scholarly journals Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 2970-2975 ◽  
Author(s):  
Martha Q. Lacy ◽  
Jacob B. Allred ◽  
Morie A. Gertz ◽  
Suzanne R. Hayman ◽  
Kristen Detweiler Short ◽  
...  
Keyword(s):  
Partial Response ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Minor Response ◽  
Overall Response ◽  
Excellent Activity ◽  
Dosing Strategies ◽  
Sequential Phase ◽  
Good Partial Response

Abstract Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.

Cyclophosphamide, Bortezomib and Dexamethasone (CyBORD) Is a Feasible and Active Regimen for Non-Transplant Eligible Multiple Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5751-5751 ◽  
Author(s):  
Victor H Jimenez Zepeda ◽  
Peter Duggan ◽  
Paola E. Neri ◽  
Nizar J Bahlis
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Median Time ◽  
Light Chain ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Novel Drugs ◽  
Good Partial Response

Abstract Introduction With the advent of novel drugs for the treatment of Multiple Myeloma (MM), the clinical outcomes have significantly improved over the last decade both in the setting of stem cell transplant eligible and non-eligible patients. Combinations of novel drugs have improved and deepened response and this is true for CyBORD, a regimen able to induce rapid and deep responses. Based on the above mentioned, we aimed to assess the role and feasibility of CyBORD as upfront therapy for non-transplant eligible patients with MM. Methods. All consecutive patients with documented symptomatic MM not eligible for transplant treated with CyBORD at our Institution were evaluated. Treatment consisted of a 28-day cycle of bortezomib 1.3 mg/m2 or 1.5 mg/m2 intravenously or subcutaneously on days 1, 8, and 15, cyclophosphamide 300 mg/m2 orally administered on days 1, 8, and 15 and dexamethasone 20-40 mg orally on weekly basis. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. The primary endpoint of the study was to assess the efficacy and feasibility of CyBORD in this group of patients. All analyses were performed using the SPSS 20.0 software and all p-values were 2-sided and statistically significant if <0.05. Results Between 07/11 and 07/14, 20 patients were identified for the study. Clinical and laboratory characteristics are listed in Table 1. The median age for this cohort of patients was 76 years (range 66-90). Sixty-five percent of patients had IgG isotype, 5% had IgA, and 30% had light chain only disease. After a median of 5 cycles, the overall response rate was 95% (19/20) with 70% of patients achieving VGPR or better response. (Table 2 ) The median time to first response was 6 weeks with majority of cases achieving at least PR after 2 cycles of therapy. At a median follow-up of 9.5 months, all patients are alive and 5 had already progressed at a median time of 12 months. With regards to toxicity, 6 patients experienced non-hematological grade 3/4 adverse events (20%), including muscle weakness, sepsis and pneumonia. Neutropenia and thrombocytopenia were seen in 2 patients (10%), both patients required dose reduction of cyclophosphamide with one patient being discontinued of cyclophosphamide after 2 cycles but still receiving bortezomib and dexamethasone. In conclusion, CyBORD is a highly active and viable option for the treatment of non-transplant eligible patients with MM. As suggested by other studies, elderly patients required dose adjustments and special considerations while receiving active therapy, balancing the efficacy and toxicity given by the different drug combinations. Table 1. Clinical and Laboratory characteristics of non-transplant eligible MM patients treated with CyBORD Characteristic N Median Range % Age (years) 20 76 66-90 Gender -Male -Female 11 9 55% 45% ISS Stage I II III 5 7 8 25% 35% 40% Heavy chain IgG IgA Free light chain only Light chainKappa Lambda 13 1 6 11 9 65% 5% 30% 55% 45% Hemoglobin (g/L) 20 106 73-158 Creatinine (µmol/L) 20 117 49-671 Calcium (µmol/L) 20 2.4 2.0-2.99 LDH (IU/L) 20 229 118-814 B2-microglobulin (mg/L) 20 4.1 1.41-19 Albumin (g/L) 20 32 22-37 FISH Cytogenetics Standard risk High risk 18 2 90% 10% Table 2. Response rates for non-transplant eligible MM patients treated with CyBORD Characteristic Median (Range) N % Number of cycles 5 (1-12) Overall Response rate 19/20 95% Near Complete Response Complete Response 1 2 5% 10% Very Good Partial Response 11 55% Partial Response 5 25% Less than PR 1 5% Progression 5/20 25% Time to progression (months) 12 (3-15) Alive 20 100% CyBORD: Cyclophosphamide, bortezomib and dexamethasone Disclosures Jimenez Zepeda: Janssen Ortho: Honoraria. Bahlis:Celgene: Honoraria, Research Funding.

