Allogeneic hematopoietic cell transplantation in intermediate risk acute myeloid leukemia negative for FLT3-ITD, NPM1- or biallelic CEBPA mutations.

BACKGROUND: The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1). PATIENTS AND METHODS: We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. The NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML subgroup comprised 497 patients, aged 18-60 years. RESULTS: In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3-0.9, P = 0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3-1.1, P = 0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37-0.9, P = 0.02) and relapse-free survival (HR 0.51, 95% CI 0.34-0.76; P = 0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer. CONCLUSION: Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate risk NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML in CR1. CINICALTRIALS.GOV IDENTIFIER: NCT00180115, NCT00180102.

Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML--long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL).

BACKGROUND: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. PATIENTS AND METHODS: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. RESULTS: The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). CONCLUSION: A 5-day course of Ara-C 2 × 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. CLINICAL TRIAL NUMBER: LN_NN_2004_39/EudraCT number 2014-000083-18.

A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

Heart failure resulting from giant left atrial synovial sarcoma metastasis.

Synovial sarcoma metastasis affecting the heart and infiltrating the mitral valve is a very rare pathology. We report the case of a 44-year-old male treated with chemotherapy for atypical synovial sarcoma of the oral mucosa who presented to our clinic after cardiac decompensation with a presumptive diagnosis of myxoma of the left atrium. A large necrotic tumour positive for CK 22, EMA, CD 99 and BCL-2 but negative for translocation in COBRA-FISH analysis by break-apart probe could be excised and revealed a very rare subtype of synovial sarcoma metastasis arising from the endocard of the left atrium. The tumour was resected and the mitral valve reconstructed through ring annuloplasty.

Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40-66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9-36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1-14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.

Role of poly(ADP-ribose) polymerase activity in imatinib mesylate-induced cell death.

Imatinib targets Bcr-Abl, the causative event of chronic myelogenous leukemia (CML), and addresses leukemic cells to growth arrest and cell death. The exact mechanisms responsible for imatinib-induced cell death are still unclear. We investigated the role of poly(ADP-ribose) polymerase (PARP) activity in imatinib-induced cell death in Bcr-Abl-positive cells. Imatinib leads to a rapid increase of poly(ADP-ribosyl)ation (PAR) preceding loss of integrity of mitochondrial membrane and DNA fragmentation. The effect of imatinib on PAR can be mimicked by inhibition of phosphatidylinositol 3-kinase (PI3-K) implicating a central role of the PI3-K pathway in Bcr-Abl-mediated inhibition of PAR. Importantly, inhibition of PAR in imatinib-treated cells partially prevented cell death to an extent comparable to that observed after caspase inhibition. Simultaneous blockade of both caspases and PAR revealed additive cytoprotective effects indicating that both pathways function in parallel. In conclusion, our results suggest that in addition to the well-documented caspase-dependent pathway, imatinib also induces a PARP-mediated death process.

Requirement for Mdm2 in the survival effects of Bcr-Abl and interleukin 3 in hematopoietic cells.

The p53/Mdm2 pathway plays an important role in the induction of cell cycle arrest or apoptosis in response to genotoxic stress. Both the oncogene Bcr-Abl and physiological growth factors such as interleukin (IL)-3 can modulate the outcome of cellular exposure to DNA damage. To determine whether Bcr-Abl and growth factors can affect the p53/Mdm2 pathway, we studied the expression of Mdm2 in the IL-3-dependent pre-B cell line BaF3 and its bcr-abl-transfected derivative BaF3p185 after IL-3 deprivation or treatment with the c-Abl tyrosine kinase inhibitor STI571. We found that both growth factor withdrawal and inhibition of Bcr-Abl kinase lead to a down-regulation of Mdm2 preceding the induction of apoptosis. Apoptotic cell death induced by STI571 is partially dependent on p53. The early decrease of Mdm2 protein was not attributable to transcriptional regulation or to caspase-mediated cleavage. On the other hand, it could be completely blocked by the proteasomal inhibitor lactacystin. Targeted down-regulation of Mdm2 protein by antisense oligodeoxynucleotides overcame the survival effects of IL-3 and Bcr-Abl and resulted in accelerated apoptosis. Taken together, survival signals provided either by physiological growth factors or by oncogenic Bcr-Abl can positively regulate Mdm2, whereas Mdm2 ablation can reduce cell survival. These findings imply that, similarly to physiological growth factors such as IL-3, Bcr-Abl can promote cell survival through modulating the p53-Mdm2 pathway.

