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Histone deacetylase inhibitors (HDIs) are emerging as valuable new agents in the treatment of acute myeloid leukaemia (AML). However, since response rates to these agents alone are low, we sought to identify markers associated with responsiveness. In a trial of 20 patients treated with the HDI sodium valproate (VPA) in combination with all trans retinoic acid and theophylline, three patients responded clinically with one complete remission (CR) and two partial remissions. The in vivo response of the CR patient was mirrored by high in vitro sensitivity of their blasts to VPA, indicating that similar factors determine both in vivo and in vitro sensitivity. Microarray analysis of the primary AMLs and a panel of haemato-lymphoid cell lines, with a similar range of VPA sensitivities as the primary leukaemic blasts, identified elevated FOSB-expression as a potential marker of VPA sensitivity. Quantitative polymerase chain reaction confirmed overexpression of FOSB in the CR patient blasts compared to patients failing to achieve CR, and in a subset of a larger panel of AML samples. Overexpression of FOSB in K562 myeloid cells significantly increased in vitro sensitivity to VPA. Thus, we propose that FOSB is a novel, potential marker of VPA sensitivity in AML. [ABSTRACT FROM AUTHOR]

The efficacy of human recombinant erythropoietin (rEPO) in myelodysplastic syndromes (MDS) has generally been best in untransfused patients with ‘refractory anaemia’ according to the World Health Organization (WHO). We treated 63 MDS patients [excluding refractory anaemia with excess blasts, type 2 (RAEB2)] with a previously tested combination of 13- cis-retinoic acid and dihydroxylated vitamin D3 ± 6-thioguanine in addition to rEPO. Most patients were categorized as refractory cytopenia with multilineage dysplasia and RAEB1, with intermediate 1 International Prognostic Scoring System (IPSS) score; all had Hb <95 g/l, and 70% required regular erythrocyte transfusions. Treatment was well tolerated, and erythroid response rate according to new International Working Group criteria was 60%: 50% in RAEB1 and 64% in non-RAEB patients ( P = 0·383). Response rate was not affected by transfusion requirement (63%; 58% in untransfused), IPSS and WHO Prognostic Scoring System scores, and weekly rEPO dosage (30–50 000 U vs. 80 000 U). Median response duration was 16 months. Median survival reached 14 months for RAEB1 and 55 months for non-RAEB patients, with a significant difference in the latter between responders and non-responders (median 82 months vs. 44 months; P = 0·036). Our combined therapy, independent of rEPO dosage, achieved in patients with unfavourable response predictors, a rate of anaemia improvement comparable to the best obtained in lower risk patients by high-dose rEPO. [ABSTRACT FROM AUTHOR]

While supportive care remains the best option for most well children with sickle cell disease (SCD), increasing awareness of early signs of chronic organ damage in childhood has focused attention on therapy which modulates the natural history of the disease. Since cure by stem cell transplantation is only feasible for a minority and gene therapy remains developmental, pharmacological modification by Haemoglobin F (HbF)-inducers, is the most widely used approach in SCD. Currently, the only HbF modulator with a clear place in the management of childhood SCD is hydroxycarbamide for which the main indications are frequent painful crises and recurrent acute chest syndrome. In the majority of SCD children treated with hydroxycarbamide there is clear evidence of clinical benefit and the drug is well tolerated. The main disadvantages are the need for frequent monitoring and uncertainity about long-term risks of carcinogenicity and impaired fertility, although these risks appear to be very low. The role of hydroxycarbamide in sickle-associated central nervous system disease remains to be established. Decitabine and butyrate derivatives show some promise although robust data in children with SCD are lacking. A number of other drugs are currently under investigation for their effects on HbF production including thalidomide and lenolidamide. [ABSTRACT FROM AUTHOR]

Horse anti-thymocyte globulin (h-ATG) and ciclosporin are the initial therapy for most patients with severe aplastic anaemia (SAA), but there is no practical and reliable method to predict response to this treatment. To determine whether pretreatment blood counts discriminate patients with SAA who have a higher likelihood of haematological response at 6 months to immunosuppressive therapy (IST), we conducted a single institution retrospective analysis on 316 SAA patients treated with h-ATG-based IST from 1989 to 2005. In multivariate analysis, younger age, higher baseline absolute reticulocyte count (ARC), and absolute lymphocyte count (ALC) were highly predictive of response at 6 months. Patients with baseline ARC ≥ 25 × 109/l and ALC ≥ 1 × 109/l had a much greater probability of response at 6 months following IST compared to those with lower ARC and ALC (83% vs. 41%, respectively; P < 0·001). This higher likelihood of response translated to greater rate of 5-year survival in patients in the high ARC/ALC group (92%) compared to those with a low ARC/ALC (53%). In the era of IST, the baseline ARC and ALC together serve as a simple predictor of response following IST, which should guide in risk stratification among patients with SAA. [ABSTRACT FROM AUTHOR]

The article presents a case study of a man diagnosed with Ehlers Danlos syndrome Type III. Blood tests diagnosed aceruloplasminaemia and magnetic resonance imaging (MRI) revealed deposition of iron. He was given deferiprone (DFP) as there was central nervous system(CNS) involvement. Combines therapy of DFP and deferoxamine showed improvements in terms of decreased iron loading in the heart.

The article discusses the efficiency of bortezomib, cyclophosphamide and dexamethasone in the treatment of multiple myeloma. It mentions comparison between bortezomib-thalidomide- dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy. It mentions that higher dosing of cyclophosphamide is recommended to treatment effectiveness.

