Impact of Long-Term Tyrosine Kinase Inhibitor Exposure on Spermatogenesis in Juvenile Rats

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1884-1884 ◽  
Author(s):  
Vera Girke ◽  
Josephine Tabea Tauer ◽  
Ingmar Glauche ◽  
Lorenz Hofbauer ◽  
Meinolf Suttorp
Keyword(s):  
Research Funding ◽  
Wistar Rats ◽  
Pediatric Patients ◽  
High Dose ◽  
Testis Weight ◽  
Ki 67 ◽  
Juvenile Rats ◽  
Alpha Beta ◽  
Dose Dependent

Abstract Background: Pediatric patients with chronic myeloid leukemia (CML) are exposed to off-target side effects from long-term treatment with tyrosine kinase inhibitors (TKIs) which have been observed with increasing watchfulness in the last years (Hijiya N, et al. BLOOD 127:392, 2016). TKIs inhibit c-kit and platelet-derived growth factor receptors (PDGF-R alpha/beta) which are known to regulate spermatogenesis (Zhang M, et al. SCI REP 4:5936, 2014). The influence of TKIs on spermatogenesis in pediatric patients with CML is not fully understood yet (Samis J, et al. PEDIATR BLOOD CANCER 63:1332, 2016). Therefore, we studied testicular tissue in juvenile rats following exposure to TKIs imatinib (IMA) and dasatinib (DASA) in a time and dose-dependent manner. Methods: Using an established model (Tauer JT, et al. PLOS ONE 10:e0131192, 2015) of juvenile still growing Wistar rats, animals (age: 4 weeks [w]) were exposed to IMA or DASA at different dosages for 10 w (low dose [LD], high dose [HD], intermittently high dose [ID]; total number of rats: 20 to 32 animals, 5 - 8 rats per cohort). At defined developmental stages, that is at prepubertal age (6 w), pubertal age (8 w), and postpubertal age (14 w), testis weight as well as cellularity (spermatogonia, spermatocytes, spermatids, Ki-67 positive cells) were evaluated histopathologically in seminiferous tubule microscopic cross sections after continuous IMA treatment. Expression of genes involved in spermatogenesis comprising SCF and PDGF-alpha/beta as well as their corresponding receptors c-kit and PDGFR-alpha/beta (Nurmio M, et al. REPRODUC TOXICOL 25:442, 2008) was studied after continuous DASA exposure. Results: Testis weight remained unchanged compared to non-exposed controls by exposure to any TKI. However, spermatogenic cell counts decreased significantly by 10% after IMA HD-exposure. In spermatogenesis cell cycle, the stage of the dominant cell proportion (stage VII according to Perey B, et al. AM J ANAT 108:47, 1961) was shifted to more immature stages (stage II/III) as well. LD- and ID-exposure with IMA attenuated these findings. Cell proliferation as investigated by Ki-67+ expression was significantly lowered by 10% - 20% at all applied IMA doses. Long-term DASA treatment at LD, HD and ID resulted in significantly reduced gene expression of SCF, c-kit and PDGF-R alpha/beta. Gene expression of PDGF-alpha was significantly decreased in HD and ID but not LD, whereas PDGF-beta showed no significant reduction postpubertally. Conclusion: Long-term TKI toxicity in still growing organisms can easily be modelled in juvenile rats and emulates well the so-far clinical experience with regard to osseous side effects of TKIs (Millot F, et al. EUR J CANCER, 50:3206, 2014). Assessment of gonadal toxicity by isolated determination of testis weight represents a rather unspecific approach and will neglect subtle histopathological changes. With regard to spermatogenesis long-term TKI exposure resulted in reduced progenitor cell proliferation and downregulation of involved genes in a cumulative dose-dependent fashion. Thus, at least in juvenile, still growing Wistar rats a long-lasting negative effect of long-term TKI exposure on spermatogenesis has to be taken into account. Improved preclinical testing in well-established leukemia models should help to prioritize TKI agents in the clinical studies pipeline for pediatric patients with CML. Long-term follow-up of pediatric and adolescent patients who are given new targeted agents is mandatory and will prospectively explore potential late effects, and hopefully also provide corrective or preventive measures. Disclosures Glauche: Bristol Meyer Squib: Research Funding. Suttorp:Novartis, Bristol Meyer Squib, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Long-Term Follow up of Pediatric Patients with Hodgkin Lymphoma Treated with High Dose Therapy and Autologous Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2000-2000
Author(s):  
Lisa Giulino Roth ◽  
Tara O'Donohue MD ◽  
Tanya Trippett ◽  
Elizabeth Klein ◽  
Nancy A. Kernan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Disease Free Survival ◽  
Cancer Center ◽  
High Dose ◽  
Advisory Committees ◽  
Relapsed Disease

