scholarly journals Use of Bone-Modifying Agents and Outcomes of Myeloma Therapy: A Population-Based Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 709-709 ◽  
Author(s):  
Adam J Olszewski ◽  
Peter Barth ◽  
John L. Reagan
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Propensity Score ◽  
Research Funding ◽  
Cox Model ◽  
Large Population ◽  
Intraclass Correlation ◽  
Population Based ◽  
Novel Agents ◽  
Oncology Research

Abstract Background. The International Myeloma Working Group guideline recommends administration of bone-modifying agents (BMA) for all patients starting therapy for myeloma (Terpos et al, JCO 2013). In clinical trials, BMA lower the risk of skeletal-related events (SRE), and, unexpectedly, they have improved overall survival (OS, Morgan et al, Lancet 2010). The American Society of Clinical Oncology (Anderson et al, JCO 2018) recommends use of zoledronate, pamidronate, or denosumab, however adherence to this guideline in clinical practice is unknown. Our objective was to examine the use of BMA among Medicare beneficiaries treated for myeloma, associated incidence of SRE, and OS. Methods. From the linked Medicare and Surveillance, Epidemiology, and End Results (SEER-Medicare) data base, we selected patients age ≥65 with myeloma diagnosed in 2007-2013, who had complete Medicare claims (including oral immunomodulatory anti-myeloma drugs [IMiDs]) and who received outpatient chemotherapy. We defined the "use of BMA" as administration of zoledronate, pamidronate, or denosumab within 90 days of first chemotherapy. We examined factors associated with omission of BMA in a hierarchical generalized linear model for relative risk (RR, with 95% confidence intervals, CI). To avoid guarantee-time bias and late complications, we analyzed time-to-event outcomes using time at risk between 90 days and 3 years from the start of therapy. We identified incident SRE (defined as axial or extremity fracture, or cord compression), and OS. Cumulative incidence function (CIF) of SRE was compared in a competing risk model (reporting subhazard ratio, SHR), and OS in a Cox model (reporting hazard ratio, HR). We then applied 1:1 propensity score matching to compare the average effect of BMA on SRE and OS among treated patients. We also conducted a sensitivity analysis in the subcohort of patients receiving novel agents (proteasome inhibitors and/or IMiDs) as first-line regimen. Results. Among 4,670 patients with median age 76 years (50% women), 51% received BMA (83% zoledronate, 16% pamidronate, 1% denosumab) within 90 days of the start of chemotherapy. Median number of BMA doses was 5 (interquartile range [IQR], 3-6) within 6 months, and 9 (IQR, 5-11) with 12 months from the start of chemotherapy. In a multivariable model (Table), omission of BMA was significantly more frequent (by 11-16%) among patients aged ≥80 compared with those aged <70. It also increased with the number of comorbidities, was 17% more likely among patients with chronic kidney disease, and 16% more likely in hospital-based facilities compared with physician offices. Omission of BMA was significantly less likely in patients with prior SRE (by 30%), hypercalcemia (by 25%), or use of radiation (by 30%). It was also less likely in patients treated with the combination of bortezomib and IMiD compared with other regimens. BMA use was not significantly associated with sex, race, socioeconomic or performance status, or prior use of oral bisphosphonates. We observed a weak (16.5%) intraclass correlation by treating physician. Median follow-up from start of chemotherapy was 4.6 years. SRE occurred in 729 patients, with a 3-year CIF of 13.6% (95% CI, 12.2-15.0). BMA use was associated with a lower risk of SRE in the entire analytic cohort (adjusted SHR, 0.83; 95% CI, 0.70-0.98), and in the propensity score-matched subcohort (N=3,152; SHR, 0.78; 95% CI, 0.64-0.94, Fig. A). Estimated 3-year CIF of SRE was 11.2% with BMA and 14.1% without BMA. Median OS in the entire cohort was 3.1 years (95% CI, 2.9-3.2). Receipt of BMA was associated with better OS (adjusted HR, 0.84; 95% CI, 0.77-0.92). Survival did not significantly differ between different BMAs (P=.73). Significantly better OS among patients receiving BMA was also observed in the propensity-score matched subcohort (HR, 0.88; 95% CI, 0.80-0.97; Fig. B), and in the subgroup treated with novel agents (adjusted HR, 0.85; 95% CI, 0.76-0.96). Conclusions. Despite guidelines and benefit demonstrated in clinical trials, only about half of Medicare patients actively treated for myeloma receive the recommended BMA. In this large population-based sample, using a causal inference method, we confirmed the association between the BMA use, risk of SRE, and OS. Clinicians should strive to consistently provide BMA as an important component of quality care for myeloma. Further research should address barriers to BMA use in clinical practice. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Reagan:Takeda Oncology: Research Funding; Pfizer: Research Funding; Alexion: Honoraria.

