scholarly journals Results from a Phase IIa Study of the Anti-CXCL12 Spiegelmer Olaptesed Pegol (NOX-A12) in Combination with Bendamustine/Rituximab in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1996-1996 ◽  
Author(s):  
Michael Steurer ◽  
Marco Montillo ◽  
Lydia Scarfò ◽  
Francesca Romana Mauro ◽  
Johannes Andel ◽  
...  
Keyword(s):  
Single Dose ◽  
High Risk ◽  
Partial Response ◽  
Peripheral Blood ◽  
Overall Response Rate ◽  
Response Rate ◽  
Tp53 Gene ◽  
Overall Response ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background Olaptesed pegol (NOX-A12) is a novel, potent, L-stereoisomer RNA aptamer that binds and neutralizes CXCL12/SDF-1, a chemokine which attracts and activates immune- and non-immune cells via interaction with the receptors CXCR4 and CXCR7. Signaling of CXCL12 is pivotal to the interactions of leukemic cells with bone marrow microenvironment. The therapeutic concept of olaptesed is to inhibit such tumor-supporting pathways and thereby mobilizing and sensitizing CLL cells to therapy. Here we aim to assess the activity and safety of olaptesed in combination with bendamustine and rituximab (BR) in patients with relapsed / refractory CLL. Methods Twenty-eight relapsed or refractory CLL patients were enrolled and treated in this open-label, single-arm Phase IIa study. To investigate PK/PD, a pilot dose of 1 to 4 mg/kg olaptesed alone was administered to 3 patients per dose group (plus one additional replacement pt) before start of the regular treatment regimen (pilot group). Patients were treated using a dose titration design with intravenous (IV) olaptesed at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg at cycles 1, 2 and 3, respectively, at 1 hour before rituximab treatment. During cycles 4 to 6, olaptesed was dosed at the highest individually titrated dose. Rituximab was administered IV at doses of 375 mg/m² on day 1 of the 1st28-day cycle and 500 mg/m² on day 1 of subsequent cycles. Bendamustine (70 - 100 mg/m²) was given IV on days 2-3 (cycle 1) or days 1-2 (cycles 2-6) of each 28-day cycle following administration of rituximab. Clinical response was assessed according to NCI-WG Guidelines (Hallek M et al. Blood 111; 2008: 5446-56). Results To date, 24 patients completed treatment (12 women, 12 men) with a median age of 68.5 years (range 52 to 79). At screening 5, 9 and 10 patients presented with Binet stage A, B and C, respectively. The median number of prior treatment lines was 1 (range 1-2). Seven high-risk patients presented an unfavorable disease state being relapsed within 24 months after fludarabine/bendamustine treatment (5 pts) and/or presenting a deletion/mutation of the TP53 gene (3 pts). Most patients (19 of 24) were previously treated with fludarabine or bendamustine. A flow cytometric analysis of CD19+/CD5+CLL cells showed a rapid mobilization into the peripheral blood by a single dose of olaptesed which lasted throughout the observational time of 72h. Interestingly, CXCR4 expression levels increased on CLL cell surface in the periphery after olaptesed treatment. This increase, which peaked at 24h, likely reflects the extended circulation of CLL cells in the periphery due to the sustained blockade of CXCL12 by olaptesed. Reduction of lymphadenopathy by ≥ 50% was achieved in 14 out of 21 evaluable patients with reported enlarged lymph nodes by the end of treatment. Concomitantly, rapid reduction of lymphocytosis in peripheral blood with normalization by treatment cycle 2 – 3 was observed and the CLL to leukocyte ratio significantly improved. Efficacy was assessed at the end of cycles 3 and 6. In the full-analysis-set, which excludes two non-evaluable patients (drop-out after the 1st cycle due to adverse events), the overall response rate was 96%: Three patients (14%) achieved a complete response at end of cycle 6 (2 confirmed, 1 investigator reported) and eighteen patients (82%) achieved a partial response (fifteen at end of cycle 6 and three at end of cycle 3). Notably, all seven high-risk patients (defined as relapsed within 24 months after fludarabine/bendamustine treatment and/or presenting a deletion/mutation of the TP53 gene) responded to treatment with olaptesed + BR with a partial response. One patient had a progressive disease. Olaptesed at 1, 2 and 4 mg/kg at a single dose and in combination with BR was safe and well tolerated. The observed adverse reactions were qualitatively and quantitatively as expected for patients treated with BR. Conclusion Olaptesed in combination with BR was safe and well tolerated. Compared with historical data, olaptesed showed superiority over baseline therapy with regards to overall response rate and increasing rates of complete remission, warranting further development of this Spiegelmer in CLL. Disclosures Montillo: Janssen: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment.

