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Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukaemia ( AML) blasts to chemotherapy. A Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also demonstrated an encouraging response rate. The Southwestern Oncology Group ( SWOG) trial, SWOG S0919, was a Phase 2 trial evaluating the complete remission ( CR) rate in a larger number of patients with relapsed AML treated with idarubicin, cytarabine and pravastatin. This study closed to accrual after meeting the defined criterion for a positive study. Thirty-six patients with a median age of 59 years (range 23-78) were enrolled. The median time from diagnosis to registration was 18 months. Relapse status was first relapse, 17 patients (47%); second relapse, 15 patients (42%); third relapse, two patients (5·5%) and fourth relapse, two patients (5·5%). The response rate was 75% [95% confidence interval: 58-88%; 20 CRs, 7 CR with incomplete count recovery ( CRi)], and the median overall survival was 12 months. The P-value comparing 75-30% (the null response rate based on prior SWOG experience) was 3·356 × 10−4. Given the encouraging CR/ CRi rate, this regimen should be considered for testing in a prospective randomized trial against best conventional therapy. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes. [ABSTRACT FROM AUTHOR]

Follicular helper T-cells (Tfh cells) are a subset of CD4+ T-cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 ( PD-1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T-cell non-Hodgkin lymphoma: angioimmunoblastic T-cell lymphoma ( AITL) and ~20% of peripheral T-cell lymphoma not otherwise specified ( PTCL- NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET 2 and DNMT 3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL- NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre-clinical development. [ABSTRACT FROM AUTHOR]

Treatment-free remission ( TFR) has recently emerged as a goal of treatment in chronic myeloid leukaemia ( CML). Molecular remission is sustained in around 30% of imatinib-treated patients who stop treatment after ≥2 years with undetectable minimal residual disease ( UMRD) by conventional real-time reverse transcription polymerase chain reaction. An additional 20-30% of patients will lose UMRD, but remain in stable major molecular remission off treatment. Most patients with molecular recurrence have a significant increase in BCR- ABL1 within the first 6 months off treatment, but there are also rare late relapses. As re-treatment with imatinib restores control, a trial of TFR is safe so long as careful molecular monitoring is provided to enable prompt re-treatment. The minimum eligibility criteria for a trial of TFR are not yet defined, but the available data support a MRD level of around a molecular response of 4·5 log for at least 2 years. Factors associated with a higher probability of TFR include low risk Sokal score, prior interferon treatment, longer total duration of imatinib treatment and higher numbers of natural killer cells at the time of imatinib discontinuation. Preliminary data suggest that the rate of TFR in patients treated with more potent tyrosine kinase inhibitors will probably be higher. The biology that underlies TFR is an area of active investigation. [ABSTRACT FROM AUTHOR]

The article presents a study which estimated the proportion of thrombotic events following prothrombin complex concentrate (PCC) infusion in healthy subjects. Topics discussed include characteristics of studies evaluating PCC infusion in healthy subjects, effect of PCC administration in healthy subjects, and the need for further studies to dissect whether specific factors are boosting the potential PCC-associated thrombogenicity.

Follicular Lymphoma ( FL) is the second most common non-Hodgkin lymphoma ( NHL) subtype and its course is heterogeneous. At diagnosis, some patients with FL manifest a detectable leukaemic phase ( FL- LP), but this feature has been seldom described and is poorly characterized. Among 499 patients diagnosed with FL in Lyon-Sud hospital, 37 (7·4%) had characteristic FL- LP (by cytological blood smears and flow cytometric analysis). In addition, 91/1135 FL patients from the PRIMA study presented FL- LP at study entry. In order to evaluate the outcome of this Lyon-Sud cohort, FL- LP patients were matched with 111 newly diagnosed FL without LP according to the Follicular Lymphoma International Prognostic Index ( FLIPI) score, age and treatment. Presence of FL- LP was associated with shorter progression-free survival ( PFS) and overall survival ( OS) ( P = 0·004 and P = 0·031, respectively). Presence of FL- LP and high FLIPI score remained independent prognostic factors in a Cox model for time to progression ( TTP). A number of circulating lymphoma cells ( CLC) >4 × 109/l was the most significant predictor for a shorter TTP in this Cox model. The prognostic impact of FL- LP on TTP was validated in the PRIMA cohort ( P = 0·0004). In conclusion, FL- LP is a rare event associated with shorter PFS and patients with CLC >4 × 109/l have a poorer outcome. These patients should be monitored carefully to consider alternative therapeutic options. [ABSTRACT FROM AUTHOR]

The article discusses the role of immunoglobulin ratio in identification of monoclonal gammopathy of patients that are at high risk of progression to multiple myeloma. Topics discussed include risk factors of monoclonal gammopathy, the increase in monoclonal immunoglobulin during progression risk to multiple myeloma, and the analysis of heavy/light chain (HLC) pairs in cohort of monoclonal gammopathy patients.

