scholarly journals Progression-Free Survival Subset Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1969-1969 ◽  
Author(s):  
Evangelos Terpos ◽  
Wolfgang Willenbacher ◽  
Kazuyuki Shimizu ◽  
Ramon García-Sanz ◽  
Anthony Glennane ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Board Of Directors ◽  
Research Funding ◽  
Steering Committee ◽  
First Line ◽  
Primary Analysis ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Travel Grant ◽  
To Receive

Abstract Introduction: The full primary analysis of the international, double-blind, double-dummy, randomized controlled phase 3 study (20090482) that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing skeletal-related events (SREs) in newly diagnosed patients with multiple myeloma (NDMM) met the primary noninferiority endpoint of time to first on-study SRE (Raje N, et al. Lancet Oncol. 2018). Overall survival, a secondary endpoint, was similar in both arms; however, this result was based on a limited number of events having occurred (denosumab 14.1% vs zoledronic acid 15.0%), which might have affected the ability to detect a difference and also may have been further diluted by multiple subsequent lines of therapy. In addition, results from an exploratory endpoint, progression-free survival (PFS), demonstrated a clinically meaningful 10.7 months median PFS benefit (hazard ratio [HR], 0.82; 95% CI, 0.68-0.99; descriptive P=0.036; Table 1) of denosumab versus zoledronic acid on top of standard of care first-line anti-myeloma treatment. This result provided suggestive clinical evidence of a potential anti-myeloma effect based on RANKL inhibition. Here we present further analysis of PFS according to prespecified subgroups of patients from the 20090482 study. Methods: Adult NDMM patients with ≥1 documented lytic bone lesion were included in this study. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo every 4 weeks. Both groups also received investigators' choice of first-line anti-myeloma therapy. The exploratory endpoint PFS (time from randomization to date of first overall disease progression or death due to any cause, investigator identified) was estimated using the Kaplan-Meier method and analyzed using a Cox proportional hazards model stratified by randomization stratification factors and adjusted for baseline covariates. PFS subgroup analyses were conducted according to the novel first-line therapy use (proteasome inhibitor [PI] use, immunomodulatory drug [IMiD] use, PI and IMiD use) and the intent to receive an autologous stem cell transplant (ASCT; yes, no). Results: Overall, 1718 patients (denosumab, n=859; zoledronic acid, n=859) were included in the primary analysis. By the time of the primary analysis cut-off, 219 patients (25.5%) in the denosumab group and 260 patients (30.3%) in the zoledronic acid group had a PFS event. The percentages of patients receiving novel first-line therapy were balanced between the two groups (see Table 1). For patients who had received first-line PI-based therapy, PFS favored denosumab vs zoledronic acid (median, 40.0 vs 35.4 months; HR, 0.74; 95% CI, 0.58-0.95; descriptive P=0.019; Table 1). For patients who had received first-line IMiD only-based therapy, median PFS was not reached with denosumab therapy and was 34.3 months with zoledronic acid therapy (HR, 0.85; 95% CI, 0.53-1.35; descriptive P=0.49). Median PFS was also not reached for either denosumab or zoledronic acid for patients who had received first-line PI plus IMiD therapy (HR, 0.95; 95% CI, 0.62-1.46; descriptive P=0.82). For patients with the intent at baseline to receive an ASCT (54% in each treatment group; Table 1), PFS favored denosumab vs zoledronic acid (median, 46.1 vs 35.7 months; HR, 0.65; 95% CI, 0.49-0.85; descriptive P=0.002). Conclusion: Overall results from this subanalysis indicated PFS impact and benefit of denosumab on top of anti-myeloma therapy, independent from first-line novel therapy which was balanced among treatment arms, mainly in the subgroup of patients receiving PI only-based first-line therapy. In addition, benefit was observed in patients with the intent to receive ASCT, described with an impressive HR of 0.65. Disclosures Terpos: Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; BMS: Consultancy; Novartis: Consultancy. Willenbacher:Amgen: Honoraria, Other: Steering board, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria. Shimizu:Daiichi-Sankyo, Co., Ltd: Consultancy; Fujimoto Pharmacuetical Corp: Consultancy; Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member. García-Sanz:Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership. Niepel:Amgen Inc.: Employment, Equity Ownership. Raje:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; Amgen Inc.: Consultancy.