Analysis of Peripheral Blood Lymphocytes of AIDS and High-Risk Patients for Human Cytomegalovirus Transforming DNA Sequences

Intervirology ◽  
1991 ◽  
Vol 32 (1) ◽  
pp. 10-18 ◽  
Author(s):  
Abdur Razzaque ◽  
Stephen M. Peters ◽  
Edward P. Gelmann ◽  
Michael J. Sheridan ◽  
Leonard J Rosenthal
Keyword(s):  
High Risk ◽  
Human Cytomegalovirus ◽  
Dna Sequences ◽  
Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
Blood Lymphocytes ◽  
High Risk Patients ◽  
Risk Patients

Real-World Clinical Outcomes By Cytogenetic Risk Category in Relapsed or Refractory Multiple Myeloma: Evidence from a Cohort Review in France

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4784-4784
Author(s):  
Huamao Mark Lin ◽  
Keith L Davis ◽  
James A. Kaye ◽  
Katarina Luptakova ◽  
Lu Gao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Research Funding ◽  
Complete Response ◽  
Line Treatment ◽  
Second Line ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk

Abstract INTRODUCTION: Multiple Myeloma (MM) is an incurable hematologic cancer characterized by multiple recurrences. With each recurrence, patients have a lower probability of response and duration of response is shorter. Therefore, there is an unmet need to improve outcomes in relapsed/refractory multiple myeloma (RRMM). There is a shortage of data describing clinical features and outcomes in these patients in real-world practice, particularly with regard to differences in outcomes by baseline cytogenetic risk. To help address this information gap, this study analyzed data from a cohort of RRMM patients in France. METHODS: A retrospective observational review of medical records was conducted in a cohort of 200 patients with RRMM in France. Patients were selected (based on randomly generated first letter of last name) from the caseloads of 40 hematology/oncology providers across France practicing mainly in academic hospitals. Inclusion criteria were: ≥18 years of age at initial MM diagnosis; first determined to have RRMM between January 1, 2009 and December 31, 2011, where RRMM was defined by (1) first-line (induction) regimen of chemotherapy with or without stem cell transplant (SCT) and with or without other post-induction/SCT therapy and (2) disease progression while on or at any time after completion of first-line therapy. Patients could be alive or deceased at the time of record abstraction. Baseline cytogenetic risk was defined as follows: high-risk: cytogenetic abnormalities del(17p), t(4:14), or t(14;16); unknown/unassessed risk: patients for whom cytogenetics were unavailable; or standard-risk: all patients with known cytogenetics not classified as high-risk. Patients were assessed for treatment response, overall survival (OS) and progression-free survival (PFS) from date of first relapse (study index date). All analyses were descriptive. Survival was assessed using the Kaplan-Meier (K-M) method. RESULTS: Demographic and clinical characteristics of the study sample are presented in Table 1. A total of 55 high-risk and 113 standard-risk patients were identified; risk category was unknown or unassessed for 32 patients. Among all patients, mean (SD) age at RRMM diagnosis was 66.3 (8.9) years and 62% of the sample was male. Lenalidomide + dexamethasone was the most common second-line systemic regimen initiated (50% of high-risk patients, 59.5% of standard-risk patients receiving second-line treatment). A total of 114 patients (57%) initiated a third-line treatment. Despite clinical response in second-line treatment occurring sooner in high-risk patients (median: 106 days) than in standard-risk patients (median: 237 days), physician-assessed overall response rate (ORR) was lower in high-risk patients (63%: 17% complete response, 46% partial response) than standard-risk patients (91%: 26% complete response, 65% partial response) across all second-line treatments combined (Table 2).. For third-line treatment, ORR was lower in high-risk patients (54%: 12% complete response, 42% partial response) than standard-risk patients (74%: 9% complete response, 65% partial response). Among patients who initiated a second-line treatment (n = 192), 47.4% were deceased at the time of data collection. From second-line initiation, K-M estimates of 1- to 5-year OS and PFS were substantially lower for high-risk patients versus standard-risk. Specifically, the proportions of patients still alive 1, 3, and 5 years after second-line treatment initiation were 73%, 51%, and 36%, respectively, for high-risk patients and 94%, 73%, and 61% for standard-risk patients. The proportions of patients without disease progression at 1, 3, and 5 years after second-line initiation were 48%, 13.5%, and 5% for high-risk patients and 82%, 42%, and 14% for standard-risk patients. CONCLUSIONS: The importance of cytogenetic risk classification as a prognostic factor in RRMM was apparent in this retrospective review, in which patients with high-risk cytogenetics had less favorable outcomes in terms of ORR, OS, and PFS than standard-risk patients. Decreased response rate and lower PFS and OS was documented among patients with high-risk cytogenetics, which is in contrast to shorter time needed to achieve best clinical response in this subgroup. Results from this real-world study provide further confirmation of the unmet medical need presented by RRMM, especially for patients with high-risk cytogenetics. Disclosures Lin: Takeda: Employment. Davis:Takeda: Research Funding. Kaye:Takeda: Research Funding. Luptakova:Takeda Oncology: Employment. Gao:Takeda: Employment. Nagar:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

