Exploring Indicators of Hepatotoxicity-Related Post-Marketing Regulatory Actions: A Retrospective Analysis of Drug Approval Data

Background: Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders such as drug regulatory authorities. Objective: To explore the potential of drugs, pre-approval regulatory factors as predictors for the occurrence of hepatotoxicity-related post-marketing regulatory actions. Pre-approval factors were specified as: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. Methods: Using publicly accessible FDA data, we examined clinical review documents for drugs approved in the USA during the period from 2011 to 2016 to evaluate their hepatic safety profile, identifying the 3 specified indicators for analysis. Predictors (Covariates): We assessed whether these medications meet: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. Outcome (Dependent Variable): Post-marketing regulatory action related to hepatotoxicity including products withdrawal and updates to either warning, precaution or adverse effects sections. Statistical Analysis: Drugs that were approved between 2011 and 2016 were included in the analysis with follow-up time from the date of approval until end of December 2019 or the date of first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. Results: A total of 192 medications were included in the study. We classified 48 drugs with grade ≥3 hepatotoxicity, 43 with accelerated approval status, and 74 with labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17–2.23), 0.92 (95% CI, 0.29–2.93) for drug approved via accelerated approval program, and 0.91 (95% CI, 0.33–2.56) for drugs with labeled hepatotoxicity information at approval time. Conclusion: Hy’s Law with hepatotoxicity grade ≥3, accelerated approval, and label information on hepatotoxicity were not identified as predictors for post-marketing additional regulatory actions concerning liver adverse effects. However, the evidence is inconclusive due to small sample size and potential channeling bias.

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Association of Particulate Matter with Autoimmune Rheumatic Diseases among Adults in South Korea

Rheumatology ◽

10.1093/rheumatology/keab127 ◽

2021 ◽

Author(s):

Jun Seok Park ◽

Seulggie Choi ◽

Kyuwoong Kim ◽

Jooyoung Chang ◽

Sung Min Kim ◽

...

Keyword(s):

Particulate Matter ◽

Adverse Effects ◽

South Korea ◽

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Cox Regression ◽

Statistical Significance ◽

Cox Regression Analysis ◽

Autoimmune Rheumatic Diseases ◽

Quartile Group

Abstract Objective The primary objective is to investigate adverse effects of ambient particulate matter (PM) in various size on the incidence of prevalent autoimmune rheumatic diseases (AIRDs): Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), and Systemic Lupus Erythematosus (SLE). Methods We investigated 230,034 participants in three metropolitan cities of South Korea from the National Health Insurance Service-National Sample Cohort (NHIS-NSC). Starting from January 2010, subjects were followed up until the first event of prevalent AIRDs, death, or December 2013. 2008-2009 respective averages of PM2.5 (< 2.5μm) and PMcoarse (2.5μm to 10μm) were linked with participants’ administrative district codes. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis in one- and two-pollutant model. Results Adjusted for age, sex, region, and household income in two-pollutant model, RA incidence was positively associated with 10μg/m³ increment of PM2.5 (aHR = 1.74, 95% CI: 1.06-2.86), but not with PMcoarse (aHR = 1.27, 95% CI: 0.87-1.85). In one-pollutant model, an elevated incidence rate of RA was slightly attenuated (PM2.5 aHR = 1.61, 95% CI: 0.99-2.61; PMcoarse aHR = 1.13, 95% CI: 0.80-1.61), with marginal statistical significance of PM2.5. RA incidence was also higher in 4th quartile group of PM2.5 compared to 1st quartile group (aHR = 1.83, 95% CI: 1.07-3.11). No adverse effects of PM were found on AS or SLE in one- and two-pollutant models. Conclusion Important components of PM10 associated with RA incidence were fine fractions (PM2.5), while no positive association was found between PM and AS or SLE.

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Short-term outcomes associated with temozolomide or PCV chemotherapy for 1p/19q-codeleted WHO grade 3 oligodendrogliomas: a national evaluation

Neuro-Oncology Practice ◽

10.1093/nop/npac004 ◽

2022 ◽

Author(s):

Nayan Lamba ◽

Malia McAvoy ◽

Vasileios K Kavouridis ◽

Timothy R Smith ◽

Mehdi Touat ◽

...

