Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence.

The specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional networks and suppresses protein biosynthesis in ALL cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence thereby significantly reducing the cytoprotective effect of adipocytes against chemotherapy and other extrinsic stressors. These data establish how adipocyte driven restrictions of the ALL proteome benefit ALL tumours, preventing their elimination, and suggest ways to manipulate adipocyte-mediated ALL resistance.

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts.

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

Cost-effectiveness of lenalidomide plus dexamethasone vs. bortezomib plus melphalan and prednisone in transplant-ineligible U.S. patients with newly-diagnosed multiple myeloma.

OBJECTIVE: To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective. METHODS: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually. RESULTS: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes. CONCLUSIONS: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML.

By retrospective analysis of 88 patients from the British Society of Blood and Marrow Transplantation registry, we investigated the effect of in vivo T-cell depletion in HLA-identical sibling reduced-intensity conditioning (RIC) allografts for adult AML by comparing patients who received alemtuzumab with those without alemtuzumab conditioning. Both groups were equivalent for age, sex, karyotype and disease status at transplant. With a median follow-up of 27 months (3-72 months) and 48 months (7-72 months), the 2- and 5-year overall survival, with or without alemtuzumab, is 60 and 60% (P=0.80) and 61 and 53%, respectively (P=0.85). The 2-year non-relapse mortality is 12% with alemtuzumab, and 17% without alemtuzumab (P=0.49). The 2-year relapse rate is 35% with alemtuzumab compared with 19% without alemtuzumab (P=0.28). Grades II-IV acute GVHD occurred in 22% (8/37) without alemtuzumab compared with 14% (7/51) given alemtuzumab (P=0.25). Extensive chronic GVHD occurred in 47% (14/30) not given alemtuzumab compared with 4% (2/45) who were given alemtuzumab (P=0.001). Among evaluable patients, the risk of infections was higher in those treated with alemtuzumab compared with those not treated with alemtuzumab (79 vs 57%, respectively, P=0.02). In conclusion, alemtuzumab has a beneficial effect by reducing chronic GVHD without affecting overall survival. Further studies are warranted before alemtuzumab can be recommended as standard in RIC allografts for AML.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant.

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl < or =50 vs >50 ml min(-1) (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl < or =50 vs >50 ml min(-1). These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.

Position statement on the use of bortezomib in multiple myeloma.

Bortezomib (Velcade) is a boron containing molecule which reversibly inhibits the proteasome, an intracellular organelle which is central to the breakdown of ubiquinated proteins and consequently crucial for normal cellular homeostasis. Phase II clinical trials demonstrate it is effective for the treatment of relapsed refractory myeloma, and a phase III trial comparing bortezomib to dexamethasone in second/third line treatment showed superiority in progression free and overall survival. It is administered intravenously in the outpatient setting on days 1, 4, 8 and 11 of a 21-day cycle and regular monitoring for side effects is essential. It is currently approved for the treatment of multiple myeloma patients who have received at least one prior therapy and who have already undergone or are unsuitable for transplantation. Given the strength of this data the UK Myeloma Forum and British Committee for Standards in Haematology believe that bortezomib should be available for prescription by UK haematologists according to its licensed indication in patients with relapsed myeloma.

The risk of antimalarials in patients with renal failure.

We present here a patient with end stage renal failure who received two weeks antimalarial prophylaxis at full dose leading to life threatening toxicity with severe acute megaloblastic anaemia, symptomatic pancytopenia and exfoliative dermatitis. Prompt recognition and treatment can rapidly reverse these fatal effects but more importantly, education of patients before travel is imperative in preventing such events.

A complication of steroid therapy in acute leukaemia--a case report.

Common complications associated with steroid therapy are well documented. We report a rare and fatal complication, in which oesophageal erosion secondary to the use of steroids was associated with pneumopericardium.

Low dose antithymocyte globulin for the treatment of older patients with aplastic anaemia.

