Histone Deacetylase Inhibitors in Myelodysplastic Syndrome

Abstract Background Myelodysplastic Syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increase risk of progression to acute leukemia. Histone deacetylase inhibitors (HDACi) modulate the epigenetics of cancer cells to promote differentiation and programmed cell death. Our aim is to study the efficacy and safety of HDACi in patients with MDS/ acute myeloid leukemia (AML). HDACi can be a safer alternative in patients with high risk MDS who are not eligible for stem cell transplantation or high intensity chemotherapy. Methods A comprehensive literature search was done using following 5 databases: (Pubmed,Embase,Web of Science,Cochrane library,Clinical Trials.Gov) in accordance with the PRISMA guidelines. We included 21 trials (Phase II/III ) with a total 1654 patients,of which 1030 patients recieved HDACi and were evaluable for respone. Our primary objective was to determine efficacy of HDACi based regimen in terms of overall response rate (ORR) and composite complete response rate (CCR). A meta-analysis was done for regimen that were evaluated in more than one trials to report ORR and CRR.CMA software V.3 was used to run metaanalysis to calculate the response and the heterogenity among studies were assesed by using I2 test.A random -effect model was applied. Results: The pooled analysis (95% CI) with 1030 evaluable patients in MDS/ AML showed an overall response rate of 37.1% (32.3-42.3 : I2= 86.105 )with composite response (comp CR=CR+Cri+mCR) of 30.8%(26.8-35.1) .The median overall survival of those who received HDACi ranges from 8 -25 months.The Base line Characterstics,Outcome and Toxicity of HDACi in MDS/AML are summarized in Table 1. In the meta-analysis (n=57) of two trials (Garcia et al, 2007 & Luger et al. 2013), combination regimen of Mocetinostat- Azacytidine had an ORR of 54%(95% CI: 10.2-92.3) and composite complete response (CCR) of 18.9% (95% CI :9.3-34.7) in patients with MDS/AML. Combination of Vorinostat-Cytarabine-Idarubicin had an ORR of 50.7% (95% CI :40.7-96.5) and CCR of 30.1% (95% CI: in 111 patients with MDS/AML in a meta-analysis of trials by Prebet et al. 2013 and Manero et al. 2012. The meta-analysis of 3 trials evaluating Vorinostat-Azacitadine regimen (Craddock et al. 2017; Sekers et al. 2017 & Montalbano et al. 2016) had an ORR 38.3%( 95 % CI :18-63) CCR of 29%(95% CI: 11-58) in a total patient population of 274 patients. The regimen of Valproate- Deictibine/Cytarabine was evaluated in 3 separate trials with a total patient population of 156 which showed an ORR of 41.6% (95 % CI :20.9-65.6)and a CCR of 28.3%(95% CI 18.9-42.7) in the metanalysis. The meta-analysis of 3 trials evaluating a three-drug regimen of Valproate-Azacytadine-All trans retinoic acid(ATRA) showed an ORR of 32.2%(95% CI :24.2-41.3) and CCR of 23.7%(95 %CI 13.1-39.0) in 144 MDS/AML patients. In a trial by Manero et al (2017), the combination of Pracinostat and Azacitadine had an ORR of 67.5% (95% CI :51.7-80.01) CCR of 60%(95% CI 44.3-73.8) in 51 AML/MDS patients. A single trial evaluating regimen of Panobinostat and Azacitadine (n=40) had an ORR of 37.5% and CCR of 27.5%. Combination of Panobinostat and Decitabine in a trial by Geoffry et al in 2017 (n=52), the ORR was 21.2% and CCR of 19.2%.The Overall response rate and Composite response rate of HDACi in MDS/AML are mentioned in Table 2 and Table 3. Conclusion: Most of the HDACi like Mocetinostat,Valproic acid ,Pracinostat when used in combination with either Hypomethylating agents(Azacytidine ,decitabine) or purine analogs (cytarabine/idarubicin) produced a good response.Pracinostat in combination with azacytidine showed the best ORR among the studies but there was only single study mentioning this combination.Single agent studies with resposne were also not evaluable.Most of MDS patients get resistant to hypomethlating agent thus there is need to explore newer agents and HDACi agents is a promising group. Disclosures No relevant conflicts of interest to declare.