scholarly journals FINAL Results of an Phase, Multicenter, Randomied, Controlled OPEN LEVEL Trial: Decitabine Therapy in Patients with Myelodysplastic Syndromes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3865-3865
Author(s):  
Zonghong Shao ◽  
Hui Liu ◽  
Hao Jiang ◽  
Hongyan Tong ◽  
Ruixiang Xiang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Overall Response Rate ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Study Drug ◽  
Overall Response ◽  
To Receive

Abstract Background: DNA hypomethylating agent, decitabine, has become the current standard therapy for patients with higher-risk myelodysplastic syndromes (MDS). Decitabine was launched in China in August 2009 without clinical trials. According to some retrospective studies, the efficacy and safety are similar to those reported in other countries, but there is still a lack of large-scale prospective clinical trials. So we start a prospective clinical trial in China to compare the effect and safety of decitabine in MDS, which was registered at clinicaltrials.gov (NCT02013102). Design: Adults with intermediate or high risk MDS by the International Prognostic Scoring System (IPSS≥0.5) were randomized to receive either decitabine 20 mg/m2 IV daily for 5 days (arm Ⅰ) or decitabine 12 mg/m2 IV daily for 8 days (arm Ⅱ) every four weeks. Patients continued to receive study drug for 4 cycles until death, disease progression, intercurrent illness preventing further administration of treatment, unacceptable adverse event or decision by the patient to withdraw from the study. And supportive care were permitted. The primary end point was overall response rate (ORR, CR+mCR+PR) by International Working Group (IWG 2006) criteria, secondary end points included CR, mCR, PR, HI, safety, et al. Results: We enrolled a total of 198 patients between 8/2013 and 12/2017, among which 7 patients didn't take decitabine, and 191 were included in the analysis. 94 in arm Ⅰ recieved decitabine and 97 in arm Ⅱ. 32.8% of patients withdrew from the study for a variety of reasons, including progression and death (5.1%), personal decision (13.6%), adverse events (6.6%), and other causes (7.6%). The median age of patients in arm Ⅰ was 54.88 years old and 54.82 years old in arm II. The median follow-up was 106 days for patients in both arms. The patients received a mean 2.5 cycles of decitabine therapy for arm Ⅰ and 2.0 cycles for arm Ⅱ. The overall response rate was 39.3% in total, and 41.5% and 38.1% (p=0.6598) for patients in arm Ⅰ and arm Ⅱ, respectively. And CR was 18.1% and 14.4% (p= 0.5584) , PR was 6.4% and 3.1% (p=0.3257) , mCR was 17.0% and 20.6% (p=0.5814) , HI was 3.2% and 1.0% (p=0.3633) , for patients in armⅠand armⅡ, respectively (Table 1). Among all patients, 38.7% were intermediate-1 risk, 40.3% were intermediate-2 risk, 20.4% were high risk. Analysis of response by MDS patient subtypes is shown in Table 2. Those who were higher risk experienced higher ORR and CR, while the difference is not significant between two arms (p>0.05). As expected, cytopenias were the most frequent complications (76.4%). Grade 3-4 neutropenia, thrombocytopenia and anemia considered to be at least possibly related to the study drug occurred at rates of 23.0%, 34.6%, and 34.6% of patients, respectively. Nonhematologic adverse events were also common including abnormal metabolism and nutrition (23.40% vs 18.56%), abnormal gastrointestinal function (29.79% vs 41.24%), cardiac disorders (11.70% vs 14.43%), infection and infectious diseases (32.98% vs 36.08%), abnormal skin and subcutaneous tissue and so on, which were no significant differences between two ams. During the study there were 17 SAE, only 7 cases were possibly related to drug therapy, such as pulmonary infection, Sepsis, myelosuppression, intracranial hemorrhage, hepatic failure, and arrhythmia. Conclusions: The use of 5-day and 8-day schedule decitabine is safe and effective in patients with intermediate and high risk MDS, among which there was no significant differences. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ανάλυση και συσχέτιση των απεικονιστικών ευρημάτων με την ανταπόκριση στη (α) Λιποπλατίνη και Γεμσιταβίνη και (β) Σισπλατίνη και Γεμσιταβίνη σε ασθενείς με μη μικροκυτταρικό καρκίνο του πνεύμονα σταδίου ΙΙΙΒ / ΙV

2017 ◽  
Author(s):  
Φωτεινή Λαζαριώτη
Keyword(s):  
Partial Response ◽  
Stable Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Recist 1.1