scholarly journals Novel Drugs and Clinical Trial-Based Treatments Prolong Survival of Peripheral T-Cell Lymphomas (PTCL) Patients: Single Institution Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3486-3486
Author(s):  
Helen Ma ◽  
Enrica Marchi ◽  
Bin Cheng ◽  
Govind Bhagat ◽  
Owen A. O'Connor
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
T Cell ◽  
Histone Deacetylase ◽  
Research Funding ◽  
Novel Agents ◽  
Second Line ◽  
First Line ◽  
Oncology Research ◽  
Third Line

Introduction Peripheral T-cell lymphomas (PTCL) are a group of rare and heterogeneous diseases associated with unfavorable prognoses. Conventional chemotherapy has been the standard of care, but is considered marginally effective. This outcome has been attributed to the fact that most PTCL treatments are derived from the management of aggressive B-cell lymphomas. While relapse is common, subsequent line therapies are heterogeneous, and can include many lines of non-specific chemotherapy. Recently approved novel agents, such as pralatrexate and histone deacetylase (HDAC) inhibitors, and clinical trials however, tend to either not be used or used too late in the natural history of the disease. Herein, we compared the efficacy of chemotherapy and novel therapies, in first line, second line and third line, to identify factors that might influence the outcome of PTCL patients in a single institutional cohort. Methods A search of the electronic medical record and clinical trial databases from January 1, 1994 to May 31, 2019 was performed to identify patients with PTCL. Only patients 18 years and older with pathology-confirmed PTCL and complete clinical data were included. Due to substantially different disease characteristics, behavior, and treatment, we excluded patients with T/NK large granular lymphocytic leukemia and primary cutaneous T-cell lymphoma, with the exception of transformed mycosis fungoides. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Kaplan-Meier curves were generated and compared based on the log-rank test. Cox proportional hazard models were used to investigate the association by adjusting for the type of treatments and the lines of therapy. Statistical analyses were performed with SAS version 9.4. Results There were 213 patients (1.2 males:1 female) included in the analysis with a median age of diagnosis of 56.9 years (range 18.1-90.3). Front-line therapies typically consisted of chemotherapy, including CHOP, CHOEP, and EPOCH. The use of clinical trials and novel agents increased as patients progressed through multiple lines of therapy. Figure 1A showed that patients who achieved a CR with first line chemotherapy had a better overall survival than patients who did not (median 8.9 years vs 0.83 years, p&lt;0.0001), with trends suggesting improvement in survival with novel combinations and single agents. Although limited by small numbers, patients with primary refractory or relapsed disease were generally given additional lines of chemotherapy, and the percentage of patients who achieved CR trended down more drastically (42% first line in Figure 1A, 16% second line in Figure 1D, 21% third line in Figure 1G) than patients who received novel combinations (50% first line in Figure 1B, 23% second line in Figure 1E, 30% third line in Figure 1H) or single agents (27% first line in Figure 1C, 40% second line in Figure 1F, 20% third line in Figure 1I). There were no significant differences in the frequency of radiotherapy or autologous stem cell transplantation over the study period. Our data demonstrate that exposure to novel agents (p=0.002) in Figure 2A and novel combinations (p=0.003) in Figure 2B, especially histone deacetylase inhibitors (HDACI, p=0.045) in Figure 2D, during the treatment course of PTCL patients, was associated with prolonged overall survival. Pralatrexate had a trend toward improving outcomes in the first ten years as shown in Figure 2C, but this was not statistically significant. Conclusions Clinical trials and novel therapies improve outcomes and should be considered earlier in the therapy of patients with PTCL. Patients who obtain CR early have the best overall survival. Our findings suggest that patients with R/R PTCL who fail chemotherapy should be enrolled in clinical trials or be given novel approved agents rather than repeated rounds of non-specific cytotoxic therapy. Disclosures Marchi: Spectrum Pharmaceuticals, Verastem Oncology: Research Funding. O'Connor:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding; TG Therapeutics: Other: Travel Support, Research Funding. OffLabel Disclosure: Drugs that are approved for the treatment of patients with relapsed and refractory peripheral T-cell lymphoma, such as pralatrexate (a novel antifolate) and histone deacetylase inhibitors, were used in the front line setting when patients were not candidates for chemotherapy or enrolled in clinical trials. Outcomes are also described for non-FDA approved drugs used as monotherapy or in combination in clinical trials as well as FDA approved drugs for other indications used in clinical trials are described though not explicitly listed.

Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 723-732 ◽  
Author(s):  
Marianna Prokopi ◽  
Giordano Pula ◽  
Ursula Mayr ◽  
Cécile Devue ◽  
Joy Gallagher ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mononuclear Cells ◽  
Lectin Binding ◽  
Large Population ◽  
Protein Composition ◽  
Population Based ◽  
Endothelial Progenitor ◽  
Cardiovascular Research ◽  
Proteomic Approach ◽  
Cellular Phenotypes

Abstract The concept of endothelial progenitor cells (EPCs) has attracted considerable interest in cardiovascular research, but despite a decade of research there are still no specific markers for EPCs and results from clinical trials remain controversial. Using liquid chromatography–tandem mass spectrometry, we analyzed the protein composition of microparticles (MPs) originating from the cell surface of EPC cultures. Our data revealed that the conventional methods for isolating mononuclear cells lead to a contamination with platelet proteins. Notably, platelets readily disintegrate into platelet MPs. These platelet MPs are taken up by the mononuclear cell population, which acquires “endothelial” characteristics (CD31, von Willebrand factor [VWF], lectin-binding), and angiogenic properties. In a large population-based study (n = 526), platelets emerged as a positive predictor for the number of colony-forming units and early outgrowth EPCs. Our study provides the first evidence that the cell type consistent with current definitions of an EPC phenotype may arise from an uptake of platelet MPs by mononuclear cells resulting in a gross misinterpretation of their cellular progeny. These findings demonstrate the advantage of using an unbiased proteomic approach to assess cellular phenotypes and advise caution in attributing the benefits in clinical trials using unselected bone marrow mononuclear cells (BMCs) to stem cell-mediated repair.

scholarly journals Effect of Timing and Duration of Statin Exposure on Risk of Hip or Knee Revision Arthroplasty: A Population-based Cohort Study

2019 ◽  
Vol 47 (3) ◽  
pp. 441-448 ◽  
Author(s):  
Michael J. Cook ◽  
Antony K. Sorial ◽  
Mark Lunt ◽  
Tim N. Board ◽  
Terence W. O’Neill
Keyword(s):  
Propensity Score ◽  
Statin Therapy ◽  
Cox Regression ◽  
Large Population ◽  
Revision Arthroplasty ◽  
Population Based ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Adjusted Model ◽  
Reduced Risk

Objectives.To determine whether the timing and duration of statin exposure following total hip/knee arthroplasty (THA/TKA) influence the risk of revision arthroplasty.Methods.Subjects from the Clinical Practice Research Datalink, a large population-based clinical database, who had THA/TKA from 1988 to 2016, were included. Propensity score adjusted Cox regression models were used to determine the association between statin exposure and the risk of revision THA/TKA, (1) at any time, and (2) if first exposed 0–1, 1–5, or > 5 years following THA/TKA. We also investigated the effect of duration of statin exposure (< 1, 1–2, 2–3, 3–4, 4–5, > 5 yrs).Results.The study included 151,305 participants. There were 65,032 (43%) exposed to statins during followup and 3500 (2.3%) had revision arthroplasty. In a propensity score adjusted model, exposure to statins was associated with a reduced risk of revision arthroplasty (HR 0.82, 95% CI 0.75–0.90). Participants first exposed within 1 year and between 1 and 5 years following THA/TKA (vs unexposed) had a reduced risk of revision arthroplasty (HR 0.82, 95% CI 0.74–0.91 and HR 0.76, 95% CI 0.65–0.90, respectively). In relation to duration of statin therapy, participants exposed for more than 5 years in total (vs < 1 yr) had a reduced risk of revision (HR 0.74, 95% CI 0.62–0.88).Conclusion.Statin therapy initiated up to 5 years following THA/TKA may reduce the risk of revision arthroplasty.