We report a single center experience in treating 24 consecutive patients ≥60 years old for aplastic anaemia (AA) with immunosuppressive therapy (IST). The main outcomes of interest were the tolerability and toxicity of IST, response rate and survival. Median age was 70 years (range 61–78). Seven patients received standard IST consisting of standard dose antithymocyte-globulin (ATG) with or without ciclosporin (CsA), and 17 patients received attenuated IST consisting of at least a 50% dose reduction of ATG with CsA or CsA alone. Six patients (25%) had early deaths, mostly due to infection. Early mortality appeared higher in the standard IST group although this was not statistically significant (43% vs. 18%, P = 0·4). The 2-year cumulative incidence of response was 42% [95% confidence interval (CI) 26–69%]. Responders had significantly better survival than non-responders ( P = 0·0002). The 3-year probability of overall survival was 49% (95% CI 27–68%). Moderate or severe co-morbidities ( P = 0·03) as determined by Charlson Co-morbidity Index and very severe AA ( P = 0·007) were associated with significantly inferior overall survival while age was not. Nine out of 14 evaluable patients in the attenuated IST group had durable responses to treatment, suggesting that patients not suitable for standard IST can still benefit from attenuated IST. [ABSTRACT FROM AUTHOR]

Many controlled clinical trials have proven that rituximab improves the clinical outcome of patients with mature B cell lymphoma. This study was conducted to assess the contribution of rituximab in the actual clinical practice. Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The endpoint was to evaluate the rituximab benefit based on 2-year progression-free survival (PFS) and 2-year overall survival (OS). A total 1126 patients received chemotherapies. Of these, 762 were diagnosed as diffuse large B cell lymphoma (DLBCL) and 215 as follicular lymphoma (FL). PFS and OS were markedly improved in the rituximab group compared with the non-rituximab group in patients with DLBCL (both P < 0·001) and in patients with FL ( P < 0·001 and P = 0·003 respectively). Rituximab, when used for remission induction therapy, significantly improved the clinical outcome of the mature B cell lymphoma patient in actual clinical practice. [ABSTRACT FROM AUTHOR]

Oblimersen sodium plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) patients. Oblimersen was administered as a continuous intravenous infusion at a daily dose of 3 mg/kg/d for 7 d on alternate weeks for 3 weeks. Rituximab was given at a weekly dose of 375 mg/m2 for six doses. Patients with stable disease or objective response were allowed to receive a second course of treatment. The overall response rate (ORR) was 42% with 10 complete responses (CR) and eight partial responses (PR). Twelve (28%) patients achieved a minimal response or stable disease. Among the 20 patients with follicular lymphoma the ORR was 60% (eight CR, four PR). Three of the responders were refractory to prior treatment with rituximab, and two of the responses occurred in patients who had failed an autologous stem cell transplant. Median duration of response was 12 months. Most toxicities were low grade and reversible. In conclusion, oblimersen sodium can be safely combined with rituximab. The combination appears to be most beneficial in patients with indolent NHL and warrants further investigation in a large randomized trial. [ABSTRACT FROM AUTHOR]

A combination of clarithromycin, low dose of thalidomide and low dose dexamethasone was used in a phase II study to treat patients with relapsed and refractory myeloma. Thirty patients received clarithromycin 250 mg twice daily and thalidomide 50 mg at night on an ongoing basis with 4-d pulses of 10 mg dexamethasone given monthly. Eight patients had permitted escalation of thalidomide dosage up to 200 mg daily. The combination was well tolerated and could be given to elderly, infirm and severely cytopenic patients. Response rates were high, with 89% achieving at least 50% reduction in paraprotein and a 96% overall response rate. Although clarithromycin has only minimal anti-myeloma properties when used as a single agent, its combination with thalidomide and dexamethasone appears very effective, allowing these to be used in lower and more tolerable doses with good clinical effects. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSPs) are a super family of highly conserved molecular chaperone proteins, which are induced in response to stress. HSP70 has been demonstrated to inhibit apoptosis induced by a number of chemotherapeutic agents. Previous investigations have suggested the development of drug resistance in multiple myeloma (MM) cells after adhesion to stroma. This study used MM cell lines and primary plasma cells to determine if HSP70 had a role in development of chemo resistance. Adhesion of MM cells to either bone marrow stromal cells or fibronectin (FN) enhanced HSP70 expression. Inhibition of the HSP70 expression decreased 8226 cell adhesion to stroma or FN and induced more apoptosis in FN-adhered 8226 cells than in suspension cultures at 24 h. Further, HSP70 inhibitors enhanced melphalan-induced apoptosis and reversed melphalan-induced cell adhesion-mediated drug resistance (CAM-DR) phenotype. In addition, compared to parental cells, KNK-437, a heat shock factor inhibitor caused more apoptosis in melphalan-resistant 8226/LR5 cells and sensitized them to melphalan. Primary CD138 positive cells showed high expression of HSPA4 mRNA, and KNK-437 caused apoptosis in these cells. In conclusion, our data suggest inhibition of HSP70, reduced adhesion and caused apoptosis of both acquired and de novo drug resistant MM cells. [ABSTRACT FROM AUTHOR]

Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10·5 years, range 7·3–12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m2 and the area under the plasma concentration-time curve (AUC) was 4·49 and 5·40 mg/l × min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5·2; P = 0·036), or AUC values below median (RR 5·8; P = 0·025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies. [ABSTRACT FROM AUTHOR]

The hallmark of acute promyelocytic leukaemia (APL) is the reciprocal translocation t(15;17), which leads to the expression of the promyelocytic leukaemia/retinoic acid receptor α (PML/RARα) fusion protein and a cell differentiation blockade at the promyelocytic stage. PML/RARα is directly targeted by all- trans-retinoic acid (ATRA), which degrades the oncoprotein and induces complete remission of malignancies. The aberrant function of PML/RARα, together with the constitutive activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK/ERK) signalling pathway, regulates the ability of haematopoietic cells to proliferate, differentiate, and escape from apoptotic episodes. The role of the MEK/ERK pathway in PML/RARα expression, differentiation, proliferation and apoptosis in APL cells was analysed using specific MEK inhibitors. The blockade of MEK/ERK pathway resulted in caspase-dependent degradation of PML/RARα, and attenuation of the cell differentiation induction. To our knowledge, this is the first report to show that PML/RARα was suppressed by MEK/ERK inhibition, through a mechanism dependent on caspase activation. ATRA co-operated with MEK inhibitor to increase degradation of PML/RARα and exhibited a convergence point in caspase activation with MEK inhibitors. Taken together, our data suggest a new role of MEK/ERK pathway in the pathogenesis of APL, thus supporting the use of MEK/ERK inhibitors as an efficient therapeutic strategy for this haematological malignancy. [ABSTRACT FROM AUTHOR]

