High-dose melphalan with or without stem cell support before myeloablative allo-SCT for remission induction in patients with advanced relapsed or refractory AML

Treatment strategies for relapsed/refractory AML are limited and disappointing. Recently, high-dose melphalan (HDM) chemotherapy and autologous hematopoietic SCT (HSCT) has been proposed for AML re-induction. We investigated the impact of HDM remission induction in highly advanced relapsed/refractory AML patients planned for allogeneic HSCT. A total of 23 patients with relapsed/refractory AML were prospectively scheduled for HDM with or without stem cell support followed by myeloablative allogeneic HSCT. Patients included nine individuals with a history of previous HSCT (seven allogeneic, two autologous). A total of 18 patients (78%) achieved a leukemia-free state and an additional four had substantial reduction of the initial leukemia burden warranting treatment continuation. There were no differences between patients with or without immediate stem cell support regarding mucositis or other organ toxicity. A total of 20 patients proceeded to myeloablative allogeneic HSCT. Outcome of allogeneic HSCT was poor: 11 patients (55%) relapsed, 7 patients (35%) died from TRM and only 2 patients (10%) were alive at the last follow-up. Our study shows that HDM is effective in inducing a leukemia-free state in patients with highly advanced relapsed/refractory AML. Leukemia burden reduction with HDM, however, did not translate into improved OS.

Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose-escalation of cytarabine

The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis

This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study

In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m(2) every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 x 10(9)/L and neutrophils 0.5 x 10(9)/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.

Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series

OBJECTIVE: To evaluate the effect of IL-6 blockade using tocilizumab in inducing remission of arterial large vessel vasculitides (LVV). METHODS: Five consecutive patients with giant-cell arteritis (GCA) and two with Takayasu’s arteritis (TA) were treated by tocilizumab infusions (8 mg/kg). Tocilizumab was given every other week for the first month and once monthly thereafter. Clinical symptoms of disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and glucocorticoid (GC) dosage necessary to maintain remission were prospectively assessed. MR angiography was performed to monitor local inflammation. RESULTS: Of the seven patients three were newly diagnosed and four showed GC resistance, i.e. GC could not be lowered to less than 7.5 mg/day. The mean follow-up time was 4.3 months (range 3–7 months). All patients achieved a rapid and complete clinical response and normalisation of the acute phase proteins. Remarkably, prednisone dosage could be reduced within 12 weeks to a mean of 2.5 mg/day (range 0–10 mg/day). No relapse and no drug-related side effects were noted. CONCLUSION: Collectively the data suggest that IL-6 blockade using tocilizumab qualifies as a therapeutic option to induce rapid remission in large vessel vasculitides.

Induction of complete and sustained remission of rheumatoid pachymeningitis by rituximab

Aseptic pachymeningitis is a rare and serious complication of rheumatoid arthritis (RA). Herein, we describe a patient with rheumatoid factor-positive and anti-cyclic citrullinated peptide-positive RA who experienced a focal seizure, with aphasia and convulsions of the right side of the body. The findings of magnetic resonance imaging and histologic analysis led to a diagnosis of rheumatoid pachymeningitis. Because the patient had a large number of CD20-expressing B lymphocytes, therapy with rituximab was started and has resulted in complete and sustained remission of both the pachymeningitis and the RA for >2 years. Despite a decrease in immunoglobulins, the patient has remained free of infections, which illustrates the favorable outcome that can result from therapeutic B cell depletion in this potentially lethal manifestation of RA.

Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis. METHODS In this single centre, phase 2, randomised, double-blind, placebo-controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 American College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals until week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation generated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0·1 mg/kg per day at week 12. All analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01450137. RESULTS Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis. 17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11-79; p=0·0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36-94; p=0·0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7-17; p<0·0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p=0·0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events. INTERPRETATION Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis. FUNDING Roche and the University of Bern.