Keyword(s):

Cox Regression ◽

Extent Of Resection ◽

First Line ◽

Short Term ◽

Who Grade ◽

Cox Regression Analysis ◽

Significant Difference ◽

Pcv Chemotherapy ◽

Grade 3 ◽

National Analysis

Abstract Background The optimal chemotherapy regimen between temozolomide and procarbazine, lomustine, and vincristine (PCV) remains uncertain for W.H.O. grade 3 oligodendroglioma (Olig3) patients. We therefore investigated this question using national data. Methods Patients diagnosed with radiotherapy-treated 1p/19q-codeleted Olig3 between 2010-2018 were identified from the National Cancer Database. The OS associated with first-line single-agent temozolomide vs. multi-agent PCV was estimated by Kaplan-Meier techniques and evaluated by multivariable Cox regression. Results 1,596 radiotherapy-treated 1p/19q-codeleted Olig3 patients were identified: 88.6% (n=1,414) treated with temozolomide and 11.4% (n=182) with PCV (from 5.4% in 2010 to 12.0% in 2018) in the first-line setting. The median follow-up was 35.5 months (interquartile range [IQR] 20.7-60.6 months) with 63.3% of patients alive at time of analysis. There was a significant difference in unadjusted OS between temozolomide (5yr-OS 58.9%, 95%CI: 55.6-62.0) and PCV (5yr-OS 65.1%, 95%CI: 54.8-73.5; p=0.04). However, a significant OS difference between temozolomide and PCV was not observed in the Cox regression analysis adjusted by age and extent of resection (PCV vs. temozolomide HR 0.81, 95%CI: 0.59-1.11, p=0.18). PCV was more frequently used for younger Olig3s, but otherwise was not associated with patient’s insurance status or care setting. Conclusions In a national analysis of Olig3s, first-line PCV chemotherapy was associated with a slightly improved unadjusted short-term OS compared to temozolomide; but not following adjustment by patient age and extent of resection. There has been an increase in PCV utilization since 2010. These findings provide preliminary data while we await the definitive results from the CODEL trial.

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Five-Year Outcomes of Stereotactic Body Radiation Therapy (SBRT) for Prostate Cancer-The Largest Experience in China

10.21203/rs.3.rs-190455/v1 ◽

2021 ◽

Author(s):

Xianzhi Zhao ◽

Yusheng Ye ◽

Haiyan Yu ◽

Lingong Jiang ◽

Chao Cheng ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Cox Regression ◽

Progression Free Survival ◽

Cox Regression Analysis ◽

Gu Toxicity ◽

Biochemical Progression ◽

Grade 3 ◽

Very High

Abstract Objective To evaluate the efficacy and toxicity of SBRT for localized prostate cancer (PCa). Moreover, it is the largest-to-date pilot study to report 5-year outcomes of SBRT for localized PCa from China. Methods In this retrospective study, 133 PCa patients in our center were treated by SBRT with CyberKnife (Accuray) from October 2012 to July 2019. Follow-up was performed every 3 months for evaluations of efficacy and toxicity. Biochemical progression-free survival (bPFS) and toxicities were assessed using the Phoenix definition and the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 respectively. Factors predictive of bPFS were identified with COX regression analysis. Results 133 patients (10 low-, 21 favorable intermediate-, 31 unfavorable intermediate-, 45 high-, and 26 very high risk cases on the basis of the NCCN risk classification) with a median age of 76 years (range: 54–87 years) received SBRT. The median dose was 36.25Gy (range: 34-37.5Gy) in 5 fractions. Median follow-up time was 57.7 months (3.5–97.2 months). The overall 5-year bPFS rate was 83.6% for all patients. The 5-year bPFS rate of patients with low-, favorable intermediate-, unfavorable intermediate-, high-, and very high risk PCa was 87.5%, 95.2%, 90.5%, 86.3%, and 61.6% respectively. Urinary symptoms were all alleviated after SBRT. All the patients tolerated SBRT with only 1 (0.8%) and 1 (0.8%) patient reporting grade-3 acute and late genitourinary (GU) toxicity, respectively. There were no grade 4 toxicities. Gleason score (P < 0.001, HR = 7.483, 95%CI: 2.686–20.846) was the independent predictor of bPFS rate after multivariate analysis Conclusion SBRT is an efficient and safe treatment modality for localized PCa with high 5-year bPFS rates and acceptable toxicities.

