diagnosis should be considered in young patients with spontaneous and bilateral DVT.

High-dose ifosfamide in combination with etoposide and epirubicin (IVE) in the treatment of relapsed/refractory Hodgkin's disease and non-Hodgkin's lymphoma: a report on toxicity and efficacy.

One hundred and seven patients (61 with diffuse large B-cell non-Hodgkin's lymphomas and 46 with Hodgkin's disease) in relapse or following of primary therapy received ifosfamide 3 g/m2 i.v. daily for 3 days in combination with epirubicin 50 mg/m2 i.v. day 1 and etoposide 200 mg/m2 i.v. days 1-3. Of the 46 patients with Hodgkin's disease (28 male, 18 female, and a median age of 28 years) 85% of patients had a response to treatment, with 17 achieving complete remission and 11 good partial remission. Twenty-eight proceeded to autologous bone marrow or peripheral blood stem cell transplantation. Twenty-three patients remain alive in continuous remission with a follow-up of 12-61 months. The median overall survival time for all patients in this group is 36 months. Haematological toxicity, particularly WHO Grade IV neutropenia, occurred in all patients but improved over the three courses of treatment. There was no major non-haematological toxicity. Further trials of this regimen in this clinical situation are indicated. The patients with non-Hodgkin's lymphomas in this study had diffuse large B-cell lymphomas and had only received first-line treatment. Twenty had primarily refractory disease, 15 had only achieved partial remissions (PR), and 26 had developed relapse following primary treatment. The overall response rate was 43%; it was 60% for those who had achieved initial PR, 58% for those in relapse after an initial CR or very good PR following initial therapy, but only 10% for those with primarily refractory disease. Tolerance to the regimen was similar to that observed in treatment of the patients with Hodgkin's disease and many were able to undergo stem cell collection, following mobilization with this regimen. The 2-year overall survival result was 22% for patients with some response to first-line treatment but 0% for primary refractory patients.

The bioavailability of oral fludarabine phosphate is unaffected by food.

INTRODUCTION: A prospective, open and randomized, two-way crossover study was conducted to evaluate the pharmacokinetics and bioavailability of oral fludarabine phosphate when taken on a full versus an empty stomach. The effectiveness of therapy was also assessed after two cycles of treatment, four weeks apart MATERIALS AND METHODS: Patients with chronic lymphocytic leukemia or low-grade non-Hodgkin's lymphoma were randomly assigned to two groups, both of which received two cycles of treatment with 90 mg of oral fludarabine phosphate administered when either fed or fasted. Patients in Group 1 (n = 8) received oral treatment on a full stomach for the first cycle then on a fasted stomach for the second, while those in Group 2 (n = 10) received their treatment in the reverse sequence. Oral fludarabine phosphate was administered on the first day of the two study cycles and intravenous fludarabine phosphate was administered on days 3-6. RESULTS AND CONCLUSION: Of 22 patients recruited, 18 (CLL n = 10; NHL n = 8) were eligible for efficacy and safety evaluation, and 16 for bioavailability and pharmacokinetic analyses. The response to oral 2-F-ara-AMP was rapid: by two treatment cycles, 12 out of 18 patients (66.7%) had achieved partial response. Of the six patients who did not respond, five patients (27.7%) had stable disease. There was no notable difference in the rate of response between patients with B-CLL and lg-NHL. There was a marginal increase in total systemic availability of fludarabine phosphate when administered orally on a fed stomach (2-F-ara-A AUC((0-24 h)) = 3.28 +/- 1.48 microg.h/ml) compared to a fasted stomach (2-F-ara-A AUC((0-24 h)) = 3.05 +/- 1.56 microg.h/ml). Time to peak plasma concentration was slightly extended by the presence of food (2.2 +/- 1.0 versus 1.3 +/- 0.74 h) but the terminal half-life was unaffected. The minor differences in the pharmacokinetics of oral fludarabine phosphate when taken after food were not statistically significantly different and seem unlikely to be clinically relevant. The efficacy and safety data closely paralleled previous experience with the intravenous formulation.

Myeloid leukaemic cells can lyse fibrin directly.

Purified preparations of circulating leukaemic blast cells from patients with acute myeloid (M1-7) or acute lymphoblastic leukaemia, and the myeloid or lymphoid cells from patients with chronic myeloid or lymphocytic forms of leukaemia, were incorporated into clots prepared from fibrinogen and plasminogen. Patterns of lysis were followed and measured by light transmission in a microtitre plate reader. Mature polymorphonuclear and mononuclear cell fractions from normal individuals were studied concurrently for comparison. Blast cells from the myeloid forms of acute leukaemia (M2-4) and 'myeloid' cell fractions from patients with chronic myeloid leukaemia were capable of lysing plasminogen-containing clots; this activity was neutralized by addition of immunoglobulin against urokinase plasminogen activator (u-PA), but not by anti-tissue plasmogen activator (t-PA). Mature polymorphonuclear and mononuclear cells from normal individuals lacked lytic activity, as did the leukaemic cells from patients with acute lymphoblastic or chronic lymphocytic leukaemia. Lysed blast cells showed the presence of free plasminogen activator on sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) with overlay zymography, also neutralized by anti-u-PA, whereas normal polymorphonuclear and mononuclear cells did not. These observations suggest that mechanisms underlying some forms of severe bleeding in acute myeloid leukaemias have a critical fibrinolytic component generated by the blast cells themselves.

Sight-threatening varicella zoster virus infection after fludarabine treatment.

Varicella zoster virus (VZV) infection involving the posterior segment of the eye after fludarabine treatment has not previously been described. Two patients, who had completed fludarabine treatment 3 and 18 months previously, presented with visual loss that had been preceded by a recent history of cutaneous zoster. The use of the polymerase chain reaction (PCR) for VZV DNA from ocular specimens allowed rapid confirmation of clinical diagnosis and treatment with a good outcome in one patient. With the increasing use of fludarabine and other purine analogues, an awareness of such complications is important because of their potentially sight-threatening consequences.

H RAS mutations in haematologically normal individuals.

INTRODUCTION: Point mutations in N, K and H RAS have been found in adverse haematological malignancies. The background frequency of RAS mutations in the normal population has yet to be determined. Here we report the results of a screen for RAS mutations from normal individuals. MATERIALS AND METHODS: DNA from peripheral blood or bone marrow from 115 haematologically normal individuals was screened for point mutations in N, K and H RAS, at amino acid positions 12, 13 and 61. The screening was done using polymerase chain reaction and oligonucleotide hybridisation and candidate mutations were subsequently confirmed by cloning and sequencing. RESULTS AND CONCLUSION: Point mutations were identified in DNA from two of the 115 individuals. Both mutations resulted in an amino acid substitution at position 12 in H RAS. Both individuals with detectable H RAS mutations remain haematologically normal.

Translocation (X;5)(q13;q33) in essential thrombocythemia.

We report a novel chromosomal translocation (X;5)(q13;q33) in a woman with no history of prior chemotherapy or radiotherapy, found to have essential thrombocythemia. Aberrations in chromosome 5, mostly deletions of 5q, have been described in essential thrombocythemia; however, a t(X;5) translocation has not been reported.