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02)

BACKGROUND: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. PATIENTS AND METHODS: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery. RESULTS: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. CONCLUSIONS: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis

BACKGROUND Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50-60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effective post-remission therapy is urgently needed. Although often no post-remission therapy is given to elderly patients, it might include chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning. We aimed to assess the comparative value of allogeneic HSCT with other approaches, including no post-remission therapy, in patients with acute myeloid leukaemia aged 60 years and older. METHODS For this time-dependent analysis, we used the results from four successive prospective HOVON-SAKK acute myeloid leukaemia trials. Between May 3, 2001, and Feb 5, 2010, a total of 1155 patients aged 60 years and older were entered into these trials, of whom 640 obtained a first complete remission after induction chemotherapy and were included in the analysis. Post-remission therapy consisted of allogeneic HSCT following reduced-intensity conditioning (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=44), autologous HSCT (n=23), or no further treatment (n=366). Reduced-intensity conditioning regimens consisted of fludarabine combined with 2 Gy of total body irradiation (n=71), fludarabine with busulfan (n=10), or other regimens (n=16). A time-dependent analysis was done, in which allogeneic HSCT was compared with other types of post-remission therapy. The primary endpoint of the study was 5-year overall survival for all treatment groups, analysed by a time-dependent analysis. FINDINGS 5-year overall survival was 35% (95% CI 25-44) for patients who received an allogeneic HSCT, 21% (17-26) for those who received no additional post-remission therapy, and 26% (19-33) for patients who received either additional chemotherapy or autologous HSCT. Overall survival at 5 years was strongly affected by the European LeukemiaNET acute myeloid leukaemia risk score, with patients in the favourable risk group (n=65) having better 5-year overall survival (56% [95% CI 43-67]) than those with intermediate-risk (n=131; 23% [19-27]) or adverse-risk (n=444; 13% [8-20]) acute myeloid leukaemia. Multivariable analysis with allogeneic HSCT as a time-dependent variable showed that allogeneic HSCT was associated with better 5-year overall survival (HR 0·71 [95% CI 0·53-0·95], p=0·017) compared with non-allogeneic HSCT post-remission therapies or no post-remission therapy, especially in patients with intermediate-risk (0·82 [0·58-1·15]) or adverse-risk (0.39 [0·21-0·73]) acute myeloid leukaemia. INTERPRETATION Collectively, the results from these four trials suggest that allogeneic HSCT might be the preferred treatment approach in patients 60 years of age and older with intermediate-risk and adverse-risk acute myeloid leukaemia in first complete remission, but the comparative value should ideally be shown in a prospective randomised study. FUNDING None.

Efficacy and safety of certolizumab pegol induction therapy in an unselected Crohnʼs disease population

Switzerland was the first country to approve certolizumab pegol (Cimzia, CZP) for the treatment of patients with moderate to severe Crohn's disease (CD) in September 2007. This phase IV study aimed to evaluate the efficacy and safety of CZP in a Swiss multicenter cohort of practice-based patients.

Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia

The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The role of the UPR during leukemogenesis is unknown so far. Here, we studied the induction of mediators of the UPR in leukaemic cells of AML patients. Increased expression of the spliced variant of the X-box binding protein 1 (XBP1s) was detected in 17.4% (16 of 92) of AML patients. Consistent with activated UPR, this group also had increased expression of ER-resident chaperones such as the 78 kD glucose-regulated protein (GRP78) and of calreticulin. Conditional expression of calreticulin in leukaemic U937 cells was found to increase calreticulin binding to the CEBPA mRNA thereby efficiently blocking translation of the myeloid key transcription factor CEBPA and ultimately affecting myeloid differentiation. Consequently, leukaemic cells from AML patients with activated UPR and thus increased calreticulin levels showed in fact suppressed CEBPA protein expression. We identified two functional ER stress response elements (ERSE) in the calreticulin promoter. The presence of NFY and ATF6, as well as an intact binding site for YY1 within these ERSE motifs were essential for mediating sensitivity to ER stress and activation of calreticulin. Thus, we propose a model of the UPR being activated in a considerable subset of AML patients through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation.

Assessment of in vivo genotoxicity of the rodent carcinogen furan: evaluation of DNA damage and induction of micronuclei in mouse splenocytes