New requirements for phase I trials: a challenge for Italian clinical research

2018 ◽  
Vol 104 (1) ◽  
pp. 15-21 ◽  
Author(s):  
Emanuela Marchesi ◽  
Manuela Monti ◽  
Oriana Nanni ◽  
Lisette Bassi ◽  
Martina Piccinni-Leopardi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Phase I ◽  
Good Clinical Practice ◽  
Phase I Trials ◽  
Highly Qualified ◽  
Phase I Clinical Trials ◽  
Oncology Research ◽  
Standard Operating ◽  
Near Future

Background: In 2015, the Italian Medicines Agency (Agenzia Italiana del Farmaco; AIFA) issued the Determination 809/2015 with new requirements for phase I clinical trials. Before it came into force, we explored the extent to which several Italian oncology centers were working to implement it. Methods: A survey was conducted among 80 Italian centers involved in clinical trials. Investigators and research coordinators were surveyed. Results: Answers from 42 institutions were collected: among them 88.1% were involved in oncology research. In the last 5 years, 55% had conducted from 1 to 5 phase I trials, and only 16.7% more than 5. A third were involved in not-first-in-human research and none with healthy volunteers. The majority (57.1%) of the centers did not run any projects and trials are non-commercial, and about 35%, no more than 2. While 9.5% already met the standards for self-certification, 71.4% were working to achieve them. Standard operating procedures dedicated to research and the required good clinical practice training had been established by 57.1% and 76.2%, respectively. Fifty percent of laboratories were almost compliant with the Determination. After 10 months from its coming into force, 98 sites had applied for certification, of which 34 were oncology units. Conclusions: The new AIFA Determination imposes a certified organizational model on units and laboratories involved in phase I trials. Our results showed that great efforts were made to qualify for phase I research suggesting that other oncology units will apply for certification in the near future. Predictably, Italy will set the pace as a highly qualified country in which to conduct early-phase research.

Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5444-5444
Author(s):  
Sæmundur Rögnvaldsson ◽  
Ingemar Turesson ◽  
Magnus Björkholm ◽  
Ola Landgren ◽  
Sigurður Yngvi Kristinsson
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Large Population ◽  
Diagnostic Delay ◽  
Population Based ◽  
Lymphoproliferative Disorders ◽  
First Year ◽  
Advisory Committees ◽  
Population Based Study ◽  
Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Baseline Characteristics Of Patients With Chronic Myeloid Leukemia In a Prospective Observational Study (SIMPLICITY)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4026-4026 ◽  
Author(s):  
Jorge E. Cortes ◽  
Rüdiger Hehlmann ◽  
Carlo Gambacorti-Passerini ◽  
Stuart Goldberg ◽  
H. Jean Khoury ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Chronic Myeloid Leukemia ◽  
Clinical Research ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
First Line ◽  
Historical Cohort ◽  
Prospective Cohorts

