Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial.

We report the 12-year follow-up of the prospective randomized EBMT LYM1 trial to determine whether the benefit of brief duration rituximab maintenance (RM) on progression-free survival (PFS) in patients with relapsed follicular lymphoma (FL) receiving an autologous stem cell transplant (ASCT) is sustained. One hundred and thirty-eight patients received RM with or without purging. The median follow-up after random assignment is 12 years (range 10-13) for the whole series. The 10-year PFS after ASCT is 47% (95% CI 40-54) with only 4 patients relapsing after 7.5 years. RM continues to significantly improve 10-year PFS after ASCT in comparison with NM [P = 0.002; HR 0.548 (95% CI 0.38-0.80)]. Ten-year non-relapse mortality (NRM) was not significantly different between treatment groups (7% overall). 10-year overall survival (OS) after ASCT was 75% (69-81) for the whole series, with no significant differences according to treatment sub-groups. 10-year OS for patients who progressed within 24 months (POD24T) was 60%, in comparison with 85% for patients without progression. Thus the benefit of rituximab maintenance after ASCT on relapse prevention is sustained at 12 years, suggesting that RM adds to ASCT-mediated disease eradication and may enhance the curative potential of ASCT.

Relaxation versus exercise for improved quality of life in lymphoma survivors-a randomised controlled trial.

PURPOSE: Lymphoma survivors experience persisting needs as a consequence of disease and treatment, which have an impact on quality of life (QoL). There is evidence supporting the use of relaxation and exercise to improve QoL, but there is no agreement on which is more beneficial. This study aims to compare a relaxation intervention versus an exercise intervention to determine which has a greater impact on QoL post-chemotherapy. METHODS: Eligible participants (n = 46) were randomised to a relaxation or exercise intervention for 12 weeks. QoL was assessed at baseline, 6 weeks and post-intervention using the European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30) questionnaire, which is a valid and reliable tool. The summary score and all EORTC domains were assessed. RESULTS: There was a significant difference in QoL post-intervention between groups (p = 0.029) while adjusting for baseline QoL, with the exercise group demonstrating a larger improvement. Within-group QoL significantly improved pre- to post-intervention in both the relaxation (p = 0.036) and exercise (p = 0.004) groups. CONCLUSIONS: A self-management intervention of either exercise or relaxation can help significantly improve QoL in lymphoma survivors following chemotherapy. While exercise is preferred, a relaxation intervention would also have a beneficial impact on QoL. IMPLICATIONS FOR CANCER SURVIVORS: Lymphoma survivors should be routinely screened and those with decreased QoL referred for an exercise programme, or relaxation for survivors who are unable to exercise or choose not to. A home-based programme can have a significant positive impact on QoL and is a feasible and effective method in the current climate. TRIAL REGISTRATION NUMBER: Clinical Trials ID NCT02272751.

Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.

BACKGROUND: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. PATIENTS AND METHODS: Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). RESULTS: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0). CONCLUSIONS: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).

Lymphoma survivors' experience of participation in a home-based intervention post-chemotherapy.

PURPOSE: Further research on patient experience and involvement is recommended in order to develop evidence-based and meaningful care pathways for lymphoma survivors. This study aims to explore the experience of a sample of lymphoma survivors participating in a home-based intervention following chemotherapy. METHODS: Eligible participants who completed a 12-week home-based intervention were invited to complete the End of Study Questionnaire designed to explore perceptions, preferences and barriers to participation. Content analysis was used to generate codes, describe frequencies and identify themes. RESULTS: Participating in a home-based intervention post-treatment was a positive experience overall, and aided recovery in this sample of lymphoma survivors (n = 35). Participants felt the programme provided structure, motivation and liked contact with the researcher. Participants highlighted their need for advice on healthy lifestyle, diet in particular. CONCLUSIONS: Lymphoma survivors in this study reported participation in a home-based intervention following treatment beneficial and aided recovery. IMPLICATIONS FOR CANCER SURVIVORS: A large proportion of lymphoma survivors would benefit from a rehabilitation intervention post-chemotherapy. Intervention programmes should include follow-ups to monitor progress and provide support and motivation. Health professionals should recommend healthy lifestyle guidelines to survivors on completion of treatment or refer patients to appropriate services for rehabilitation and advice.

Trends in incidence and medical resource utilisation in patients with chronic lymphocytic leukaemia: insights from the UK Clinical Practice Research Datalink (CPRD).