In recent years, several surveys have highlighted the presence of the rodent carcinogen furan in a variety of food items. Even though the evidence of carcinogenicity of furan is unequivocal, the underlying mechanism has not been fully elucidated. In particular, the role of genotoxicity in furan carcinogenicity is still not clear, even though this information is considered pivotal for the assessment of the risk posed by the presence of low doses of furan in food. In this work, the genotoxic potential of furan in vivo has been investigated in mice, under exposure conditions similar to those associated with cancer onset in the National Toxicology Program long-term bioassay. To this aim, male B6C3F1 mice were treated by gavage for 4 weeks with 2, 4, 8 and 15 mg furan/kg b.w./day. Spleen was selected as the target organ for genotoxicity assessment, in view of the capability of quiescent splenocytes to accumulate DNA damage induced by repeat dose exposure. The induction of primary DNA damage in splenocytes was evaluated by alkaline single-cell gel electrophoresis (comet assay) and by the immunofluorescence detection of foci of phosphorylated histone H2AX (gamma-H2AX). The presence of cross-links was probed in a modified comet assay, in which cells were irradiated in vitro with gamma-rays before electrophoresis. Chromosome damage was quantitated through the detection of micronuclei in mitogen-stimulated splenocytes using the cytokinesis-block method. Micronucleus induction was also assessed with a modified protocol, using the repair inhibitor 1-beta-arabinofuranosyl-cytosine to convert single-strand breaks in micronuclei. The results obtained show a significant (P < 0.01) increase of gamma-H2AX foci in mitogen-stimulated splenocytes of mice treated with 8 and 15 mg furan/kg b.w. and a statistically significant (P < 0.001) increases of micronuclei in binucleated splenocytes cultured in vitro. Conversely, no effect of in vivo exposure to furan was observed when freshly isolated quiescent splenocytes were analysed by immunofluorescence and in comet assays, both with standard and radiation-modified protocols. These results indicate that the in vivo exposure to furan gives rise to pre-mutagenic DNA damage in resting splenocytes, which remains undetectable until it is converted in frank lesions during the S-phase upon mitogen stimulation. The resulting DNA strand breaks are visualized by the increase in gamma-H2AX foci and may originate micronuclei at the subsequent mitosis.

Efficacy of rituximab and cladribine in patients with chronic lymphocytic leukemia and feasibility of stem cell mobilization: a prospective multicenter phase II trial (protocol SAKK 34/02)

This phase II trial investigated rituximab and cladribine in chronic lymphocytic leukemia. Four induction cycles, comprising cladribine (0.1 mg/kg/day days 1-5, cycles 1-4) and rituximab (375 mg/m(2) day 1, cycles 2-4), were given every 28 days. Stem cell mobilization (rituximab 375 mg/m(2) days 1 and 8; cyclophosphamide 4 g/m(2) day 2; and granulocyte colony-stimulating factor 10 microg/kg/day, from day 4) was performed in responders. Of 42 patients, nine achieved complete remission (CR), 15 very good partial remission, and two nodular partial remission (overall response rate 62%). Stem cell mobilization and harvesting (> or = 2 x 10(6) stem cells/kg body weight) were successful in 12 of 20 patients. Rituximab infusion-related adverse events were moderate. The main grade 3/4 adverse events during induction were neutropenia and lymphocytopenia. Rituximab plus cladribine was effective; however, the CR rate was modest and stem cell harvest was impaired in a large number of responding patients.

A novel mode of action of the putative sphingosine kinase inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II): induction of lysosomal sphingosine kinase 1 degradation

Sphingosine kinase 1 (SK1) is a key enzyme in the generation of sphingosine 1-phosphate (S1P) which critically regulates a variety of important cell responses such as proliferation and migration. Therefore, inhibition of SK-1 has been suggested to be an attractive approach to treat tumor growth and metastasis formation.

Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid

Although death receptors and chemotherapeutic drugs activate distinct apoptosis signaling cascades, crosstalk between the extrinsic and intrinsic apoptosis pathway has been recognized as an important amplification mechanism. Best known in this regard is the amplification of the Fas (CD95) signal in hepatocytes via caspase 8-mediated cleavage of Bid and activation of the mitochondrial apoptosis pathway. Recent evidence, however, indicates that activation of other BH3-only proteins may also be critical for the crosstalk between death receptors and mitochondrial triggers. In this study, we show that TNF-related apoptosis-inducing ligand (TRAIL) and chemotherapeutic drugs synergistically induce apoptosis in various transformed and untransformed liver-derived cell lines, as well as in primary human hepatocytes. Both, preincubation with TRAIL as well as chemotherapeutic drugs could sensitize cells for apoptosis induction by the other respective trigger. TRAIL induced a strong and long lasting activation of Jun kinase, and activation of the BH3-only protein Bim. Consequently, synergistic induction of apoptosis by TRAIL and chemotherapeutic drugs was dependent on Jun kinase activity, and expression of Bim and Bid. These findings confirm a previously defined role of TRAIL and Bim in the regulation of hepatocyte apoptosis, and demonstrate that the TRAIL-Jun kinase-Bim axis is a major and important apoptosis amplification pathway in primary hepatocytes and liver tumor cells.