The significance of paroxysmal nocturnal haemoglobinuria ( PNHpos) cells and leucocyte subset telomere lengths in paediatric aplastic anaemia ( AA) is unknown. Among 22 children receiving immunosuppressive therapy ( IST) for AA, 73% (16/22) were PNHpos, of whom 94% achieved at least a partial response ( PR) to IST; 11/16 (69%) achieved complete response ( CR). Only 2/6 (33%) PNHneg patients achieved PR. PNHpos patients were less likely to fail IST compared to PNHneg patients (odds ratio 0·033; 95% confidence interval 0·002-0·468; P = 0·012). Children with AA had short granulocyte ( P = 7·8 × 10−9), natural killer cell ( P = 6·0 × 10−4), naïve T lymphocyte ( P = 0·002) and B lymphocyte ( P = 0·005) telomeres compared to age-matched normative data. [ABSTRACT FROM AUTHOR]

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients ( n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population ( n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment. [ABSTRACT FROM AUTHOR]

To evaluate the association between haemoglobinuria and chronic kidney disease ( CKD) in sickle cell anaemia ( SCA), we analysed 356 adult haemoglobin SS or Sβo thalassaemia patients from the University of Illinois at Chicago ( UIC) and 439 from the multi-centre Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk- PHa SST) cohort. CKD was classified according to National Kidney Foundation Kidney Disease Outcomes Quality Initiatives guidelines. Haemoglobinuria, defined as positive haem on urine dipstick with absent red blood cells on microscopy, was confirmed by enzyme-linked immunosorbent assay in a subset of patients. The prevalence of CKD was 58% in the UIC cohort and 54% in the Walk- PHa SST cohort, and haemoglobinuria was observed in 36% and 20% of the patients, respectively. Pathway analysis in both cohorts indicated an independent association of lactate dehydrogenase with haemoglobinuria and, in turn, independent associations of haemoglobinuria and age with CKD ( P < 0·0001). After a median of 32 months of follow-up in the UIC cohort, haemoglobinuria was associated with progression of CKD [halving of estimated glomerular filtration rate or requirement for dialysis; Hazard ratio ( HR) 13·9, 95% confidence interval ( CI) 1·7-113·2, P = 0·0012] and increasing albuminuria ( HR 3·1, 95% CI: 1·3-7·7; logrank P = 0·0035). In conclusion haemoglobinuria is common in SCA and is associated with CKD, consistent with a role for intravascular haemolysis in the pathogenesis of renal dysfunction in SCA. [ABSTRACT FROM AUTHOR]

ATOH8 has previously been shown to be an iron-regulated transcription factor, however its role in iron metabolism is not known. ATOH8 expression in HEK293 cells resulted in increased endogenous HAMP mRNA levels as well as HAMP promoter activity. Mutation of the E-box or SMAD response elements within the HAMP promoter significantly reduced the effects of ATOH8, indicating that ATOH8 activates HAMP transcription directly as well as through bone morphogenic protein ( BMP) signalling. In support of the former, Chromatin immunoprecipitation assays provided evidence that ATOH8 binds to E-box regions within the HAMP promoter while the latter was supported by the finding that ATOH 8 expression in HEK293 cells led to increased phosphorylated SMAD1,5,8 levels. Liver Atoh8 levels were reduced in mice under conditions associated with increased erythropoietic activity such as hypoxia, haemolytic anaemia, hypotransferrinaemia and erythropoietin treatment and increased by inhibitors of erythropoiesis. Hepatic Atoh8 mRNA levels increased in mice treated with holo transferrin, suggesting that Atoh8 responds to changes in plasma iron. ATOH8 is therefore a novel transcriptional regulator of HAMP, which is responsive to changes in plasma iron and erythroid activity and could explain how changes in erythroid activity lead to regulation of HAMP. [ABSTRACT FROM AUTHOR]

The age at which it is necessary to start Cardiovascular Magnetic Resonance ( CMR) T2* screening in thalassaemia major ( TM) is still uncertain. To clarify this point, we evaluated the prevalence of myocardial iron overload ( MIO), function and fibrosis by CMR in TM patients younger than 10 years. We retrospectively selected 35 TM patients enrolled in the Myocardial Iron Overload in Thalassaemia network. MIO was measured by T2* multislice multiecho technique. Biventricular function parameters were evaluated by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired. Patients' age ranged from 4·2 to 9·7 years. All scans were performed without sedation. Nine patients showed no MIO, 22 patients had heterogeneous MIO with a T2* global value ≥20 ms; two patients had heterogeneous MIO with a T2* global value <20 ms and two patients showed homogeneous MIO. No patient showed myocardial fibrosis. Among the patients with heart T2*<20 ms, the youngest was 6 years old, none showed heart dysfunction and the iron transfused was <35 g in all cases. Cardiac iron loading can occur much earlier than previously described. The first cardiac T2* assessment should be performed as early as feasible without sedation, especially if chelation is started late or if poor compliance is suspected. [ABSTRACT FROM AUTHOR]