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.

scholarly journals Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Blood ◽  
2016 ◽  
Vol 128 (14) ◽  
pp. 1821-1828 ◽  
Author(s):  
Torben Plesner ◽  
Hendrik-Tobias Arkenau ◽  
Peter Gimsing ◽  
Jakub Krejcik ◽  
Charlotte Lemech ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Adverse Events ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Overall Response ◽  
Key Points ◽  
The Individual ◽  
Good Partial Response

Key Points Daratumumab plus lenalidomide/dexamethasone elicited an overall response rate of 81% (63% very good partial response or better). Adverse events were manageable and in accord with the individual toxicity profiles of daratumumab and lenalidomide/dexamethasone.

Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

2011 ◽  
Vol 29 (26) ◽  
pp. 3559-3566 ◽  
Author(s):  
Kirsten Fischer ◽  
Paula Cramer ◽  
Raymonde Busch ◽  
Stephan Stilgenbauer ◽  
Jasmin Bahlo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Overall Response

Purpose The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients and Methods Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m2 on days 1 and 2 combined with rituximab 375 mg/m2 on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses. Results On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

scholarly journals Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4091-4101
Author(s):  
Arne Kolstad ◽  
Tim Illidge ◽  
Nils Bolstad ◽  
Signe Spetalen ◽  
Ulf Madsbu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20

Abstract For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

High Overall Response Rate in Calcineurin Inhibitor-Free Treatment with the mTOR Inhibitor Everolimus in Advanced Extensive Chronic GvHD after Allogeneic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2210-2210 ◽  
Author(s):  
Anne Klink ◽  
Kristina Schilling ◽  
Katrin Rapp ◽  
Klaus Höffken ◽  
Herbert G. Sayer
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Free Treatment ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Background: The mammalian target of rapamycin (mTOR) inhibitor Everolimus (RAD001, Certican®) is a new immunosuppressive drug and beside of sirolimus used and approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with calcineurin inhibitors (CNI) showed clinical responses in chronic graft-versus-host disease (cGvHD). In this single centre retrospective analysis, we report on 29 patients (pts) with severe cGvHD treated with Everolimus without CNI. Patients and Methods: Twenty-nine pts (17 AML, 3 CML, 4 ALL, 3 CLL, 2 NHL) with a median age of 44 years [range: 25–61] underwent allogeneic stem cell transplantation between September 1999 and August 2007. Myeloablative conditioning was used in 21 pts, reduced-intensity conditioning in 8 pts. Except for one patient receiving bone marrow, all pts received peripheral blood stem cells for transplantation. Family donors (2 non-fully HLA matched) were used in 7 pts (24%) and unrelated donors (7 non-fully HLA-matched) in 22 pts (76%). GvHD-prophylaxis consisted of CNI (cyclosporine or tacrolimus) in 4 pts, CNI+Methotrexate (MTX) in 8 pts, CNI+Mycophenolate (MPA) in 8 pts and CNI+MPA+MTX in 9 pts. Antithymocyte globulin (ATG) as in vivo T-cell depletion was used in 9 pts. Cytomegalovirus (CMV)-serostatus was positive in 14 pts, with seronegative donors in 5 pts. Acute GvHD occurred in 27/29 (93.3%), grade II-IV in 25 (86.2%). At the same time, CMV reactivation/infection was observed in 11 pts and thrombotic microangiopathy (TMA) in 3 pts. All pts developed severe cGVHD with extensive disease. Organ involvement included skin with scleroderma in 21 pts, mucous membranes in 22 pts, eyes in 22 pts, lungs in 8 pts, liver in 11 pts, gut in 9 pts and arthralgia in 6 pts. At the time of treatment start with everolimus (0.75 mg Certican ® twice a day orally), CNI medication was stopped. The intended plasma therapeutic levels of everolimus were 3–8 mg/l. In addition all pts received prednisone and in 18 pts (62%) MPA as third immunosuppressive agent was continued. Results: Median treatment duration was 8.4 months [range: 2.5–21.7]. None of the pts developed CMV disease or TMA. Adverse events were: arterial hypertension in 1 patient, atrial fibrillation in 1 patient, pneumonia in 1 patient, sinusitis in 1 patient, herpes labials infection in 1 patient, renal insufficiency grade II in 2 pts and myalgia in 2 pts. 96.6% are still alive, 1 patient (3.4%) died due to relapse of ALL. Two pts (6.9%) achieved a complete response of their cGvHD and 18 pts (62.1%) a partial response resulting in an overall response rate of 69.0% (n=20) according to the recent consensus NIH report (Biol. Blood Marrow Transplant. 2006 May; 12(5): 491–505). No change was observed in 3 pts (10.3%) and progression occurred in 6 pts (20.7%). Complete response in HLA-identical related donors was 20% (1/5) and with HLA-matched unrelated donors was 6.7% (1/15). 100% (n=2) of pts with a HLA-mismatched related donor achieved a partial remission and 85.7% (n=6) of pts with a HLA-mismatched unrelated donor. The gender of recipient or donor did not impair the observed responses with everolimus. Prednisone could be tapered in 62.1% of all pts (18/29). In the triple combination with MPA, MPA could be tapered in 22.2% (4/18) and could be stopped in 38.9% (7/18). Conclusions: A CNI-free treatment of advanced extensive cGvHD with everolimus seems to be feasible and effective with a high overall response rate of nearly 70 %. It should be emphasized that a low toxicity profile without TMA was observed. Our data supports further clinical and immunological investigations with m-TOR inhibitor everolimus in treating GvHD.

