scholarly journals Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5608
Author(s):  
Sylvain Garciaz ◽  
Colombe Saillard ◽  
Yosr Hicheri ◽  
Marie-Anne Hospital ◽  
Norbert Vey
Keyword(s):  
Myeloid Leukemia ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Iii ◽  
Preclinical Models ◽  
Cytochrome C Release ◽  
Antiapoptotic Proteins ◽  
Low Intensity ◽  
The Poor ◽  
Combination Regimens

Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery.

scholarly journals Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse–Bordeaux DATAML Registry Study

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 773 ◽  
Author(s):  
Sarah Bertoli ◽  
Pierre-Yves Dumas ◽  
Emilie Bérard ◽  
Laetitia Largeaud ◽  
Audrey Bidet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Intensive Chemotherapy ◽  
Line Treatment ◽  
First Line ◽  
Low Intensity ◽  
First Line Treatment ◽  
Acute Myeloid

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse–Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0–32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27–45), 24.7% (95%CI: 1–33) and 19.7% (95%CI: 1–28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

Decitabine Is Effective and Safe In Patients with Chronic Myelomonocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4032-4032
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
A. Megan Cornelison ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Median Survival ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chronic Myelomonocytic Leukemia ◽  
Phase Iii ◽  
White Blood Count ◽  
Survival Duration ◽  
Overall Response ◽  
Myelomonocytic Leukemia

Abstract Abstract 4032 Background: Chronic myelomonocytic leukemia (CMML) is a rare yet indolent disease. The median survival duration in CMML is 12 to 18 months and patients with poor prognostic features do even worse, with median survival time ranging 3 to 6 months. Activity with decitabine in CMML has been previously reported. We sought to analyze the clinical experience of 17 adults with a diagnosis of CMML treated on two decitabine studies. Methods: A subset of patients with CMML from a pivotal phase III 3-day dosing and an open-label trial of 5-day dosing were identified and reviewed to determine the overall response rate (ORR, based on IWG 2006 criteria), duration of response, time to response, and overall survival (OS). Results: A total of 17 patients with CMML were included in this review. Mean age at diagnosis was 71 years (range, 47 to 81 years) with a mean time from diagnosis of 406.4 days. The majority of CMML patients had de novo (94.1%), good risk cytogenetics (58.8%) with an IPSS classification of Intermediate-1 (64.7%). Baseline mean white blood count (WBC), hemoglobin (HGB), and platelets (plts) were 7.5 × 103/μ L, 14.6 g/dL and 81.9 × 103/μ L, respectively. A larger proportion of CMML patients at baseline were plt and RBC transfusion independent. Objective response rate (ORR) was 41% [17.6% complete response (CR) and 23.5% marrowCR (mCR)]; Hematologic improvement (HI) was observed in 11.7% and stable disease in 29.4% of patients. Median survival was 391 (95% CI 239, 678) days and 2 (11.7%) patients progressed to AML. The adverse event profile was similar to observations in previous trials with myelosuppression and infectious complications. Conclusions: This retrospective review of responses in CMML patients supports previous findings of decitabine experience in this population. In this analysis an overall response rate of 41.4% was achieved. Decitabine provided anti-CMML activity with an acceptable safety profile. Disclosures: Jabbour: Eisai Inc.: Editorial and statistical support from Eisai Inc., Honoraria. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy. Ravandi:Eisai Inc.: Research Funding; Eisai Inc.: Honoraria. Borthakur:Eisai Inc.: Research Funding. Cortes:Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding.

Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma

Blood ◽  
2013 ◽  
Vol 122 (12) ◽  
pp. 2104-2113 ◽  
Author(s):  
Jennifer E. Amengual ◽  
Sean Clark-Garvey ◽  
Matko Kalac ◽  
Luigi Scotto ◽  
Enrica Marchi ◽  
...  
Keyword(s):  
Stable Disease ◽  
Clinical Studies ◽  
Overall Response Rate ◽  
Response Rate ◽  
Class I ◽  
Preclinical Models ◽  
Overall Response ◽  
Key Points ◽  
Synergistic Cytotoxicity ◽  
Relapsed Lymphoma

Key Points Treatment of DLBCL with the combination of sirtuin and DAC inhibitors leads to synergistic cytotoxicity and acetylation of Bcl6 and p53. The overall response rate of relapsed lymphoma patients treated with vorinostat and niacinamide was 24%, and an additional 57% achieved stable disease.

5-fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary.

