Search

Purpose: The prognosis of patients with multiple myeloma (MM) is still dismal despite recent improvements achieved by introducing new therapeutic agents. However, there remains an urgent need for progress in myeloma drug development. We here show that novel marine-derived compounds can exert potent anti-myeloma activity., Experimental Design: Nine marine-derived compounds were applied at low nM concentrations (0.1-100 nM) to MM cell lines (OPM-2, NCI-H929, U266, RPMI-8226), to primary human myeloma cells and to peripheral blood mononuclear cells. Apoptosis was determined by flow cytometry. In addition, eGFP-transgenic MM cell lines growing with mesenchymal cells from bone marrow were used to visualize tumors by fluorescence stereomicroscopy. Anti-myelomaactivities were studied in vitro in 3D spheroids and in vivo in myeloma xenografts on chicken embryos. Tumor size was analyzed by measuring GFP content with a GFP ELISA. Anti-angiogenic activities of compounds were tested in an in vivo gelatin sponge assay with conditioned media from primary bone marrow-derived endothelial cells., Results: We identified a subset of marine compounds with strong anti-myeloma activity in vitro and in vivo. Moreover, some of the compounds inhibited myeloma-related angiogenesis in the in vivo gelatin sponge assay. They merit further drug development to improve treatment options for MM.

Background: Prognosis of patients with multiple myeloma (MM) has substantially improved in recent years due to the incorporation of novel drugs into their treatment. However, older drugs should be kept in mind when modern drugs have failed., Case Report: We report on a 62-year-old female patient with high-risk, refractory light-chain myeloma who initially presented with acute renal failure and was consecutively treated with six different therapies without achievement of sustained disease control. Therapy of cyclophosphamide orally at 50 mg/day (100 mg twice a week) and dexamethasone at 24 mg once weekly was initiated, resulting in a very good partial response which was maintained for more than 21 months. Low-dose cyclophosphamide in combination with dexamethasone was well-tolerated and no significant hematological or nonhematological side-effects were noted., Conclusion: We suggest that older drugs should be kept in mind as treatment options for patients with disease refractory to multiple therapies, including novel agents., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Primary lymphoma of the lung or pleural is a very rare condition. Due to the outdated literature data, the approximate occurrence of primary and secondary lung and/or pleural involvement according to the most common B cell lymphoma entities is unknown. To answer this open question in Austria, we screened the Tyrolean registry for B cell non-Hodgkin's lymphomas regarding primary and secondary lung involvement. Of 854 patients affected by B cell lymphoma, 7.5% had lung/pleural disease. This organ was the primary site in only 0.7%, while a secondary involvement was registered in 6.8%. Most of them were affected by diffuse large B cell lymphoma (DLBCL; 29/368, 8%) followed by follicular lymphoma (7/188, 4%), mantle cell lymphoma (7/57, 12%), mucosa-associated tissue lymphoma (10/37, 27%), posttransplant lymphoproliferative disease (6/24, 25%), Burkitt lymphoma (3/19, 16%), other lymphomas (1/32, 3%) and Richter transformation (1/11, 9%). Moreover, primary lung/pleural lymphoma is one of the rarest neoplasias affecting the lung, accounting for only 0.4% of cases. Lung/pleural involvement is a very rare condition among B cell lymphomas since it mainly occurs in the setting of a generalized disease. A large majority of patients with secondary organ involvement are affected by DLBCL and have similar clinical features at diagnosis to others with advanced-stage disease., (© 2014 S. Karger AG, Basel.)

Background: The Oncotyrol - Center for Personalized Cancer Medicine is an international and interdisciplinary alliance combining research and commercial competencies to accelerate the development, evaluation and translation of personalized healthcare strategies in cancer. The philosophy of Oncotyrol is to collaborate with relevant stakeholders and advance knowledge "from bench to bedside to population and back". Oncotyrol is funded through the COMET Excellence Program by the Austrian government via the national Austrian Research Promotion Agency (FFG). This article focuses on the role of health technology assessment (HTA) and outcomes research in personalized cancer medicine in the context of Oncotyrol., Methods: Oncotyrol, which currently comprises approximately 20 individual projects, has four research areas: Area 1: Biomarker and Drug Target Identification; Area 2: Assay Development and Drug Screening; Area 3: Innovative Therapies; Area 4: Health Technology Assessment and Bioinformatics. Area 4 translates the results from Areas 1 to 3 to populations and society and reports them back to Area 3 to inform clinical studies and guidelines, and to Areas 1 and 2 to guide further research and development., Results: In a series of international expert workshops, the Oncotyrol International Expert Task Force for Personalized Cancer Medicine developed the Methodological Framework for Early Health Technology Assessment and Decision Modeling in Cancer and practical guidelines in this field. Further projects included applications in the fields of sequential treatment of patients with chronic myeloid leukemia (CML), benefit-harm and cost-effectiveness evaluation of prostate cancer screening, effectiveness and cost-effectiveness of multiple cervical cancer screening strategies, and benefits and cost-effectiveness of genomic test-based treatment strategies in breast cancer., Conclusion: An interdisciplinary setting as generated in Oncotyrol provides unique opportunities such as systematically coordinating lab and bench research, product development, clinical studies and decision science/HTA and transparent joint planning of research and development with a partnership of researchers, manufacturers and health policy decision makers. However, generating a joint research and legal framework with numerous partners from different sectors can be challenging, particularly in the starting period of such an endeavor. The journey to translational personalized medicine through multidisciplinary collaborations may still be long and difficult, but it is evident that it must be continued to turn vision into reality., (Copyright © 2015. Published by Elsevier GmbH.)