Successful treatment of metastatic renal cell carcinoma with a biologically active dose of recombinant interferon-gamma.

We tested the clinical efficacy of a biologically active dose (BAD) of interferon (IFN)-gamma for treatment of progressive renal cell carcinoma (RCC). Twenty-two RCC patients with disease progression subsequent to nephrectomy were entered on a phase II clinical trial. During an initial dose-finding phase, biochemical responses to repeated once-weekly subcutaneous injections of 10, 100, or 500 micrograms of recombinant IFN-gamma were tested in 16 patients. Results indicated that 100 micrograms IFN-gamma applied once weekly was biologically active with induction of serum beta 2-microglobulin and neopterin. Such a dose induced a nearly maximum response of both markers lasting more than 4 days. This dose was also associated with minimal side effects. A dose of 100 micrograms IFN-gamma given once weekly was, therefore, subsequently given weekly for long-term treatment. During a median time of therapy of 10 months (range, 2 to 32 months) two complete (CR; 20+, 20+ months) and four partial tumor responses (PR; 6+, 7+, 8+, 24+ months) were seen (30% CR plus PR; 95% confidence limits, 12% to 54%) among 20 patients evaluable for response. Patients with refractory disease had significantly lower IFN-gamma-induced increments of serum beta 2-microglobulin than those who achieved clinical remission or stable disease.

Studies on the optimal dose and the mode of action of alpha-interferon in the treatment of hairy cell leukemia.

The therapeutic efficacy and side effects of alpha-2c-interferon (IFN-alpha 2c) treatment of hairy cell leukemia were compared between two different dose regimen: 10 patients received maximum tolerable doses of IFN-alpha 2c for 1 year (group A), and 11 patients received minimum doses of IFN-alpha 2c, which induced an optimal biological response (group B). Induction of neopterin excretion was chosen as the marker to define biological response and the dose of IFN-alpha 2c applied was on average only one tenth of that in group A cases. Average time of treatment in group B was 42 weeks. The data indicate that both dose levels are effective in the treatment of advanced hairy cell leukemia but that the low dose regimen is free of toxicity. Laboratory investigations on the mechanism of IFN-mediated remission in HCL further revealed that hairy cells are resistant to lysis by IFN-alpha activated large granular lymphocytes and that improved natural killer function subsequent to IFN-alpha treatment in vivo is primarily due to the disappearance of leukemic hairy cells which dilute the natural killer effector cells. These findings support the view of a direct antitumor activity of IFN-alpha as the main therapeutic principle.

Comparison of clinical efficacy and toxicity of conventional and optimum biological response modifying doses of interferon alpha-2C in the treatment of hairy cell leukemia: a retrospective analysis of 39 patients.

Hairy cell leukemia (HCL) has been shown to be extraordinarily sensitive to treatment with alpha-interferon (IFN). In order to define clinically effective IFN doses associated with minimal toxicity, the therapeutic efficacy and side effects of recombinant IFN-alpha-2C treatment of HCL were compared for two different dose regimens: 18 patients (group A) received conventional doses of recombinant IFN-alpha-2C (2 x 10(6)U/m2) for a median time of 35 weeks (range 26-52 weeks), and 21 patients (group B) received optimum biological response-modifying doses of IFN-alpha-2C (0.2-0.6 x 10(6)U/m2) for a median time of 31 weeks (range 12-52 weeks). Interferon was administered daily subcutaneously for 3 months and then every second or third day. Induction of neopterin excretion was chosen as the marker for definition of biological response. The smallest IFN dose causing maximum in vivo induction of biosynthesis of the GTP-degradation product neopterin was deemed "biologically optimal." Both dose regimens were effective, but the low-dose regimen was almost free of toxicity. Thus, in HCL patients alpha-IFN related toxicity can be separated from its antineoplastic activity. Low doses of alpha-IFN should be considered for treatment of HCL patients who develop toxic side effects and for primary treatment of HCL patients with severe cytopenia.

Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C.

We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.

Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects.

Safety, local and systemic immunomodulation, and tumor response to treatment with aerosolized natural interleukin 2 (nIL-2) applied five times a day were studied in a Phase I trial in 16 patients with pulmonary malignancies refractory to conventional therapy. The toxicity of inhaled nIL-2 was different from that observed after systemic administration. Reversible airway irritation causing a nonproductive cough represented the dose-limiting toxicity. Mild to moderate reduction of the vital capacity and forced expiratory volume (FEV1) with minor effects on relative FEV1, peak expiratory flow, airway resistance, and PaO2 was experienced by individual patients. In 14 patients suffering from pulmonary metastases due to renal cell cancer, one durable complete response, one partial response, and one mixed response were observed. Inhalation of nIL-2 aerosol resulted in a dose-dependent expansion of pulmonary immunocompetent cells in bronchoalveolar lavage fluid. Posttreatment bronchoalveolar lavage showed an activated lymphocyte phenotype with increased HLA-DR expression. The only systemic biological effect detectable in peripheral blood was a marked increase of soluble interleukin 2 receptor serum levels. We conclude that treatment with aerosolized nIL-2 is an effective means for site-specific immunomodulation and deserves further investigation for the treatment of malignant and inflammatory lung disease.

The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X.

CGP 57148 is a potent inhibitor of the ABL protein tyrosine kinase and a promising new compound for the treatment of a variety of BCR-ABL-positive leukemias. We used this enzyme inhibitor to characterize the biological effects of BCR-ABL in primary cells and two growth factor-dependent BCR-ABL-transfected cell lines. The effect of CGP 57148 on primary cells is dependent on the stage of differentiation. The growth of maturing chronic myeloid leukemia cells is independent of BCR-ABL in the presence of growth factors. However, the proliferation of leukemic immature cobblestone-forming area cells is almost completely blocked after the inhibition of the BCR-ABL kinase. In the BCR-ABL-transfected cell lines, M07/ p210 and Ba/F3/p185, CGP 57148 induces apoptosis by releasing cytochrome c, activating caspase 3, and cleavage of PARP. No alteration of the expression level of the apoptosis regulator BCL-2 was observed. In contrast, BCL-X was down-regulated after exposure to CGP 57148. Inhibitors of signal transduction proteins such as PI-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase kinase, and Janus-activated kinase 2 pathways were not capable of a comparable down-regulation of BCL-X. The Fas/Fas ligand system was not involved either in the induction of apoptosis by CGP 57148. We conclude that the inhibition of the BCR-ABL kinase by CGP 57148 (a) preferentially inhibits the growth of immature leukemic precursor cells, (b) efficiently reverts the antiapoptotic effects of BCR-ABL by down-regulation of BCL-X, and (c) is more effective than the inhibition of the downstream signal transduction pathways of PI-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase kinase, and Janus-activated kinase 2.

Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer.

A phase I study was conducted to characterize the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of a single dose followed by three times weekly s.c. injections of recombinant human interleukin 12 (rHuIL-12). The study encompassed 28 patients with advanced renal cell carcinoma. rHuIL-12 was administered on day 1, followed by an observation period of 7 days. Starting on day 8, repeated s.c. injections were administered 3 times a week for 2 weeks. The MTD of the initial injection was evaluated at dose levels of 0.1, 0.5, and 1.0 microg/kg. DLT was observed at 1.0 microg/kg and consisted of fever, perivasculitis of the skin, and leukopenia. The MTD of the subsequent repeated injections after 1 week of rest was studied at dose levels 0.5, 1.0, and 1.25 microg/kg. DLT at 1.25 microg/kg comprised deterioration of performance status, fever, vomiting, mental depression, and leukopenia. Other notable toxicities were oral mucositis and elevation of hepatic enzymes. Fever, leukopenia, and elevation of hepatic enzymes were more severe after the initial injection than after repeated injections at the same dose level. At dose level 0.5 microg/kg, the mean area under the plasma concentration-time curve decreased from 7.4 ng/h/ml after the first injection to 3.3 ng x h/ml (P = 0.034) after repeated administrations, and at dose level 1.0 microg/kg, it ranged from 31.8 ng/h/ml to 6.0 ng x h/ml (P = 0.041). One patient had a partial response and seven had stable disease. The MTD of a single s.c. injection of rHuIL-12 was 0.5 microg/kg, and the MTD of three subsequent administrations per week was 1.0 microg/kg. In comparison with a single administration, the three times weekly administrations at the same dose level was accompanied with a milder pattern of side effects and a reduction of the area under the plasma concentration-time curve.