Abstract Introduction: Despite improved outcomes for children with Hodgkin lymphoma (HL), relapsed and refractory disease remain a challenge for a subset of patients. High dose therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for relapsed disease, largely based on data from studies in adults. As new therapies emerge for HL, risk stratification of pediatric patients with relapsed disease will be essential to determine which patients are likely to benefit from ASCT and which patients should be selected for alternative therapy. In this study we report the long-term outcome of 34 pediatric patients with HL who underwent ASCT at a single institution. Methods: We conducted a retrospective analysis of 34 consecutive pediatric patients with HL who underwent ASCT at Memorial Sloan Kettering Cancer Center from 1989-2013. Data collected included age, histology, treatment prior to ASCT, disease status at the time of transplant, conditioning regimen, and outcome after ASCT. Given recent data supporting a Childhood Hodgkin International Prognostic Score (CHIPS) for risk stratification in first-line therapy(Schwartz et al, ASH Abstract #3649, 2011), this score was calculated at the time of relapse to evaluate its prognostic relevance in the relapse setting. One point was awarded for each of the following: stage IV disease, bulky mediastinal adenopathy, albumin <3.5, and fever. Kaplan-Meier survival analysis was used to estimate the probability of overall survival (OS) and disease-free survival (DFS). Patient Characteristics: Pathologic classification included nodular sclerosis (n=30), mixed cellularity (n=1), lymphocyte predominant (n=2), or subtype unspecified (n=1). The median age was 17.9 yrs (range 9.7-21) and 47% of patients were male. Thirty-three patients had relapsed disease; one patient had primary refractory disease. The median time from diagnosis to first relapse was 13 months (range 5-60). Twenty-five patients (73.5%) had chemotherapy responsive disease at the time of transplant (CR or PR). Others had stable disease (n=6), mixed response (n=2) or progressive disease (n=1). Thirty-one of 34 patients received radiation therapy either during initial treatment or as part of a salvage regimen. Four patients received brentuximab vedotin at the time of relapse. ASCT preparative regimen consisted of cyclophosphamide-etoposide + total lymphoid irradiation (n=14) or + carmustine (n=16), while 4 patients received the BEAM regimen. All but two patients treated after 1997 received chemotherapy-only preparative regimens. Results: The median follow up for the cohort was 70.5 months (range 2.5-144). The 12-year OS and DFS were 65.1% and 63.6% respectively. The cause of death included HL (n=7), sepsis (n=1) and end stage renal disease (n=1). Patient age, stage at diagnosis, and time from diagnosis to relapse were not associated with differences in DFS. Patients who received an ASCT after 1997 had a better outcome than those who received an ASCT before 1997 (DFS 44.9% vs. 81.8%, p=0.012). Patients with chemotherapy sensitive disease at the time of transplant had a superior DFS (74.5% vs. 33.3%, p=0.005). Although not statistically significant, there was a trend toward improved outcome among patients with early stage disease at relapse (stage I/II) compared to advanced stage (III/IV) (DFS 81.3% vs. 54.2%, p=0.098). Among 21 patients with data available to calculate CHIPS at time of relapse, there was a superior OS among those with a lower CHIPS with OS of 100%, 70%, 50%, and 0% for patients with a CHIPS of 0, 1, 2, and 3 respectively (p=0.021). There were no patients with a CHIPS of 4. There was a trend toward improved DFS among patients with a low CHIPS, however this was not statistically significant (DFS of 100%, 70%, 66.7%, and 0% in patients with a CHIPS of 0, 1, 2, and 3 respectively, p=0.176). Conclusions: ASCT offers the prospect of durable, disease free survival for a significant proportion of pediatric patients with relapsed HL. The outcome among patients who received an ASCT in recent years (1997-2013) was high (DFS 81.8%). Chemotherapy sensitive disease at the time of transplant was associated with superior DFS. To our knowledge this is the first report evaluating the potential utility of CHIPS in the relapse setting. Despite the small sample size (n=21) CHIPS was predictive of OS, suggesting that this measure should be studied further as a potential prognostic marker in relapsed HL. Disclosures Trippett: Seattle Genetics, Inc.: Research Funding; OSI Pharmaceuticals: Research Funding. Kernan:Gentium S.p.A.: Research Funding. Prockop:Atara Biotherapeutics: Other: I have no financial disclosures, but Atara Biotherapeutics has exercised a licensing agreement with Memorial Sloan Kettering Cancer Center and MSKCC and some investigators at MSKCC have a financial interest in Atara.. Scaradavou:National Cord Blood Program- New York Blood Center: Employment. Moskowitz:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding.

Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

1987 ◽  
Vol 17 (4) ◽  
pp. 869-873 ◽  
Author(s):  
C. Schmauss ◽  
J.-C. Krieg
Keyword(s):  
Low Dose ◽  
Matched Control ◽  
Control Group ◽  
High Dose ◽  
Withdrawal Therapy ◽  
The Mean ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

scholarly journals Therapy-Related Myeloid Neoplasm Has a Distinct Pro-Inflammatory Bone Marrow Microenvironment and Delayed DNA Damage Repair

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Monika M Kutyna ◽  
Li Yan A Wee ◽  
Sharon Paton ◽  
Dimitrios Cakouros ◽  
Agnieszka Arthur ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Cytotoxic Therapy ◽  
Advisory Committees ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
Damage Repair

Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

scholarly journals Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

scholarly journals Lacosamide-Induced Dyskinesia in Children With Intractable Epilepsy

2020 ◽  
Vol 35 (10) ◽  
pp. 662-666
Author(s):  
Nadine Madani ◽  
Jennifer A. O’Malley ◽  
Brenda E. Porter ◽  
Fiona M. Baumer
Keyword(s):  
Upper Extremity ◽  
Pediatric Patients ◽  
Focal Epilepsy ◽  
Intractable Epilepsy ◽  
High Dose ◽  
Drug Induced ◽  
Potential Side Effect ◽  
Increased Risk ◽  
The Face ◽  
Dose Dependent

Lacosamide, an antiepileptic drug prescribed for children with refractory focal epilepsy, is generally well tolerated, with dose-dependent adverse effects. We describe 4 children who developed a movement disorder in conjunction with the initiation and/or uptitration of lacosamide. Three patients developed dyskinesias involving the face or upper extremity whereas the fourth had substantial worsening of chronic facial tics. The patients all had histories suggestive of opercular dysfunction: 3 had seizure semiologies including hypersalivation, facial and upper extremity clonus while the fourth underwent resection of polymicrogyria involving the opercula. Onset, severity, and resolution of dyskinesias correlated with lacosamide dosing. These cases suggest that pediatric patients with dysfunction of the opercular cortex are at increased risk for developing drug-induced dyskinesias on high-dose lacosamide therapy. Practitioners should be aware of this potential side effect and consider weaning lacosamide or video electroencephalography (EEG) for differential diagnosis, particularly in pediatric patients with underlying opercular dysfunction.

Deferasirox Treatment for up to 3 Years in Iron-Overloaded Pediatric Patients Reduces Serum Ferritin with a Manageable Safety Profile

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1028-1028 ◽  
Author(s):  
Amal El-Beshlawy ◽  
Mohsen Elalfy ◽  
Lee Lee Chan ◽  
Yongrong Lai ◽  
Kai-Hsin Lin ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Growth Velocity ◽  
Research Funding ◽  
Pediatric Patients ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Positive Growth ◽  
History Of ◽  
Extension Period