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) [time-averaged mean velocity (TAMV) 170–199 cm/s] have increased risk of primary stroke, but receive no specific therapy. Some will convert to abnormal velocities (TAMV ≥200 cm/s) with further increase in stroke risk. In 2003, our centre initiated universal TCD screening, targeting all children (aged 2–16 years) with SCA. TCD examinations were repeated at intervals based on initial results. To determine rates and risk factors for TCD conversion, we reviewed all examinations since 2003, excluding patients receiving hydroxycarbamide (hydroxyurea) or transfusions. Of the eligible population, 274 children (98%) were screened at a median age of 7·1 years (range 1·7–18·2). Fifty-four patients (20%) had conditional TAMV either on initial screening or a subsequent examination. The 18-month cumulative incidence of conversion from conditional to abnormal TAMV was 23%. Age, initial TAMV, laboratory values, blood pressure and oxygen saturation were not significantly associated with conversion. Our cohort provides systematic longitudinal evaluation of an unselected paediatric population universally screened and retested at regular intervals. Our data document a high conversion rate to abnormal velocities among untreated children with SCA. Therapy should be considered for the prevention of conversion to abnormal TCD velocities. [ABSTRACT FROM AUTHOR]

Activating mutations of the FMS-like tyrosine kinase 3 gene ( FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase–signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease. [ABSTRACT FROM AUTHOR]

Immunochemotherapy with cyclophosphamide, adriamycin, vincristine, prednisone and rituximab (R-CHOP) is the standard treatment in non-immunosuppressed patients with diffuse large B-cell lymphoma (DLBCL), but its adequacy has not been definitively established in patients with human immunodeficiency virus (HIV)-related lymphoma. This phase II trial aimed to evaluate the safety and efficacy of six cycles of R-CHOP in patients with HIV-related DLBCL and to determine whether response to highly active antiretroviral therapy (HAART) had prognostic impact. Patients were eligible if they had performance status <3 and absence of active opportunistic infections. Eighty-one patients were enrolled, 57 in stages III or IV, International Prognostic Index (IPI) 0 or 1 ( n = 26), 2 ( n = 19), 3 ( n = 20) and 4 or 5 ( n = 16), and median CD4 lymphocyte count of 0·158 × 109/l. The main adverse events were neutropenia (48% of cycles) and infections (10% of cycles), which were fatal in seven patients. Complete response was achieved in 55 (69%) patients, with an estimated 3-year disease-free survival of 77% and 3-year overall survival of 56%. IPI score and virological response to HAART were the prognostic parameters for response and survival. In HIV-related DLBCL R-CHOP is feasible, safe and effective. The prognosis depends on lymphoma-related parameters and on the response to HAART. [ABSTRACT FROM AUTHOR]

CD19 and CD21 (CR2) are co-receptors found on B-cells and various B-cell lymphomas, including non-Hodgkin lymphoma. To evaluate their suitability as targets for therapy of such lymphomas using internalization-dependent antibody-drug conjugates [such as antibody-4-( N-maleimidomethyl)cyclohexane-1-carboxylate, ( N2′-deacetyl- N2′-(3-mercapto-1-oxopropyl)-maytansine) (MCC-DM1) conjugates, which require lysosomal degradation of the antibody moiety for efficacy], we examined uptake of antibodies to CD19 and CD21 in a panel of B-cell lines. Anti-CD21 antibodies were not sufficiently internalized even in the highest CD21-expressing Raji cells, resulting in lack of efficacy with anti-CD21-MCC-DM1 conjugates. Anti-CD19 antibody uptake was variable, and was unexpectedly negatively correlated with CD21 expression. Thus, high CD21-expressing Raji, ARH77 and primary B-cells only very slowly internalized anti-CD19 antibodies, while CD21-negative or low expressing cells, including Ramos and Daudi, rapidly internalized these antibodies in clathrin-coated vesicles followed by lysosomal delivery. Anti-CD19-MCC-DM1 caused greater cytotoxicity in the faster anti-CD19-internalizing cell lines, implying that the rate of lysosomal delivery and subsequent drug release is important. Furthermore, transfection of Ramos cells with CD21 impeded anti-CD19 uptake and decreased anti-CD19-MCC-DM1 efficacy, suggesting that CD21-negative tumours should respond better to such anti-CD19 conjugates. This may have possible clinical implications, as anti-CD21 immunohistochemistry revealed only approximately 30% of 54 diffuse large B-cell lymphoma patients lack CD21 expression. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphoma (NHL) is rarely observed during infancy and data on its incidence, characteristics and outcome are scarce. The present study aimed to assess the prevalence, clinical presentation and treatment results of all infants who were diagnosed with NHL between October 1986 and December 2002 among 2084 patients treated according to the NHL-BFM (Berlin-Frankfurt-Münster) multicentre trials 86, 90 and 95. We identified 20 (1%) infants with NHL including five with T-cell lymphoblastic lymphoma (T-cell LBL), seven with precursor B-cell LBL (pB-cell LBL), two with a mature Burkitt neoplasm, five with anaplastic large cell lymphoma (ALCL) and one with peripheral T-cell lymphoma (PTCL). The PTCL patient, 3/7 pB-cell LBL and 1/5 ALCL patients relapsed. One patient each from the T-cell LBL and Burkitt lymphoma groups suffered from a second malignancy and one patient each with ALCL and Burkitt leukaemia died from treatment-related toxicity. The 5-year event-free survival rate was 53 ± 12% for the 20 cases. This study has provided preliminary evidence that infants with NHL have a dismal prognosis and showed that infant NHL differed to lymphomas in older patients with respect to the distribution of gender, histopathologic subtypes as well as the ratio of T- to pB-cell LBL and the frequency of relapses of pB-cell LBL. [ABSTRACT FROM AUTHOR]