scholarly journals Functional Cure, Defined As PFS of More Than 7 Years, Is Achieved in 9% of Myeloma Patients in the Era of Conventional Chemotherapy and of First-Generation Novel Anti-Myeloma Agents; A Single-Center Experience over 20-Year Period

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1968-1968
Author(s):  
Evangelos Terpos ◽  
Maria Roussou ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Nikolaos Kanellias ◽  
Despina Fotiou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
First Generation ◽  
Steering Committee ◽  
First Line ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Travel Grant

Abstract Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period after first-line therapy. The aim of this analysis was to evaluate the characteristics of patients who achieved at least 7-year of PFS after frontline therapy and compare them with those of all other patients who were treated in a single center during the same time period. Between January 1994 and December 2010, 406 consecutive newly diagnosed MM patients received first line therapy in the Department of Clinical Therapeutics (Athens, Greece). All patients had symptomatic disease, based on the IMWG criteria of that period (at least one CRAB symptom to start anti-myeloma therapy). Thirty-six (8.8%; 23M/13F) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. The median PFS of these 36 patients is 10 years, while the other patients had a median PFS of 22 months. Long PFS patients were younger (median age 56 vs 68 years; p<0.001), had bigger body surface area (median: 1.85 m2 vs. 1.76 m2; p=0.013) and lower ECOG performance status (score 0-1: 71% vs 52%; p=0.014) compared to all others. Long PFS patients had higher hemoglobin (11.4 g/dl vs 10.2 g/dl; p=0.001), higher platelet count (278 vs 224 x109/l; p<0.001) and higher creatinine clearance (CrCl, based on the MDRD formula: 88 vs 67 ml/min; p<0.001; no patient in the long PFS group presented with CrCl <45 ml/min at diagnosis). There was no difference between the two groups regarding percentage of patients with high LDH, presence of osteolysis, type of myeloma (IgG vs IgA vs others), levels of serum and/or urine M-protein, and percentage of plasma cell infiltration in the bone marrow. However, more patients in the long PFS group had ISS-1 or ISS-2 disease (86% vs 61%; p=0.002) and normal pattern of marrow infiltration in the MRI of the spine and pelvis (24% vs 15%; p=0.035). Regarding chromosome abnormalities at diagnosis, no patient in the long PFS group had high-risk cytogenetics (defined as presence of del17p, t(4;14) or t(14;16) vs 32% in all other patients. All patients received either conventional chemotherapy (CC) or first-generation novel anti-myeloma agent (bortezomib (B), thalidomide (T) or lenalidomide (R)-based regimens as frontline therapy. There was no difference between the two groups regarding CC versus novel agent-based induction treatment. Out of 36 long-term PFS patients, 11 (30%) received CC, 8 (22%) B-based, 8 (22%) RD, 6 (17%) T-based, and 3 (8%) VTD; 10 (28%) patients received first-line therapy participating in a clinical trial. Long PFS patients had received more often autologous stem cell transplantation (ASCT, 61% vs 23%; p=0.001) as part of first line therapy; therefore, more long PFS patients had also received consolidation and/or maintenance (50% vs 15%; p=0.001). Higher proportion of patients achieved at least VGPR (74% vs 41%) or at least CR (32% vs 18%) in the long PFS group. We performed next generation flow cytometry in 23 patients of the long PFS group to evaluate minimal residual disease (MRD) and 14 (61%) of them were MRD (-) at the level of the 10-6. The probability of achieving long PFS (≥7 years) for patients who managed to be progression-free at 2, 3 and 4 years was 11.6%, 13.2% and 15.3%, respectively. In the multivariate analysis, only younger age was associated with probability for long PFS (p<0.001). The median OS of the whole group of patients was 5 years; in the long-PFS group median OS has not been reached yet while in all other patients the median OS was 4.3 years. In conclusion, our study in an unselected group of patients, the majority of whom did not participate in clinical trials, showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years (median: 10 years) even in the era of CC or first-generation novel agents. These patients have low risk disease, mainly of ISS-1 or -2, no high-risk cytogenetics, no or mild renal impairment, and achieve deep responses after ASCT. These patients may be considered as "functionally" cured. The incorporation of novel treatment approaches may lead to a significant improvement in the probability of achievement of this "functionally" cured status. Disclosures Terpos: Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding. Kastritis:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria.

Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1518-1518 ◽  
Author(s):  
Jackie Vandermeer ◽  
Allison M Winter ◽  
Ajay K. Gopal ◽  
Ryan D. Cassaday ◽  
Brian T. Hill ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

scholarly journals Patient Profile and Treatment Patterns in a Commercially Insured Population with Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5880-5880
Author(s):  
Nathan H Fowler ◽  
Yanni Hao ◽  
Stephen Lim ◽  
Guifang Chen ◽  
Frank Li ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Second Line ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Third Line ◽  
Line Of Therapy

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. Patient characteristics and burden of FL are incomplete and vary from previous studies. This study evaluated patient profile, including patient characteristics, treatment patterns, and duration using real-world data. Methods: Using the Truven MarketScan® databases, patients with FL who were newly initiated with FL indicated regimens were identified from 1/1/2010-12/31/2013 (initial treatment identification period). Patients were selected if they were ≥18 years old, had 1 FL ICD-9 code (202.0) as primary or secondary diagnosis, at least 1 FL commonly prescribed systemic anti-cancer therapy after the diagnosis, and did not use any FL indicated regimen in the past 6 months prior to first agent included in the initial treatment identification period. These patents were followed ≥3 months or to June 30, 2018. Primary outcomes were the distribution of regimens by line, the number of patients who switched from first- to second-line therapies, and from second- to third-line therapies. The treatment duration by line of therapy and regimen were also analyzed. Discontinuation was defined as 3 months without receiving a regimen after treatment. Results: This study identified 4,970 patients who initiated treatment for FL. Of these patients, 48.1% were female (n=2,390), with a mean age of 62.0 (SD: 14.0) years. The average follow-up time was approximately 2 years (median: 733 days). In this analysis, 4,970 patients with FL received first-line therapy for 153 days (median: 94 days), 1,985 received second-line therapy (39.9% of patients who received first-line therapy) for 208 days (median: 80 days), and 664 received third-line therapy (13.4% of patients who received first-line therapy) for 117 days (median: 43 days). Of the 4,970 patients on first-line therapy, 453 (9.1%) remained on first-line therapy, 2,532 (51.0%) discontinued treatment, and 1,985 (39.9%) patients switched to the next line of therapy during the follow-up period. Of the 1,985 patients who switched to second-line therapy, 328 (16.5%) remained by the end of follow-up period, 993 (50.0%) discontinued, and 664 (33.4%) switched to the next line of therapy during the follow-up period. Of the 664 patients who switched to third-line therapy, 125 (18.8%) remained, 269 (40.5%) discontinued, and 270 (40.7%) switched to the next line of therapy. The most common first-line regimens in descending order received by patients were rituximab (n=1,478, 29.7%), R-CHOP (n=1,368, 27.5%), BR (n=1,050, 21.1%), R-CVP (n=371, 7.5%), and FCR (n=63, 1.3%). Second-line treatment regimens were (N=1,985) rituximab (n=992, 50.0%), BR (n=202, 10.2%), R-CHOP (n=138, 7.0%), and R-CVP (n=120, 6.1%). Third-line treatment regimens were (N=664) rituximab (n=228, 34.3%), BR (n=91, 13.7%), R-CHOP (n=75, 11.3%), cyclophosphamide (n=35, 5.3%) and R-CVP (n=31, 4.7%). Conclusion: This data set describes the percentage of patients that transition from first- to second-line and second- to third-line treatment for FL. The primary regimens used across the treatment lines conform to those recommended by the NCCN guidelines. In addition, smaller numbers of non-recommended regimens were reported. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lim:Novartis Pharmaceuticals Corporation: Employment. Chen:Novartis Pharmaceuticals Corporation: Consultancy, Employment. Li:Novartis Pharmaceuticals Corporation: Employment. Arcona:Novartis Pharmaceuticals Corporation: Employment.

scholarly journals Metformin Restores AMPK Alpha-Mediated Autophagy and Prevents Carfilzomib-Induced Cardiotoxicity In Vivo

