Ruxolitinib Ajayi, Stefanie; Becker, Heiko; Reinhardt, Heike ...
Recent results in cancer research,
2018, Volume:
212
Journal Article
Peer reviewed
Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of Janus kinase (JAK) 1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis (MF) ...by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, followed by the approval for the treatment of hydroxyurea (HU)-resistant or -intolerant polycythemia vera (PV) in 2014. Both MF and PV are myeloproliferative neoplasms (MPNs) which are characterized by the aberrant activation of the JAK-STAT pathway. Clinically, MF features bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. PV is characterized by the overproduction of primarily red blood cells (RBC), risk of thrombotic complications, and development of secondary MF. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of MF patients and may also have a favorable effect on survival. In PV, ruxolitinib effectively controls the hematocrit and reduces splenomegaly. Since recently, ruxolitinib is also under investigation for the treatment of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Toxicities of ruxolitinib include myelosuppression, which results in dose-limiting thrombocytopenia and anemia, and viral reactivations. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently under investigation for MPNs or other immuno-inflammatory diseases.
Background
At Freiburg University Medical Center, chemotherapy prescriptions are processed via a computerized physician order entry (CPOE) tool and clinically checked by a designated chemotherapy ...surveillance team. Any error detected is reported instantly, corrected, and prospectively recorded. The objective of the current study was to gain insight into the causes, potential consequences, and future preventability of chemotherapy prescribing errors.
Methods
A detailed analysis of 18,823 consecutive antineoplastic orders placed in 2013 through 2014 was performed. In cooperation with information technology (IT) specialists, the intercepted errors were analyzed for effective future prevention using IT measures. Potential error consequences were determined by case discussions between pharmacists and physicians.
Results
Within 24 months, a total of 406 chemotherapy prescribing errors were intercepted that affected 375 (2%) of the total orders. Errors were classified as clinically relevant in 279 of the chemotherapy orders (1.5%). In these cases, reduced therapeutic efficacy (0.44%), the need for increased monitoring (0.48%), prolonged hospital stay (0.55%), and fatality (0.02%) were avoided as potential consequences. The most efficient conventional measures for error prevention comprised checking the order history and patient’s medical record, and a detailed knowledge of chemotherapy protocols. Of all the errors analyzed, 61% would be avoided through further software development. The improvements identified are implemented through a validated next‐generation CPOE tool.
Conclusions
The upgraded CPOE tool can be shared across other hospitals to raise safety standards and spread potential benefits across a wider patient population. The current analysis also highlighted that approximately 30% to 40% of errors cannot be avoided electronically. Therefore, pharmacovigilance initiatives remain indispensable.
Chemotherapy prescribing errors are a potential threat to patient safety. The current study demonstrates how a system of control mechanisms combined with information technology has the potential to efficiently reduce patient harm when shared across a wider range of cancer services.
Pomalidomide Engelhardt, Monika; Ajayi, Stefanie; Reinhardt, Heike ...
Recent results in cancer research,
2018, Volume:
212
Journal Article
Peer reviewed
Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as immunomodulatory. Pomalidomide, the recent immunomodulatory agent ...(IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide. Moreover, pomalidomide achieved very convincing responses in relapsed and refractory multiple myeloma (RRMM) patients, including those, who are refractory to both lenalidomide and bortezomib. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free survival (PFS) and overall survival (OS) than high-dose dexamethasone or pomalidomide alone, subsequent trials have pursued or are still investigating pomalidomide triplet combinations, using cyclophosphamide or other novel agents, such as proteasome inhibitors (PI: bortezomib, carfilzomib) or antibodies, like elotuzumab or daratumumab. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis MF), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV, and-for AL amyloidosis and MF-has already been proven to be remarkably active. Due to its potency, pomalidomide was approved for RRMM by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2013 and for drug combination with low-dose dexamethasone in 2015. In June 2017, the FDA further expanded approval for pomalidomide in combination with daratumumab and low-dose dexamethasone for patients with RRMM.
Introduction: Over the last decade MM diagnosis and therapy have greatly improved; notably due to an increasing number of “novel agents” (NA; e.g. PIs, IMiDs, mAbs, HDAC-, PD1/PD-L1-inhibitors). ...Anti-MM-therapy has gained complexity; orientation towards “state of the art” chemotherapy (CTx) protocols and international guidelines, as well as their continuous evaluation is highly important. According to the international literature, analyses of CTx management and particularly the use of novel substances have mainly been performed in the context of clinical trials (CT), therefore in a selected minority of patients (pts). In order to determine, whether guideline recommendations on MM therapy are thoroughly implemented in- and outside CT settings, we performed a real-world data analysis on clinical MM practice patterns. Substance use was analyzed in view of treatment lines and evaluated for “MM-pathway conformity”.