Εισαγωγή: O καρκίνος του πνεύμονα αποτελεί το 28% όλων των θανάτων που σχετίζονται με καρκίνο και περίπου στο 80% των περιπτώσεων αφορά στο Μη Μικροκυτταρικό καρκίνωμα. H σισπλατίνη είναι από τα δραστικότερα και πιο αποτελεσματικά κυτταροτοξικά φάρμακα στη θεραπεία των επιθηλιακών κακοηθειών, που όμως οι σοβαρές ανεπιθύμητες ενέργειες και η αντίσταση στην χορήγηση της, εγείρουν την ανάγκη βελτιωμένων μορφών αυτού του φαρμάκου. Mία λιποσωμιακή μορφή της σισπλατίνης, είναι η Λιποπλατίνη (Lipoplatin™), η οποία αναπτύχθηκε με σκοπό να μειώσει τη συστηματική τοξικότητα της σισπλατίνης και να αυξήσει τη δραστικότητά της έναντι των όγκων. Σκοπός: Η ανάλυση και εκτίμηση των απεικονιστικών ευρημάτων, στα οποία κατά κύριο λόγο βασίζεται η αξιολόγηση της ανταπόκρισης στη χημειοθεραπεία (σύμφωνα με τα κριτήρια RECIST 1.1) η συσχέτιση τους με τον ιστολογικό τύπο του καρκίνου σε ασθενείς που λαμβάνουν μέρος σε τυχαιοποιημένη, συγκριτική, ανοιχτής αγωγής, προοδευτική μελέτη φάσης II και η εκτίμηση του ποσοστού αντικειμενικής ανταπόκρισης (Overall Response Rate-ORR) στους ασθενείς των δύο ομάδων. Οι συνδυασμοί χημειοθεραπείας είναι για την πρώτη ομάδα της μελέτης, Λιποπλατίνη και γεμσιταβίνη, ενώ για την δεύτερη ομάδα σισπλατίνη και γεμσιταβίνη, ως θεραπείες πρώτης γραμμής σε Μη Μικροκυτταρικού τύπου, καρκίνο του πνεύμονα (Στάδιο IIIβ/ IV).Δευτερεύοντες στόχοι είναι να συγκριθούν στις δύο ομάδες : το ποσοστό ελέγχου της ασθένειας (DCR), η επιβίωση χωρίς εξέλιξη της νόσου (PFS), η διάρκεια της ανταπόκρισης, η συνολική επιβίωση, η ασφάλεια και η ανεκτικότητα του συνδυασμού θεραπείας.Ασθενείς και Μέθοδος: Η Μελέτη πραγματοποιήθηκε στο νοσοκομείο Μεταξά (2η παθολογική κλινική, υπεύθυνος ερευνητής: Μυλωνάκης Νικόλαος). Τα βασικά κριτήρια συμπερίληψης ασθενών στη μελέτη είναι η ιστολογικά ή κυτταρολογικά επιβεβαιωμένη διάγνωση Μη μικροκυτταρικού καρκίνου του πνεύμονα (NSCLC) σε ασθενείς άνω των 18 ετών με τοπικά προχωρημένο ή μεταστατικό NSCLC.Τα κυριότερα κριτήρια αποκλεισμού είναι η προηγηθείσα χορήγηση άλλου είδους χημειοθεραπεία, βεβαρημένο ιατρικό ιστορικό και η είσοδος στη μελέτη σε χρονικό διάστημα λιγότερο των 3 εβδομάδων από μεγάλη χειρουργική επέμβαση.Οι ασθενείς τυχαιοποιούνται κεντρικά κατά την εισαγωγή τους στην ομάδα Α (Λιποπλατίνη και γεμσιταβίνη) ή στην ομάδα Β (σισπλατίνη και γεμσιταβίνη). Τo θεραπευτικό σχήμα της ομάδας A αποτελείται από: Λιποπλατίνη 120 mg/m2 (ημέρες 1, 8, 15 σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους) και γεμσιταβίνη 1000 mg/m2 (ημέρες 1, 8 σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους). Στην ομάδα Α δεν θα γίνεται προ- ή μετά- ενυδάτωση και δεν θα χρησιμοποιείται φυσιολογικός ορός, ενώ ο ρυθμός έγχυσης θα πρέπει να είναι αργός ιδίως στην αρχή αυτής. Το σχήμα της ομάδας B (χημειοθεραπευτική αγωγή αναφοράς) αποτελείται από σισπλατίνη 100 mg/m2 (ημέρα 1, σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους) και γεμσιταβίνη 1000 mg/m2 (Hμέρες 1, 8 σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους). Η σισπλατίνη θα χορηγείται ως δίωρη ενδοφλέβια έγχυση με ένα λίτρο φυσιολογικού ορού προενυδάτωση και βεβιασμένη διούρηση. Σε αμφότερες τις ομάδες θα συνεχιστεί η ίδια θεραπευτική αγωγή για 3 κύκλους