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3214-3214
Author(s):  
Georgios Kremastiotis ◽  
Panagiotis Efentakis ◽  
Aimilia Varela ◽  
Constantinos H. Davos ◽  
Maria Tsoumani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Board Of Directors ◽  
Molecular Mechanism ◽  
Research Funding ◽  
Steering Committee ◽  
Control Group ◽  
Advisory Committees ◽  
Pp2a Activity ◽  
Travel Grant

Abstract Introduction: Carfilzomib (Cfz) significantly prolongs progression-free survival in relapsed or refractory multiple myeloma patients, as highlighted in the ENDEAVOR trial. However, Cfz has high incidences of cardiotoxicity and heart failure, leading to treatment cessation. Thus, there is an imperative need for preventive therapies. The study aimed to i) establish an in vivo Cfz cardiotoxicity protocol, ii) investigate the molecular mechanism, identify molecular targets and iii) based on initial results, investigate the potential protective effect and mechanism of Metformin (Met). Methods: Male, C57BL/6 mice, were randomized in groups as following: Acute protocol (6 days): Control (n=7), Cfz (n=8); Sub-chronic protocol (14 days): Control (n=5), Cfz (n=8); Pharmacological intervention protocol (6 days): Control (n=8), Cfz (n=8), Cfz+Met (n=8), Met (n=4). Cfz (8 mg/kg, ip) was administered on alternate days and Met (140 mg/kg, po) daily. Glucose levels were monitored following Met administration. Mice underwent echocardiography on baseline and at the end of treatments. Blood and myocardial tissue samples were obtained for histology, proteasome activity, PP2A activity and signaling pathways focused on PI3K/Akt/eNOS axis, NO homeostasis and AMPKα-mTOR-mediated autophagy. Results: Following acute administration, echocardiography in Cfz group presented a significant reduction in fractional shortening (FS%) vs. Control group (39.87±0.47 vs. 43.03±0.50 respectively, p<0.001), combined with reduced thickness in the left ventricular (LV) posterior wall (LVPW diastole (mm): 0.69±0.01 vs. 0.76±0.01, p<0.01; LVPW systole (mm): 1.17±0.01 vs. 1.24±0.02, p<0.01). Sub-chronic Cfz administration resulted in moderate LV dilation (LV end-diastole diameter (mm): 3.24±0.03 vs. 3.04±0.04, p<0.01; LV end-systole diameter (mm): 1.88±0.02 vs. 1.71±0.02, p<0.01) and borderline FS% reduction (42.07±0.46 vs. 43.52±0.25, p<0.05). Following both protocols, Cfz did not cause major tissue lesions. Signaling pathways were studied in the acute protocol that demonstrated suppressed myocardial contractility. Cfz resulted in significant inhibition of proteasome in both myocardium (55.5% inhibition, p<0.05) and peripheral mononuclear blood cells (PBMCs) (90.6% inhibition, p<0.001) - inhibitory effect was comparable to clinical practice. Cfz, independently of PTEN expression, reduced phospho-PI3K (p<0.05), phospho-Akt (p<0.001) and phospho-eNOS (p<0.001), and increased iNOS expression (p<0.01). Cfz reduced phospho-AMPKα (p<0.001) and phospho-Raptor (p<0.05) leading to inhibition of autophagy, indicated by reduced LC3-II expression (p<0.01), without affecting phospho-mTOR or Beclin 1. Co-administration of Met prevented FS% reduction (Cfz group: 41.55±0.43 vs. 43.24±0.50 and 43.39±0.56, Control and Cfz+Met respectively, p<0.05), without exerting glucose lowering actions. Met did not interfere with Cfz-induced proteasome inhibition; Cfz and Cfz+Met groups had significantly reduced proteasomal activity vs. Control group in myocardium (p<0.05) and PBMCs (p<0.001 and p<0.01 respectively). Histology presented mild to moderate vascular congestion in Cfz+Met and Met vs. Control and Cfz groups (p<0.05), appearing to be non-specific finding that did not collocate with haemorrhage, vascular obstruction or tissue lesions. On a molecular level, Cfz+Met group presented increased phospho-Akt (p<0.01) vs. Cfz group, independently of PTEN, PI3K and eNOS/iNOS. Cfz+Met group restored phospho-AMPKα (p<0.05), phospho-Raptor (p<0.001) and LC3-II expression (p<0.05) vs. Cfz group, without inducing changes in mTOR and Beclin 1. Cfz inactivated Akt and AMPKα through increased PP2A activity (p<0.05), without altering PP2A expression; Met did not interfere with PP2A activity. Conclusions: Cfz exhibits decreased global LV function in vivo, without inducing tissue lesions. The molecular mechanism consists of increased PP2A activity leading to inactivation of AMPKα-mTOR and PI3K/Akt/eNOS pathways - combined with NO homeostasis deregulation. In an intervention approach, Met preserved cardiac function via restoring AMPKα-mediated autophagy. Met administration did not restore NO production and homeostasis; these pathways require further investigation. Met emerges to be a promising preventive therapy for Cfz-induced cardiotoxicity. Disclosures Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria. Dimopoulos:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding.