Differential effect of type I interferons on hematopoietic progenitor cells: failure of interferons to inhibit IL-3-stimulated normal and CML myeloid progenitors.

We observed a differential effect of type I interferons (IFNs) in inhibiting the proliferation of various hematopoietic progenitor cell types. Upon stimulation with interleukin-3 (IL-3), IFN-alpha and IFN-beta failed to inhibit colony formation of myeloid progenitors (day-14 colony-forming units-granulocyte/macrophage [CFU-GM]) obtained from peripheral blood (PB) and bone marrow (BM) of untreated chronic myelogenous leukemia (CML) patients in chronic phase even at IFN doses as high as 10,000 U/mL. In contrast, day-7 CFU-GM stimulated with granulocyte colony-stimulating factor (G-CSF) and burst-forming units-erythroid (BFU-E) were readily inhibited by moderate doses of IFNs. IFN-resistant myeloid progenitor cells were also detected in normal BM but not in normal PB cells. When suboptimal doses of IL-3 were used in clonal progenitor cell assays, day-14 CFU-GM were not protected from the inhibitory action of IFN. The failure of IFN to inhibit immature myeloid progenitors was confirmed in normal and CML cells highly enriched in CD34-expressing cells. Combinations of growth factors were required for sufficient colony formation in these cells, whereas IL-3 alone provided only an inadequate stimulation, which was further inhibited by IFN. In purified CD34+ cells, day-14 CFU-GM were protected from IFN-mediated inhibition only upon stimulation with stem cell factor (SCF) in combination with IL-3 or G-CSF.

Inhibition of interleukin-11 by interferon-alpha in human bone marrow stromal cells.

Interleukin-11 (IL-11), which has been detected as a stromal cell-derived cytokine, regulates multiple steps of early hematopoiesis. Synthesis of IL-11 is induced by IL-1 and transforming growth factor-beta (TGF-beta) in stromal cells and fibroblasts, but the cytokines that inhibit its production remain to be defined. In the present study, we demonstrate that interferon-alpha (INF-alpha) downregulates IL-1-induced IL-11 in human bone marrow stromal cultures. In Northern blot experiments, expression of IL-11 mRNA was reduced in the presence of INF-alpha; this inhibiton was prevented by the addition of cycloheximide. In eight independent experiments, IL-1-stimulated production of IL-11 was significantly inhibited by INF-alpha (p = 0.0117) as measured in stromal cell supernatants by specific enzyme-linked immunosorbent assay (ELISA). Dose titration experiments revealed a dose-dependent inhibition already beginning at a dose level of 10 U/mL IFN. These results are in keeping with our previous observation defining an inhibitory role of INF-alpha in the production of hematopoietic growth factors produced by the bone marrow microenvironment.

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

Hematopoietic cell transplantation in patients with intermediate and high-risk AML: results from the randomized Study Alliance Leukemia (SAL) AML 2003 trial.