επιπλέον, κατόπιν ανταπόκρισης ή σταθεροποίησης της νόσου. Η αξιολόγηση των ασθενών θα γίνεται σε 4 χρονικές περιόδους: πριν από την έναρξη της θεραπείας, εβδομαδιαία αξιολόγηση (την έβδομη ημέρα μετά από κάθε έγχυση), μετά από 3 και 6 κύκλους θεραπείας και κάθε 3 μήνες δια βίου. Ο έλεγχος των ασθενών θα περιλαμβάνει ιατρικό ιστορικό, φυσική εξέταση, γενική αίματος και πλήρη βιοχημικό έλεγχο με καταγραφή των ανεπιθύμητων ενεργειών. Η αξιολόγηση των ασθενών απεικονιστικά πριν την έναρξη και μετά από 3 και 6 κύκλους θεραπείας. Οι απεικονιστικές μέθοδοι περιλαμβάνουν ακτινογραφία και αξονική τομογραφία θώρακος, αξονικές τομογραφίες κοιλίας, εγκεφάλου και σπινθηρογράφημα οστών αν είναι απαραίτητο. Όλες οι απεικονιστικές εξετάσεις θα διενεργούνται σύμφωνα με τα συνήθη διεθνή πρωτόκολλα, όχι απαραίτητα σε προεπιλεγμένα κέντρα αφού η εισαγωγή και παρακολούθηση των ασθενών στη μελέτη θα πραγματοποιείται κατόπιν διάγνωσης NSCLC σε οποιοδήποτε κέντρο.Αποτελέσματα: Τα απεικονιστικά ευρήματα ανά ιστολογικό τύπο, των ασθενών που έλαβαν μέρος στη μελέτη δεν ήταν διαφορετικά από αυτά που αναφέρονται στην βιβλιογραφία. Η εντόπιση του αδενοκαρκινώματος είναι στις περισσότερες περιπτώσεις περιφερική. Το καρκίνωμα εκ πλακωδών κυττάρων έχει κεντρική εντόπιση στο μεγαλύτερο ποσοστό των ασθενών. Στο σύνολο των ασθενών η εντόπιση υπερέχει στον δεξιό πνεύμονα και στον άνω λοβό. Η κοιλοποίηση, οι αποτιτανώσεις και η προσβολή των πλευρών είναι πιο συχνή στο εκ πλακωδών κυττάρων καρκίνωμα. Η ανάλυση της αποτελεσματικότητας της μελέτης πραγματοποιήθηκε με βάση τα απεικονιστικά ευρήματα χρησιμοποιώντας τα κριτήρια RECIST 1.1. Μερική ανταπόκριση (Partial Response-PR) μετά από την ολοκλήρωση 3 κύκλων παρουσίασε το 31,7% των ασθενών στο Α σκέλος και το 25,6% στο Β αντίστοιχα. Σταθερή νόσος (Stable Disease-SD) παρατηρήθηκε στο 39% των ασθενών στο Α σκέλος, ενώ στο Β ήταν 30,8%. Σε κανένα σκέλος δεν υπήρξε πλήρης ανταπόκριση (Complete Response-CR). Αν και η διαφορά στην ανταπόκριση μεταξύ των δύο ομάδων δεν είναι στατιστικά σημαντική ωστόσο τα αποτελέσματα είναι ενθαρρυντικά αφού η Λιποπλατίνη όχι μόνο δεν υπήρξε υποδεέστερη της σισπλατίνης αλλά επιπλέον είχε μικρότερη τοξικότητα συγκριτικά με την σισπλατίνη. Μια διαφορά που ήταν στατιστικά σημαντική μεταξύ των δύο ομάδων ήταν στη νεφροτοξικότητα. Επιπροσθέτως στην περίπτωση του αδενοκαρκινώματος φαίνεται ότι η Λιποπλατίνη έχει πολύ καλύτερη ανταπόκριση συγκριτικά με την σισπλατίνη (16,7% πρόοδο νόσου έναντι 45,8%) ενώ στην περίπτωση του καρκινώματος εκ πλακωδών κυττάρων τα αντίστοιχα ποσοστά ήταν 46,1% και 37,5%. Συμπέρασμα: Η λιποσωμιακή μορφή της σισπλατίνης παρουσιάζει λιγότερες παρενέργειες συγκριτικά με την σισπλατίνη όταν συνδυάζεται με την γεμσιταβίνη και ειδικότερα στατιστικά σημαντική μικρότερη νεφροτοξικότητα. Ιδιαίτερα σημαντικό επίσης είναι το γεγονός ότι στους ασθενείς της ομάδας που έλαβαν Λιποπλατίνη δεν έγινε προ ενυδάτωση ούτε βεβιασμένη διούρηση. Επιπροσθέτως η Λιποπλατίνη παρουσιάζει μία μεγαλύτερη αποτελεσματικότητα η οποία δεν είναι στατιστικά σημαντική λόγω του μικρού δείγματος ασθενών ωστόσο στην περίπτωση του αδενοκαρκινώματος παρουσιάζει μία στατιστικά σημαντική διαφορά στην ανταπόκριση έναντι της σισπλατίνης.

Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8051-8051
Author(s):  
Sham Mailankody ◽  
Meghan Salcedo ◽  
Elizabet Tavitian ◽  
Neha Korde ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Overall Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Pilot Trial ◽  
Progression Free Survival ◽  
Overall Response ◽  
Smoldering Multiple Myeloma ◽  
Increased Risk

8051 Background: Patients with high risk smoldering multiple myeloma (HR-SMM) have an increased risk of progression to multiple myeloma (MM)- median time < 2 years. The standard management of these patients currently is close clinical monitoring; however, randomized trials show longer progression-free and overall survival in in HR-SMM patients treated with the oral immunomodulatory drug lenalidomide. We report the use ixazomib, the first oral proteasome inhibitor, in combination with dexamethasone in the setting of HR-SMM. Because proteasome inhibitors can provide deep clinical responses in patients with MM, we set the pre-specified threshold for efficacy high (overall response rate of ≥75%). Methods: In this single arm pilot trial of ixazomib/dexamethasone, patients received 12 4-week cycles of ixazomib/dexamethasone followed by ixazomib maintenance for 24 cycles. The primary endpoint is best overall response after 12 cycles and second objectives include duration of response, safety, and progression free survival. Results: 14 patients with HR-SMM were enrolled between 06/2016 and 03/2018. The median age is 65 years and 10 (71%) of patients were male. 11 (79%) patients were high-risk by the PETHEMA criteria, 2 (14%) by the Mayo Clinic criteria and 1 (7%) by both. At data cut-off (02/07/2019), patients completed a median of 17 cycles and 10 (71%) are continuing treatment. 4 patients have stopped treatment (2 patients for raise in serum markers without progression to MM, and 1 each for toxicities, and co-morbidities unrelated to treatment). 9 (64%) achieved an objective response (8 PR, and 1 VGPR) and no patient has progressed to MM. Non-heme adverse events included 3 grade 1 GI events, 2 grade 3 lung infection, 1 grade 2 acute kidney injury, and 1 had grade 1 fatigue that was possibly related to treatment. Conclusions: Ixazomib/dexamethasone appears well tolerated with high overall response (9/14; 64%) in patients with HR-SMM. Although the trial does not meet our pre-specified threshold for efficacy (i.e. best overall response rate of 75%), with a median follow-up of 17 months, no patient progressed to MM and only 2 patients had serologic progression. These results support further evaluation of ixazomib/dexamethasone alone and in combination with other agents as treatment for patients with HR-SMM. Clinical trial information: NCT02697383.

Gemtuzumab Ozogamicin Is an Acceptable Alternative to Anthracyclines in Combination with Standard Dose Infusional Cytarabine as Induction Therapy for Elderly Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1856-1856 ◽  
Author(s):  
Gail J. Roboz ◽  
Ellen K. Ritchie ◽  
Michael W. Schuster ◽  
Tsiporah Shore ◽  
Tania J. Curcio ◽  
...  
Keyword(s):  
Single Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Liver Toxicity ◽  
Single Agent ◽  
Gemtuzumab Ozogamicin ◽  
Left Ventricular ◽  
Historical Cohort ◽  
Secondary Aml ◽  
Overall Response