Phase Ib dose escalation study of oral quisinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8530-8530
Author(s):  
Xavier Leleu ◽  
Cyrille Touzeau ◽  
Lotfi Benboubker ◽  
Thierry Facon ◽  
Martine Delain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Mononuclear Cells ◽  
Response Rate ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Overall Response ◽  
Aggresome Formation

8530 Background: Aggresome formation is a mechanism of resistance to agents (e.g., bortezomib) which block proteasome activity. HDACi (e.g., quisinostat) prevents aggresome formation by deacetylation of tubulin that allows the transport of unfolded proteins to lysosomes for degradation. Methods: Patients received quisinostat (Q) at escalated doses (6, 8, 10 and 12 mg) on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamic biomarkers. Results: Eighteen patients (3, 3, 6, and 6 in increasing Q doses) were enrolled: 56% male; median age = 69 (range 50-82) years; multiple myeloma stage: IA = 11% and IIIA = 89%; prior lines of therapy: 1 = 100%, 2 = 55.6%, and 3 = 11.1%; prior VELCADE treatment = 50%. At the highest dose (12 mg) 2 patients had dose-limiting toxicity, 1 with QTc prolongation and 1 with atrial fibrillation. The MTD was established at the 10 mg Q for the Q+V+D regimen. The most common adverse events (≥ 10% of patients) were diarrhea (39%), asthenia (33%), peripheral oedema (22%), nausea (17%), thrombocytopenia (17%), alopecia (11%), constipation (11%), and vomiting (11%); most were grade 2 or lower in toxicity. To date, 13 patients have discontinued treatment, of which 5 completed 11 cycles of treatment. The overall response rate was 87.5% (14/16, 95% CI: 61.7% to 98.5%), including 1 complete response, 2 very good partial response, and 11 partial responses. Most patients (9/11) showed a decrease in number of circulating multiple myeloma cells after 1 cycle. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusions: The MTD is 10 mg quisinostat in combination with VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma and has an acceptable safety profile. Clinical trial information: NCT01464112.

Carboplatin plus ifosfamide as salvage treatment of epithelial ovarian cancer: a pilot study.

1993 ◽  
Vol 11 (10) ◽  
pp. 1952-1956 ◽  
Author(s):  
V Lorusso ◽  
A Catino ◽  
B Leone ◽  
M Rabinovich ◽  
G Gargano ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Complete Response ◽  
Salvage Treatment ◽  
Previous Response ◽  
Overall Response ◽  
Platinum Resistant