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Effectiveness and safety of eribulin in Japanese patients with HER2-negative, advanced breast cancer: a 2-year post-marketing observational study in a real-world setting

Investigational New Drugs ◽

10.1007/s10637-019-00890-5 ◽

2020 ◽

Vol 38 (5) ◽

pp. 1540-1549

Author(s):

Kenichi Inoue ◽

Masato Takahashi ◽

Hirofumi Mukai ◽

Takashi Yamanaka ◽

Chiyomi Egawa ◽

...

Keyword(s):

Breast Cancer ◽

Observational Study ◽

Confidence Interval ◽

Advanced Breast Cancer ◽

Advanced Breast ◽

Line Treatment ◽

Second Line ◽

Treatment Groups ◽

Post Marketing ◽

Grade 3

Summary Background Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8–17.6), 22.8 (17.3–31.0), 16.3 (12.4–19.9), and 12.6 (11.2–15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7–4.4), 5.2 (3.7–5.9), 4.2 (3.7–5.1), and 3.8 (3.5–4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan.

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Post marketing surveillance of suspected adverse drug reactions through spontaneous reporting: current status, challenges and the future

Therapeutic Advances in Drug Safety ◽

10.1177/2042098620938595 ◽

2020 ◽

Vol 11 ◽

pp. 204209862093859 ◽

Cited By ~ 2

Author(s):

Muaed Alomar ◽

Ali M Tawfiq ◽

Nageeb Hassan ◽

Subish Palaian

Keyword(s):

Adverse Effects ◽

Health Professionals ◽

Healthcare Professionals ◽

Spontaneous Reporting ◽

Future Prospects ◽

Innovative Strategies ◽

Post Marketing Surveillance ◽

The Future ◽

Post Marketing ◽

Reporting Programs

Background: To highlight the importance of spontaneous reporting programs in post marketing surveillance of medicines. Authors also aimed at providing various dimensions of spontaneous programs, including the strengths and weakness, and providing an insight on the future prospects of pharmacovigilance systems. Methods: Various literature related to post marketing surveillance and spontaneous reporting programs were reviewed and the relevant ones highlighting the strengths and weaknesses are summarized. A balance of information on strengths and weaknesses is listed. The health professionals’ awareness regarding existing spontaneous reporting programs is highlighted. Future prospects of pharmacovigilance are discussed. Results: Though beneficial, spontaneous reporting programs encounter several limitations and difficulties in diagnosing adverse drug reaction. Under-reporting and bias are major challenges. Online signal detection tools and innovative methods are needed to strengthen the spontaneous reporting programs. We provide the various issues to be considered while depending on spontaneous reporting programs as a method of post marketing surveillance. Conclusion: To strengthen the spontaneous reporting programs as an effective post marketing surveillance method, more awareness among health professionals and innovative strategies is needed. Integrating pharmacogenetic data can be a potential aspect of future pharmacovigilance. Plain language summary Monitoring adverse effects of marketed medicines through reporting by healthcare professionals and its challenges and way forward Introduction: This article highlights the importance of safety monitoring of medicines after they are launched in the market, mainly through reporting by healthcare professionals. We also highlight the strengths and weaknesses, and provide an insight on the future prospects of pharmacovigilance systems. Methods: Various literature related to the topic were reviewed and the relevant ones highlighting the strengths and weaknesses are summarized. A balance of information on strengths and weaknesses is listed. Health professionals’ awareness regarding existing programs on reporting safety of medicines is highlighted. Results: Though beneficial, reporting of adverse effects by healthcare professionals who deal with patient lacks clarity in diagnosing the adverse effects. Under-reporting and bias are the major challenges. Online software is needed to strengthen reporting by healthcare professionals. We list the various issues to be considered while depending on healthcare professionals’ reporting of adverse effects as a method of post marketing surveillance. Conclusion: To strengthen medicine safety monitoring and reporting by healthcare professionals, more awareness among health professionals and innovative strategies are needed. Integrating the genetic data of patients can be beneficial in predicting adverse effects, therefore avoiding them and enhancing safe prescribing and dispensing by healthcare professionals.

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Use of Machine-Learning Algorithms in Intensified Preoperative Therapy of Pancreatic Cancer to Predict Individual Risk of Relapse

Cancers ◽

10.3390/cancers11050606 ◽

2019 ◽

Vol 11 (5) ◽

pp. 606 ◽

Cited By ~ 3

Author(s):

Pablo Sala Elarre ◽

Esther Oyaga-Iriarte ◽

Kenneth H. Yu ◽

Vicky Baudin ◽

Leire Arbea Moreno ◽

...