Evidence regarding the efficacy of gemtuzumab ozogamicin ( GO) addition to standard induction chemotherapy in newly diagnosed acute myeloid leukaemia ( AML) is conflicting. This systematic review aimed to identify and summarize all evidence regarding the benefits and harms of adding GO to conventional chemotherapy for induction treatment of AML. A comprehensive literature search of two databases ( PUBMED and Cochrane) from inception up to November 22, 2012, and 4 years of proceedings from four major haematology/oncology conferences was undertaken. Endpoints included benefits (complete remission, relapse-free, event-free, and overall survival), and harms (early mortality and incidence of hepatic veno-occlusive disease/sinusoidal obstructive syndrome). Seven trials (3942 patients) met all inclusion criteria. Addition of GO showed improved relapse-free [ Hazard Ratio ( HR) = 0·84 (95% confidence interval ( CI) 0·71-0·99)] and event-free survival [ HR = 0·59 (95% CI 0·48-0·74)] but not overall survival [ HR = 0·95 (95% CI 0·83-1·08)]. Addition of GO resulted in higher rate of early mortality [ Risk Ratio = 1·60 (95% CI 1·07-2·39)]. Improved overall survival was observed in studies using a lower cumulative GO dose (<6 mg/m2) [ HR = 0·89 (95% CI 0·81-0·99)]. Addition of GO to conventional chemotherapy as induction therapy may improve relapse-free and event-free survival, but does not impact overall survival and significantly increases early mortality in AML. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis ( ECP) is an established second line treatment option for graft-versus-host disease ( GVHD) post-haematopoietic progenitor cell transplant. At our centre, the Therakos™ Cellex® has replaced the Therakos™ UVAR- XTS™ machine for ECP since 2009. We reviewed the records of 385 procedures using the Therakos™ Cellex® for safety and tolerability. Nine patients underwent ECP for GVHD. The median age was 13·5 years (range 3·7-24) and weight was 49·2 kg (range 18·5-86·3). The mean duration per procedure was 106 min (range 60-205). Fifteen (3·9%) procedures were cancelled and 10 (2·6%) were delayed, with central venous line ( CVL) issues being the most frequent problem. With the use of prophylactic tissue plasminogen activator, fewer CVL-related occlusions were observed (4·7% vs. 2·3%). There was one episode of a CVL-associated thrombosis and one episode of delayed bleeding. There were four episodes of viral reactivation, four CVL-associated infections (1142 catheter days) and one episode of systemic inflammatory response syndrome. No patient experienced symptomatic hypotension. This is the first report outlining the safety and tolerability of the Therakos™ Cellex® device for ECP in children and young adults. [ABSTRACT FROM AUTHOR]

This study aimed to verify the impact of heart magnetic resonance imaging on chelation choices and patient compliance in a single-institution cohort as well as its predictive value for heart failure and arrhythmias. Abnormal cardiac T2* values determined changes in treatment in most subjects. Heart T2* was confirmed to be highly predictive over 1 year for heart failure and arrhythmias. The choice of chelation regimens known to remove heart iron efficiently was not sufficient by itself to influence the risk. Compliance with treatment had a more remarkable role. [ABSTRACT FROM AUTHOR]

Tremendous progress has been made in the care of individuals with sickle cell over the past several decades. Major successes have been comprehensive infection prophylaxis, prediction and prevention of stroke, and better transfusion care, the latter including both prevention of alloimmunization and treatment of iron overload. However, definitive therapies remain limited to hydroxycarbamide (hydroxyurea) and stem cell transplantation, both of which have been in use for at least two decades. Despite knowing the progressive natural history of the disease with organ dysfunction, failure, and ultimately death at a young age, definitive therapies are considered for only a small proportion of individuals. Consequently, while life expectancy has improved dramatically from the last century, the ongoing pace of advancement has slowed or stalled. We believe that it is time to broaden the use of definitive therapy for those with asymptomatic disease, being cautiously more aggressive in our approach. [ABSTRACT FROM AUTHOR]

Mastocytosis can lead to organ failure as well as systemic symptoms that can be disabling, with considerable deterioration in quality of life. Beside symptomatic treatments, interferon-α and purine analogues have been shown to be effective but complete or long-term remission is rarely obtained with these drugs. We conducted a phase II, multicentre, study to investigate thalidomide in severely symptomatic indolent and aggressive systemic mastocytosis. Twenty patients were enrolled of whom 16 were analysed for response. The overall response rate was 56%. Responses were observed in the skin in 61% of patients with a significant decrease in the pruritus score. Mast cell mediator-related symptoms responded in 71% of cases and 25% of aggressive systemic mastocytosis patients had a response in terms of B/ C findings (borderline/cytoreduction needed). Bone marrow mast cell infiltration decreased in five of the eight evaluable patients. There was no significant improvement in the AFIRMM ( Association Française pour les Initiatives de Recherche sur le Mastocyte et Les Mastocytoses), Quality of Life or Hamilton scores. Grade 3-4 toxicities consisted of peripheral neuropathy (11%) and myelosuppression (neutropenia: 5%; thrombocytopenia: 11%). In conclusion, thalidomide might be useful in mastocytosis and in the treatment of mast cell-related symptoms. It might be considered in selected patients, taking into account the benefit/risk balance and the individual patient evaluation. [ABSTRACT FROM AUTHOR]