PURPOSE This study aimed to evaluate the activity and toxicity of carboplatin (PPL) and ifosfamide (IFO) in patients with epithelial ovarian cancer previously treated with cisplatin (CDDP)-containing regimens. PATIENTS AND METHODS From July 1989 to December 1991, 35 patients with epithelial ovarian cancer relapsed or refractory to CDDP as first-line chemotherapy were treated. PPL was administered at a dose of 300 mg/m2 intravenously (IV) on day 1 and IFO at a dose of 1,500 mg/m2 IV on days 1 to 3 every 3 to 4 weeks. Criteria for evaluating previous response to CDDP were strictly defined. RESULTS The overall response rate was 43% (complete response [CR], 6%; partial response [PR], 37%) and the median duration of response was 7 months (range, 3 to 16). In potentially platinum-sensitive (PPS; relapsed) patients, the overall response rate was 56%. None of the primary platinum-resistant (PPR) patients obtained a clinical response to PPL plus IFO, whereas one of five secondary platinum-resistant (SPR) patients obtained a PR. The regimen was easily manageable. CONCLUSION PPL plus IFO is useful and well-tolerated combination in salvage treatment of patients with advanced ovarian cancer. However, clear synergism between PPL and IFO that could overcome intrinsic or acquired CDDP resistance was not observed. The advantage of PPL plus IFO as compared with CDDP-containing regimens is represented by the increased tolerability and the reduced neurotoxicity, nephrotoxicity, and ototoxicity as compared with CDDP-containing regimens. It is essential that the patient population be defined according to their previous response to platinum therapy in trials involving second-line therapy of ovarian cancer.

Antigenic Variation of Hairy Cell Leukemia Defines a CD25 Negative Variant with a Uniform Immunophenotype and Distinct Clinicopathologic Features.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1102-1102
Author(s):  
Henry Y. Dong
Keyword(s):  
Flow Cytometry ◽  
Hairy Cell Leukemia ◽  
Standard Therapy ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Overall Response

Abstract Classical hairy cell leukemia (HCL) coexpressing both CD25 and CD103 is highly responsive to the treatment with cladribine and pentostatin (complete response rate, 75–95%; overall response rate, 86–100%). HCL variant in the literature is characterized by HCL-like morphology, lack of CD25 coexpression, and variable immunophenotypes indistinguishable from those of splenic marginal zone B cell lymphoma (Matutes, et al. Leukemia2001; 15:184). Importantly, HCL variant is associated with a poor response to standard therapy. It is unclear if HCL cases lacking CD25 but otherwise phenotypically identical to classical HCL belong to HCL or HCL variant, and if the standard therapy is effective in these patients. To further delineate features of HCL and its variants, we analyzed immunophenotyping data, by flow cytometry or immunohistochemistry, or by both when feasible, in 260 consecutive patients with HCL (Dong, et al. Mod Pathol2003; 16:230A). The diagnosis was established by hairy cell morphology together with coexpression of strong CD20 and CD22, bright CD11c, and CD103. Clinical data were obtained for a subset of cases in which expression of CD25 was distinctly absent. Our results were consistent with the literature in that HCL has a consistent and unique immunophenotypic profile, which allowed detection of residual HCL by flow cytometry at levels as low as 0.1% of total cells. In addition, approximately 20% and 37% of classical HCL coexpressed CD10 and BCL-1 respectively, which may significantly confuse the diagnosis in an incomplete work-up. Interestingly, there were 43 cases (20% of all CD103+ cases) that lacked CD25 but were otherwise identical to classical HCL in their uniform phenotypic profiles. Compared with classical HCL, patients with the CD25- HCL were generally older (medium age: 59yrs vs. 79yrs; p=0.001) and frequently had leukocytosis (medium WBC: 3.0x109/L vs. 24.5x109/L; p=0.014). Among 14 patients with follow up data, 7 were treated with cladribine or pentostatin. The complete response (CR) rate was 14.3% (1/7) and the overall response rate was 57.1% (4/7). Three patients had no response. One patient who had an initial partial response (PR) to pentostatin died of the disease 10 months after the diagnosis. Of others, an additional two patients achieved CR and PR upon initial treatment with fludarabine and Rituxamab respectively. Four patients were untreated and were alive with disease (follow up, 21–41 months). One patient died of the disease in 2 years and treatment for this patient was unknown. These clinical features overlapped with those of HCL variant in the literature. However, unlike the HCL variant that has significant phenotypic heterogeneity, including lack of CD11c and CD103 in a substantial number of cases, the CD25- HCL was remarkably uniform in phenotype and can be easily identified by immunophenotyping. In conclusion, these results suggest that lack of CD25 in HCL defines a clinically distinct chronic lymphoproliferative disorder, which appears to require different clinical management.

Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5299-5299 ◽  
Author(s):  
Michael Y. Choi ◽  
Januario E. Castro ◽  
Sheila Hoff ◽  
Hongying Li ◽  
Laura Rassenti ◽  
...  
Keyword(s):  
Partial Response ◽  
Interim Analysis ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Free Survival ◽  
Safety And Efficacy ◽  
Overall Response ◽  
Grade 3

Abstract Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL. Methods Patients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy. Results By April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q). 5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients. Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype. Conclusions The combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes. Disclosures: Choi: Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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