Abstract Abstract 1028 Background: To prevent complications associated with iron overload in patients with transfusion-dependent anemias, iron chelation therapy is required throughout life starting from early childhood. Long-term studies of iron chelation therapy are therefore required, particularly in pediatric patients. The 1-year open-label, single-arm, multicenter EPIC (Evaluation of Patients' Iron Chelation with Exjade®) trial evaluating the efficacy and safety of deferasirox in patients with transfusion-dependent iron overload enrolled 577 pediatric patients across 23 countries. In an extension period of up to 18 months, or until deferasirox was available locally, patients completing the core study could continue to receive deferasirox, thus providing long-term efficacy and safety data of deferasirox in iron-overloaded pediatric patients. Methods: At enrolment, transfusion-dependent pediatric patients (defined as ≥2–<16 years at enrollment) had serum ferritin ≥1000 ng/mL OR <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg red blood cells transfused) and liver iron concentration >2 mg Fe/g dw confirmed by R2 magnetic resonance imaging. Deferasirox starting dose was 10–30 mg/kg/day depending on frequency of blood transfusions, with protocol-specified adjustments of 5–10 mg/kg/day (range 0–40 mg/kg/day) based on 3-monthly serum ferritin trends and safety. Biochemistry analysis including serum ferritin was performed on a monthly basis, and growth was monitored every 12 weeks, with continuous assessment of safety parameters. Creatinine clearance was calculated using the Schwarz formula for pediatric patients. Changes from the start of deferasirox treatment (core baseline) are presented. Results: 267 pediatric patients aged 2–<6 (n=68), 6–<12 (n=114) and 12–<16 (n=85) years entered the extension period (n=141 [52.8%] male; n=248 [92.9%] with underlying thalassemia; n=33 [12.4%] with a history of hepatitis B and/or C). Median duration of deferasirox exposure was 101.3 weeks (range 55.6–159.9) with mean ± SD deferasirox dose 25.7 ± 5.8 mg/kg/day (13.4–40.0). Median serum ferritin decreased from a baseline of 3222 ng/mL (951–16,944) to 2431 ng/mL (238–29,681) at the end of the extension (absolute change from baseline –528 ng/mL [–6354 to 25,127]; P<0.0001; last observation carried forward). Overall, 257/267 (96.3%) patients completed the extension; main reasons (more than two patients) for discontinuation were unsatisfactory therapeutic effect (n=4, 1.5%) and consent withdrawal (n=3; 1.1%). The most common (>5%) investigator-assessed drug-related AEs were increased alanine aminotransferase (ALT; n=47, 17.6%), increased aspartate aminotransferase (AST; n=44, 16.5%), increased blood creatinine (n=24, 9.0%) and rash (n=23, 8.6%). ALT and AST increases were mostly mild in severity, transient, non-progressive and managed with dose adjustments. There were no reported drug-related serious AEs and no deaths occurred. 45/267 (16.9%) patients had two consecutive ALT values >5 × upper limit of normal (ULN). Of these 45 patients, 40 had high ALT levels at baseline and 30 had ALT or AST >2.5 × ULN at baseline; 13/45 had a history of hepatitis B and/or C. 6/267 (2.2%) patients had two consecutive serum creatinine values >33% above baseline and >ULN; all had normal values at baseline. The relative change in creatinine clearance from baseline to end of the extension was between –10 and –20% for the majority of patients (n=52, 19.5%), although changes in both directions were variable. Stature, growth and weight assessments indicated positive growth velocity. For all patients combined, mean ± SD growth velocity at end of extension was 5.9 ± 43.3 cm/year (median 2.6 cm/year). Conclusions: Deferasirox therapy for up to 3 years in pediatric patients significantly decreased serum ferritin, similar to previous reports. The majority of patients with elevated liver enzymes during the study also had elevated levels at baseline; renal safety was consistent with previous reports. While patient age and gender will influence individual growth rates, positive growth velocity was nonetheless maintained during treatment. Disclosures: Lin: Novartis: Honoraria. Aydinok:Novartis: Honoraria, Research Funding, Speakers Bureau; Ferrokin: Research Funding. Galanello:Novartis: Research Funding, Speakers Bureau; Apopharma: Research Funding, Speakers Bureau; Ferrokin: Research Funding. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

Updated Efficacy and Safety, and Exploratory Ki-67 Results For The MCL-001 Study Of Lenalidomide In Mantle Cell Lymphoma Patients Who Relapsed Or Were Refractory To Bortezomib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3057-3057 ◽  
Author(s):  
Andre Goy ◽  
Michael E. Williams ◽  
Sevgi Kalayoglu Besisik ◽  
Johannes Drach ◽  
Radhakrishnan Ramchandren ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
High Dose ◽  
Efficacy And Safety ◽  
High Dose Therapy ◽  
Ki 67 ◽  
Mantle Cell ◽  
Heavily Pretreated