Following reduced intensity-conditioned allogeneic stem cell transplantation ( RIC allo- SCT) for chronic lymphocytic leukaemia ( CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease ( GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo- SCT and pre-emptive donor lymphocyte infusions ( DLI) for mixed chimerism or minimal residual disease ( MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17p−). Of patients who were not in complete remission ( CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4·3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p−). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6·4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD. [ABSTRACT FROM AUTHOR]

The article presents information that the treatment of human immunodeficiency virus infection in patients with the Burkitt lymphoma (HIV-BL) is a difficult challenge which requires multidisciplinary efforts and demanding strategies. It informs that the use of highly active antiretroviral therapy (HAART) has resulted in improved tolerability and efficacy of standard chemotherapy in the HIV-positive patients with diffused large B-cell lymphomas.

Thirty myelofibrosis patients (21 males, nine females) with relapse ( n = 27) or graft-rejection ( n = 3) after dose-reduced allografting underwent a salvage strategy including donor lymphocyte infusions ( DLIs) and/or second allogeneic haematopoietic stem cell transplantation ( HSCT). Twenty-six patients received a median number of three (range, 1-5) DLIs in a dose-escalated mode starting with a median dose of 1·2 × 106 (range, 0·003-8 × 106) up to median dose of 40 × 106 T-cells/kg (range, 10-130 × 106). 10/26 patients (39%) achieved complete response ( CR) to DLIs. Acute (grade II- IV) and chronic graft- versus-host ( GvHD) disease occurred in 12% and 36% cases. Thirteen non-responders to DLI and four patients who did not receive DLI due to graft-rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative ( n = 15) or the same ( n = 2) donor. One patient (6%) experienced primary graft-failure and died. Acute ( II- IV) and chronic Gv HD were observed in 47% and 46% of patients. Overall responses after second HSCT were seen in 12/15 patients (80%: CR: n = 9, partial response: n = 3). The 1-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6%, and the cumulative incidence of relapse was 24%. After a median follow-up of 27 months, the 2-year overall survival and progression-free survival for all 30 patients was 70% and 67%, respectively. In conclusion, our two-step strategy, including DLI and second HSCT for non-responding or ineligible patients, is an effective and well-tolerated salvage approach for patients relapsing after reduced-intensity allograft after myelofibrosis. [ABSTRACT FROM AUTHOR]

The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma ( BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples ( n = 30) by studying MDM4, MDM2, and CDKN1 A (p21) protein and m RNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1 A protein, and CDKN1 A m RNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and m RNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and m RNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases. [ABSTRACT FROM AUTHOR]

Prior to the introduction of the International Network for Cancer Treatment and Research ( INCTR) protocol INCTR 03-06, survival of patients with Burkitt lymphoma at four tertiary care centres in equatorial Africa was probably no more than 10-20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non-cross resistant second-line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first-line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid ( CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first- and second-line therapy, but verification will require a further clinical study. [ABSTRACT FROM AUTHOR]

The guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology ( BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the ' GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post- PV MF) and post-thrombocythemic myelofibrosis (post- ET MF) in both adult and paediatric patients. [ABSTRACT FROM AUTHOR]

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ-specific complications of chronic graft-versus-host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse. [ABSTRACT FROM AUTHOR]

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate ( ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission ( CR), and two achieved partial remission ( PR) for an ORR of 13%. Stable disease ( SD) and progressive disease ( PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival ( OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens. [ABSTRACT FROM AUTHOR]

To define high-risk acute graft- versus-host disease ( GVHD) at onset, we examined the initial GVHD stage and grade of 864 patients at the University of Minnesota who received uniform therapy with prednisone 60 mg/m2 per d. We compared the prognostic utility of the Minnesota ( MN; modified from Consensus) versus Center for International Blood and Marrow Transplant Research ( CIBMTR) GVHD organ stage-derived grading systems. As neither GVHD grading system optimally predicted outcomes, a novel acute GVHD risk score was devised by combining the MN and CIBMTR systems. Using multiple regression analysis, we could dichotomize patients into high risk ( HR, n = 86) acute GVHD with initial grade IIIC, IIID or IVD who were less likely to respond to steroid therapy by day 28 [relative risk ( RR), 0·3, P < 0·001] and had a higher risk for transplant-related mortality ( RR, 2·0, P < 0·001) than patients with standard risk ( SR, initial grade IA- IIIB, n = 778) GVHD. Using this novel acute GVHD Risk Score, HR GVHD is either skin stage 4, lower gastrointestinal ( GI) stage 3+, liver stage 3+, or skin stage 3 and lower GI or liver stage 2+ GVHD. Patients with HR acute GVHD have a poor prognosis, require alternative initial therapy and should be the focus of novel therapeutic trials. [ABSTRACT FROM AUTHOR]