Keyword(s):

Machine Learning ◽

Pancreatic Cancer ◽

Learning Algorithms ◽

Small Sample ◽

Machine Learning Algorithms ◽

Individual Risk ◽

Relapse Risk ◽

Grade 3 ◽

Risk Of Relapse

Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse. Methods: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques. Results: A R0 resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56–0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset. Conclusion: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations.

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Brigatinib: Novel ALK Inhibitor for Non–Small-Cell Lung Cancer

Annals of Pharmacotherapy ◽

10.1177/1060028018824578 ◽

2019 ◽

Vol 53 (6) ◽

pp. 621-626 ◽

Cited By ~ 7

Author(s):

Sara A. Spencer ◽

Angela C. Riley ◽

Adia Matthew ◽

Anthony J. Di Pasqua

Keyword(s):

Lung Cancer ◽

Adverse Effects ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

English Language ◽

Small Cell ◽

Small Cell Lung ◽

Once Daily ◽

Anaplastic Lymphoma ◽

Accelerated Approval

Objective: We review here the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions and place in therapy of brigatinib for abnormal anaplastic lymphoma kinase (ALK) specific non–small-cell lung cancer (NSCLC). Data Sources: A literature search using PubMed was conducted using the terms brigatinib and ALK positive NSCLC from January 2013 to November 2018. Study Selection and Data Extraction: All English-language articles evaluating brigatinib were analyzed for this review. Data Synthesis: Brigatinib was granted approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. It is administered at a dose of 90 mg orally once daily for the first 7 days then, if tolerated, increased to a dose of 180 mg orally once daily. Common adverse effects include nausea, fatigue, diarrhea, increased creatine phosphokinase levels, headache, dyspnea, and hypertension. Serious treatment-emergent adverse effects were pulmonary related. Relevance to Patient Care and Clinical Practice: This article discusses the clinical trials that led to the accelerated approval of brigatinib for its ability to overcome crizotinib-resistant mutations and for its increased central nervous system penetration properties. Conclusion: Brigatinib was granted accelerated approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In a subset of NSCLC patients, brigatinib increases survival for approximately 1 year; however, side effects were detected.

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Response to Bortezomib in Combination after Relapse o Non-Response to First Treatment with Bortezomib Alone in Myeloma Multiple Patients.

Blood ◽

10.1182/blood.v108.11.5094.5094 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5094-5094

Author(s):

Araceli Rubio-Martinez ◽

Valle Recasens ◽

Pilar Delgado ◽

Juan Carlos Garcia-Zueco ◽

Daniel Rubio-Felix ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Effects ◽

Adverse Events ◽

Second Line ◽

Dexamethasone Group ◽

Limited Experience ◽

Grade 3 ◽

Multiple Patients ◽

Grade Iii

Abstract Background: Bortezomib has been shown to be effective in multiple myeloma (MM), but there is a limited experience in response to re-treatment. Aims: To evaluate the efficacy of Bortezomib in refractory/relapsed MM. Patients and methods: 41 patients treated with Bortezomib (1,3 mg/m2 on days 1,4,8,11 in a 21-day cycle) in second or more line as clinical practice protocol were included. The response was evaluated according EGBMT criteria (Bladé J, Samson D, Reece E et al). Patients that no have reached response after 4 courses or relapsed after CR or PR received a combination of: bortezomib+dexamethasone (group BD) or bortezomib+melphalan+prednisone (group BMP). Adverse effects were registered. Results: 39 valuable patients (males 43.0%). Mean age 59.9 years (34–82), over 65 years (66.6%). Bortezomib was administered in second line: 10 (25.6%), in third or more: 29 (74.3%). Overall Response: 76.4%: (CR+PR 70.5%, MR 5.9%), (CR 41.1%/CR-IFE negative 14.7%), Mean courses to reached response: 4.7. No relation to response and presence or not chromosomal aberrations. At 32 months on follow-up 9 patients had dead (26.4%) and 15 (44.1%) maintained response without therapy. In 17 patients (43.5%), a combination of BD (10 patients) or BMP (7 patients) were administrated by relapse or progression. Responses: group BD 6 PR, 3 NR; 1NV group BM P 3 PR, 3 NR, 1NV. Adverse events: thrombocytopenia 38.4 (grade III: 17.9), fatigue 38.5%, peripheral neuropathy 33.3, constipation 35.8%, diarrhea 20.5%, ZHV 12.8%, infection 33.3, pyrexia 10.2%, hypotension 5.1%, grade 3 leucopenia 12.8%. In 3 patients (7.6%) the therapy was disrupted by toxicity. We haven’t found any differences in adverse events in patients treated with bortezomib in combination. Conclusions: Related to the synergism of Bortezomib in combination, the re-treatment induces response (60%) in refractory MM without severe adverse effects. In spite of the scarce follow-up some patients could be benefit in re-treatment with Bortezomib. It is necessary to explore more combinations and to know the results of clinical trials. When there is not response after the 4th course of Bortezomib it is recommendable to use in combination