Previous studies suggested that patients with chronic lymphocytic leukaemia (CLL) are at a three- to fivefold increased risk of developing a second lymphoproliferative disorder (LPD). This observational cohort study used the Mayo Clinic CLL Database to identify factors associated with developing a second LPD. A second LPD was identified in 26 (2·7%) of 962 CLL patients during a median follow-up of 3·3 years. Diffuse large B-cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Patients previously treated for CLL had a trend toward higher prevalence of second LPD (4%) compared with previously untreated patients (2%; P = 0·053). More strikingly, patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008). No statistically significant association was observed between risk of second LPD and other CLL characteristics (ZAP-70, CD38, IgV H mutation status or cytogenetic abnormalities). In this series, prior treatments with PNA or anthracyclines were the only significant factors associated with risk of developing a second LPD in patients with CLL. Physicians should strictly adhere to established criteria to initiate treatment for CLL patients who are not participating in clinical trials. [ABSTRACT FROM AUTHOR]

Thalidomide maintenance has unresolved issues regarding dosage and toxicity. We evaluated this in five dose cohorts in 100 patients. At a median follow-up of 32·3 months, 23 patients had stopped thalidomide for disease progression, 54 for side effects. 3-year overall and progression-free survival was 76% and 41% respectively. Dosage did not influence disease outcome but greatly affected toxicity. Fifteen patients converted from partial remission to complete remission on thalidomide at a median of 13·5 months. Maintenance doses >200 mg were largely unachievable and peripheral neuropathy was the main toxicity. Lower doses enabled more patients to stay on the drug for a useful period of time. [ABSTRACT FROM AUTHOR]

We hypothesized that ciclosporin (CSA) as adjunct to plasma exchange (PE) improves the efficacy of PE in idiopathic thrombotic thrombocytopenic purpura (TTP) via suppression of the antibody inhibitor of ADAMTS13. Our preliminary findings with CSA and PE as the upfront treatment of TTP suggested that the addition of CSA to PE significantly decreased the exacerbation (disease recurrence within 30 d of the last PE) rates compared to a cohort that received corticosteroids and PE as their upfront therapy of TTP. We present an updated analysis with long-term follow-up of 18 patients with idiopathic TTP treated with concurrent CSA and PE with analysis of serial measurements of ADAMTS13 activity, antigen and inhibitor concentration in the context of clinical outcome data. Overall, 16/18 (89%) patients achieved remission, similar to historical remission rates in idiopathic TTP with PE with only one patient suffering an exacerbation. Clinical responses correlated with improvements in ADAMTS13 activity and suppression of the antibody inhibitor of ADAMTS13. These data suggest that the efficacy of CSA is at least in part related to its suppression of the antibody inhibitor of ADAMTS13 and a subsequent improvement in ADAMTS13 activity and antigen. [ABSTRACT FROM AUTHOR]

This review outlines the main chelator groups studied to date, and the evidence for their clinical effectiveness. For each treatment, the strength of evidence was documented according to the guidelines from the American College of Cardiology and the American Heart Association. Three main haematological diseases were considered as models: thalassaemia major, sickle-cell disorders and myelodysplasia. Although the data in the literature do not allow firmly evidence-based conclusions, the findings suggest that in thalassaemia major: (i) deferoxamine remains the drug of choice for chelation treatment; (ii) if there is deferoxamine intolerance or a change of treatment is suggested, the options are deferiprone or, if the liver iron concentration is high, deferasirox treatment; and (iii) if the ferritin level is >2500 μg/l and liver iron concentation is >7 mg/g/dry weight, continuous subcutaneous (s.c.) or intravenous (i.v.) deferoxamine, or combined treatment with deferiprone and deferoxamine is advised. In case of heart failure, there is currently more solid documentation to support continuous s.c. or i.v. deferoxamine treatment than combined treatment with deferiprone and deferoxamine. However, more recent data in the literature suggest that the latter could be a satisfactory alternative. Finally, if iron chelation is required for sickle-cell disorders or myelodysplastic syndromes, the current data support the use of deferoxamine treatment. [ABSTRACT FROM AUTHOR]

We report the final results of a prospective multi-centre trial testing the combination of chemotherapy (fludarabine, cytosine arabinoside and idarubicin; FLAI) followed by low-dose gemtuzumab ozogamicin (GO), for induction treatment of patients with CD33+ acute myeloid leukaemia (AML). Forty-six consecutive patients were treated: the median age was 66 (range: 60–80) years; the karyotype was unfavourable in 12 patients (26%), intermediate in 33 (71%) and favourable in one (3%). Eleven major infectious complications were recorded. There was one early death. Of the 45 evaluable patients, 24 achieved a complete response (CR; 52%), 66% and 33% in good-intermediate/poor karyotype patients. Median duration of CR was 7 (3–24) months. The cumulative incidence of relapse was 37% with an actuarial 2-year survival of 54%. These results were compared with 47 patients matched for age and karyotype who received FLAI, without GO. The proportion of patients achieving CR was comparable. However, patients with de novo AML receiving GO ( n = 26) had a significantly lower risk of relapse at 2 years when compared with patients not receiving GO ( n = 35) (40% vs. 80%, P = 0·01) and significantly better overall 2-year survival (40% vs. 14% P = 0·02). Patients with secondary AML had comparable outcome whether or not they received GO. This GO-based induction chemotherapy has a good toxicity profile. In keeping with a recent prospective randomised trial, the addition of GO seems to prolong disease-free survival. [ABSTRACT FROM AUTHOR]

B-lymphocyte stimulator (BLyS) acts as survival factor for B lymphocytes. As Hodgkin and Reed-Sternberg (HRS) cells express receptors through which BLyS promotes their growth and chemotherapy resistance, we investgated whether this molecule was increased in sera from patients with classical Hodgkin lymphoma (cHL) and whether it correlates with clinical-pathological features and outcomes. Enzyme-linked immunosorbent assay was used to measure soluble BLyS (sBLyS) in sera from 87 patients and 33 donors; higher levels were detected in patients (mean ± standard error 4493·9 ± 264·9 pg/ml vs. 2687·0 ± 200·9 pg/ml; P < 0·0001). Levels above the median value (4242·0 pg/ml) were associated with age ≥45 years ( P = 0·042), advanced stages of disease ( P = 0·005), systemic symptoms ( P = 0·014) and extranodal involvement ( P = 0·009). Five-year failure-free survival (FFS) of patients with sBLyS below or equal to median levels was 88·6% as compared to 65·1% of those with levels above the median ( P = 0·009). Statistical analyses confirmed the prognostic significance of sBLyS ( P = 0·046). When patients were analysed according to variables associated with high levels, sBLyS showed an independent predictive power in terms of FFS. Our findings support the involvement of BLyS in cHL pathogenesis. The association between high serum levels and an inferior FFS indicates that sBLyS is a possible prognostic predictor with a potential significance as a therapeutic target. [ABSTRACT FROM AUTHOR]