Summary This study analysed the effects of growth factor on outcome after haematopoietic stem-cell transplantation ( HSCT) with >9 years follow-up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen ( HLA)-identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils ( P < 0·0001), but reduced platelet counts ( P = 0·0002). Graft-versus-host disease ( GVHD)-free survival (no acute GVHD grade II-IV or chronic GVHD) at 10 years was 12 ± 2% (± SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio ( HR) 0·81, P = 0·001]. Similar differences in GVHD-free survival were seen in patients with or without conditioning with total body irradiation ( TBI). Non-relapse mortality ( NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [ HR = 1·48; 95% confidence interval (CI): 1·15-1·9; P = 0·002; HR = 1·59; 95% CI: 1·07-2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse ( HR = 0·96; 95% CI: 0·78-1·18; P = 0·71). Leukaemia-free survival ( LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls ( HR = 0·70; 95% CI: 0·60-0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS > 10 years after HSCT, regardless of conditioning with TBI. [ABSTRACT FROM AUTHOR]

Summary In order to investigate whether the clinical behaviour of extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) varies by race within a geographic region, we identified a total of 213 non-Hispanic whites, Hispanics and Asians/Pacific islanders (APIs) diagnosed with ENKTL in the California Cancer Registry between 2001 and 2008. The incidence and outcomes of the disease in these racial groups were analysed. The incidence rates in non-Hispanic whites, Hispanics and APIs were 0·05, 0·18 and 0·23 per 100 000 person-years, respectively, among males; and 0·03, 0·07 and 0·10 per 100 000 person-years, respectively, among females. The overall survival (OS) at 5 years was 28·6% in non-Hispanic whites, 30·4% in Hispanic, and 24·0% in APIs. In multivariate analysis, distant versus local/regional disease (Hazard Ratio [HR] = 2·01, 95% confidence interval [CI]: 1·36, 2·96), initial treatment with chemotherapy plus radiotherapy (HR = 0·39, 95% CI: 0·22, 0·70) or radiotherapy alone (HR = 0·48, 95% CI: 0·23, 0·99) versus no therapy were associated with OS. However, OS was not affected by age, sex, race, chemotherapy alone, socioeconomic status, or human immunodeficiency virus infection. In conclusion, ENKTL is more common and clinically more similar among Hispanics and APIs than non-Hispanic whites with poor outcome in all racial groups. [ABSTRACT FROM AUTHOR]

Summary Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n = 34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n = 53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n = 63) ( N = 150). Response rates after four cycles of treatment were: ≥near complete response (nCR), 12% vs. 2% vs. 41%, P < 0·0001 and very good partial response or better, 35% vs. 30% vs. 65%, P = 0·0003, respectively. With all cycles of therapy considered, ≥nCR was 35%, 15% and 41%, P = 0·006. However, there is no evidence that one regimen produced superior progression-free survival (PFS) (median: 3·2 vs. 2·3 vs. 2·7 years, P = 0·11) or overall survival (3-year: 88% vs. 79% vs. 88%, P = 0·23). Transplantation did not impact PFS (median: 2·7 vs. 2·3 years, P = 0·41) but was associated with improved OS (3-year: 93% vs. 75%, P ≤ 0·001). High genetic risk patients ( n = 40) had earlier relapse despite lenalidomide or bortezomib (median: 2·1 vs. 2·7 years, P = 0·45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4 years. [ABSTRACT FROM AUTHOR]

Summary Monogenic hereditary diseases, such as haemophilia A and B, are ideal targets for gene therapeutic approaches. While these diseases can be treated with protein therapeutics, such as factor VIII (FVIII) or IX (FIX), the notion that permanent transfer of the genes encoding these factors can cure haemophilia is very attractive. An underlying problem with a gene therapy approach, however, is the patient's immune response to the therapeutic protein (as well as to the transmission vector), leading to the formation of inhibitory antibodies. Even more daunting is reversing an existing immune response in patients with pre-existing inhibitors. In this review, we will describe the laboratory and clinical progress, and the challenges met thus far, in achieving the goal of gene therapy efficacy, with a focus on the goal of tolerance induction. [ABSTRACT FROM AUTHOR]

Summary The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20 mg/m2 on days 1-5 and temsirolimus 25 mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3·5 months, and median overall survival was 4 months (9·1 months for responders). The most common non-haematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50% in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P = 0·0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen. [ABSTRACT FROM AUTHOR]