1986 ◽  
Vol 4 (3) ◽  
pp. 395-399 ◽  
Author(s):  
R M Goldberg ◽  
F P Smith ◽  
W Ueno ◽  
J D Ahlgren ◽  
P S Schein
Keyword(s):  
Median Survival ◽  
Overall Response Rate ◽  
Tumor Response ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Primary Site ◽  
Phase Iii ◽  
Unknown Primary ◽  
Phase Iii Trial ◽  
Complete Tumor

The combination of 5-fluorouracil (5-FU), doxorubicin, and mitomycin (FAM) is often recommended for empiric management of patients with adenocarcinoma of unknown primary. This recommendation is based on the activity of FAM for adenocarcinomas of specific known sites of origin. A literature search disclosed no reports of the efficacy of FAM in this clinical entity. We report on 45 patients with biopsy-proven adenocarcinoma in whom investigation revealed no primary site and who were treated in a phase II trial with FAM. Of 43 evaluable patients, four achieved a complete tumor response, and nine obtained a partial response for an overall response rate of 30%. The median survival for all patients was greater than 10 months. The median survival for patients whose tumors were unresponsive to FAM was 6 months, and median survival was greater than or equal to 14 months in patients with stable disease or FAM-responsive tumors. A phase III trial comparing no therapy or 5-FU with FAM is warranted. For patients not treated in an investigative setting, FAM compares favorably with reported series using other regimens.

An Open-Label Phase II Study to Investigate the Safety and Efficacy of Rituximab Plus Chlorambucil in Previously Untreated Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukaemia (CLL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3428-3428 ◽  
Author(s):  
Peter Hillmen ◽  
John G. Gribben ◽  
George A Follows ◽  
Donald W. Milligan ◽  
Hazem A. Sayala ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Open Label ◽  
Overall Response ◽  
Binet Stage ◽  
The Uk

Abstract Abstract 3428 Poster Board III-316 Introduction Despite the increasing use of fludarabine (F) plus cyclophosphamide (C), and recently rituximab (R)-FC combinations in CLL, chlorambucil (Chl) remains a first-line treatment option, particularly for elderly patients and those with co-morbidities with chronic lymphocytic leukemia (CLL). However, rates of complete response (CR) are relatively low (up to 7%) as are overall responses (approximately 65%) with Chl. In this study we assessed the feasibility of adding R to Chl in order to improve outcomes. Methods Previously untreated patients with CLL who required therapy according to IWCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1-7; 10mg/m2/day p.o.) repeated every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in patients with continuing clinical response at 6 cycles. The primary endpoint was the adverse event (AE) profile. Secondary endpoints included response rates, progression-free and overall survival and assessment of minimal residual disease. Efficacy results from this study were compared with historical data from patients in the UK LRF CLL4 study who received Chl at the same dose but as monotherapy between 1999 and 2004. Each of the 50 patients in the Chl-R trial were matched to 3 patients from the CLL4 trial by Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age. Results This is a planned interim analysis (IA) based on the first 50 patients out of the total 100 patients from 12 centres. Of these 47 patients were evaluable (2 missing bone marrow at time of IA; 1 protocol violation received only 1 cycle). The median age of patients was 70.5 years (range 48–86), 62% were male and 52% had Binet stage C CLL. The most common AEs were gastrointestinal disorders. There were 25 serious AEs (SAEs) reported in 17 patients. The most common SAEs were infections (10 SAEs, in 6 patients). Additionally there were 3 SAEs (in 3 patients) of febrile neutropenia – grade 3 or 4 neutropenia was reported in 40% of patients. Overall response rate on an intent-to-treat analysis was 84%. When compared with the well matched subset of Chl patients from the UK LRF CLL4 study, the overall response rate was 17.3% higher (95% CI 4.7% - 30.0%), indicating that the Chl-R patients have improved responses. Conclusions Based on this planned interim analysis, the addition of R to Chl is a feasible combination with no unexpected AEs. The combination of R and Chl was effective for untreated patients with CLL. It is important to note that the median age of patients in this study was considerably greater than the median age of patients in the UK LRF CLL4 and other large trials in CLL, and more representative of the typical age of patients presenting with CLL in the clinic. The combination of R and Chl was well-tolerated and effective for untreated patients with CLL who cannot tolerate a more intensive regimen, and suggest investigation in a Phase III study is warranted. Disclosures Hillmen: Alexion Pharmaceuticals: Consultancy; F.Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Schering: Consultancy. Hayward:F.Hoffmann-La Roche Ltd: Former Employee.