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

Blood Advances ◽

10.1182/bloodadvances.2020002583 ◽

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.

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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 ◽

10.1182/blood.v112.11.2210.2210 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2210-2210 ◽

Cited By ~ 3

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.

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Update of the NCI multiinstitutional phase II trial of romidepsin, FK228, for patients with cutaneous or peripheral T-cell lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8027 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8027-8027 ◽

Cited By ~ 20

Author(s):

R. Piekarz ◽

R. Frye ◽

J. Wright ◽

W. Figg ◽

S. Allen ◽

...

Keyword(s):

T Cell ◽

Histone Deacetylase Inhibitors ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

T Cell Lymphoma ◽

Cell Transplant ◽

Overall Response ◽

Prior Therapy

8027 Background: The histone deacetylase inhibitors (HDIs) are a class of differentiating agents undergoing clinical testing. Like other HDIs, romidepsin (FK228) modulates expression of genes involved in cell cycle regulation and markers of differentiation in cancer cell lines, leading to induction of differentiation or apoptosis. Romidepsin has demonstrated clinical activity in patients with T-cell lymphoma. Methods: Patients with CTCL (42) or PTCL (36) were enrolled in the NCI multi-institutional trial and assigned to cohorts based on extent of prior therapy and pathology. Romidepsin is administered on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14mg/m2. Responses for patients with PTCL are measured using Cheson criteria, and CTCL using RECIST criteria. Results: Cohort one, composed of 27 patients who had previously received no more than 2 prior cytotoxic regimens of chemotherapy, has completed enrollment. Responses observed include 3 patients with CR and 7 patients with partial responses, yielding an overall response rate of 37%. Of note, responses were observed independent of stage of disease. Among 18 patients with stage IV disease, 6 patients had a complete or partial response, including 3 patients with Sézary syndrome. When including patients with greater than 2 prior cytotoxic regimens, the overall response rate was 31%. A replicate arm has been opened with the goal of confirming the response rate observed in the first cohort. Response data have not been evaluated from this arm at this time. Responses observed in 36 patients with refractory or relapsed PTCL includes 3 patients with CR and 8 patients with partial responses, comprising an overall response rate of 30%. Responses were observed independent of prior therapy, with some patients having undergone prior stem-cell transplant. Molecular endpoint analysis was performed on peripheral mononuclear cells (PBMNCs) and tumor biopsies from treated patients evaluating histone acetylation and changes in gene expression. Conclusions: Romidepsin as a single agent appears to have significant single agent activity in patients with CTCL and PTCL. Combination therapy with romidepsin may increase efficacy and should be pursued. This protocol remains open to accrual. No significant financial relationships to disclose.

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8530 ◽

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.

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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

10.12681/eadd/40548 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.10.1952 ◽

1993 ◽

Vol 11 (10) ◽

pp. 1952-1956 ◽

Cited By ~ 13

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.

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The efficacy and safety of lenvatinib in the treatment of solid tumors: an up-to-date meta-analysis

Future Oncology ◽

10.2217/fon-2020-0327 ◽

2021 ◽

Author(s):

Wen jie Xie ◽

Shuai Zhang ◽

Lei Su ◽

Yan hong Li ◽

Xi Zhang ◽

...

Keyword(s):

Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Meta Analysis ◽

Severe Infection ◽

Progression Free Survival ◽

Hazard Ratio ◽

Efficacy And Safety ◽

Free Survival ◽

Overall Response

Aim: We performed an updated meta-analysis to evaluate the efficacy and safety of lenvatinib in cancer patients. Materials & methods: Databases were searched to identify relevant trials. Data were extracted to evaluate overall survival, progression-free survival, overall response rate and grade ≥3 adverse events. Results: The pooled analysis demonstrated that lenvatinib significantly improved progression-free survival (hazard ratio: 0.43; 95% CI: 0.23–0.80; p = 0.008), overall survival (hazard ratio: 0.85; 95% CI: 0.75–0.97; p = 0.013) and overall response rate (relative risk: 6.89; 95% CI: 2.22–21.36; p = 0.001) compared with control therapy. However, the use of lenvatinib can increase the risk of severe infection. Conclusion: Lenvatinib-containing regimens are associated with better progression-free survival, overall survival and overall response rate, but can induce severe infection.

