Ingo G. H. Schmidt-Wolf

Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma

Thalidomide as part of initial treatment of multiple myeloma improves pre- and post-transplant response by increasing the proportion of patients achieving a very good partial response. In the prospective phase 3 HOVON-50/GMMG-HD3 trial, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate (at least PR) after induction compared with patients randomized to VAD (vincristine, adriamycin, dexamethasone, 72% vs. 54%, p<0.001). Complete remission (CR) and very good partial remission (VGPR) were also higher after TAD. After High Dose melphalan 200mg/m2 response was comparable in both arms, 76% and 79% respectively. However, CR plus VGPR were significantly higher in the patients randomized to TAD (49% vs. 32%, p<0.001). CTC grade 3–4 adverse events were similar in both arms.

Enhancing adherence to capecitabine chemotherapy by means of multidisciplinary pharmaceutical care

PurposeIn this prospective multi-centre observational cohort study, we investigated the effect of an intensified multidisciplinary pharmaceutical care programme on the adherence of cancer patients treated with capecitabine, a prodrug of fluorouracil.Patients and methodsTwenty-four colorectal and 24 breast cancer patients participated in this study. Patients of the control group (nu2009=u200924) received standard care, patients of the intervention group (nu2009=u200924) received intensified pharmaceutical care consisting of written and spoken information. Adherence to capecitabine chemotherapy was measured using an electronic medication event monitoring system (MEMS™).ResultsPatients in the intervention group exhibited an enhanced but not significantly different mean overall adherence compared to the control group (97.9% vs 90.5%, pu2009=u20090.069). Mean daily adherence was significantly higher in the intervention group (96.8% vs 87.2%, pu2009=u20090.029). Variability of both adherence parameters was considerably reduced when pharmaceutical care was provided. At the end of the observation period of 126xa0days, the probability of still being treated with capecitabine was found to be 48% in the control group and 83% in the intervention group (pu2009=u20090.019, log-rank test). The relative risk for a deviating drug intake interval, i.e. <10 or >14 instead of 12xa0h, in the intervention group was found to be 0.51 (95% CI, 0.46–0.56) compared with the control group (pu2009<u20090.05, Chi-square test).ConclusionsThe provision of intensified pharmaceutical care can enhance adherence to and prolong treatment with capecitabine. The results underline the importance of multidisciplinary care to assure the effectiveness of oral chemotherapy.

Transcriptional Profiling of the Nuclear Factor-κB Pathway Identifies a Subgroup of Primary Lymphoma of the Central Nervous System With Low BCL10 Expression

Abstract Recent studies point to a role of nuclear factor (NF)-&kgr;B signaling in a subset of diffuse large B cell lymphomas. We have analyzed the expression of 21 genes encoding NF-&kgr;B family members, upstream modulators, and targets in 32 primary central nervous system lymphomas (PCNSLs) by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with nonmalignant germinal center centroblasts, expression of BCL10, REL, IAP1, and TRAF1 was significantly lower in PCNSLs, whereas that of BAX, BCLXL, BCL2, MALT1, CARD9, CARD10, CARD11, CARD14, CCND2, cFLIP, RELA, RELB, NFKB1, NFKB2, and IRF4 was higher. Hierarchical clustering of gene expression data revealed two distinct subgroups of PCNSLs, which were characterized by significantly different transcriptional levels, predominantly of BCL10, but also of REL and IAP1. Thus, these quantitative RT-PCR data with expression of genes of the NF-&kgr;B family as well as NF-&kgr;B-regulated genes together with immunohistochemical detection of nuclear RELA and REL indicate activation of the NF-&kgr;B pathway in PCNSLs, which may contribute to their high proliferative activity and the low level of apoptosis.

An update on new adoptive immunotherapy strategies for solid tumors with cytokine-induced killer cells

Introduction: Cytokine-induced killer (CIK) cells are mainly CD3+CD56+ NKT cells exhibiting non-MHC-restricted cytotoxicity against a broad range of tumors. Much research is going on to improve CIK cell effectivity and to evaluate the clinical benefit of different combinations with conventional therapies. Areas covered: This review provides an update on in vitro/in vivo studies and clinical trials applying CIK cells for the treatment of solid tumors. This comprises attempts using additional cytokines, genetic engineering and combinations with different conventional and modern therapies. Expert opinion: Since our last review, much effort has been made to improve CIK cell cytotoxicity and clinical effectivity. Targeted CIK cell therapy and combinations of CIK cells with antiangiogenic drugs or oncolytic viruses are examples of recent outstanding achievements in the field of adoptive CIK cell therapy. The clinical application of CIK cells in combination with conventional therapies, especially, obtained promising results. However, the best combination and the optimal therapy schedule have yet to be defined.