Diffuse large B-cell lymphoma (DLBCL) is a rather aggressive disease and the natural course of this lymphoma is very dismal. However, first the introduction of anthracycline-containing chemotherapy regimens and then the addition of rituximab were important steps forward. Since no complete real-life analyses have yet been published, we analyzed all patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the whole region of Tyrol and compared the results to a historical CHOP(-like)-treated cohort. Two hundred and nineteen consecutive patients underwent R-CHOP and 72% achieved a complete remission (CR); 20% suffered a relapse and 31% died. 5-Year progression-free survival (PFS) and overall survival (OS) were 56% and 69%, respectively. We identified several parameters influencing PFS and OS significantly in univariate analysis, but only stage III/IV and hemoglobin <13 g/dl were independent prognosticators for PFS and age >60 years for OS. In comparison to the CHOP(-like)-treated group, the CR rate was similar, while the percentage of relapse was nearly twice in the historical cohort, namely 44%. This translated into a dramatically improved PFS and OS for the R-CHOP group. In conclusion, in a real-life setting R-CHOP results in high percentages of response and long-term remission. Moreover we showed that in the rituximab era, factors other than the single parameters of the international prognostic index significantly influence PFS and OS. Finally, we confirm the independent impact of rituximab on the outcome of an unselected population with DLBCL.

Idiopathic Bence-Jones proteinuria (BJP) is a rare plasma cell dyscrasia, of which the clinical and biological characteristics are yet unclear. Historical data suggested that they are at higher risk of progression to multiple myeloma or other related neoplasms, while recent findings are contradictory. To address these open questions, we evaluated a series of both BJP and monoclonal gammopathy of undetermined significance (MGUS) with production of an intact immunoglobulin plus Bence-Jones proteinuria (MGUS+BJP) with long-term follow-up, regarding their clinical characteristics and progression to multiple myeloma, amyloidosis or other related B cell lymphoproliferative disorders. Two hundred and twenty-nine persons fulfilling the 2004 criteria of MGUS were included in the final analyses: 31 had BJP and 198 had MGUS+BJP. At the time of diagnosis, significantly more persons in the BJP group had renal impairment, anaemia and polyneuropathy. A more detailed analysis revealed discrepancies between the serum and urine light chain type in nine cases, reflecting clonal heterogeneity. The number of disease progressions was higher in MGUS+BJP (n = 30) when compared to BJP (n = 1), with a rate of 1.6 and 0.4 progressions per 100 person-years, respectively. In conclusion, BJP has distinct clinical characteristics and a lower risk of progression when compared to MGUS+BJP. Our data suggest that MGUS+BJP being closer to malignant transformation may be due to the higher portion of genetically heterogeneous, pre-malignant plasma cell subclones.

Background: Guidelines for using granulocyte colony-stimulating factor (G-CSF) in patients receiving chemotherapies with 10-20% (intermediate) risk for febrile neutropenia (FN) recommend additional assessment of patient-related FN risk factors., Objective: The current study evaluated adherence to guideline recommendations and analysed modalities of pegfilgrastim use., Methods: Adult cancer patients scheduled to receive a chemotherapy regimen assessed by the investigators as intermediate FN risk and who received pegfilgrastim were prospectively enrolled in this observational study from 2007-2010. Risk factors at study entry, treatment modalities and FN assessment were documented by investigators, whereas guideline adherence was centrally checked in a post-hoc analysis, according to guideline categorizations., Results: Thirty-seven centres enrolled 335 evaluable patients with solid and hematologic neoplasias. Although physicians initially rated the FN risk of all chemotherapies as intermediate, after central re-assessment this applied only to 63.9% of regimens; 21.2% were reassessed as low risk and 14.9% as high risk. Pegfilgrastim was used as primary prophylaxis in 80.3% of all patients. The most frequent FN risk factors considered by physicians when deciding to use pegfilgrastim were female gender, advanced disease, age ≥ 65 years, and anaemia. FN incidence was higher in patients with ≥ 4 FN risk factors than those with <4 risk factors (10% vs. 4.3%; p = 0.055) and in patients with severe comorbidity than those without (13.6% vs. 4.5%; p = 0.014). Overall FN rate was 5.7%., Limitations: Due to the observational design of the study, findings are descriptive in nature. Post-hoc assessment of chemotherapy FN risk was determined by author's opinion in some cases., Conclusions: Overall, there was good adherence of Austrian physicians to guideline recommendations; however, there are chemotherapy regimens and clinical settings in which FN risk assignment is unclear in the literature. FN incidence with pegfilgrastim prophylaxis was similar to that reported in other observational and randomized studies.