Abstract Gemtuzumab ozogamicin (GO), a humanized IGG4 anti-CD33 antibody conjugated to calicheamicin, has demonstrated single agent efficacy in relapsed AML. Combination with other anti-leukemic drugs has required a significant dose reduction of GO to avoid excess liver toxicity. The maximally tolerated dose of GO in combination with cytarabine 100 mg/m2 by 24 hr infusion for 7 days, was established at 6 mg/m2 day 1 and 4 mg/m2 day 8 in a phase I trial involving relapsed patients as well as untreated adults with AML above the age of 60. From 7/03 to 7/05, 31 adults (M-17, F-14) with a median age of 70 (range 60–83) were treated with this regimen on a phase II trial. Patients with residual disease on day 14 were given cytarabine 100 mg/m2 by 24 hr infusion daily for 5 days without GO. Post remission therapy, generally included repetitive cycles of cytarabine 50 mg/m2 twice daily by subcutaneous injection in combination with rotating cycles of 6-thioguanine, cyclophosphamide, or daunorubicin. Patients with an antecedent hematological disorder (AHD) or secondary AML were not excluded, and prior treatment for myelodysplastic syndrome was allowed. An AHD was documented in 13/30 (43%) of patients and 3/30 (10%) had secondary AML. Unfavorable cytogenetics (−5, −7, 11q2,3 abnormalities and complex karyotypes) were present in 17/30 (56%) patients. Of the first 7 patients treated, 4 developed severe and fatal hyperbilirubinemia in conjunction with ascites, fluid retention and encephalopathy consistent with sinusoidal occlusion syndrome (SOS). Subsequent patients were treated with 6 mg/m2 of GO without the day 8 dose. Of these 24 patients, 4 developed grade 3 hyperbilirubinemia which was transient and not associated with SOS. Apart from this toxicity, other non-hematologic effects, including infusional reactions, mucositis, diarrhea, nausea, vomiting and anorexia were mild to moderate. No cardiac toxicity was observed in any patients including 3 patients with reduced left ventricular function documented prior to treatment. Overall 9/31 (29%) patients achieved a complete response (CR) and 1 achieved a CRp for an overall response rate of 32%. Of the 24 patients who received 1 dose of GO (6 mg/m2), the overall response rate was 9/24 (36%). The induction mortality rate in these 24 patients was 5/24 (21%). The median duration of response is 10.5 months (range 6 to 12 months) with 2 patients in ongoing CR at 12 months and 18 months respectively. This data demonstrates that GO administered on day 1 and day 8 leads to unacceptable liver toxicity in unselected patients with AML above the age of 60 yrs. However, in patients receiving a single dose of GO (6 mg/m2) in combination with cytarabine, the overall response rate and toxicity profile is comparable to a historical cohort of similarly unselected elderly AML patients treated with daunorubicin and cytarabine at our institution. We conclude that a single dose of GO (6mg/m2) is an equally safe and effective alternative to anthracycline in combination with standard doses of infusional cytarabine in adults with AML above the age of 60.

Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 330-330 ◽  
Author(s):  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Carmen D Schweighofer ◽  
Raymonde Busch ◽  
Jasmin Renschler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Overall Response ◽  
Grade 3

Abstract Introduction: Bendamustine, an alkylating agent with additional properties of a purine analogue, has shown considerable activity in monotherapy for solid and lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory and previously untreated Non-Hodgkin’s lymphoma. This phase II trial represents the first study evaluating the efficacy and toxicity of bendamustine in combination with rituximab in patients (pts) with relapsed or refractory CLL. Patients and Methods: 81 pts with a median number of 2 (1–3) pretreatments were enrolled between March 2006 and June 2007. Patients received 70 mg/m² bendamustine on day 1 and 2 combined with 375mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH) and analysis of the immunoglobulin heavy chain (IgVH) mutational status prior to the first treatment course. Assessment for minimal residual disease (MRD) was performed by four-colour flow cytometry of peripheral blood and bone marrow. Primary endpoint of the trial was the overall response rate (ORR). Secondary endpoints included toxicity, duration of response, event-free survival, MRD response rate and overall response rate in biological defined risk groups. Results: 81 pts (mean age 66.7 years) received a total of 328 treatment cycles. A mean number of 4.5 courses was administered. In total 123 CTC grade 3/4/5 adverse events were reported, most frequently on myelosuppression and infections: grade 3/4 anemia occurred in 6.1%, grade 3/4 leukopenia/neutropenia and thrombocytopenia in 11.9% and 9.1% of all given courses, respectively. 16 episodes (4.9%) of CTC grade ≥3 infections were documented, most of them could be successfully managed. However, treatment related mortality occurred in 3.7% of pts: three pts died due to severe infections associated with treatment related neutropenia including 1 fatal pneumonia, one sepsis after diagnosis of Richter’s syndrome and 1 urosepsis. In 62 pts data for response assessment were available: 19 pts were not evaluable for response due to withdrawal or missing of consent, violation of enrolment criteria or early discontinuation of therapy. The overall response was 77.4% with complete remissions (CR) in 14.5% (9 pts) and a partial response (PR) in 62.9% of pts (39 pts). An MRD level below 10E-4 was measured after completion of therapy in 2 of 30 evaluable pts in peripheral blood, while none of the pts achieved MRD negativity in bone marrow. Stable disease (SD) was achieved in 17.7% (11 pts) whereas 3 pts (4.8%) had progressive CLL (PD). Differences in response were observed among genetic subgroups: 12 of 13 pts with 11q- achieved a remission with 11 PR and 1 CR (ORR: 92.3%). Accordingly, 8 of 8 patients with +12 responded (7 PR, 1 CR). In the high-risk group with 17p-, four of nine pts showed a partial remission (ORR: 44,4%). 29 of 39 pts (ORR: 74.4%) with unmutated IgVH status were responsive to BR. Conclusion: Bendamustine plus rituximab is an effective treatment regimen for pts with relapsed and/or refractory CLL and has notable activity in high-risk CLL disease. Major but tolerable treatment toxicities were myelosuppression and infections. Ongoing trial follow-up analysis will define response duration and long-term safety. In a forthcoming trial the German CLL Study group will investigate the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) for first-line treatment of CLL.