scholarly journals Optimizing Deep Response Assessment for AL Amyloidosis Using Involved Free Light Chain Level at End of Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3227-3227
Author(s):  
Eli Muchtar ◽  
Angela Dispenzieri ◽  
Nelson Leung ◽  
Francis K. Buadi ◽  
David Dingli ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Response Assessment ◽  
Al Amyloidosis ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Organ Response

Abstract Introduction: Light chain burden in light chain (AL) amyloidosis is often low, making accurate response assessment challenging. Methods: AL amyloidosis patients achieving very good partial or complete response to first line therapy and had serial sFLC studies during and after completion of therapy were included (n=396). Involved free light chain (iFLC), difference in involved-to-uninvolved free light chains (dFLC) and sFLC ratio (sFLCR) were assessed at the end of first line therapy and at nadir iFLC. Survival analysis was done using the Kaplan-Meier method. Hematological progression-free survival (hemPFS) was defined as the time from diagnosis until hematological progression or death, where patients known to be alive and progression-free at the end of follow-up were censored. Hematological progression was defined according to consensus criteria or upon initiation of second line therapy, whichever came first. Results: The median iFLC and dFLC at the end of therapy was 1.7 mg/dL and 0.5 mg/dL, respectively. sFLCR normalization occurred in 70% of patients. iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL were associated with a longer hemPFS compared to their counterparts (Figure). Only iFLC ≤2 mg/dL was associated with a significantly longer overall survival (Figure). sFLCR normalization did not predict hemPFS or overall survival. Organ response was predicted by iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL (Table), with best discrimination seen with iFLC ≤2 mg/dL. Organ response was not predicted by sFLC normalization (Table). The median nadir iFLC was 1.4 mg/dL and was reached 3.9 months from the end of therapy, longer in transplanted patients compared to patients treated with non-transplant regimens (7.3 vs 1.8 months, respectively; P<0.001). iFLC ≤2 mg/dL at the completion of therapy and nadir iFLC reached >12 months from the end of therapy were favorable predictors of hemPFS/OS in a multivariate analysis. Conclusion: iFLC at the end of first line therapy better predicts for organ response and survival than dFLC among deep responders. Normalization of sFLCR does not predict for organ response or survival and should not be used as measure of therapeutic efficacy. Figure. Figure. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Abbvie: Consultancy; annexon: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Research to Practice: Consultancy; Medscape: Consultancy; Apellis: Consultancy; Teva: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Physicians Education Resource: Consultancy.

The Survival Outcome of the Patients with Relapsed/Refractory Anaplastic Large-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2738-2738 ◽  
Author(s):  
Dai Chihara ◽  
Michelle A. Fanale ◽  
Mansoor Noorani ◽  
Jason R Westin ◽  
Loretta Nastoupil ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Survival Outcome ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Large Cell Lymphoma