Abstract Introduction Patients with mantle cell lymphoma (MCL) typically respond to initial therapy and almost inevitably relapse with frequent chemoresistance over time and poor outcome. Multiple phase II studies have established the efficacy and safety of lenalidomide, an immunomodulatory agent with tumoricidal and antiproliferative properties, in relapsed/refractory MCL. The prospective phase II multicenter MCL-001 “EMERGE” study led to FDA approval of lenalidomide for patients with relapsed/refractory MCL after 2 prior treatments, that included bortezomib. The activity of lenalidomide was seen regardless of MIPI, number of prior therapies, prior high dose therapy, bulky disease or high tumor burden. One of the most established prognostic factors in MCL is the proliferation index Ki67 (MIB1), now confirmed both in standard and dose-intensive high-dose therapy strategies. We present here longer follow-up of efficacy and safety from the MCL-001 study in patients relapsed/refractory to bortezomib and the potential relationship between Ki-67 and efficacy outcomes. Methods Patients with heavily pretreated MCL, that included prior bortezomib, received lenalidomide 25 mg/day PO, days 1-21 in 28-day cycles until disease progression or intolerability. Primary study endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Response rates and time-to-event data were analyzed by independent central reviewers per modified IWG criteria and Kaplan-Meier estimates respectively (data cut-off March 20, 2013). Ki-67 was examined as an exploratory endpoint by immunohistochemistry for 81/134 patients (60%) either performed on biopsy samples for 24 patients, or based on the Ki-67 scores reported in local pathology reports for 57 patients. Results Median age for the enrolled intent-to-treat patient population (N=134) was 67 years (range, 43-83; 63% ≥65 years). The median number of previous therapies was 4 (range, 2-10; 78% received ≥3), 93% stage III/IV, and 72% were <6 months from last prior treatment. At a median follow-up of 13.2 months, the ORR was 28% (CR/CRu 8%), with a median DOR of 16.6 months (95% CI, 9.2-26.7; median not reached in patients with CR/CRu) by central review. Median TTR was 2.3 months (95% CI, 1.7-13.1), with a median time to CR/CRu of 4.1 months (95% CI, 1.9-13.2). Median PFS was 4.0 months (95% CI, 3.6-6.9), and median OS was 20.9 months (95% CI, 13.7-24.4). The average dose intensity of lenalidomide was 20 mg/day, for a median duration of 94.5 days (range, 1-1,256). Dose reductions or interruptions due to adverse events (AEs) occurred in 40% and 58% of patients, respectively. Neutropenia (44%), thrombocytopenia (28%), and anemia (11%) were the most common treatment-related grade 3/4 AEs. Ki-67 results were available in 81/134 patients, and efficacy data were categorized using 30% and 50% cut-off thresholds for Ki-67 expression (Table 1). Although patient numbers were limited, the ORR was similar in both lower and higher Ki-67 group, but those with lower Ki-67 levels demonstrated better CR rates, DOR and survival outcomes compared with patients with elevated Ki-67. Conclusions Single-agent lenalidomide in heavily pretreated patients with relapsed/refractory MCL post-bortezomib showed durable long-term efficacy with a consistent safety profile. Consistent with what is reported in the literature, high Ki-67 is associated with poor outcome in our cohort with shorter OS. Though based on retrospective evaluation and subsets of patients, the ORR to lenalidomide was similar in both low and high Ki-67 groups, suggesting lenalidomide can be active in patients expressing high levels of Ki67. Prospective studies are needed to confirm these findings. Disclosures: Goy: Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Williams:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Drach:Celgene: Honoraria. Ramchandren:Celgene: Research Funding. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Heise:Celgene: Employment, Equity Ownership. Witzig:Celgene: Research Funding.

Cardiac Failure In Juvenile Rats Caused By Continuous Long-Term Exposure To The Tyrosine Kinase Inhibitor Dasatinib Can Be Circumvented By An Intermittent Application Schedule

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3984-3984 ◽  
Author(s):  
Paula Geidel ◽  
Josephine Tabea Tauer ◽  
Nadine Steinbronn ◽  
Roland Jung ◽  
Ivo Leuschner ◽  
...  
Keyword(s):  
Mast Cell ◽  
Body Weight ◽  
Tyrosine Kinase ◽  
Cardiac Failure ◽  
Drug Exposure ◽  
Standard Dose ◽  
High Dose ◽  
Dose Cohort ◽  
Juvenile Rats