Abstract Background Oral BCR-ABL tyrosine kinase inhibitors (TKIs), including imatinib (IM), dasatinib (DAS) and nilotinib (NIL), have improved survival in chronic-phase chronic myeloid leukemia (CP-CML). Few data are available that compare TKIs in daily clinical practice across multiple regions. Methods SIMPLICITY is an ongoing observational cohort study of adult patients with newly diagnosed CP-CML receiving first-line treatment with IM, DAS or NIL in the USA and Europe (Eu) outside of clinical trials (NCT01244750). The primary objective is to assess effectiveness of these TKIs in clinical practice. The study includes three ‘prospective’ cohorts of patients treated with IM, DAS or NIL since 2010 (the study opened after first-line approval of all three TKIs) and a ‘historical’ cohort treated with IM since 2008. Preliminary baseline demographics are presented for prospective cohorts. Results 860 prospective patients (Eu: 32%, USA: 68%) were enrolled through June 20, 2013, receiving IM (n=399), DAS (n=229) or NIL (n=232). Median age at initiation of first-line TKI was 56 years, with significant differences in pairwise comparisons between DAS and IM and NIL and IM (Table). Demographics were consistent across cohorts. Only 30% of patients had Hasford or Sokal scores recorded. ECOG performance status (PS) was available in 54% of patients. The number of baseline comorbidities per patient (mean: 3.2 + 2.7) was balanced across cohorts; 51% of patients presented with ≥3 comorbidities. Patients in the IM cohort had a higher prevalence of gastrointestinal comorbidities (P=.006 and .007 for DAS vs IM and NIL vs IM, respectively), and the NIL cohort had a higher prevalence of musculoskeletal comorbidities than the DAS cohort (P=.015). The proportions of patients with cardiovascular comorbidities were 38%, 36% and 42% in the DAS, NIL and IM cohorts, respectively, consisting primarily of hypertension (31%) and hyperlipidemia (17%) (P>.05 across cohorts). Coronary artery disease was present in 9%, cardiac arrhythmias in 6%, myocardial infarction in 3% and peripheral arterial disease in 2% of patients. The proportion of patients with diabetes was 10%. Clinicians reported effectiveness as the most common reason for TKI selection; familiarity and cost were also cited as reasons for IM selection (P<.001 vs DAS and NIL). Comorbidities were not drivers of TKI selection in this analysis. Conclusions This is the first report from the prospective cohorts of SIMPLICITY. Demographics were consistent across cohorts. Overall, the SIMPLICITY population is older with potentially more comorbidities than patients enrolled in first-line clinical trials with restrictive inclusion criteria (NEJM 2003 348 994; NEJM 2010 362 2260; NEJM 2010 362 2251). Initial TKI selection does not appear to be driven by baseline comorbidity, rather by perceived effectiveness, cost and familiarity. Hasford/Sokal scores were not recorded in the majority of patients prior to starting first-line TKI therapy. Outcomes data are being collected across cohorts that will inform about a multi-region population treated outside clinical trials. Disclosures: Cortes: Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Hehlmann:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Oncology: Honoraria, Research Funding, Speakers Bureau; Ariad: Honoraria, Research Funding, Speakers Bureau. Khoury:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Teva: Honoraria. Mauro:Novartis Oncology: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Paquette:Ariad: Consultancy; Incyte: Consultancy, Honoraria; Novartis: Consultancy. Foreman:ICON Clinical Research: Employment, My employer ICON Clinical Research receives research funding from pharmaceutical companies including manufacturers of CML drugs Other. Mohamed:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Hirji:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment.

Comparative Effectiveness of Rituximab-Based Immunochemotherapy in Waldenstrom's Macroglobulinemia (WM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2986-2986 ◽  
Author(s):  
Adam J Olszewski ◽  
Steven P Treon ◽  
Jorge J Castillo
Keyword(s):  
Clinical Trials ◽  
Comparative Effectiveness ◽  
Research Funding ◽  
Randomized Clinical Trials ◽  
Single Agent ◽  
The United States ◽  
Population Based ◽  
First Line ◽  
Prophylactic Measures ◽  
Significant Difference