Abstract Purpose: We assessed the survival outcome of patients with anaplastic large cell lymphoma (ALCL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of brentuximab vedotin (BV), and survival outcome of patients with ALCL who experienced progression after BV. Patients and Methods: A total of 176 patients (74 ALK+, 102 ALK-) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OS2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the ALK status focusing on the use of BV. Results: The median age of the patients was 50 (range: 18-89). With a median follow up of 64 months, 111 patients (38 ALK+, 73 ALK-) experienced progression/relapse after the first-line therapy, of which 4 ALK- patients were post upfront stem cell transplant (SCT). Thirty and 15 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. The median PFS1 and OS1 in patients with ALK+ALCL and ALK-ALCL were 8.4 and 28.5 months, and 13.1 and 47.7 months, respectively. In patients with ALK+ALCL, the median PFS1, PFS2 and PFS3 were 53.6, 5.2 and 2.3 months, respectively. The median OS1, OS2 and OS3 were not reached, 47.3 and 6.1 months, respectively. In patients with ALK-ALCL, the median PFS1, PFS2 and PFS3 were 12.9, 3.0 and 2.0 months, respectively. The median OS1, OS2 and OS3 were 54.3, 10.8 and 5.8 months, respectively. Interestingly, there were no significant difference in PFS2 between ALK+ALCL and ALK-ALCL. However, OS2 was significantly longer in patients with ALK+ALCL, suggesting possibly continued chemosensitivity of recurrent ALK+ALCL. A total of 30 patients received BV in 1st salvage (15 patients) and after 2nd salvage (15 patients).The use of BV at 1st salvage was associated with significantly longer PFS2 and OS2 both in patients with ALK-ALCL but not with ALK+ALCL likely due to small number of cases. Mutivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of BV (at any point in the salvage setting) is significantly associated with longer OS2 (HR: 0.43, 95%CI: 0.23-0.80). Overall, 12 patients experienced relapse/progression after BV treatment. The median OS after BV failure was 1.4 months (95%CI: 0.5-9.5 months) (Figure). Summary: Survival outcome for relapsed/refractory patients with ALK+ and ALK- patients is improved with BV. However, survival outcome after BV failure is very poor. A new treatment strategies to consolidate or maintain the response after BV and to develop more safe and better therapeutic options are needed. Figure 1. Figure 1. Disclosures Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Westin:Spectrum: Research Funding. Nastoupil:Celgene: Honoraria; Genentech: Honoraria; AbbVie: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Wang:Celgene: Research Funding.

scholarly journals Real-World Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma (MFMM) in the Era of Novel Therapies: A Study of the Greco-Israeli Collaborative Myeloma Working Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3295-3295 ◽  
Author(s):  
Eirini Katodritou ◽  
Efstathios Kastritis ◽  
Moshe E. Gatt ◽  
Yael C Cohen ◽  
Irit Avivi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Steering Committee ◽  
Novel Therapies ◽  
Advisory Committees ◽  
Lytic Lesions ◽  
Travel Grant