Complete response (CR) is still considered an important surrogate marker for outcome in multiple myeloma (MM). Long-term survival after transplantation, however, has been observed in a substantial proportion of patients who never achieved CR. The tandem transplant trial, Total Therapy 2, enrolled 668 patients, who were randomised up-front to thalidomide (THAL) or no THAL; 56 patients were identified as having had, for at least 6 months prior to initiation of therapy, monoclonal gammopathy of undetermined significance (MGUS, n = 21), smouldering MM (SMM, n = 22) or solitary plasmacytoma of bone (SPC, n = 13). The clinical characteristics and outcomes of patients with such ‘evolved’ MM (E-MM) and of those with ‘unknown’ prior history (U-MM) were compared. Fewer patients with MGUS/SMM-E-MM had anaemia or renal failure; CR was lower (22% vs. 48%) but 4-year estimates of event-free survival (54% vs. 56% with U-MM) and overall survival (65% vs. 70% with U-MM) were similar to those with SPC-E-MM or U-MM. In the latter group, achieving CR was associated with prolonged survival. In comparison with U-MM, E-MM evolved from MGUS/SMM was associated with lower CR rate without adversely affecting survival. In contrast, CR was an independent favourable feature for survival in U-MM. [ABSTRACT FROM AUTHOR]

The effectiveness of melphalan plus dexamethasone (M-Dex) with melphalan plus prednisone (MP) as induction therapy and dexamethasone with observation as maintenance therapy was compared in 585 older patients with multiple myeloma. Randomization to the M-Dex arm was stopped as a result of an analysis performed which met a predetermined event-related criterion. Of 466 patients randomised to MP or M-Dex, no differences were detected in the respective median progression-free survivals (PFS) [1·8 vs. 1·9 years; Hazard Ratio (HR) = 0·88, 95% CI 0·72–1·07; P = 0·2] or overall survivals (OS) (2·5 vs. 2·7 years; HR = 0·91, 95% CI 0·74–1·11; P = 0·3). Of the initial 585 patients, 292 remained evaluable for maintenance therapy. Patients randomised to maintenance dexamethasone had a superior median PFS (2·8 years vs. 2·1 years; HR = 0·61, 95% CI 0·47–0·79; P = 0·0002). No difference in median OS was detected (4·1 years vs. 3·8 years; HR = 0·88, 95% CI 0·65–1·18; P = 0·4). The maintenance therapy results were robust when analysed by using two additional methodologies. Dexamethasone did not improve clinical outcome when combined with melphalan during induction; maintenance dexamethasone improved PFS, but this did not translate into a detectable survival advantage. [ABSTRACT FROM AUTHOR]

After decades of stagnation, the prognosis of patients with follicular lymphomas (FL) has changed substantially within the last few years due to new and effective therapeutic modalities. These include myeloablative therapy followed by autologous stem cell transplantation (ASCT) in younger patients in first remission, which showed a significant prolongation of remission duration in three prospective randomised trials while the impact on overall survival still needs to be determined. Adding the anti-CD 20 antibody Rituximab to conventional chemotherapy resulted in a significant increase in remission rate, remission duration and, in two of four currently available prospective randomised studies, even in a longer overall survival. A prolongation of remission duration was also seen when Rituximab was given as maintenance after cytoreductive therapy including Rituximab. Radio-immunotherapy (RIT) with radioisotopes coupled to monoclonal antibodies produced encouraging data in several phase II studies. New therapeutic perspectives have also emerged from increasing insights into the biology of the disease that unravel molecular targets for novel agents, some of which have entered clinical evaluation already. [ABSTRACT FROM AUTHOR]

In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty-six percentage achieved remission with survival after relapse (5 years) 34 ± 4%. Of 122 patients who received re-induction therapy, 77% entered remission with 40 ± 5% survival. Remission rates were similar for different re-induction regimens but fludarabine, cytarabine, granulocyte colony-stimulating factor-based therapy had low treatment-related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 ± 5% compared with 48 ± 6% in late relapse. For children receiving re-induction therapy, survival in early relapse was 29 ± 6% and 51 ± 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 ± 9, 5 ± 5 and 41 ± 5%, respectively. Survival was 62 ± 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re-induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%. [ABSTRACT FROM AUTHOR]

The impact of the combination therapy fludarabine plus cyclophosphamide (FC) in comparison with fludarabine alone regarding the incidence and severity of infections among previously untreated patients with chronic lymphocytic leukaemia (CLL) was evaluated within a multicentre phase III study. A total of 375 patients, up to 65 years old, were randomised between fludarabine or FC for first line therapy. No routine anti-infective prophylaxis was provided. A total of 196 infectious episodes, including 33 severe infections, were documented. In the fludarabine arm, 32·9% of the patients developed an infectious complication compared with 39·9% in the FC arm (P = 0·2). No difference was observed in the rate of severe infections (Common Toxicity Criteria grades III and IV) between both treatment arms. Dose reductions were performed more frequently in FC-treated patients. Granulocyte colony-stimulating factor (G-CSF) was administered due to leucopenia in 5% of all patients. A multivariate regression model identified only elevated thymidine kinase, but not the treatment arm, as a statistically independent risk factor for infections. In summary, FC was not associated with a higher rate of infections compared with fludarabine alone. No routine antibiotic or virostatic prophylaxis, or pre-emptive treatment with G-CSF, is necessary in first line therapy with fludarabine-based regimens in younger patients with CLL, if adequate dose reduction is performed. The combination therapy FC is not associated with a higher rate of infections compared with fludarabine alone. No routine antibiotic or virostatic prophylaxis as well as pre-emptive treatment with G-CSF is necessary in first line therapy with fludarabine-based regimen in younger patients with CLL, if adequate dose reductions due to cytopenia or previous infections are performed. [ABSTRACT FROM AUTHOR]

Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment-related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced-intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty-seven patients were transplanted; 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5–63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low-risk patients according to Cervantes score or between sibling and unrelated donor transplantations. [ABSTRACT FROM AUTHOR]

Mucositis is a known complication of autologous stem cell transplantation (ASCT). This study retrospectively reviewed 191 patients with lymphoid malignancies undergoing ASCT following a uniform mobilising regimen of etoposide (VP-16)/granulocyte colony-stimulating factor and a uniform high-dose preparative regimen of busulfan/cyclophosphamide/VP-16. Eighty-seven patients experienced severe mucositis (modified Oral Mucositis Assessment Scale ≥1). Patient characteristics compared between mucositis groups were balanced according to disease status, prior exposure to radiation therapy, time from radiation therapy and actual body weight. Log-rank analysis revealed that severe mucositis was associated with inferior overall survival ( P = 0.002). A 12-month landmark analysis showed this difference in survival occurred within 1 year post-transplant. Multivariate analysis of all-cause mortality showed lower pretransplant albumin and severe mucositis to be significant risk factors. Multivariate analysis for relapse mortality revealed severe mucositis to be a risk factor ( P = 0.047), while lower pretransplant albumin was significant for non-relapse mortality (NRM; P = 0.009). Kaplan–Meier estimates of survival based on relapse and NRM were significantly worse for patients with severe mucositis. Reduced pretransplant forced expiratory volume in 1 s ( FEV1) and carbon monoxide (CO) diffusing capacity (DLCO) were also associated with severe mucositis. Our data suggest that studies of new treatment strategies for mucositis should include relapse and survival endpoints and that pretransplant factors, such as FEV1 and DLCO may be useful to risk-stratify patients entered onto such trials. [ABSTRACT FROM AUTHOR]

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60–64 years) on survival in a prospective, population-based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population-based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta-2-microglobulin and age <60 years vs. 60–64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0·001) and 60–64 years (median 50 months vs. 27 months; P = 0·001). We conclude that in a population-based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60–64 years but with less superiority than in younger patients. [ABSTRACT FROM AUTHOR]

Increased oxidant stress has been suggested to play a role in the process of phosphatidylserine (PS) externalisation in the red blood cells of sickle cell patients. Inhibition of the ATP-driven translocation from outer to inner monolayer (flippase) by sulphydryl modification has been established. The present study showed that phospholipid scrambling was also sensitive to protein sulphydryl modification. Treatment with N-ethylmaleimide lead to enhanced PS exposure and a lower Ca++ requirement for scrambling. In contrast, pyridyldithioethylamine treatment inhibited PS exposure. Red blood cells from a murine model for sickle cell disease exhibited a reduced response to both reagents, suggestive of previous sulphydryl modifications to the protein(s) involved in phospholipid scrambling. We conclude that sulphydryl modifications to both scramblase and flippase underlie the enhanced formation of PS-exposing cells in sickle cell disease. [ABSTRACT FROM AUTHOR]

Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.− 1639G > A polymorphism of the vitamin K-epoxide reductase ( VKORC1) gene. However, its association with the acenocoumarol dose in patients under anticoagulant therapy has not been studied. The c.− 1639G > A genotype of VKORC1 was determined in 113 patients on stable anticoagulation requiring low ( n = 42), medium ( n = 42) or high ( n = 21) acenocoumarol doses. To evaluate the association between acenocoumarol requirements and the c.− 1639G > A variant, multivariate logistic regression models were fitted, adjusting for age, gender, and the c.430C > T and c.1075A > C variants of cytochrome P450 2C9 ( CYP2C9). A total of 90·5% of the patients in the low acenocoumarol dose group carried the A allele of VKORC1:c.− 1639G > A. The A allele independently increased the odds of requiring a low acenocoumarol dose [odds ratio (OR) 9·4; 95% confidence interval (CI) 1·9–46·4; P = 0·006], especially when the homozygous form was present (OR 44·2; 95% CI 5·5–354·6; P < 0·001). The A allele was less frequent in the high dose group showing an inverse association with the requirement for high doses (OR 0·04; 95% CI 0·01–0·22; P < 0·001). The A allele of the c.− 1639G > A polymorphism of VKORC1 is therefore associated with a low-dose requirement for acenocoumarol in patients receiving anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Patients with refractory or early relapsed anaplastic large cell lymphoma (ALCL) have a poor chance of survival. We report 20 children and adolescents with high-risk relapsed or refractory ALCL who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively analysed 20 patients who relapsed between December 1991 and April 2003 during (six patients) or soon after first-line Berlin–Frankfurt–Münster-type chemotherapy (14 patients) and underwent allogeneic HSCT. Nine patients received allogeneic HSCT after the first relapse and 11 after multiple relapses. Eight patients received their transplants from matched sibling donors, eight from unrelated donors and four from haploidentical family donors. The conditioning regimen was based on total body irradiation in 15 patients. Two patients relapsed after allogeneic HSCT and died. Three patients died of transplant-related toxicity. Event-free survival at 3 years after allogeneic transplant was 75 ± 10%. There was no influence of donor type or conditioning regimen on outcome. Two of six patients with progressive disease during frontline therapy survived compared with 13/14 patients with a first relapse after frontline therapy. Two of three patients who were transplanted with active lymphoma and all five patients who received allogeneic HSCT for relapse following autologous HSCT survived disease-free. Allogeneic HSCT is effective and has acceptable toxicity as rescue therapy for high-risk ALCL relapse. It even offers cure for patients refractory to chemotherapy, suggesting a graft- versus-ALCL effect. [ABSTRACT FROM AUTHOR]

The International Prognostic Index (IPI) is the most commonly used prognostic model for mantle cell lymphoma (MCL). However, the prognostic value of the IPI is limited. The recently published Follicular Lymphoma International Prognostic Index (FLIPI) is built on variables, which are pertinent to MCL. This study was conducted to evaluate the prognostic value of FLIPI in a population-based series of 93 patients with MCL diagnosed in a 7-year period. End points of the study were response to therapy, overall survival, and disease-free survival (DFS) according to the IPI and FLIPI. Applied to the whole series, the FLIPI identified three risk groups with markedly different outcome with 5-year overall survival rates of 65%, 42%, and 8% respectively. Notably, the high-risk group comprised 53% of patients. In contrast, the IPI only allocated 16% of cases to the high-risk group and had a lower overall predictive capacity. When both the FLIPI and IPI were included in a multivariate analysis, only the FLIPI was related to survival. Multivariate analysis of DFS also identified the FLIPI, and not the IPI, as independently significant. Thus, in the present study, the FLIPI was superior as a prognostic model compared with the IPI and can therefore be recommended as a clinical prognostic index for MCL. [ABSTRACT FROM AUTHOR]