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

Blood ◽

10.1182/blood.v104.11.1102.1102 ◽

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.

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Head-to-Head Comparison of 5-Azacitidine Versus Decitabine for the Treatment of Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v120.21.2843.2843 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2843-2843

Author(s):

Yun-Gyoo Lee ◽

Inho Kim ◽

Sung-Soo Yoon ◽

Seonyang Park ◽

June-Won Cheong ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Lower Risk ◽

Overall Response Rate ◽

Response Rate ◽

Hazard Ratio ◽

Phase Iii ◽

Comparable Efficacy ◽

Overall Response ◽

Risk Of Death ◽

Grade 3

Abstract Abstract 2843 Introduction The hypomethylating agents (HMAs) 5-azacitidine (AZA) and decitabine (DAC) provided significant overall response rates (40–60%) in myelodysplastic syndrome (MDS), and improved the outcome of higher risk MDS. However, phase III trials comparing AZA or DAC to conventional treatment including best supportive care have shown discrepant results. The aim of this study is to compare the efficacy and safety between AZA and DAC in patients with MDS. Methods We evaluated 203 patients in lower risk with significant cytopenia and higher risk MDS who received AZA and 97 patients who received DAC in Korea between January 2004 and December 2011. AZA 75mg/m2/day was given subcutaneously for 7 days every 4 weeks. DAC 20mg/m2/day was given intravenously over one hour for 5 days every 4 weeks. We compared overall response rate (complete responses, partial responses, marrow complete responses, and hematologic improvements), overall survival (OS) and adverse outcomes with the use of propensity-score matching in the overall cohort according to HMAs. Results Among 300 patients, propensity matching for the entire cohort created 97 matched pairs of patients. The International Prognostic Scoring System risk category was Intermediate-2/High in 40.2%. A median of 5 courses (range 1–24) were delivered in AZA and 5 courses (range 1–14) in DAC. In the overall matched cohort, there was no significant difference between AZA and DAC in overall response rate (44.2% vs. 52.1%, P=.28), OS (28 vs. 23 months; hazard ratio for AZA, 1.14; 95% confidence interval [CI], 0.75 to 1.72, P=.54) with a median follow-up duration of 29.6 months. Among the patient under 65, no significant differences were noted for OS between AZA and DAC group. Among the patient over 65, however, the patients who received DAC showed higher risk of death than those who received AZA with borderline significance (hazard ratio for AZA, 1.58; 95% CI 0.91 to 2.73, P=.10). The cumulative hazard of transformation to acute myeloid leukemia (AML) was 16.3% in AZA and 21.9% in DAC at one year, and 32.2% in AZA and 55.3% in DAC at two year. The incidence of grade 3 & 4 neutropenia was significantly higher in DAC than AZA (P=.026). Among 1151 assessable treatment courses (604 in AZA, 547 in DAC), AZA group have less likely to experience fever episodes requiring intravenous antibiotics than DAC group (8.6 vs. 15.7 episodes per 100 courses; risk ratio, 0.55; P<.001). Conclusions In a cohort of patients in lower risk with significant cytopenia and higher risk MDS, AZA and DAC showed comparable efficacy in terms of overall response rate, OS and risk of transformation to AML. However, patients receiving DAC experienced more frequent grade 3 & 4 neutropenia and fever episodes than patient receiving AZA. When both AZA and DAC are available, safety profiles as well as treatment efficacy need to be considered. Disclosures: No relevant conflicts of interest to declare.

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Hochrisiko-CLL: Zielgerichtete Kombinationstherapie verbessert das Überleben

Karger Kompass Onkologie ◽

10.1159/000517059 ◽

2021 ◽

pp. 1-3

Author(s):

Katja Zirlik

Keyword(s):

Cardiac Arrest ◽

High Risk ◽

Adverse Events ◽

Chronic Lymphocytic Leukaemia ◽

Overall Response Rate ◽

Lymphocytic Leukaemia ◽

Response Rate ◽

Complete Response ◽

Overall Response ◽

To Receive

Background: Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. Methods: We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2–6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. Findings: 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n = 64) or ibrutinib alone (n = 62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7–47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p = 0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. Interpretation: The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. Funding: TG Therapeutics.

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