We report 14 older patients with aplastic anaemia (AA) who were treated with 'low dose' antithymocyte globulin (ATG). The aims of the study were to assess the efficacy and safety of reduced dose ATG in patients over the age of 60 years. Median age was 71 years (range 62-74 years). At the study endpoint (response to treatment at 6 months) 12 patients were evaluable. All patients received lymphoglobuline (horse ATG; Genzyme) at a dose of 0.5vials/10kg/day for 5 days (5mg/kg/day, equivalent to one-third of the standard dose). There were no deaths attributed to ATG. Two patients died during follow-up, from sepsis and anaphylaxis following platelet transfusion, respectively. Only one of the 12 evaluable patients responded to treatment and remains transfusion independent at 14 months after ATG. These results suggest that this lower dose of ATG, though well tolerated, had low efficacy in the treatment of AA.

Guillain Barré syndrome precipitated by the use of antilymphocyte globulin in the treatment of severe aplastic anaemia.

This report describes the case of a 54 year old woman with very severe aplastic anaemia who was treated with antilymphocyte globulin (ALG) and developed Guillain Barré syndrome (GBS). No antecedent infective aetiology was identified. Although there are numerous reports of autoimmune disease after treatment with ALG in aplastic anaemia, and GBS after immunosuppressive treatment, there are none reporting GBS after the use of ALG for severe aplastic anaemia. The occurrence of autoimmune disease after immunosuppressive treatment, in particular ALG, is discussed, together with the possible mechanisms that result from T cell depression.

Incidence and outcome of critical illness amongst hospitalised patients with haematological malignancy: a prospective observational study of ward and intensive care unit based care.

To determine the incidence and outcome of critical illness amongst the total population of hospital patients with haematological malignancy (including patients treated on the ward as well as those admitted to the intensive care unit), consecutive patients with haematological malignancy were prospectively studied. One hundred and one of the 1437 haemato-oncology admissions (7%) in 2001 were complicated by critical illness (26% of all new referrals). Fifty-four (53%) of these critically ill patients survived to leave hospital and 33 (34%) were still alive after 6 months. The majority (77/101) were not admitted to the intensive care unit but were managed on the ward, often with the assistance of the intensive care team. Independent risk factors for dying in hospital included hepatic failure (odds ratio 5.3, 95% confidence intervals 1.3-21.2) and central nervous system failure (odds ratio 14.5, 95% confidence intervals 1.7-120.5). No patient with four or more organ failures or a Simplified Acute Physiology Score II >/= 65 survived to leave hospital. There was close agreement between actual and predicted mortality with increasing Simplified Acute Physiology Score II for all patients, including those not admitted to intensive care.

Subacute immune response to primary EBV infection leading to post-transplant lymphoproliferative disease in a renal transplant patient.

A 23-year-old man sero-negative for Epstein-Barr virus (EBV) developed recurrent sore throats 3 and 6 months after a renal transplant from an EBV sero-positive donor. Tonsillar biopsy at 9 months post-transplant showed post-transplant lymphoproliferative disease (PTLD) caused by EBV. Following reduction of immunosuppressive treatment, he developed further signs and symptoms, and serological evidence of infectious mononucleosis followed by resolution of lymphadenopathy. This case emphasizes the difficulty in interpreting EBV serology in immunosuppressed patients and the importance of pre-transplant EBV serology.

Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting.

PURPOSE: To evaluate the use of reduced-intensity (RI) conditioning with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical family donors in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). PATIENTS AND METHODS: Sixteen patients (median age, 54 years; range, 37 to 66 years) underwent RI-HSCT using a conditioning regimen of fludarabine 25 mg/m2 daily for 5 days and either cyclophosphamide 1 g/m2 daily for 2 days (14 patients) or melphalan 140 mg/m2 for 1 day (two patients). The median number of CD34+ cells and CD3+ cells infused per kilogram of recipient weight was 4.5 x 106 (range, 1.8 to 7.3 x 106 cells) and 2.9 x 108 (range, 0.1 to 9.6 x 108 cells), respectively. RESULTS: There was no transplant-related mortality (TRM) within 100 days of HSCT. Grade 1 to 2 acute graft-versus-host disease (GVHD) occurred in three patients, but neither grade 3 nor grade 4 disease was observed. Chronic GVHD occurred in 10 patients. One patient had cytomegalovirus (CMV) reactivation but did not develop CMV disease. With a median follow-up of 26 months (range, 15 to 45 months), 11 patients are alive (nine in continuous complete remission and one in complete remission after a second transplantation), and five have died (four from disease progression and one from bone-marrow aplasia induced by cyclosporine withdrawal). The 2-year actuarial overall and event-free survival rates were 69% (95% confidence interval [CI], 40% to 86%) and 56% (95% CI, 30% to 68%), respectively. CONCLUSION: This strategy of RI-HSCT resulted in reliable engraftment with low incidence of acute GVHD and TRM. Durable remissions were observed in patients with MDS and AML consistent with a graft-versus-leukemia effect.