Summary Guidelines on hereditary spherocytosis (HS) published in 2004 (Bolton-Maggs et al, 2004) are here replaced to reflect changes in current opinion on the surgical management, (particularly the indications for concomitant splenectomy with cholecystectomy in children with mild HS, and concomitant cholecystectomy with splenectomy in those with asymptomatic gallstones). Further potential long term hazards of splenectomy are now recognised. Advances have been made in our understanding of the biochemistry of the red cell membrane which underpins the choice of tests. Biochemical assays of membranes proteins and genetic analysis may be indicated (rarely) to diagnose atypical cases. The diagnostic value of the eosin-5-maleimide (EMA) binding test has been validated in a number of studies with understanding of its limitations. [ABSTRACT FROM AUTHOR]

Summary Children with chromosomal instability syndromes have an increased risk of developing lymphoma and leukaemia. The treatment of these malignancies is hampered by therapy-associated toxicity and infectious complications. This retrospective analysis evaluated the therapy outcome of 38 children with Ataxia teleangiectasia or Nijmegen-breakage syndrome with acute lymphoblastic leukaemia (ALL, n = 9), Non-Hodgkin lymphoma (NHL, n = 28) and Hodgkin lymphoma (HL, n = 1). All patients with NHL or ALL were treated in accordance to Berlin-Frankfurt-Münster (BFM)- or Co-operative study group for childhood ALL (CoALL)-oriented chemotherapy schedules. 22 patients received significantly reduced-intensity chemotherapy. After a median follow-up of 3·7 years the 10-year overall survival was 58%. Dosage-reduction of chemotherapeutic drugs seemed to have no disadvantages and reduced toxic side effects. On the other hand, reduced-intensity chemotherapy did not prevent second malignancies, which occurred in ten patients with a 10-year incidence of 25%. After individual treatment approaches three of these patients with second malignancies were in complete clinical remission for more than 5 years. We conclude that BFM- or CoALL-oriented chemotherapy is effective and can be administered in children with AT or NBS. Moreover, we show that even second lymphoid malignancies can successfully be treated in these patients. [ABSTRACT FROM AUTHOR]

Summary Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4-dgRTA) and CD19 (HD37-dgRTA). Pre-clinical data demonstrated that Combotox was effective in killing both pre-B-ALL cell lines and cells from patients with pre-B ALL. A clinical study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this study. This study was a Phase I, dose-escalation trial using Combotox in adults with refractory or relapsed B-lineage-ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m2 per dose. Seventeen patients, aged 19-72 years, were enrolled in this multi-institution study. The maximum tolerated dose was 7 mg/m2/dose (21 mg/m2/cycle) and vascular leak syndrome was the dose-limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 72-year-old woman with persistent circulating malignant T-cell clone and was treated with alemtuzumab. The patient was advised to undergo high dose chemotherapy and radiotherapy (HDT) with autologous stem cell transplantation (ASCT) (HDT-ASCT) considering the poor prognosis of T-cell lymphomas. Furthermore, the efficacy of alemtuzumab in treating circulating clonal T-cell lymphomas before cell mobilization and transplantation is discussed.

Peripheral T-cell lymphoma (PTCL) has a poorer prognosis than diffuse large B-cell lymphoma (DLBCL). We administered the CyclOBEAP regimen (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) to patients with DLBCL, and reported its safety and efficacy. Here, we report the results of a multicentre phase II study of the CyclOBEAP regimen in patients with PTCL. In addition, NME1 remained a prognostic factor for survival, as shown in patients who were treated with CyclOBEAP. There were 84 eligible patients and the median age was 54 years. The 5-year overall survival (OS) rate was 72% and progression-free survival (PFS) rate was 61%. The 5-year OS was 93% among the anaplastic large-cell lymphoma cases, 74% among the angioimmunoblastic T-cell lymphoma cases, and 63% among the cases of PTCL-not otherwise specified. When the patients were divided according to the International Prognostic Index or Prognostic Index for PTCL, the 5-year OS and PFS rates did not significantly differ among the risk groups. Positivity for NME1 was found to be a significant independent prognostic factor. Grade 4 neutropenia was observed in 80 patients and thrombocytopenia in nine patients. Our results suggest that the CyclOBEAP therapy is safe and effective for PTCLs. Furthermore, the NME1 protein may be an important prognostic factor in PTCL. [ABSTRACT FROM AUTHOR]

Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non-relapse mortality (NRM), overall survival (OS) and progression-free survival (PFS) were analysed. One hundred and forty-seven patients, aged 20-68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre-transplant thrombocytopenia. Four-year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31-50), 32% (95%CI: 24-43) and 39% (95%CI 30-48), respectively. Multivariate analysis indicated that HLA-identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS. [ABSTRACT FROM AUTHOR]