Abstract Background: Waldenström macroglobulinemia (WM) is difficult to study in randomized clinical trials because of its rarity, and higher incidence among older patients (pts). The most recent published trial focusing on WM (Leblond et al., J Clin Oncol 2013) compared chlorambucil with fludarabine-treatments no longer in common use. Recent data (Olszewski et al., Oncologist 2016) show that over 80% of WM pts in the United States are now treated with rituximab (R) alone or in combination with chemotherapy, although the effect of R on overall survival (OS) in WM has not been shown in clinical trials (Buske et al., Leukemia, 2009). Our objective was to provide comparative evidence of therapeutic efficacy for R-based immunochemotherapy in WM by applying causal inference methods to population-based, observational data. Methods: Using Medicare claims from 1999-2013, linked to the Surveillance, Epidemiology and End Results registry data, we identified WM patients (pts) >65 years old, who initiated first-line chemotherapy with or without R, with purine analogues (PUR, fludarabine or cladribine) and/or classic alkylating agents (ALK, chlorambucil or cyclophosphamide). Pts receiving both fludarabine and cyclophosphamide were grouped as PUR. Factors associated with treatment selection were studied in multivariable mixed-effects logistic models. We then conducted 3 separate comparative analyses: 1) regimens with R versus without R, 2) R monotherapy versus combination immunochemotherapy, and 3) PUR- versus ALK-based regimens. In each case, we balanced baseline characteristics (age, sex, race, socioeconomic status, comorbidities, performance status, time from diagnosis), and indicators of WM severity previously validated to correlate with OS (anemia, transfusions, plasmapheresis) using propensity score analysis, to minimize indication bias and simulate a randomized experiment. We then compared OS and select adverse events within 90 days of treatment (hospitalization, transfusion, or plasmapheresis) using survival or log-binomial models weighted by inverse probability of treatment (IPT), reporting hazard ratio (HR) or relative risk (RR) with 95% confidence intervals (CI). Results: Among 1,310 pts (median age 78 years, 43% women), 54% received first-line R monotherapy, 12% R+PUR, 12% R+ALK, 14% PUR-(without R)- and 8% ALK-(without R)-based regimen. Receipt of R was more likely among pts with metropolitan residence, diagnosis after 2003, and baseline neuropathy, and significantly varied by treating physician (intra-class correlation, 45%, CI 25-66%, P<.0001). Unadjusted 5-year OS was 42.0% (CI, 36.1-47.8) for chemotherapy without R, 51.9% (CI, 46.0-57.6) for chemotherapy with R, and 50.6% (CI, 46.4-54.7) for R alone. In each comparative analysis, we achieved adequate balance of confounding variables using propensity scores. In the IPT-weighted outcome models, OS was significantly better for pts who received R as part of their therapy compared with those who did not (HR, 0.77; CI, 0.64-0.93; P=.0058; Fig. A), without difference in the studied toxicities. Within 3 months of starting therapy, there was an overall 20.4% frequency of transfusion, 9.6% of hospitalization, and 4.4% of plasmapheresis. The RR for plasmapheresis after R-based regimen was 1.09 (CI, 0.63-1.90, P=.76). There was no significant difference in OS between pts receiving R alone or in combination with chemotherapy (HR, 0.90, CI, 0.74-1.08, P=.25, Fig. B), but the risk of transfusions (RR, 0.71; CI, 0.56-0.88; P=.002) and hospitalizations (RR, 0.52; CI, 0.34-0.79; P=.002) was lower after single-agent R. Furthermore, there was no evident difference between PUR- or ALK-based regimens in OS (HR, 1.13, CI, 0.90-1.42, P=.30, Fig. C), or in the studied toxicities. Conclusions: This population-based, comparative effectiveness study provides evidence of OS benefit of R (as monotherapy or combination immunochemotherapy) for Medicare beneficiaries (>65 years old) with WM. Toxicity of single-agent R was lower compared with combination regimens, without a difference in survival, thus confirming its utility as a treatment option for older pts who do not have a strong indication for cytotoxic therapy. Acknowledging likely pre-selection on the basis of (unrecorded) IgM levels, and possible uncaptured prophylactic measures, R-based therapy did not appear to result in a higher risk of plasmapheresis or hospitalization. Figure Figure. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy. Treon:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy. Castillo:Janssen: Honoraria; Millennium: Research Funding; Pharmacyclics: Honoraria; Abbvie: Research Funding; Otsuka: Consultancy; Biogen: Consultancy.

scholarly journals Minimal Residual Disease (MRD) Analysis Using Multiparametric Flow Cytometry (MFC) and Identification of Differences in Subpopulations Using Next Generation Sequencing (NGS) in the Bone Marrow (BM) of Multiple Myeloma (MM) Patients (pts)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3222-3222
Author(s):  
Sandra M. Dold ◽  
Veronika Riebl ◽  
Dagmar Wider ◽  
Marie Follo ◽  
Stefan J. Mueller ◽  
...  
Keyword(s):  
Research Funding ◽  
Plasma Cells ◽  
Residual Disease ◽  
Expression Patterns ◽  
High Sensitivity ◽  
Novel Agents ◽  
Expression Levels ◽  
Dna And Rna ◽  
Oncology Research ◽  
Equity Ownership