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had ≥2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study. [ABSTRACT FROM AUTHOR]

There is an increasing use of monoclonal antibodies in the treatment of haematological malignancies. Alemtuzumab (Campath-1H; Ilex Pharmaceuticals, San Antonio, TX, USA) is a monoclonal antibody reactive with the CD52 antigen used as first and second line therapy for two types of lymphoproliferative disorders: chronic lymphocytic leukaemia (CLL), and T-cell lymphomas [both peripheral (PTCL) and cutaneous (CTCL)]. With alemtuzumab therapy, viral, bacterial and fungal infectious complications are frequent, and may be life threatening. An understanding of the patients at highest risk and duration of risk are important in developing recommendations for empirical management, antimicrobial prophylaxis and targeted surveillance. This review discusses the infection risks associated with these lymphoproliferative disorders and their treatment, and provide detailed recommendations for screening and prophylaxis. [ABSTRACT FROM AUTHOR]

Despite significant improvements in the treatment of childhood acute lymphoblastic leukaemia (ALL), the prognosis for relapsing patients remains poor. The aim of this study was to generate a transcriptional profile of relapsed ALL to increase our understanding of the mechanisms involved in therapy failure. RNA was extracted from 11 pairs of cryopreserved pre-B ALL bone marrow specimens taken from the same patients at diagnosis and relapse, and analysed using HG-U133A microarrays. Relapse specimens overexpressed genes that are involved with cell growth and proliferation, in keeping with their aggressive phenotype. When tested in 72 independent specimens of pre-B ALL and T-ALL, the identified genes could successfully differentiate between diagnosis and relapse in either lineage, indicating the existence of relapse mechanisms common to both. These genes have functions relevant for oncogenesis, drug resistance and metastasis, but are not related to classical multidrug-resistance pathways. Increased expression of the top-ranked gene ( BSG) at diagnosis was significantly associated with adverse outcome. Several chromosomal loci, including 19p13, were identified as potential hotspots for aberrant gene expression in relapsed ALL. Our results provide evidence for a link between drug resistance and the microenvironment that has previously only been considered in the context of solid tumour biology. [ABSTRACT FROM AUTHOR]

Patients with E/ β0 thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long-term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18–20 mg/kg) for 24 ± 9 months, hydroxyurea with sodium phenyl butyrate ( n = 8) and hydroxyurea with erythropoietin ( n = 9), each for ∼6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1·3 g/dl steady-state increase in haemoglobin in 40% of patients, and a milder response (≤1 g/dl) in the others. Baseline haemoglobin F was significantly associated with an increase in haemoglobin ( P < 0·001). Combined treatment with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate had no effect. Of the 27/45 patients who discontinued regular transfusions before the study, 13 remained transfusion independent during long-term follow-up, 6/13 continued hydroxyurea. Hydroxyurea moderately increased steady-state haemoglobin in a sub-group of E/ β0 thalassaemia patients and can be considered for patients with intermediate severity disease, thus delaying or avoiding the need for life-long transfusions. Continuous monitoring of toxicity and growth is required. [ABSTRACT FROM AUTHOR]

Pulmonary embolism (PE) is a common and often fatal disease. In the US, an estimated 40–53 people per 100 000 are diagnosed with PE annually and approximately 60 000 die from the disease. Diagnosis is difficult because symptoms are non-specific; however, a quick and accurate diagnosis is critical because, with appropriate therapy, the risk of recurrent (and potentially fatal) PE can be greatly reduced. Recent publication of prediction rules and improved non-invasive diagnostic tools have simplified diagnostic algorithms for PE. The efficacy of the standard treatment for PE, initial administration of continuous i.v. unfractionated heparin overlapped with long-term oral anticoagulation, is well established. However, newer treatment options such as low-molecular-weight heparins and the pentasaccharides may offer similar efficacy with improved convenience. [ABSTRACT FROM AUTHOR]

An elevated erythrocyte arginase activity with a corresponding decrease in nitric oxide (NO) level has been implicated in the pathophysiology of sickle cell disease (SCD). Recent studies have shown that hydroxyurea (HU) increases the production of NO, which increases the soluble guanylate cyclase activity and fetal haemoglobin (HbF) synthesis. To study the effects of HU on the arginase and nitric oxide synthase (NOS) activities in SCD patients, we compared levels of arginase activity and NO metabolites in red blood cells and plasma, respectively, from 23 patients with SCD (HbSS) receiving HU therapy, with those of 12 SCD patients not receiving HU treatment. Patients on HU therapy showed significantly lower arginase activity than that of HbSS patients not on HU therapy (1·36 ± 0·2 U/108 cells vs. 3·31 ± 0·29 U/108 cells). NOS activity was higher in patients on HU therapy than in untreated patients (0·72 ± 0·4 nmol/ml/min vs. 0·35 ± 0·15 nmol/ml/min, P < 0·05). Among the HU-treated patients, the decreased level of arginase activity correlated ( r = 0·71) with HbF level as well as the mean corpuscular haemoglobin content. These data suggest that one of the beneficial effects of HU in vivo may involve the regulation of arginase activity and a concomitant induction of NOS activity, which may lead to an increased production of NO. The outcome of this study may lead to the development of improved NO-based treatments for SCD. [ABSTRACT FROM AUTHOR]

We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)–interferon- α2b (IFN- α2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN- α2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P = 0·81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0·99, 95% confidence interval (CI): 0·74–1·33, P = 0·97] and overall survival (median: 34 months vs. 37 months; HR: 1·16, 95% CI: 0·85–1·59, P = 0·35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2–4) was the predominant risk factor for poor survival followed by age >65 years, high β2-microglobulin, and impaired renal function. There was more grades 3–4 dyspnoea and cardiac impairment and grades 1–2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP–IFN- α2b did not improve outcome. [ABSTRACT FROM AUTHOR]