AOP2014, a Novel Peg-Proline-Interferon Alpha-2b with Improved Pharmacokinetic Properties, Is Safe and Well Tolerated and Shows Promising Efficacy in Patients with Polycythemia Vera (PV)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 175-175 ◽  
Author(s):  
Heinz Gisslinger ◽  
Robert Kralovics ◽  
Bettina Gisslinger ◽  
Daniel Lechner ◽  
Veronika Buxhofer-Ausch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Iii ◽  
Molecular Response ◽  
Overall Response ◽  
Long Term Treatment

Abstract Abstract 175 AOP2014 is a next generation long-acting pegylated IFNa-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. AOP2014 has a distinct pharmacokinetic and pharmacodynamic profile which may potentially allow reduced dosing frequencies compared to other pegylated IFNs. This is being expected to result in improved tolerability, better compliance, and, finally, favorable long-term treatment outcomes. AOP2014 is a designated Orphan Drug in EU for treatment of patients with PV. The maximum tolerated dose (MTD), long term safety and efficacy of AOP2014, administered subcutaneously every 14 days, are the main objectives of the study. Patients with confirmed PV diagnosis, age equal or older 18 years, both naïve and cytoreduction pre-treated are eligible. After establishing the MTD, an extended cohort of 25 additional patients was planned to be recruited. European LeukemiaNet criteria were used for response assessment. 34 patients, treated by March 31, 2012 were included into this analysis: 25 in Phase I (dose-finding) and 9 in the Phase II (cohort extension). Median time from diagnosis was 24 months (range 0–180). 12 patients (35%) were HU pre-treated (mean past duration of HU pre-treatment 39 months, mean daily HU dose 950 mg). Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 21 patients (62%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (32%) had a history of thrombotic complications. Median Hct at baseline was 42% (range 36–51). Median WBC and platelet counts were 10.6*109/l (range 3.9–20.4) and 452*109/l (range 141–1019), respectively. 17 patients (50%) had splenomegaly at baseline. The median reported treatment duration was 41 weeks (range: 1 day – 80 weeks), 11 patients completed 1 year on treatment. Doses from 50 to 540 ug every two weeks were tested, 540 ug has been concluded as MTD as the highest tested dose, since no DLTs occurred in the study. The mean administered dose (both Phase I and II patients) was 287 ug. After 28 weeks of treatment (21 evaluable patients), 71% of patients had hematological response (7 CR, 33%; 8 PR, 38%), at week 36 (19 evaluable patients) 8 patients (42%) achieved a CR and 8 patients (42%) a PR, overall response rate (ORR, CR+PR) was 84%. At week 52 (1 year; 11 evaluable patients), 5 patients (46%) had CR and 5 (46%) PR, ORR was 91%; 8 (73%) patients presented with completely normalized blood values, all evaluable patients were phlebotomy free at this timepoint. 4 patients (of 12 evaluable for this measurement, 33%) had still enlarged spleen at week 52. At week 76, 2 evaluable patients were complete responders. At week 52, 1 patient (of 9 evaluable, 11%) developed partial molecular response, at week 68 3 patients (of 7 evaluable, 43%) had partial molecular response. One patient with allelic burden of 22% at baseline developed complete molecular response at week 36 (still ongoing). Mainly grade 1 and 2 adverse events were reported. A total of 358 adverse events occurred. 27 patients (79%) suffered from drug-related adverse events. 9 patients (26%) developed serious adverse events; 4 SAEs were considered to be treatment related. 5 patients (15%) discontinued their study participation prematurely, 3 of them due to adverse events (deterioration of underlying disease and two cases of depression). Acceptable tolerability and durable clinical benefits have been demonstrated in PV patients measured as overall response rate of above 90% with CRs of 46% at one year after treatment start. Phlebotomy independence and normalization of hematological parameters could be seen in most of the patients. The study continues to recruit and collect long term follow up information. Presented data support further development of AOP2014 in PV, a Phase III study is planned to start early 2013. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Lechner:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

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

Blood ◽  
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.

Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer.

1997 ◽  
Vol 15 (4) ◽  
pp. 1470-1477 ◽  
Author(s):  
N A Dawson ◽  
W D Figg ◽  
M R Cooper ◽  
O Sartor ◽  
R C Bergan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Poor Prognosis ◽  
Metastatic Prostate Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Karnofsky Performance Status ◽  
Severe Disease ◽  
Performance Status ◽  
Phase Iii ◽  
Overall Response

PURPOSE To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

scholarly journals Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987

2012 ◽  
Vol 30 (10) ◽  
pp. 1107-1113 ◽  
Author(s):  
Joaquim Bellmunt ◽  
Hans von der Maase ◽  
Graham M. Mead ◽  
Iwona Skoneczna ◽  
Maria De Santis ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Statistical Significance ◽  
Locally Advanced ◽  
Phase Iii ◽  
Primary Tumors ◽  
Overall Response ◽  
Metastatic Urothelial Cancer ◽  
Phase Iii Study

