Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

2018 ◽  
Vol 36 (19) ◽  
pp. 1973-1980 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Barbara Eichhorst ◽  
Johannes Schetelig ◽  
Peter Hillmen ◽  
John F. Seymour ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Median Time ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Free Survival

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10−4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10−4 was achieved in this high-risk population.

scholarly journals Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma

2019 ◽  
Vol 37 (34) ◽  
pp. 3291-3299 ◽  
Author(s):  
Philippe Armand ◽  
Scott Rodig ◽  
Vladimir Melnichenko ◽  
Catherine Thieblemont ◽  
Kamal Bouabdallah ◽  
...  
Keyword(s):  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
End Points ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Duration Of Response

PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis

2019 ◽  
Vol 26 (6) ◽  
pp. 1331-1342
Author(s):  
Irena Ilic ◽  
Sandra Sipetic ◽  
Jovan Grujicic ◽  
Milena Ilic
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival

Introduction Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. Material and methods A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. Results The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79–0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69–1.01), p = 0.06 and OR = 1.46 (95% CI 0.90–2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16–66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23–3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28–1.87, p < 0.00001). Conclusions The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

scholarly journals FCR achieves long-term durable remissions in patients with IGHV-mutated CLL

Blood ◽  
2017 ◽  
Vol 130 (21) ◽  
pp. 2278-2282 ◽  
Author(s):  
Chatree Chai-Adisaksopha ◽  
Jennifer R. Brown
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Randomized Trials ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Inclusion Criteria ◽  
Free Survival

Abstract In chronic lymphocytic leukemia (CLL) patients with mutated IGHV, 3 recent studies have demonstrated prolonged progression-free survival (PFS) after treatment with fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy. We performed a systematic review to assess the benefit of FCR for patients with CLL and identified 5 randomized trials that met our inclusion criteria. FCR improved complete remission, PFS and overall survival vs the comparator; median PFS was not reached in the subgroup of CLL patients with mutated IGHV.

Clinical effectiveness of bevacizumab in patients with recurrent brain tumours: A population-based evaluation

2016 ◽  
Vol 24 (1) ◽  
pp. 33-36 ◽  
Author(s):  
Mário L de Lemos ◽  
Adeline Markarian ◽  
Esther Chan ◽  
Kimberly Schaff ◽  
Susan Walisser
Keyword(s):  
Overall Survival ◽  
Disease Progression ◽  
Brain Tumour ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
The United States ◽  
Free Survival ◽  
Recurrent Brain Tumour

Background Bevacizumab is an antiangiogenic agent active in patients with recurrent malignant gliomas. However, evidence for its clinical efficacy is relatively limited so that bevacizumab is approved for this indication in Canada and the United States, but not in the European Union. We reviewed the effectiveness of bevacizumab in patients with recurrent brain tumour using a large population database. Methods This was a retrospective, multicentre, study conducted at the BC Cancer Agency, a public cancer care organisation for the residents of the Canadian province of British Columbia. Cases were identified from the provincial registry and drug database. Patients were eligible if they were treated with bevacizumab with or without lomustine or etoposide for recurrent brain tumour between April 2011 and March 2014. The primary end points were progression-free survival. Secondary endpoints were overall survival and objective response rate. Results A total of 160 patients were included, with a median age of 55 years. The most common diagnosis was glioblastoma multiforme (70.6%), followed by oligodendroglioma (10.6%). Half of the patients had prior metronomic dosing of temozolomide. The median duration of therapy was 3 months. The median progression-free survival was 4.0 months and the 6-month progression-free survival was 29.4%. The median overall survival was 7 months and the 9-month and 12-month overall survival was 28.1% and 20.6%, respectively. The objective response rate was 23.1%. The most common documented reason for bevacizumab discontinuation was disease progression (66.9%), followed by toxicity (6.9%). Conclusions Bevacizumab therapy seems to be effective in delaying disease progression in patients with recurrent brain tumour, but with limited benefits on the overall survival, when used outside the clinical trial setting.

A dose attenuated schedule of irinotecan and capecitabine in combination with celecoxib in advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3584-3584
Author(s):  
B. F. El-Rayes ◽  
A. F. Shields ◽  
U. Vaishampayan ◽  
L. K. Heilbrun ◽  
M. M. Zalupski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Chemotherapeutic Agents ◽  
Free Survival ◽  
Study Results ◽  
Cox 2

3584 Background: The cyclooxygenase-2 (COX-2) enzyme is overexpressed in the majority of colorectal cancers. Inhibition of the COX-2 enzyme can sensitize colorectal cancer cells to the apoptotic effects of chemotherapeutic agents and block angiogenesis. This phase II study was undertaken to determine the effects of adding celecoxib to a dose attenuated irinotecan and capecitabine regimen. Methods: The primary objective was to estimate the objective response rate of patients with metastatic colorectal cancer treated with irinotecan, capecitabine, and celecoxib. Previously untreated patients, except for adjuvant therapy, with metastatic colorectal adenocarcinoma were eligible for this study. Patients received irinotecan 70 mg/m2 (over 30 minutes) on days 1 and 8, and capecitabine 2,000 mg/m2/day from day 1 to 14 of a 21-day cycle. Celecoxib was administered at a dose of 400 mg twice-daily starting on day -7 until termination from study. Results: A total of 51 patients (median age 58 years) have been enrolled on the study. The results presented are for the first 48 patients registered to the study. Median performance status was 1. A median number of 5.5 cycles (range 0- 18) were administered. In an intention to treat analysis, objective response rate was 50%. The median progression free survival was 6.9 months (90%CI; 4.7–8.2). Median survival is ≥19.4 months. No treatment related deaths were observed. The only grade 4 toxicity was diarrhea in 2 (4%) patients. Grade 3 toxicities were diarrhea (33%), hand-foot syndrome (8%), nausea (13%), vomiting (8%) and neutropenia (12%). Conclusion: Lowering the dose intensity of irinotecan in this study did not appear to compromise the treatment outcome and markedly improved the therapeutic index of this combination. Celecoxib can be safely administered in combination with irinotecan and capecitabine. Based on the observed progression free survival and response rate, the regimen has promising activity. No significant financial relationships to disclose.