Methods: We performed a detailed analysis of 287 myeloma pts treated at our University Medical Center, part of the DSMM study group in 2014/15. The pt cohort was defined using the hospital pharmacy and tumor documentation (TBD) databases. TBD analysis enabled the detailed acquisition of pt characteristics, such as age at initial diagnosis (ID), gender, Durie and Salmon (D&S) and International Staging System stage (ISS). Status of transplantation (Tx), comorbidity (via Revised Myeloma Comorbidity Index R-MCI), CT data, treatment line/cycle and the year of CTx application were collected using electronic medical records, TBD and CTx management tools. Basic data on therapy composition was collected for the years 2005 to 2017, separating two treatment periods for 1st, 2nd and 3rd-line therapy of 2005-2012 and 2013-2017. This cut-off was carefully chosen to discriminate best between NA- and non-NA-based regimens, and between first generation PI- (bortezomib (BOR) and IMiD-use (thalidomide (THAL), lenalidomide (LEN)) and second generation NA.
Results: Pt characteristics were representative for tertiary centers with a median age of 63 years (27-89), 54% were 60-79 and 14% >80 years old. The male:female gender ratio was 58%:42% and ISS predominantly advanced (II/III:62%). Pts showed substantial comorbidities and were classified as fit, intermediate-fit and frail according to R-MCI in 33%, 56% and 11%, respectively. Of interest, 33% of pts could be enrolled in CTs and 88% received 1st line treatment at our center. 275 pts received 1st-line, 149 pts 2nd-line and 97 pts 3rd-line treatment (Fig.1). As expected, numbers of pts decreased with subsequent lines of treatment, albeit the median time to 2nd line therapy due to progression amounted to 2 years. As depicted in Fig.1, 1st line conventional CTx (cCTx) alone was rare and substantially declined over time from 12% 2005-2012 to 1% in 2013-2017. 200 pts (73%) were treated with BOR in 1st line, 63 of 106 reinduced pts received BOR in 2nd or 3rd line. IMiD 2nd and 3rd line treatment was also common within different regimens and the combination of 2 NA of both PI+IMiD increased over time (BOR+THAL, BOR+LEN). The use of second generation NA in 2nd and 3rd line treatment notably increased in 2013 to 2017 in line with their approval. Our analysis revealed that 44% of second generation NA protocols were administered outside CT settings, mainly due to tight inclusion and wide CT exclusion criteria. Maintenance was performed in 57% of pts, predominantly with LEN (60%) and within DSMM CT protocols.
Conclusion: Our analyses demonstrate that NA combinations are used predominantly today, whereas the use of cCTx alone is substantially declining. While BOR plays an important role in induction, LEN was subsequently used for maintenance and in outpatient-regimens. BOR-reinduction as a validated treatment option is also reflecting the substantial amount of BOR-based protocols worldwide. A significant percentage of second generation NA are administered outside CT settings, representing the fast and effective implementation of guideline recommendations into the real-world clinical practice at our and other MM centers. Currently, we are assessing the percentage of pts discussed in our weekly MM tumorboard, the evidence level of therapeutic interventions, PFS and OS. Results will be shown at the meeting, including the comparison of our data with others in a detailed review of the literature.
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Engelhardt:German Cancer Aid (#11424): Other: Educational Grant; Janssen Cilag GmbH: Other: Educational Grant; Celgene GmbH: Other: Educational Grant; Amgen GmbH: Other: Educational Grant.
Carfilzomib Engelhardt, Monika; Szymaniak-Vits, Magdalena; Ajayi, Stefanie ...
Recent results in cancer research,
2018, Volume:
212
Journal Article
Peer reviewed
Carfilzomib (CFZ) is a potent, second-generation proteasome inhibitor (PI), with significant activity as a single agent and in combination with other antimyeloma agents in patients with relapsed or ...refractory multiple myeloma (RRMM). CFZ binds selectively and irreversibly to its target and leads to antiproliferative and proapoptotic effects on cancer cells. This irreversible inhibition is dose- and time-dependent in vitro and in vivo. CFZ as monotherapy and in combination with other antimyeloma agents (e.g., as CFZ and dexamethasone Kd) achieved very good responses, progression-free survival (PFS) and overall survival (OS). In several ongoing studies, CFZ is being investigated in triplet and quadruplet schedules of CFZ, lenalidomide and dexamethasone (KRd), CFZ, cyclophosphamide, dexamethasone (KCd) and with antibodies, like elotuzumab or daratumumab. The multitude of completed and ongoing studies confirmed a tolerable safety profile of CFZ, a significantly lower incidence of neuropathy compared to bortezomib (BTZ) and a slightly higher incidence of cardiotoxicity, which is closely observed and precautions taken to avoid them as best as possible. In July 2012, the US Food and Drug Administration (FDA) approved CFZ as a single agent for RRMM patients with disease progression after two prior therapies, including BTZ and immunomodulatory drugs (IMiDs). The combination of KRd and Kd followed, being approved by both FDA and European Medicines Agency (EMA) in 2015 and 2016, respectively. Moreover, CFZ is being evaluated in patients with newly diagnosed MM (NDMM), in high-risk smoldering MM and for maintenance approaches.
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