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in European adults. We aimed to evaluate time trends in CLL incidence and medical resource utilisation of CLL patients in the UK. We conducted a retrospective, observational cohort analysis using the UK Clinical Practice Research Datalink (CPRD) comprising mainly primary care data. We included adult patients with newly diagnosed CLL between January 2000 and June 2012. Descriptive and trend analyses of CLL incidence and medical resource utilisation were performed. A total of 2576 patients with CLL met the eligibility criteria. At diagnosis, the majority of patients (71.7 %) were above 65 years of age. The European age-standardised CLL incidence rate in the CPRD was 6.2/100,000 (95 % confidence interval [CI] 6.0, 6.5/100,000) person-years. There was no statistically significant increase over time. The CLL patients had on average 74.6 general practitioner visits during a median follow-up of 3.3 years. Between 2000 and 2012, the average number of recorded hospitalisations and referrals per year corrected for duration of follow-up significantly (p < 0.001) increased by 8.1 % (95 % CI 6.8 %, 9.3 %) and 16.4 % (95 % CI 15.4 %, 17.3 %), respectively. Referrals and hospitalisations in the second year compared to the first year following the CLL diagnosis significantly decreased. CLL incidence rates in the CPRD were stable over the period from 2000 to 2012. Medical resource utilisation in UK primary care was well documented, but further research is needed to describe secondary and tertiary care medical resource utilisation e.g. chemotherapy administration, which is inadequately captured in the CPRD.

Impact of genetic variability and treatment-related factors on outcome in early breast cancer patients receiving (neo-) adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide, and docetaxel.

To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.

The role of HOX genes in normal hematopoiesis and acute leukemia.

The homeobox (HOX) genes are a highly conserved family of homeodomain-containing transcription factors that specify cell identity in early development and, subsequently, in a number of adult processes including hematopoiesis. The dysregulation of HOX genes is associated with a number of malignancies including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), where they have been shown to support the immortalization of leukemic cells both as chimeric partners in fusion genes and when overexpressed in their wild-type form. This review covers our current understanding of the role of HOX genes in normal hematopoiesis, AML and ALL, with particular emphasis on the similarities and differences of HOX function in these contexts, their hematopoietic downstream gene targets and implications for therapy.

Pegfilgrastim primary prophylaxis in patients with non-Hodgkin lymphoma: results from an integrated analysis.

Severe neutropenia and febrile neutropenia (FN) are serious, dose-limiting side effects of chemotherapy for aggressive non-Hodgkin lymphoma (NHL). Observational data suggest that with current practice neutropenia management up to 23% of patients receiving CHOP-like regimens experience FN, and around half of patients do not receive the planned relative dose intensity (RDI). In this integrated analysis we assessed the efficacy of pegfilgrastim for preventing FN and related outcomes in patients with NHL. A literature search was used to identify chemotherapy regimens with an FN risk ≥15% that are used to treat lymphoma. Search results were then used to identify clinical trials in which these regimens were administered with pegfilgrastim primary prophylaxis. Individual patient data were available for three trials meeting the inclusion criteria, and these were combined in an integrated analysis. The primary outcome measure was the incidence of FN in any cycle. A total of 282 patients were included in the analysis [mean age 65 years (SD ± 12.5 years); 172 (61%) aged ≥ 65 years]. All patients had NHL and 244 (87%) received RCHOP-21. The incidence of FN in any cycle was 16% (95% CI 12-20%) (13% in patients aged <65 years; 18% in patients aged ≥65 years). Chemotherapy dose delays >3 days occurred in 26% (95% CI 20-31%) of patients, and was relatively consistent across age groups. Chemotherapy dose reductions ≥10% were seen in 43% (95% CI 37-49%) of patients and were more frequent in the elderly. Overall, 83% (95% CI 78-87%) of patients received ≥90% RDI (89% of patients aged <65 years; 78% of patients aged ≥65 years). In this integrated analysis of NHL patients at higher risk of FN receiving pegfilgrastim primary prophylaxis, the overall incidence of FN was 16% and a high proportion of both younger and elderly patients achieved RDI ≥90%.

2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.

Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study.

BACKGROUND: The aim of this subgroup analysis of the Mabthera International Trial Group study was to evaluate the impact of chemotherapy and rituximab in primary mediastinal B-cell lymphoma (PMBCL) in comparison to other diffuse large B-cell lymphoma (DLBCL). METHODS: Patients were randomly assigned to six cycles of CHOP-like regimens with or without rituximab. RESULTS: Of 824 patients enrolled, 87 had PMBCL and 627 other types of DLBCL. Rituximab increased the rates of complete remission (unconfirmed) in both PMBCL (from 54% to 80%, P = 0.015) and DLBCL (from 72% to 87%, P < 0.001). In PMBCL, rituximab virtually eliminated progressive disease (PD) (2.5% versus 24%, P < 0.001), whereas without rituximab, PD was more frequent in PMBCL than in DLBCL (24% versus 10%, P = 0.010). With a median observation time of 34 months, 3-year event-free survival (EFS) was improved by rituximab for PMBCL (78% versus 52%, P = 0.012) and for DLBCL (81% versus 61%, P < 0.001). Overall survival benefit was similar for DLBCL (93% versus 85%, P < 0.001) and PMBCL (89% versus 78%, P = 0.158). CONCLUSION: In young patients with PMBCL (age-adjusted International Prognostic Index 0-1), rituximab added to six cycles of CHOP-like chemotherapy increases response rate and EFS to the same extent as other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment in PMBCL with good prognosis features.