Phase Ib trial of gemcitabine with yttrium-90 in patients with hepatic tumors of pancreatobiliary origin.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 460-460
Author(s):  
Hyun S Kim ◽  
Juan C. Camacho ◽  
Bassel F. El-Rayes
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Objective Response Rate ◽  
Response Rate ◽  
Liver Tumors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Hepatic Tumors ◽  
Free Survival ◽  
Yttrium 90

460 Background: The rationale for combining Gemcitabine (G) with Yttrium-90 (Y90) is based on G being a potent radio sensitizer and activity of Y90 against liver tumors of pancreatobiliary histology. Therefore, a safety and efficacy trial of adding G to Y90 is required. Methods: Eligibility: Chemo-naïve patients with histologic diagnosis of unresectable PC or CC with liver predominant disease. Design: Open label phase I design with 3+3 G dose escalation. Induction G on Day 1 followed by Y90 on Day 2 and subsequent pre-assigned dose levels of G until week 12. Primary objective: To determine the maximal tolerated dose of G that can be used in combination with Y90. Secondary objectives: To characterize the toxicity, evaluate hepatic progression free survival (HPFS); determine tumor response rate using RECIST and PERCIST criteria; determine the progression free survival (PFS) and overall survival (OS). Correlative Imaging: 18-FDG PET/CT with contrast at baseline and 12 weeks. Results: 14 patients were recruited and 8 met the inclusion criteria. Seven out of eight patients tolerated the dose escalation regime of G (dose level 1-400 and dose level 2-600mg/m2). All the patients developed grade 1 toxicities (Hepatobiliary 25%, Bone marrow 25%, Fatigue 100%). Three patients (37.5 %) had grade 2 hepatobiliary toxicity and one patient (12.5 %) had grade 3 hepatobiliary toxicity, which required short-term hospitalization. No radiation pneumonitis, gastrointestinal ulceration, or procedure-related mortality occurred. Six patients (75%) developed grade 1 toxicity (fatigue). All of the patients had SD in the liver by RECIST; the objective response rate was 62.5% by PERCIST (CR12.5%, PR50%, SD25% PD12.5%). Overall objective response rate was 0% by RECIST (SD62.5%, PD37.5%); and 50% for PERCIST (CR12.5%, PR37.5%, SD12.5%, PD37.5%). The median OS from diagnosis was 13.8 months (95% CI, 9.65 to 26.29 months) and from Y90 therapy 10.9 months (95% CI, 6.47 to 22.39 months). PFS was 6.92 months (95%CI, 4.37-16.5 months) and HPFS of 8.72 months (95%CI, 4.48-19.36 months). Conclusions: In patients with hepatic tumors of pancreatobiliary origin, Gemcitabine at 600mg/m2 with Y90 therapy appears to be a viable and safe therapy. Clinical trial information: NCT01434459.

scholarly journals A Phase II trial of Ofatumumab and Complement Replacement in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

2019 ◽  
Author(s):  
Joseph M Tuscano ◽  
Christina Poh ◽  
Aaron S Rosenberg ◽  
Brian A. Jonas ◽  
Gustavo Barisone ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Fresh Frozen Plasma ◽  
Lymphocytic Leukemia ◽  
Complement Activity ◽  
Fresh Frozen ◽  
Low Levels

Abstract Background: While many humanized monoclonal antibodies utilize complement dependent cytotoxicity, the complement depleting effects of these antibodies and the effect of complement replacement are not well-described. This study sought to examine complement levels and the effect of complement repletion after treatment with ofatumumab in patients with chronic lymphocytic leukemia (CLL). Methods: Twelve patients with relapsed or refractory CLL were treated with ofatumumab in combination with fresh frozen plasma used as complement replacement. The primary endpoint was objective response rate. Correlative endpoints included complement levels C3 and C4 and complement activity. Results: Adverse events were minimal, and efficacy was encouraging with an overall response rate of 83% and 2 patients (17%) achieving a complete response. While only 2 (17%) of patients had low complement activity at baseline, 8 (67%) developed low levels of complement activity. At a median follow-up time of 37 months the median progression-free survival was 12.5 months. Conclusions: While a minority of patients had low complement activity at baseline, a majority developed low levels of complement with ofatumumab treatment. The magnitude of complement depletion did not correlate with response. Future trials are needed to further explore complement replacement as a less toxic strategy to improve efficacy of monoclonal antibody-based regimens in CLL.

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