Abstract Introduction: MM is characterized by the accumulation of aberrant BM plasma cells (aPCs). The use of novel agents for anti-MM treatment has enabled the achievement of deeper responses and prolonged progression free survival (PFS) and overall survival (OS). These advances have created the need for sensitive means to detect residual PCs. MFC allows aPC detection with high sensitivity and is used with NGS in clinical trials (CTs) (Paiva, 2015-2018). It allows the detection of residual cells after anti-MM therapies and is a risk denominator of pt subgroups and post-therapeutic outcome. The incorporation of cost-effective, readily available and standardized MRD tools into CTs and clinical practice seems a key requisite. It may allow the improvement of clinical decisions: 1) timing of stem cell transplantation (SCT), 2) need for consolidation, 3) duration of maintenance, 4) therapy modulations and 5) early relapse detection. Since MRD gains importance for novel agents' potency to achieve MRD negativity, including FDA/EMA-approvals, we assessed MFC for detection of aPCs, their change to treatment and over time. Methods: We systematically validated a 6-, 8- and 10-color panel using CD38, CD138, CD19, CD45, CD27, CD56, CD28, CD81, CD117, CD200 and kappa/lambda (k/l) in 9 different MM cell lines (MMCLs) and 213 BM, PB, leukapheresis (LA), extramedullary (EM) samples of 122 different MM pts and 14 healthy individuals (HI). These were immediately analyzed after sampling, using a bulk-lysis protocol. To reach a high sensitivity, >3x106 viable nucleated cells were analyzed. MFC validation included fluorescence-minus-one-(FMO), isotype- and spike-in-controls to evaluate the reliability and sensitivity of our panels. Spike-in controls were performed using a dilution assay to recover defined MMCL cells in the PB of HI. Data analysis was accomplished using the BeckmanCoulter software Kaluza®. We compared MFC using BM and PB samples of HI, MM pts at initial diagnosis (ID) or with progression (PD), after standard therapy (ST) and SCT. Additionally, BM samples at ID were sorted into each 4 aPC- and normal PC- (nPC) subpopulations for DNA and RNA sequencing and follow-up. The study was performed with written consent of all pts and HIs and approval of the ethics committee. Results: The antigen expression levels in 9 MMCLs using our 6-, 8- and 10-color panel could be confirmed as reported. The expression levels of antigens included in all panels were similar in all MMCLs (RPMI 8226; U266; IM-9; MM1.S; MM1.R; L363; Karpas620; NCI-H929; OPM-2). For all panels, we established easy to adapt gating strategies, using commercially available software to identify aPCs vs. nPCs in all analyzed samples. Using the 6-color panel, differentiation into up to 4 phenotypic subpopulations of aPCs and nPCs in MM pts and up to 4 subpopulations of nPCs in HI was achieved, depending on the heterogeneous phenotype the individual was expressing. Moreover, both DNA and RNA of obtained subpopulations were collected and analyzed via sequencing. Since in 1% of our samples, aPCs remained undetected via 6-color panel using surface antigens exclusively, we added k/l and did detect aPCs in all pts. The 10-color panel identified aPC- and nPC-subpopulations in even more detail. We determined a MRD sensitivity of 10-5, confirmed via independent dilution assays. In 48% of BM and PB samples, aPCs were determined at ID and PD; 52% were assessed for MRD after ST and SCT. Of the latter, 55% were BM samples, of which 5% showed MRD negativity of <0.001%. The median time from ST- or SCT-treatment to 1rst MRD evaluation was 44 days; this being assessed at subsequent time points currently. These data will be shown at the meeting. Conclusion: Our 6-, 8-, and 10-color panels allow highly sensitive detection of aPCs vs. nPCs in MM samples. These panels have been validated using various controls, dilution assays, 9 MMCLs, MM pt samples and HI and can be implemented into routine diagnostics. The analysis of DNA and RNA expression patterns in distinct subpopulations will generate relevant insight, which subclones contribute to response vs. resistance mechanisms. The EuroFlow Consortium have established a two 8-color tubes test for identification of aPCs, which - albeit used worldwide - may not be applicable for every center and every pt outside CTs. Therefore, meticulously validated alternatives as shown here are of interest. Our 8-color panel has been included into our CT portfolio. Disclosures Azab: Cellatrix LLC: Equity Ownership, Other: Founder and owner; Targeted Therapeutics LLC: Equity Ownership, Other: Founder and owner; Ach Oncology: Research Funding; Glycomimetics: Research Funding. Zeiser:Jazz Pharmaceuticals: Research Funding. Wäsch:Pfizer: Honoraria.

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