Pegfilgrastim for peripheral CD34+ mobilization in patients with solid tumours.

The efficacy of pegfilgrastim+/-chemotherapy for mobilizing stem cells in patients with solid tumours was assessed. In cycle 0, a 14-day prechemotherapy cycle, patients (N=61) were randomized open-label to single doses of pegfilgrastim (6, 12 or 18 mg) on day 1, or daily filgrastim (10 microg/kg) for < or =7 days. Mean peak peripheral CD34+ cell counts increased with pegfilgrastim dose, but were significantly higher than filgrastim only at the 18 mg dose (10.17 vs 4.96 x 10(4)/ml; P=0.014). In the clinically relevant period of days 3-7, both 12 and 18 mg pegfilgrastim doses produced significantly higher peak CD34+ counts (8.18 and 9.96 vs 4.51 x 10(4)/ml for filgrastim; P=0.034 and 0.006). In cycle 1, patients received carboplatin/paclitaxel on day 1, followed from day 2 by pegfilgrastim 6-18 mg or daily filgrastim (5 microg/kg/day for < or =14 days) as per randomization in cycle 0. There were no significant differences in mean peak CD34+ count between pegfilgrastim and filgrastim, but there was an advantage for pegfilgrastim 18 mg in the relevant period of days 7-12 (3.14 vs 1.19 x 10(4)/ml; P=0.043). A single pegfilgrastim dose (> or =6 mg) could be substituted for daily filgrastim in cytokine-only peripheral CD34+ cell mobilization.

Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma.

The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.

Pegfilgrastim successfully mobilizes megakaryocyte progenitors into the peripheral blood in subjects with solid tumours.

Cytokine-mobilized PBPC transplants result in rapid neutrophil and platelet engraftment following high-dose chemotherapy. A total of 61 patients with solid tumours, sensitive to carboplatin and paclitaxol, were recruited as part of a phase I/II study and randomized to receive a single dose of 6, 12 or 18 mg pegfilgrastim on day 1 of a 14-day prechemotherapy cycle or daily filgrastim (10 microg/kg) for up to 7 days. The kinetics of megakaryocyte progenitor mobilization were studied using immunohistochemical assays and flow cytometry in a subset of 31 patients. There was no significant difference among treatment groups with respect to the timing of total progenitor colony-forming units (CFUs) and megakaryocyte progenitor (CFU-MK) mobilization, with the highest median peak falling on day 4/5 in all groups. In the pegfilgrastim 18 mg group, the mean peak total CFUs and CFU-MK were statistically significantly higher than in the filgrastim group (2.031x10(4) vs 8.06x10(3) per millilitre, P=0.024 and 1.12x10(4) vs 4.56x10(3) per millilitre, P=0.024, respectively). The kinetic profiles generated using immunohistochemical assays for CFU-MK and FACS analysis for CD41a were closely correlated suggesting that CD41a can be used as a surrogate marker for megakaryocytic mobilization.

Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation.

This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkin's lymphoma relapsing following autograft. There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy+/-radiotherapy. One group (n=38) then underwent alemtuzumab-containing RIT. The second group-historical controls (n=34), relapsing before the advent of RIT-had no further high-dose therapy. This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available. Overall survival (OS) from diagnosis was superior following RIT (48% at 10 years versus 15%; P=0.0014), as was survival from autograft (65% at 5 years versus 15%; P< or =0.0001). For the RIT group, OS at 5 years from allograft was 51%, and in chemoresponsive patients was 58%, with current progression-free survival of 42%. Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28-55). These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.

The impact of follicular lymphoma on health-related quality of life.