Currently, there is no standard systemic treatment for extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue. Both rituximab and cladribine have shown some activity in this disease, but the combination has not been tested so far. In view of this, we initiated a phase II study to assess the activity and safety of rituximab and cladribine in patients with histologically verified mucosa-associated lymphoid tissue lymphoma. Treatment consisted of rituximab 375 mg/m(2) i.v. day 1 and cladribine 0.1 mg/kg s.c. days 1 - 4 every 21 days. In case of complete remission after two courses, another two cycles of therapy were administered, while patients with a partial response or stable disease were scheduled to receive six cycles of treatment. Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as scheduled while one patient died before initiation of therapy and was rated as having progressive disease in the intent-to-treat analysis. Twenty-one patients had gastric lymphoma, while 19 suffered from extragastric mucosa-associated lymphoid tissue lymphoma. Side effects consisted mainly of hematologic toxicity including leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had a complete remission (58%) and nine had a partial remission (23%) for an overall response rate of 81%, while five had stable disease (13%) and two progressed during therapy. After a median follow-up of 16.7 months (interquartile range: 15.9 - 18.7 months), 35 patients are alive (88%) while four patients have died and one patient withdrew consent and did not allow further follow up. Our data demonstrate that rituximab plus cladribine is active and safe in patients with mucosa-associated lymphoid tissue lymphoma.

A 75-year-old female patient presented with late relapse of acute myeloid leukemia (AML). She received a single cycle of azacitidine before refusing further treatment. Around 6 weeks after this single azacitidine cycle, complete remission-according to international working group criteria-was observed with continuous improvement in peripheral blood counts to normal values, transfusion-independence, normal blast count (< 5 %) with normal morphology and flow cytometry, as well as a normal bone marrow karyotype and no dysplastic stigmata suggestive of a coexisting myelodysplastic syndrome. The patient also showed a pronounced improvement in performance status. Seven months later a second relapse occurred, followed by one additional azacitidine cycle that showed only a transient and a minor increase in thrombocytes and granulocytes, corresponding to an international working group nonresponse. As azacitidine treatment was interrupted after a single cycle, this case gives insight into the kinetics of response. The lack of response to azacitidine in AML after the second relapse suggests that azacitidine administration should be maintained after response.

Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin down-regulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 or the protein soluble hemojuvelin-Fc (HJV.Fc) to inhibit bone morphogenetic protein-Smad mediated signaling required for effective hepcidin transcription. Pharmacologic inhibition of hepcidin expression results in mobilization of iron from the RES, stimulation of erythropoiesis and correction of anemia. Thus, hepcidin lowering agents are a promising new class of pharmacologic drugs to effectively combat ACI.

Purpose: This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma., Patients and Methods: Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression)., Results: Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading., Conclusion: Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

Disease recurrence has been and remains the leading cause of treatment failure in patients with high-risk leukemia. We retrospectively analyzed outcome in 61 patients with high-risk leukemia receiving a combination of fludarabine and intermediate-dose cytarabine as induction (n = 11) or salvage therapy (n = 35). Thirty-six patients having a suitable stem cell donor proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Ten patients received fludarabine-based salvage therapy without consecutive allogeneic transplantation and 15 patients received fludarabine/intermediate-dose cytarabine because of disease relapse following allogeneic stem cell transplantation. In patients without prior allogeneic HSCT (n = 46) the complete remission rate (CR) was 41% with a CR rate of 46 and 14% in patients with acute myeloid leukemia (AML) and with acute lymphoblastic leukemia (ALL), respectively. Overall survival for patients achieving a CR was 41 versus 0% for patients not achieving CR (P < 0.0001). The best outcome was observed in patients receiving an allogeneic HSCT in CR following fludarabine/ intermediate-dose cytarabine (47 vs. 0% for patients not in CR at the time of allografting, P = 0.01). All 10 patients receiving fludarabine/intermediate-dose cytarabine without subsequent allogeneic HSCT died within 3 years either of disease relapse/progression or infection. Only 1/15 (7%) patients receiving fludarabine/intermediate-dose cytarabine because of relapse following allogeneic HSCT became a long-term survivor. By multivariate analysis achieving CR, receiving an allogeneic HSCT, and being in first relapse or untreated were the only parameters that significantly determine the outcome. Although preliminary only high-risk AML patients having a stem cell donor are candidates for fludarabine/intermediate-dose cytarabine and only those achieving a CR should be referred to subsequent allogeneic HSCT. All other patients with high-risk leukemia are candidates for experimental therapies within controlled trials.

Competitive inhibition of interleukin 2-dependent lymphocytes by daclizumab demonstrates some beneficial effects in the treatment of graft-versus-host disease (GVHD). Sixteen patients with steroid refractory GVHD received daclizumab (1 mg/kg BW) on d 1, 2 (-5), 7, 14 and 21. Twelve patients suffered from grade III-IV acute GVHD and four patients from extensive chronic GVHD. Responses were observed in nine patients (six acute, three chronic GVHD). Fourteen out of 16 patients acquired infections during daclizumab treatment and three deaths were infection related. Daclizumab demonstrates limited activity and is associated with an increased incidence of infectious complications.