Defects in the DNA damage response pathway [e.g. del(17p)] are associated with drug-resistant B-cell chronic lymphocytic leukaemia (CLL). We previously demonstrated that over-expression of DNA-dependent protein kinase (DNA-PK) correlates with chemo-resistance and that inhibition of DNA-PK sensitizes CLL cells to chemotherapeutics. Here, we investigated expression of DNA-PK and other proteins that impact on drug resistance, and evaluated the effects of a DNA-PK inhibitor (NU7441) on mitoxantrone-induced cytotoxicity in CLL cells. NU7441 sensitized cells from 42/49 CLL samples to mitoxantrone, with sensitization ranging from 2- to 200-fold Co-culture of CLL cells in conditioned stromal medium increased chemoresistance but did not reduce sensitization by NU7441. Mitoxantrone treatment induced γH2AX foci and NU7441 increased their longevity (24 h). NU7441 prevented mitoxantrone-induced autophosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) at Ser 2056, confirming that DNA-PK participates in repair of mitoxantrone-induced DNA damage. del(17p) cases were more resistant to mitoxantrone than del(13q) cases, but were resensitized (7-16 fold) by co-incubation with NU7441. Expression of DNA-PKcs, Ku80, P-glycoprotein and topoisomerase IIβ were significantly higher in del(17p) cases. PRKDC mRNA levels correlated with DNA-PKcs protein expression, which predicted shorter survival. These data confirm the potential of DNA-PK as a therapeutic target in poor prognosis CLL. [ABSTRACT FROM AUTHOR]

Abnormal iron regulation in patients with thalassaemia intermedia may lead to iron overload even in the absence of transfusions. There are limited data on iron chelator use in patients with thalassaemia intermedia and no guidelines exist for the management of iron overload. We present data from 11 patients with thalassaemia intermedia treated with deferasirox (Exjade, 10-20 mg/kg/d) for 24 months. Liver iron concentration and serum ferritin levels significantly decreased over the first 12 months ( P = 0·005) and continued to decrease over the remainder of the study ( P = 0·005). This small-scale study indicated that deferasirox may be suitable for controlling iron levels in patients with thalassaemia intermedia. [ABSTRACT FROM AUTHOR]

Summary Peripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front-line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) and compared it to CHOP/21 as front-line treatment in non-cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2-year event-free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty-eight patients were identified between 1996 and 2002 . Both arms were well balanced for patients' characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2-year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I-II were identified as two independent favourable prognostic factors influencing survival. VIP-rABVD was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas. [ABSTRACT FROM AUTHOR]

Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 ( TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases. [ABSTRACT FROM AUTHOR]

This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best supportive care or a course of GO according to one of two schedules: 3 mg/m2 on days 1, 3 and 5 (arm A), or GO 6 mg/m2 on day 1 and 3 mg/m2 on day 8 (arm B). Primary endpoint was the rate of disease non-progression (DnP), defined as the proportion of patients either achieving a response or maintaining a stable disease following GO induction in each arm. Fifty-six patients were randomized in the two GO arms (A, n = 29; B, n = 27). The rate of DnP was 38% [90% confidence interval (CI), 23–55] in arm A, and 63% (90% CI, 45–78) in arm B. Peripheral cytopenias were the most common adverse events for both regimens. The all-cause early mortality rate was 14% in arm A and 11% in arm B. The day 1 + 8 schedule, which was associated with the highest rate of DnP, met the statistical criteria to be selected as the preferred regimen for phase III comparison with best supportive care. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukaemia (APL) patients are successfully treated with all- trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 ( DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes. [ABSTRACT FROM AUTHOR]

The presence of a dicentric chromosome dic(9;20) has been reported to have an unfavourable prognosis in children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). As outcome may be influenced by type and composition of treatment, we analyzed 19 BCP-ALL patients with dic(9;20) who have been treated with ALL-BFM (Berlin-Frankfurt-Münster) protocols that included a 4-drug induction and subsequent consolidation therapy. All patients were good responders to prednisone and in complete remission after induction therapy. Eight patients had no molecular disease after induction and another eight patients had levels ≤10−4 after consolidation therapy. After a median follow-up of 3·4 years, probabilities of 5-year event-free and overall survival were 75 ± 11% and 94 ± 6%, respectively. Of note, there was a tendency for extramedullary disease in case of relapse (two of three relapses with central nervous system involvement). In conclusion, in the context of ALL-BFM protocols dic(9;20)-positivity appeared to have a favourable prognosis, which could be due to a dose- and time-intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)-positive leukemic blasts tol-asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM-like induction and consolidation therapy, may have contributed to this good outcome. [ABSTRACT FROM AUTHOR]

The article discusses the study which found that long non-coding ribonucleic acids(lncRNAs) are one of the biomarkers of subtype acute leukemia. Topics mentioned include the obtaining of profiles from bone marrow samples of cases diagnosed based on the classification system of World Health Organization, the results showed the detection of biomarker fraction, and the biological function of lncRNAs in haematological malignancies.