Azacitidine (AZA) Combined with Idarubicin in Untreated Patients with High Risk MDS – Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1720-1720 ◽  
Author(s):  
Lionel Ades ◽  
Benoit de Renzis ◽  
Ramzi Jeddi ◽  
Jacques Delaunay ◽  
Thorsten Braun ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Disease Progression ◽  
Stable Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Single Agent ◽  
Overall Response

Abstract Abstract 1720 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, if it is able to increase overall survival in MDS, AZA yields only about 30% of marrow response (including CR+PR+ mCR), Idarubicin given at conventional dose (12 mg/m2/d during 3 days) is the anthracycline of choice in the intensive chemotherapy given with cytarabine in patients with high risk MDS and, given as a single agent, induces up to 30% of complete remission (CR) in elderly AML patients. Thus, we designed a phase I/II study evaluating the safety and efficacy of 2 doses of Idarubicin combined with Azacitidine in high risk MDS patients (clinical trial NCT01305135). Methods: For this trial Azacitidine was combined with increasing doses of Idarubicin. Main Inclusion criteria were: (1) IPSS int 2 or high MDS, or CMML with WBC < 13,000/mm3 and marrow blasts > 10% or AML with 20–30% marrow blasts (corresponding to EU label for AZA) (2) Age 3 18 years (3) Performance Status (PS) <=2 (4) no prior treatment except ESAs. Patients received Azacytidine 75 mg/m2/d SC during 7 days every 4 weeks combined on day 8 of each cycle to Idarubicin 5 mg/m2 (administered by 1 hour IV infusion) in the first cohort of 10 patients, escalated to Idarubicin 10 mg/m2 IV in the second cohort of 10 patients after review of toxicity (especially hematological) of the 1st cohort by the independent DSMB r. The primary endpoint of the study was response after 6 cycles according to IWG criteria. Data were analyzed at the reference date of June, 1St 2012. Results: The 20 study patients (from 8 centers) were enrolled between Dec 2010 and Feb 2012, including 7 women and 13 men with a median age of 75 years. At inclusion, WHO classification was RCMD in 1 pt, CMML in 1 pt, RAEB-1 in 6 pts, RAEB-2 in 7 pts, AML in 3 pts and unclassified in 2 pt. Median marrow blasts were 6.5% (0–26) Karyotype (IPSS) was favorable in 7 pts, int in 3 pts and unfav in 8 pts (2 pts had cytogenetic failure). IPSS was high in all patients. PS was 0 in 28% pts, 1 in 50% and 2 in 22%. A total of 92 cycles of treatment had been administrated with a median number of 5 cycles/patient and 10 pts had received 6 or more cycles. 14 patients had terminated the study due to side effects (severe febrile pancytopenia, n=2), disease progression (n=5, after 2–10 cycles), death (disease progression, severe septic shock after Cycle 2, and unrelated coma), stable disease after 6 cycles (n=3), and patient decision (n=1). Overall 7 pt had died. 18 SAEs were reported observed in 9 patients, including 10 episodes of febrile neutropenia, 3 episodes of bleeding and 5 unrelated SAE. Of the 20 patients enrolled in the study, 19 were evaluable for response after 3 cycles, including 10/10 in the First cohort and 9/10 in the second cohort. One patient achieved CR, 2 PR, 1 mCR and 2 additional patients achieved stable disease with HI, leading to an Overall response rate of 6/19 (32%). Two patients were still on study but did not reached cycle 6. Thus, after 6 cycles, 17 patients, only could be evaluated. Among them 9/17 (53%) patients were still on study, 2 pts had died, 3 progressed, 2 had experienced sides effects and had terminated the study and 1 pt had withdrawn consent. Two patients achieved CR (including 1 already in CR at cycle 3), 2 PR and 2 additional patients achieved stable disease with HI leading to an Overall response rate of 6/17 (35%). At the time of the present analysis, none of the responder had relapsed. Conclusion: The phase I/II results presented here show that Idarubicin can be combined to Azacitidine with acceptable toxicity. Whether the azacitidine- Idarubicin combination can improve the outcome of higher risk MDS patients will be evaluated in a phase II randomized trial comparing this combination (and other combinations of azacitidine with other drugs) to azacitdine alone alone. Data of the present phase I/II trial will be updated at the meeting. Disclosures: No relevant conflicts of interest to declare.

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