Fludarabine plus cytarabine (Ara-C) and idarubicin (FLAI) is an effective and well-tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara-C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty-seven patients received FLAI, as the first induction–remission course, and 55 patients received ICE. Post-induction treatment consisted of high-dose Ara-C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara-C) and autologous stem cell transplantation (auto-SCT) or allogeneic (allo)-SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm ( P = 0·01), while death during induction was 2% and 9% respectively. Both haematological ( P = 0·002) and non-haematological ( P = 0·0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo-SCT. After a median follow-up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti-leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients. [ABSTRACT FROM AUTHOR]

The graft- versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively ( P < 0·001), and was 39% vs. 29%, respectively ( P = 0·043), for grades 2–4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2·16 [95% confidence interval (CI): 1·52–3·07], P < 0·0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively ( P = 0·084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3·3 (95% CI: 1·42–8·08), P = 0·0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0·007). Duration of immunosuppression was shorter among allo-RIC patients (35·5% vs. 68·8% required systemic immunosuppression 36 months after transplant, P = 0·028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning. [ABSTRACT FROM AUTHOR]

We report on 232 patients undergoing autologous haematopoietic stem cell transplantation (ASCT) entered into a multicentre, randomised trial comparing the efficacy and tolerability of meropenem (MPM) with that of piperacillin/tazobactam (P/T) as empirical antimicrobial first-line therapy for febrile neutropenia. In 27·6% of patients in the MPM group and 22·4% in the P/T group, therapy was initially supplemented with a glycopeptide for venous catheter infection or bacteraemia because of coagulase-negative staphylococci. Complete response rate after 72 h was 63·8% in the MPM group and 49·6% in the P/T group ( P = 0·034). Overall complete response rate after treatment modification was 94·0% in the MPM group and 93·1% in the P/T group. Median time to defervescence was 2 d in the MPM group and 3 d in the P/T group. The most frequently isolated pathogens were Gram-positive cocci. Treatment was well tolerated in both groups. One patient (0·4%) died from infection. Empirical first-line therapy with MPM as well as with P/T is safe and effective in febrile episodes emerging after ASCT. Higher response rates to primary treatment can be achieved with MPM. [ABSTRACT FROM AUTHOR]

The familial form of haemophagocytic lymphohistiocytosis (HLH) is a fatal disease, with allogeneic stem cell transplantation (SCT) being the only curative treatment. In contrast, patients with secondary (infection-associated) HLH usually do not require SCT. Since it often is difficult to distinguish primary and secondary HLH, we wanted to identify a tool that provides guidance on whether SCT is required. The clinical outcome of 65 HLH patients was analysed in relation to the recently reported four types of defects in natural killer (NK)-cell cytotoxicity in HLH. None (0%) of the 36 patients with NK-cell deficiency type 3 attained a sustained (1-year) remission after stopping therapy without receiving SCT, in contrast to 45% (13/29) non-type 3 patients (P < 0·001). Most type 3 patients (22/36) underwent SCT (14/22, 64% are alive), whereas 11 of 14 that did not receive SCT died, and the three others had received HLH-therapy during the last year of follow-up. Of 54 patients analysed for perforin expression and/or mutation, the five with perforin deficiency were all type 3 patients. The data suggests that HLH patients with NK-cell deficiency type 3 will probably require SCT to survive. Thus, NK-cell deficiency classification may provide valuable guidance in judging whether an HLH-patient needs SCT. [ABSTRACT FROM AUTHOR]

Over 60% of patients aged over 70 years, diagnosed with non-Hodgkin's lymphoma (NHL) in the Netherlands have serious comorbidity. We studied the independent influence of comorbidity on choice of treatment, dose reductions, treatment-related toxicity and prognosis, using data from a random sample of 381 patients from the population-based Eindhoven Cancer Registry. About 45% of patients over 60 years of age with NHL had high impact comorbidity at the time of cancer diagnosis. The proportion of patients with aggressive NHL who received chemotherapy decreased from 85% in patients aged 40–60 years to 70% in those over 60 years. About 65% of systematically treated patients with aggressive NHL suffered from treatment-related toxicity. Toxicity appeared to be more common among females and those with high-intermediate or high International Prognostic Index (IPI) risk. Among patients with aggressive NHL, the chance of dying for those with high impact comorbidity was twice as high compared with those without comorbidity. This was independent of the IPI risk. Dose reductions are frequently unavoidable for patients with severe comorbidity, poor performance status or chemotherapy-related toxicity. Whether the less frequent prescription of (full dose) chemotherapy for patients with advanced age and/or with comorbidity is justified remains a question for debate. [ABSTRACT FROM AUTHOR]

Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7·47 years for responders (CR and PR)versus4·89 years for non-responders;P = 0·035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7·4 years in CR groupversus5·3 years in non-CR group;P = 0·023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment. [ABSTRACT FROM AUTHOR]

Abnormalities ofp53have been associated with short survival and non-response to therapy in chronic lymphocytic leukaemia (CLL). We have evaluated the rate of response to fludarabine as first-line therapy in 54 patients with advanced stage CLL, analysing the cytogenetic profile, aberrations inp53, including the methylation status of its promoter, and the immunoglobulin heavy-chain variable-region (IGVH) mutation status. According to the advanced stage of the disease in this series, 75% of patients presented genetic aberrations associated with poor prognosis: del(17p) and/or del(11q), and no-mutatedIGVHgenes. Ten patients (18·5%) had methylation in the promoter region of p53. Eighty-three per cent of patients treated achieved a response, with a high rate of complete remission (47·6%). Although we found a significant correlation between failures and the presence ofp53aberrations (P = 0·0065), either with methylation (P = 0·018) or deletion (P = 0·015), 64% of the patients with aberrations in this gene responded to treatment (11/17), suggesting that fludarabine induces high remission rates, even in these patients. This is the first time that the significance of p53 promoter methylation status is described in this pathology, and our data support that this epigenetic phenomenon could be involved in the pathogenesis and clinical evolution of CLL. [ABSTRACT FROM AUTHOR]