The optimal timing of allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) is controversial. We report on 1179 patients with a median age of 48 years who were randomized upfront. In the control arm, sibling HCT was scheduled in the first complete remission for intermediate-risk or high-risk AML and matched unrelated HCT in complex karyotype AML. In the experimental arm, matched unrelated HCT in first remission was offered also to patients with an FLT3-ITD (FMS-like tyrosine kinase 3-internal tandem duplication) allelic ratio >0.8, poor day +15 marrow blast clearance and adverse karyotypes. Further, allogeneic HCT was recommended in high-risk AML to be performed in aplasia after induction chemotherapy. In the intent-to-treat (ITT) analysis, superiority of the experimental transplant strategy could not be shown with respect to overall survival (OS) or event-free survival. As-treated analyses suggest a profound effect of allogeneic HCT on OS (HR 0.73; P=0.002) and event-free survival (HR 0.67; P<0.001). In high-risk patients, OS was significantly improved after allogeneic HCT in aplasia (HR 0.64; P=0.046) and after HCT in remission (HR 0.74; P=0.03). Although superiority of one study arm could not be demonstrated in the ITT analysis, secondary analyses suggest that early allogeneic HCT is a promising strategy for patients with high-risk AML.

Immunomodulatory and hematopoietic effects of recombinant human interleukin-6 in patients with advanced renal cell cancer.

Interleukin-6 (IL-6) is a cytokine with pleiotropic biologic activities on B cells, T cells, and hematopoietic progenitors. The present study was undertaken to assess pharmacodynamic effects of subcutaneous administration of IL-6 on blood counts, immunologic parameters, and acute-phase reactants. Blood samples were taken from patients with advanced renal cell cancer participating in a phase II trial of recombinant human IL-6. Multiparameter FACS analyses of peripheral blood mononuclear cells were performed using antibodies against CD3, CD4, CD8, HLA-DR, CD56, CD28, CD38, CD19, sIgM, and sIgG. Serum levels of IL-10, soluble CD23 (sCD23), sCD25, IL-1 receptor antagonist protein (IL-1RA), soluble tumor necrosis factor (TNF) receptors (sTNF-R) p55 and p75, and soluble IL-6 receptor (sIL-6R) were detected by ELISA systems. Levels of C-reactive protein (CRP), neopterin, fibrinogen, beta 2-microglobulin, and immunoglobulins M, G, and A were measured by standard methods. In response to administration of IL-6, a significant increment in platelet counts was observed, reaching peak levels after 21 days of treatment. In contrast, leukocyte subsets remained unaffected. No change in number of immunophenotype of peripheral blood B cells, T cells, or natural killer cells could be detected following IL-6 administration. Blood levels of sCD23, IL-10, sIL-6R, neopterin, beta 2-microglobulin, and immunoglobulin subsets were not influenced by cytokine therapy. However, administration of IL-6 led to a slow increment of acute-phase reactants CRP and fibrinogen. Furthermore, the anti-inflammatory molecules sTNF-R p55 and p75 were induced by IL-6, whereas serum levels of IL-1RA remained unchanged. Finally, an increase in blood levels of sCD25 was observed. In conclusion, IL-6 in vivo predominantly acts as a regulator of inflammation and a megakaryocyte differentiation factor.

Low-dose gamma-interferon therapy is ineffective in renal cell carcinoma patients with large tumour burden.

The efficacy and immunomodulatory effects of low-dose gamma-interferon (gamma IFN) were investigated in an unselected population of patients with metastasising renal cell carcinoma. 36 patients suffering from metastasising renal cell carcinoma with a performance status exceeding Karnofsky index of 50 were entered into the open phase I/II trial. The majority of the patients recruited displayed a large tumour burden, and 28 patients (78%) had metastases involving two to six organ sites. Treatment was started with a 2-week cycle of either daily or weekly subcutaneous administration of either 100, 200 or 400 micrograms gamma IFN. After a therapy-free interval of 2 weeks treatment was switched to the alternate mode of administration. Subsequently, treatment was continued with the same dose applied once a week for a minimum of 3 months. Serum levels of neopterin and beta-2-microglobulin, as well as flow cytometric analyses of peripheral blood mononuclear cells, were used for the assessment of biological response. Minimal antitumour activity was observed in this high-risk patient group and only 1 patient experienced a partial response (PR) lasting 36 + months. Comparison of the patients' characteristics to those of other low-dose gamma IFN trials revealed a highly significant difference in the tumour burden and clinical response. We conclude that patient selection is a decisive parameter for the outcome of treatment with low-dose gamma IFN, and that patients with poor prognostic features and a large tumour burden are not likely to respond to this almost atoxic treatment.