PurposeThe combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival.Patients and MethodsWe conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity.ResultsFrom 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio [HR], 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as was the case in patients with bladder primary tumors. PFS was not significantly longer on PCG (HR, 0.87; P = .11). Overall response rate was 55.5% on PCG and 43.6% on GC (P = .0031). Both treatments were well tolerated, with more thrombocytopenia and bleeding on GC than PCG (11.4% v 6.8%, respectively; P = .05) and more febrile neutropenia on PCG than GC (13.2% v 4.3%, respectively; P < .001).ConclusionThe addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit that did not reach statistical significance. Novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer.

scholarly journals Clofarabine with Topotecan, Vinorelbine, and Thiotepa (TVTC) in Children and Young Adults with Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 79-79
Author(s):  
Kavitha Ramaswamy ◽  
Christopher Forlenza ◽  
Rachel Kobos ◽  
Peter G. Steinherz ◽  
Neerav Shukla
Keyword(s):  
Bone Marrow ◽  
Young Adults ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Overall Response Rate ◽  
Response Rate ◽  
Hematopoietic Stem ◽  
Induction Regimen ◽  
Children And Young Adults ◽  
Refractory Aml

Abstract Background: Relapsed or refractory pediatric acute myeloid leukemia (AML) is an unfortunate reality in approximately 40% of children and young adults diagnosed with AML. Therapeutic options are limited in this heavily pre-treated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. Non-anthracycline based salvage regimens are crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a Clofarabine-based regimen with Topotecan, Vinorelbine, and Thiotepa (TVTC) in a cohort of patients with AML. Herein, we report on an expanded cohort of AML patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2007. We report our center's experience using a Clofarabine-based regimen with Topotecan, Vinorelbine, and Thiotepa (TVTC), its overall response rate defined as complete remission (CR) and its use as a bridge to hematopoietic stem cell transplant (HSCT). Patients and Methods: All patients <25 years of age with relapsed/refractory AML, defined as >10% bone marrow involvement, who were treated with the phase 2 recommended schedule of TVTC were included in this analysis. Patients received the TVTC regimen with Topotecan 1 mg/m2/day (120 hour continuous infusion, Days 0-4), Vinorelbine 20 mg/m2/dose (Days 0, 7, 14), Thiotepa 15 mg/m2/dose (Day 2), and Clofarabine 40 mg/m2/day (Days 3-7). The regimen could be administered without hospitalization in patients who did not require hospitalization for other reasons. Most patients received antimicrobial prophylaxis starting on Day 8 with Levofloxacin and fungal prophylaxis with either Posaconazole or Voriconazole. GCSF 5mcg/kg/day was initiated on Day 8. Bone marrow evaluation was performed at the point of hematologic recovery to assess response. Overall response rate (ORR) was defined as complete remission (CR) plus complete remission without platelet recovery (CRp). Results: A total of 29 patients with relapsed (n=19) or refractory (n=10) AML were treated since 2007. Eight patients (28%) had prior hematopoietic stem cell transplantation (HSCT). The ORR of the entire cohort was 59% (17/29). The ORR of patients with relapsed vs. refractory disease was 74% (14/19) and 30% (3/10), respectively. Seventeen of 29 patients (59%) received TVTC as a 1st re-induction regimen with 59% (10/17) of those patients achieving a CR/CRp. The remaining 12 patients had TVTC as 2nd or greater regimen with 58% (7/12) of those patients achieving a CR/CRp. Among the 17 total responders in the cohort, 13 (76%) proceeded to HSCT. Of those who proceeded to HSCT, 8 of 13 are alive today (62%). Median time since HSCT is 66 months (range 14 to 107 months). The most common adverse effects were febrile neutropenia in 20 out of 29 patients (69%) which was Grade 3 or less, 3 of 29 patients (10%) with Grade 4 or greater febrile neutropenia requiring ICU admission. One patient developed an abdominal mucormycosis infection. One patient developed bone marrow aplasia and died due to sepsis 45 days after receiving TVTC. Conclusions: TVTC is an active regimen for children and young adults with relapsed/refractory AML, with an acceptable toxicity profile . Non-anthracycline containing salvage regimens are especially important as patients usually receive >400mg/m2 daunorubicin equivalents during frontline therapy. The majority of responders were successfully bridged to HSCT without exposure to additional anthracycline, with approximately half of these patients demonstrating long-term survival. TVTC warrants further exploration as a re-induction regimen in a larger cohort of patients with relapsed/refractory AML. Disclosures Kobos: Janssen Research & Development: Employment.

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