Autoimmune cytopenias in the 22q11.2 deletion syndrome.

We describe two cases of recurrent autoimmune cytopenias, which were subsequently diagnosed with a 22q11.2 deletion/DiGeorge syndrome. The cases are of particular interest as both possessed limited clinical features of this syndrome, and the investigation of haematological abnormalities led to the establishment of a definitive genetic diagnosis.

Liposomal daunorubicin (DaunoXome) in combination with cyclophosphamide, vincristine and prednisolone (COP-X) as salvage therapy in poor-prognosis non-Hodgkins lymphoma.

We treated 33 patients with a variant of the standard 3 weekly CHOP regime, replacing doxorubicin with liposomal daunorubicin (DaunoXome, NeXstar Pharmaceuticals) 120 mg/m2 (COP-X). Eighteen subjects had relapsed/refractory aggressive NHL and 15 had indolent NHL/CLL. Median number of courses received was 4 (1-8). Thirty-two patients were evaluable for efficacy and 26 (81%) responded. 88% of patients with aggressive NHL responded; three (18%) patients achieved complete remission (CR), 12 (70%) achieved partial remission (PR), 1 (6%) patient had stable disease (SD) and 1 (6%) patient progressed through treatment. Median duration of response for patients with aggressive NHL was 3 months. The response rate in indolent NHL/CLL was 73%. Four (27%) patients achieved CR, 7 (46%) PR and 4 (27%) SD. At two years post treatment, 55% of the patients with indolent NHL/CLL remain progression-free, although 4 patients have proceeded to consolidation therapy. Twenty-seven out of 28 (96%) patients developed neutropenia of short duration following one or more of their treatments. Twenty-three patients developed an infection at some stage during therapy (all associated with neutropenia) and required hospitalisation. There were two toxic deaths (infection) both of which occurred in patients who were neutropenic before starting COP-X. Platelet toxicity was mild in patients with normal platelet counts at the commencement of therapy. Alopecia and mucositis were mild. No clinical evidence of myocardial failure was observed. We conclude that the substitution of DaunoXome for doxorubicin in the CHOP regimen to form COP-X provides excellent efficacy against non-Hodgkin's lymphoma. Response durations were short but comparable to those reported with other regimens. COP-X was well tolerated with some suggestion of reduced non-haematological toxicity. The regimen should be considered as an alternative to CHOP with potentially less non-haematological toxicity, particularly cardiac; further studies are required to evaluate the regimen in this context.

Vigam-S, a solvent/detergent-treated intravenous immunoglobulin, in idiopathic thrombocytopenic purpura.

The efficacy of Vigam-S, a highly purified intravenous immunoglobulin, was investigated by an open, noncomparative study in 20 adults with chronic idiopathic thrombocytopenic purpura (ITP). Fifteen patients responded to the initial 3-day infusion of 0.4 g kg(-1) day(-1) by exhibiting an incremental increase in platelet count of >or= 30 x 10(9) L(-1), in eight of whom platelet count normalized (> 150 x 10(9) L(-1)). The peak platelet count for responders on day 4 was 163 x 10(9) L(-1) (baseline = 18 x 10(9) L(-1)). No benefit was derived from an extra 2 days infusion in nonresponders. Further treatment (either a single 0.8 g kg(-1) dose or another 3-day infusion) given to responders when platelet counts fell below 30 x 10(9) L(-1) was effective on eight of 14 occasions. Increases in total serum IgG concentration (to a mean peak of 25.3 g L(-1)) were not correlated with platelet response. There was no evidence of seroconversion to virus markers, or of alteration in renal function, following Vigam-S infusion. Most adverse events were mild and transient; however, three patients had severe headache and vomiting (possible aseptic meningitis syndrome) and one had marked superficial thrombophlebitis. Therefore Vigam-S provides effective and well tolerated therapy in the management of adults with ITP although individual patient response remains difficult to predict.