Abstract Background Treatment of chronic myeloid leukemia (CML) by tyrosine kinase inhibitors (TKIs, e.g. imatinib, dasatinib) can result in cardiac failure as these drugs exert off-target effects via so far ill-defined mechanisms. Especially in pediatric patients long-term drug exposure is of great concern as this cohort may require life-long treatment for CML. Dasatinib-induced side effects require treatment interruption or dose modification in particular due to hematologic toxicity or cardiac and pleural effusions. Here we investigated the impact of prolonged dasatinib exposure on the growing heart in juvenile rodents. In analogy to clinical data on older adults (La Rosee P, et al, Ann Hematol 2013; in press) we also questioned whether intermittent treatment would result in regression of dasatinib-dependent off-target cardiac toxicity. Methods Male 4-week old Wistar rats were exposed via the drinking water to dasatinib at a standard-dose (cohort S: 50 µM), at a high-dose (cohort H: 100 µM), and also at the high dose intermittently (cohort I; Mon.-Wed. “on”; Thu.-Sun. “off”), respectively, over 10 weeks continuously. Each cohort comprised 10 animals; controls (cohort K) received water only. Thus, the animals were challenged with drug exposure from shortly after weaning (3 weeks old) over puberty (6-8 weeks old) until young adolescence (14 weeks old). Animals' behaviour, development, and body weight gain was monitored three times weekly. Using a dedicated small animal device echocardiography to determine left ventricular ejection fraction (EF) as well as analysis of blood serums markers indicating cardiac impairment (BNP, IL-6, TNF-alpha, Troponin I) by Luminex assay (Millipore, USA) were performed every two weeks. Necropsy was performed in all rats after spontaneous death while all survivors were sacrificed after 10 weeks of exposure, respectively. Total heart weights and microscopic histopathological changes were examined. Results Dose-dependently animals died spontaneously: 8/10 animals from cohort H (high dose continuously), 6/10 animals from cohort S (standard-dose), and 1/10 animals from cohort I (high dose intermittently) , respectively. Two 2/10 controls died from infections. For ethical reason the experiment was terminated in cohort H after 5 weeks of drug exposure. Details on survival time for each cohort are shown in the Kaplan-Meier-Plots below. In concordance with survival data animals also exhibited dose-dependently impaired EF and elevated serum BNP. At necropsy median relative heart weights (% of total body weight) were found increased when compared to controls (0.35 %) for cohort H (0.45 %, p= 0.026), but not significantly higher for cohort S (0.38 %) and cohort I (0.39%), respectively. Findings of heart structural changes comprised a non-significant trend to an increased mast cell (MC) number (median MC counts per visual microscopic field: cohort K= 15 MC; cohort H= 23.5 MC; cohort S= 22.5 MC; cohort I= 17.5 MC). Conclusion Continuous long-term exposure to dasatinib at a high dosage is life-threatening to juvenile rats. However, intermittent exposure (treatment and interruption intervals of comparable lengths) will avoid cardiac failure. MCs have been identified to play an important role for cardiac adverse remodelling and increased numbers of MCs have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and secondary chronic volume overload (Levick SP, et al, 2011; Cardiovas Res 89:12). Treatment with imatinib has been shown to result in vivo and in vitro in severe bone marrow mast cell depletion via c-kit induced blockade of MC differentiation (Cerny-Reiterer S, et al, 2013; Hematology, EHA abstract P 699). However, it is still unknown whether this also holds true for dasatinib. We conclude that it might be prudent to carefully monitor cardiac function in still growing individuals with CML if treated with dasatinib continuously over long periods. JT Tauer and N Steinbronn contributed equally to the work. Disclosures: No relevant conflicts of interest to declare.

Long Term Efficacy and Safety Results and Analysis of Dose Correlations from the Phase I/II Peginvera Study of Ropeginterferon Alfa-2b, a Novel IFNa-2b, in Polycythemia Vera Patient

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4056-4056
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Schlögl ◽  
Gunther Gastl ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Group ◽  
Low Dose ◽  
Term Treatment ◽  
High Dose ◽  
Individual Response ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Long Term Treatment

Abstract Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naïve and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct)<45%, platelet count≤400*109/L, WBC count≤10*109/L, normal spleen size by sonography, and absence of thromboembolic events. Partial response (PR) is defined as Hct<45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with < 50% mutant allele burden, or a reduction ≥ 25% in patients with > 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of <300 µg ("low dose", n=36), CR as best individual response was achieved in 20 (56%) patients, and PR in 14 (39%) compared to the CR and PR in the high dose (>300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of >80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

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