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Toxicity of Bortezomib: Is There An Influence of Application Rates of Doxorubicin and Dexamethason Administration?a Clinical Monitoring

Blood ◽

10.1182/blood.v112.11.5221.5221 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5221-5221

Author(s):

Wolfram Steinborn ◽

Wolfgang Stein ◽

Sandra Klebe ◽

Michael Kiehl

Keyword(s):

Adverse Effects ◽

Autologous Transplantation ◽

Toxic Shock ◽

Peripheral Neuropathic Pain ◽

Application Rates ◽

Wide Range ◽

Acute Renal Insufficiency ◽

The Mean ◽

Grade 3 ◽

Anti Tumor Activity

Abstract Background: Bortezomib has shown significant anti-tumor activity in multiple myeloma. There are varied protocols including bortezomib, doxorubicin and dexamethason with different application rates. We observed in a retrospective analysis a wide range of toxicity, so that we have to modified our standard approach. The purpose of our analysis was to assess the frequency of toxicity and their alteration after changing the protocol. Patients and methods: Eleven patients were treated for two 28-day cycles using our standard protocol. Bortezomib was given at 1.3 mg/m2 (days 1,4,8,11) and dexamethason at 40 mg (days 1–4, 9–12, 17–20) as well as doxorubicin at 9 mg/m2 (days 1–4). Seven patients received a third modified cycle composed of Bortezomib at 1.3 mg/m2 (days 1,4,8,11), dexamethason at 40 mg days 1–4 and doxorubicin at 20 mg/m2 days 1 and 4. Results: One patient had unergone prior autologous transplantation, the other ten patients (90%) were newly diagnosed. All patients reported moderate peripheral neuropathic pain during the first two cycles. Eight patients (72%) developed severe adverse effects, twenty-five percent during the first cycle and seventy-five percent after the second one. The age of the affected patients range from 65 to 77 years (average age 70.5 years), the mean age of the unaffected is 64.7 years (54 to 72 years). Grade 3–4 toxic effects included infections (100%), neutropenia (25%), acute renal insufficiency (25%) and pulmonary edema (1 patient). Within the group of infections a pneumonia were diagnosed in six patients (75%), herpes zoster in two patients (25%) and an erysipelas in one patient. Two patients (25%) with pneumonia are died from a septic-toxic shock. The seven patients receiving the modiefied third cycle were without any grade 3–4 toxicity. Conclusions: The age seems to have an influence on adverse effects (p=0.19) but there is a high significant benefit concerning the toxicity of bortezomib depending on application rates of doxorubicin and dexamethason.

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Long-Term Outcomes and Safety of Continuous Lenalidomide Plus Dexamethasone (Len+Dex) Treatment in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v118.21.2929.2929 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2929-2929 ◽

Cited By ~ 1

Author(s):

Meletios Athanasios Dimopoulos ◽

Mohamad Hussein ◽

Arlene S Swern ◽

Donna M. Weber

Keyword(s):