BACKGROUND: The purpose of this study was to determine whether there was a relationship between disease activity and health functioning, as measured by a range of patient-reported outcome (PRO) measures in patients with follicular lymphoma (FL). PATIENTS AND METHODS: A total of 222 patients with FL were recruited from eight sites across the UK and they completed a number of PRO measures. The participants were analyzed across five disease states: 'active disease-newly diagnosed', 'active disease-relapsed', 'partial response', 'complete response' and 'disease free'. The relationship between these disease states and their level of health functioning was assessed as well as the relationship between being 'on' or 'off' chemotherapy and disease state. RESULTS: In terms of health-related quality of life (HRQoL), participants in the relapsed category had the lowest mean physical well-being, emotional well-being, functional well-being and social well-being score. In a regression analysis, the 'active disease-relapsed' group acted as a significant predictor for each PRO variable. In addition, the remission group acted as a significant predictor of high anxiety scores as measured by the Hospital Anxiety and Depression Scale. CONCLUSION: The results of this study demonstrate that various aspects of patient-reported health outcomes differ according to disease state in patients with FL. For those patients who have relapsed, they are more likely to experience worse HRQoL and other patient-reported health outcomes than patients newly diagnosed, in partial or complete remission or when completely disease free.

Current status and future perspectives for yttrium-90 ((90)Y)-ibritumomab tiuxetan in stem cell transplantation for non-Hodgkin's lymphoma.

Haematopoietic SCT is currently considered a therapeutic option mainly in relapsed or refractory non-Hodgkin's lymphoma (NHL) owing to high post-transplantation relapse rates and significant toxicity of conventional myeloablative conditioning for allogeneic SCT. Radiolabelled immunotherapy combines the benefits of monoclonal antibody targeting with therapeutic doses of radiation, and is a promising advance in the treatment of malignant lymphomas. It is now under investigation as a component of conditioning prior to SCT, with the aim of improving outcomes following SCT without increasing the toxicity of high-dose chemotherapy pre-transplant conditioning. An expert panel met at a European workshop in November 2006 to review the latest data on radiolabelled immunotherapy in the transplant setting, and its potential future directions, with a focus on (90)Y-ibritumomab tiuxetan. They reviewed data on the combination of standard/high/escalating dose (90)Y-ibritumomab tiuxetan with high-dose chemotherapy, and high/escalating dose (90)Y-ibritumomab tiuxetan as the sole myeloablative agent, prior to autologous SCT, and also (90)Y-ibritumomab tiuxetan as a component of reduced intensity conditioning prior to allogeneic SCT. The preliminary data are highly promising in terms of conditioning tolerability and patient outcomes following transplant; further phase II studies are now needed to consolidate these data and to investigate specific patient populations and NHL subtypes.

Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology.

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m(2) as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.

EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours.

Chemotherapy-induced neutropenia is not only a major risk factor for infection-related morbidity and mortality, but is also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact on the success of treatment, particularly when treatment intent is either curative or to prolong survival. The incidence of severe or FN can be reduced by prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. While several academic groups have produced evidence-based clinical practice guidelines in an effort to standardise and optimise the management of FN, there remains a need for generally applicable, European-focused guidelines. To this end, we undertook a systematic literature review and formulated recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. We recommend that patient-related adverse risk factors such as elderly age (>or=65 years), be evaluated in the overall assessment of FN risk prior to administering each cycle of chemotherapy. In addition, when using a chemotherapy regimen associated with FN in >20% patients, prophylactic G-CSF is recommended. When using a chemotherapy regimen associated with FN in 10-20% patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Finally, studies have shown that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.

Thrombopoietin, flt3-ligand and c-kit-ligand modulate HOX gene expression in expanding cord blood CD133 cells.

Haemopoietic stem/progenitor cell (HSPC) development is regulated by extrinsic and intrinsic stimuli. Extrinsic modulators include growth factors and cell adhesion molecules, whereas intrinsic regulation is achieved with many transcription factor families, of which the HOX gene products are known to be important in haemopoiesis. Umbilical cord blood CD133+ HSPC proliferation potential was tested in liquid culture with 'TPOFLK' (thrombopoietin, flt-3 ligand and c-kit ligand, promoting HSPC survival and self-renewal), in comparison to 'K36EG' (c-kit-ligand, interleukins-3 and -6, erythropoietin and granulocyte colony-stimulating factor, inducing haemopoietic differentiation). TPOFLK induced a higher CD133+ HSPC proliferation (up to 60-fold more, at week 8) and maintained a higher frequency of the primitive colony-forming cells than K36EG. Quantitative polymerase chain reaction analysis revealed opposite expression patterns for specific HOX genes in expanding cord blood CD133+ HSPC. After 8 weeks in liquid culture, TPOFLK increased the expression of HOX B3, B4 and A9 (associated with uncommitted HSPC) and reduced the expression of HOX B8 and A10 (expressed in committed myeloid cells) when compared to K36EG. These results suggest that TPOFLK induces CD133+ HSPC proliferation, self-renewal and maintenance, up-regulation of HOX B3, B4 and A9 and down-regulation of HOX B8 and A10 gene expression.