Although the substantial risk for invasive pneumococcal disease is well recognized in children after allogeneic stem cell transplantation, little is known about the specific immunity against pneumococci in children after cytotoxic therapy for acute lymphoblastic leukaemia (ALL). We therefore assessed the spontaneous reconstitution of humoral immunity against pneumococcal antigens, of total IgG and the IgG2 subclass, and of lymphocyte subsets in a total of 53 children treated for ALL. None of the patients had received pneumococcal vaccination prior to or after therapy for ALL. At 3 and 9 months after completion of chemotherapy, most patients had levels of specific antibodies to pneumococcal antigens below the presumed threshold of protection and significantly lower than those of age-matched unvaccinated healthy controls. In contrast, at 9 months after completion of therapy, only a minority of patients had immunoglobulin concentrations or lymphocyte subset counts below the age-matched reference value. Our data indicate that patients with ALL who are unvaccinated against pneumococci have a selective immunodeficiency with an impaired antibody protection against pneumococci for up to 9 months after completion of therapy. Therefore, effective prevention, including chemoprophylaxis and active immunization, has to be considered in this patient population. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) in patients with sickle cell disease (SCD) is linked to intravascular haemolysis, impaired nitric oxide bioavailability, renal dysfunction, and early mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases (NOS), is associated with vascular disease in other populations. We determined the plasma concentrations for several key arginine metabolites and their relationships to clinical variables in 177 patients with SCD and 29 control subjects: ADMA, symmetric dimethylarginine (SDMA), NG-monomethyl L-arginine (L-NMMA), N-omega-hydroxy-L-arginine (NOHA), arginine and citrulline. The median ADMA was significantly higher in SCD than controls (0·94 μmol/l vs. 0·31 μmol/l, P < 0·001). Patients with homozygous SCD had a remarkably lower ratio of arginine to ADMA (50 μmol/l vs. 237, P < 0·001). ADMA correlated with markers of haemolysis, low oxygen saturation and soluble adhesion molecules. PH was associated with high levels of ADMA and related metabolites. Higher ADMA level was associated with early mortality, remaining significant in a multivariate analysis. Subjects with homozygous SCD have high systemic levels of ADMA, associated with PH and early death, implicating ADMA as a functional NOS inhibitor in these patients. These defects and others converge on the nitric oxide pathway in homozygous SCD with vasculopathy. [ABSTRACT FROM AUTHOR]

Anthracyclines are used to treat childhood acute lymphoblastic leukaemia (ALL) but non-randomized studies suggest that cardiotoxicity may be a problem. Individual patient data from trials in childhood ALL that randomized anthracyclines or methods of reducing cardiotoxicity were analysed by standard meta-analysis methods. Results were grouped and combined according to: addition of an anthracycline to standard therapy, type of anthracycline, mode of administration, and the use of a cardioprotectant. Data from 958 patients in 4 trials, recruiting between 1972 and 1984, showed that addition of an anthracycline reduced bone marrow relapse and, non-significantly, non-bone marrow relapse, resulting in an increased relapse-free interval. However there was a non-significant increase in induction failures, and in deaths in first remission. Event-free survival at 5 years was 56·7% with anthracycline versus 52·8% without (Odds Ratio = 0·91; 95% Confidence Interval = 0·76–1·10; P = 0·3). There were no significant differences found in other treatment comparisons. The limited data from trials did not demonstrate differences in clinically evident cardiotoxicity. Anthracyclines are effective against bone marrow relapse but have not been shown to significantly increase event free survival in childhood ALL. The evidence on type of anthracycline, method of administration or use of cardioprotectant was insufficient to be able to rule out important differences. [ABSTRACT FROM AUTHOR]

The recent approval of bortezomib for the treatment of mantle cell lymphoma (MCL) by the US Food and Drug Administration is based on the results of the multicentre PINNACLE study with supportive data from a number of single and multicentre Phase 2 studies. This multicentre Phase 2 study enroled 40 patients with heavily pretreated MCL. The overall response rate (ORR) was 47%, including 5 complete remissions and 14 partial remissions. Overall, these remissions are relatively durable. The ORR in relapsed and refractory patients was 50% and 43% respectively ( P = 0·74), while both populations of patients exhibited essentially similar progression-free survival (PFS; 5·6 months vs. 3·9 months, P = 0·81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7·8 months vs. 8·4 months, respectively). The data showed similar responses in relapsed and refractory patients as well as remission durations similar to prior therapy, suggesting that there may be little cross-resistance with other conventional cytotoxic agents. Importantly, these data suggest that MCL patients with refractory or poorly responsive disease may still derive meaningful clinical benefit from treatment with bortezomib. [ABSTRACT FROM AUTHOR]

Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required. [ABSTRACT FROM AUTHOR]