Piceatannol exhibits selective toxicity to multiple myeloma cells and influences the Wnt/ beta‐catenin pathway

Aberrant activation of Wnt/β‐catenin signaling promotes development and progression of various malignant neoplasms. Recent studies observed that the Wnt pathway is constitutively active in myeloma cells and promotes an exaggerated proliferation. Thus, the Wnt signaling pathway might be an attractive therapeutic target for multiple myeloma. In this study, we identified piceatannol as an inhibitor of the Wnt/β‐catenin pathway and as a potent inducer of apoptosis in myeloma cells. Interestingly, healthy cells remained mainly unaffected. These results reveal a significant selective induction of apoptosis by piceatannol and suggest a significant in vivo effect against multiple myeloma. Copyright

Increase of CIK cell efficacy by upregulating cell surface MICA and inhibition of NKG2D ligand shedding in multiple myeloma.

Multiple myeloma, which is a monoclonal plasma cell malignancy, still remains incurable despite recent progress in our understanding of this disorder. Adoptive immunotherapy of multiple myeloma using cytokine‐induced killer cells is yielding promising results in clinical trials; however, some myeloma cells still evade immune surveillance by various unknown molecular mechanisms. This study aims at increasing the efficacy of cytokine‐induced killer cells in targeting this tumor, using selective small‐molecule inhibitors which increase and stabilize surface expression of the natural killer group 2, member D ligand, major histocompatibility complex class I polypeptide‐related sequence A (MICA) on myeloma cells. We treated 2 multiple myeloma cell lines—U266 and KMS‐12‐PE—with 3 drugs. One of these drugs (sodium butyrate) is a histone deacetylase inhibitor. Another drug which was used (matrix metalloproteinase inhibitor III) blocks ligand shedding while the third drug (phenylarsine oxide) obstructs surface ligand internalization. The effect of these drugs on cell viability was determined using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, surface ligand expression was examined using flow cytometry, and ligand shedding was assessed using enzyme‐linked immunosorbent assay. We demonstrated that cytokine‐induced killer cells have increased cytotoxicity against multiple myeloma cells after combined drug treatment than without drug pretreatment. We also established that this increased cytotoxicity was due to potent upregulation and stabilization of surface MICA on the surface of these tumor cell lines. Our study thus highlights further therapeutic options which could be used for the treatment of multiple myeloma patients.

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

BackgroundDespite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients.Methods/DesignReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm Au2009+u2009B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2xa0months after autologous stem cell transplantation (arm B) and every 3xa0months thereafter (arm Au2009+u2009B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25xa0years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS.DiscussionThis phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24).

Bendamustine in heavily pre-treated patients with relapsed or refractory multiple myeloma

PurposeTreatment options for patients with relapsed and refractory multiple myeloma have improved since the introduction of immune-modulating agents such as lenalidomide and thalidomide. However, almost all patients relapse and suffer from an increasing amount of adverse events due to multiple lines of therapy that eventually lead to a reduced quality of life.MethodsIn this bicentric retrospective analysis, 58 patients who had been treated with either bendamustine monotherapy (62xa0% of the patients) or combined steroid therapy were included. Further inclusion criteria were at least relapsed disease. Patients had previously been treated with a mean of four lines of therapy (range 1–10). They received a median of three cycles of treatment. Dosage varied from 60 to 300xa0mg/m2 (median 120xa0mg/m2) and was administered intravenously on day 1 and 2 of a 28-day cycle.ResultsObserved toxicity was mild and most commonly led to hematological side effects such as thrombopenia and anemia. Response rates were as follows: no complete response, 20xa0% partial response, 39xa0% minimal response, 27xa0% stable disease and 14xa0% progressive disease. Median overall survival (OS) was 17xa0months. Median event-free survival was 7xa0months. Patients who had not received a concomitant steroid had a median OS of 17xa0months compared to 13xa0months median OS for patients who had received a concomitant steroid.ConclusionBendamustine monotherapy is an effective treatment option for heavily pre-treated myeloma patients due to its favorable response rate and mild toxicity.

Anticancer Dose Adjustment for Patients with Renal and Hepatic Dysfunction: From Scientific Evidence to Clinical Application

Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt the dose of anticancer agents for patients with renal or hepatic dysfunction. A guideline for anticancer agents was developed based on a literature search. An algorithm was generated to enhance the efficiency of the dose adaptation process. Finally, the dosing guideline was converted into an easy-to-use ExcelTM tool. The concept was applied to a total of 105 adult patients at the Centre for Integrated Oncology, Bonn, Germany. In total, 392 recommendations for dose adaptation were made and 320 (81.6%) recommendations were responded to by the oncologists. 98.4% of the recommendations were accepted. The algorithm simplifies the decision and screening process for high-risk patients. Moreover, it provides the possibility to quickly decide which laboratory tests are required and whether a dose adjustment for a particular anticancer drug is needed. The ExcelTM tool provides a recommended individual dose for patients with renal or hepatic dysfunction. The effectiveness of this strategy to reduce toxicity should be investigated in further studies before being adopted for routine use.

Cyclophosphamide‐based stem cell mobilization in relapsed multiple myeloma patients: A subgroup analysis from the phase III trial ReLApsE

Analysis of the efficiency and toxicity of cyclophosphamide‐based stem cell mobilization in patients with relapsed multiple myeloma (RMM).