Dose Reduction ◽

Median Duration ◽

Cox Regression ◽

Incidence Rates ◽

Long Term Outcomes ◽

Cox Regression Analysis ◽

Β2 Microglobulin ◽

Grade 3

Abstract Abstract 2929 Background: Two pivotal phase 3 trials (MM-009 and MM-010) randomized 704 pts to assess Len+Dex vs placebo plus dexamethasone (Dex) in RRMM. The results demonstrated the significant overall survival (OS) benefit of Len+Dex vs Dex (38.0 vs 31.6 mos; p =.045) despite crossover of 48% of Dex pts to the Len+Dex arm at unblinding or progression (Dimopoulos MA et al. Leukemia 2009;23 :2147-52). This is an analysis of the long-term outcomes and safety of continuous Len+Dex treatment. Methods: This retrospective analysis pooled pts treated with Len+Dex in MM-009 and MM-010, with a median follow-up of 48 mos for surviving pts. A subset of pts with progression-free survival (PFS) of ≥ 2 yrs was selected. Prognostic factors for PFS within this subgroup of pts were identified by incorporating all baseline covariates with a univariate p <.15 into multivariate Cox regression analyses, and all possible models were fitted using SAS 9.2. Adverse event (AE) management and dosing for pts with PFS ≥ 2 yrs was compared with that for all pts treated with Len+Dex in order to evaluate if differences in pt management could contribute to better clinical outcomes. Incidence rates for AEs were calculated using person-yrs of follow-up. Data from pts who received Len+Dex in MM-009 (up to July 23, 2008) and MM-010 (up to March 2, 2008) were included in this analysis. Results: Among all pts treated with Len+Dex (N = 353), a total of 64 pts (18%) achieved PFS ≥ 2 yrs. For these 64 pts, median age was 61 yrs (range 33–81 yrs), 48% received > 1 prior therapy, and 57% had β2-microglobulin levels of ≥ 2.5mg/L. All these pts achieved a ≥ partial response (PR), including 67% with a ≥ very good PR and 50% with a complete response. Median time to first response was 2.8 mos (range 1.9–18.2 mos) which is comparable to that of all pts treated with Len+Dex. Median duration of response was not reached vs 15.5 mos, respectively. With median follow-up of 49 mos, the 3-yr OS is 94% (95% confidence interval [CI] 88.06–99.94). In a multivariate Cox regression analysis, shorter PFS was predicted with higher baseline β2-microglobulin level (hazard ratio [HR] 1.07; 95% CI 1.02–1.12) and lower hemoglobin (HR 0.91; 95% CI 0.84–0.99), as well as a higher number of prior therapies (HR 1.18; 95% CI 1.02–1.37). The median duration of treatment was longer among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (46.2 mos [range 11.3–58.3] vs 9.8 mos [range 3.8–24], respectively). A higher proportion of these pts had a dose reduction within 12 mos after start of therapy vs all pts treated with Len+Dex (57% vs 24%, respectively). Dex dose was reduced in 27% of pts with PFS ≥ 2 yrs. Among pts without Len dose reduction, 31% had Dex dose reduction within the first 4 cycles. Granulocyte colony-stimulating factor was administered for the management of neutropenia in 39% of pts with PFS ≥ 2 yrs vs 25% of all pts treated with Len+Dex. Low discontinuation rates due to AEs were observed in both groups (12.5% vs 18.7%, respectively). The incidence rates per 100 person-yrs for grade 3–4 AEs among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (N = 353) were, respectively: neutropenia (14.9 vs 29), febrile neutropenia (0.9 vs 2.3), thrombocytopenia (2.6 vs 10.2), anemia (4.4 vs 9.5), infection (11.8 vs 20.9), deep vein thrombosis/pulmonary embolism (2.2 vs 8.9), fatigue (2.2 vs 5.5), neuropathy (1.8 vs 3.4), and gastrointestinal disorders (5.3 vs 9.7). The incidence rates per 100 person-yrs for second primary malignancies (SPMs) were similar to that of all pts treated with Len+Dex, respectively: myelodysplastic syndromes (0 vs 0.4), solid tumor (1.8 vs 1.3), and non-melanoma skin cancer (2.3 vs 2.4). These rates are comparable to those expected in people aged > 50 yrs generally (1.4 per 100 person-yrs) (Altekruse SF et al. SEER Cancer Statistics Review, 1975–2007). Conclusions: Long-term continuous therapy with Len+Dex has demonstrated efficacy and is generally well tolerated in pts with RRMM. Overall, 18% of patients treated with Len+Dex achieve a PFS of > 2 yrs. No increase in SPMs was observed with long term Len+Dex therapy. With appropriate AE management, the incidence rates of grade 3–4 AEs remain low. This analysis demonstrates the value of AE management and the need for appropriate dose-adjustment to maintain tolerability, allowing pts to remain on therapy for maximal benefit. Disclosures: Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Hussein:Celgene Corporation: Employment. Swern:Celgene Corporation: Employment. Weber:Celgene Corporation: Honoraria, Research Funding.

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