Abstract Macrofocal Multiple Myeloma (MFMM) has been described as a distinct entity of Multiple Myeloma (MM) characterized by young age, lytic lesions and limited bone marrow infiltration by clonal plasma cells (BMPCs), in the absence of other features of symptomatic MM (i.e. anemia, renal insufficiency and hypercalcemia). Few case studies have indicated a possible favorable prognosis of MFMM patients compared to patients with typical symptomatic MM. Our aim was to investigate the incidence, characteristics and outcome of patients with MFMM, under the light of modern therapeutic approach of MM. MFMM definition required: clonal BMPCs <20%, multiple lytic lesions, absence of anemia, renal insufficiency and hypercalcemia and among 4650 MM patients (3%) registered in the MM databases of Greek and Israeli centers during 2001-2017, we identified 140 patients with MFMM (M/F: 93/47, median age: 61, range: 26-89, IgG: 86, IgA: 12, light chain: 21, IgD: 4, non-secretory: 16, IgM: 1). Most of patients with MFMM (60%) were <65 years; 68% had performance status 0-2 according to Eastern Cooperative group (ECOG) scale; 70% had advanced bone disease (>3 lytic lesions). In 20/140 (14%) patients bone plasmacytomas preceded MM diagnosis. In 95/140 (68%) patients bone, soft tissue or mixed plasmacytomas in multiple locations, were present at diagnosis or during MFMM course and this was significantly more frequent compared with standard MM. Median BMPCs infiltration was 14% (range 0-19%); immunoparesis was less common in MFMM (55% vs. 90% in standard MM). Elevated lactate dehydrogenase (LDH) and β2 microglobulin (β2Μ) ≥ 3.5mg/L were found in 9% and 20% of patients, respectively. Cytogenetics by fluorescence in situ hybridization (FISH) were available in 60% of patients and high-risk features were found in 11%; overall, adverse prognostic parameters (i.e. high LDH, advanced age, high β2Μ, high risk cytogenetics) were less common in patients with MFMM compared with others (p<0.05). According to the International staging system (ISS) patients were stratified as follows: ISS1:71%, ISS2: 25% and ISS3: 4%. Per Revised ISS the distribution was R-ISS1: 54%, RISS2: 46%, no R-ISS3). Induction therapy included novel agents in 90% of patients (bortezomib-based: 61%, thalidomide-based: 14%, bortezomib-lenalidomide-dexamethasone: 4%, lenalidomide-based: 11%); 47% underwent autologous transplantation (ASCT) upfront and 13% at 1st relapse. An objective response (ORR) was achieved in 90%: 70% had at least very good partial response (vgPR), 21% partial response, 6% stable disease and 3% had progressive disease; ORR and achievement of ≥vgPR were significantly higher compared with typical MM (p<0.05). After a median follow up of 52 months (95% CI: 40-64), 33 patients have died (MM progression: 19, lung infection: 8, other causes: 6). Early deaths (<12 months) observed in 5% of patients; 53 patients received 2nd line therapy (proteasome inhibitor-based or lenalidomide-dexamethasone: 79%) and 5 patients received only radiotherapy for plasmacytomas; early relapse (<12 months) was less common in MFMM compared with standard MM (p<0.05). Progression-free survival (PFS) and overall survival (OS) were 46 months (95% CI: 40-52) and 129 months (95% CI: 79-178) respectively, both significantly longer compared with typical MM treated during the same period (p<0.001). In the univariate analysis age <65, early stage disease (ISS1, R-ISS1), 1st line treatment with proteasome inhibitor (PI)-based regimens, ASCT, and standard risk cytogenetics predicted positively for OS in MFMM patients; treatment with PI-based therapies was the only independent predictor for OS in the multivariate analysis (HR: 3.9; p<0.001). In conclusion, MFMM is a rare entity of MM characterized by limited bone marrow infiltration, extended bone lesions and frequent presence of plasmacytomas, prior or during the diagnosis or the course of the disease. MFMM patients are younger have less often adverse prognostic features compared with standard MM and achieve high quality responses when treated with novel therapies. Treatment with PI-based regimens was the strongest predictor for OS in MFMM indicating that it is probably the best therapeutic option for these patients. Disclosures Kastritis: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Patterns of Care for Patients with Chronic Lymphocytic Leukemia (CLL): The Connect® CLL Disease Registry

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2864-2864
Author(s):  
Jeff Sharman ◽  
Christopher R Flowers ◽  
Mark Weiss ◽  
David Grinblatt ◽  
Charles Farber ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Age Groups ◽  
Age Group ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Ecog Ps ◽  
Group 1

Abstract Abstract 2864 Introduction: Clinical trials have illuminated a number of unique treatment strategies for patients with CLL. The impact of these strategies on routine practice remains unknown as trial participants may not reflect the same population encountered outside of a clinical trial setting. Many questions remain regarding the sequencing of therapies based on age and performance status. By characterizing current patterns of care; patients, treating physicians, and regulatory agencies will be able to understand the current landscape of CLL treatment. The Connect® CLL registry was designed to report the natural history and real world management of patients receiving therapy for CLL. In this first report, we characterize the therapeutic approaches used for the treatment of patients with CLL of different age groups (i.e. < 65 years, 65–75 years, and ≥ 75 years) and with an ECOG PS status score of 0 compared to 1 or greater. Methods: Connect® CLL is a prospective, longitudinal, observational, multi-center registry conducted in community and academic research centers in the United States. At present, 237 sites are actively participating with a projected study enrollment of 1500 patients. Eligible patients are to be enrolled within 2 months of being initiated on any line of therapy; whether initial therapy or salvage therapy. Each patient will be followed for up to 60 months. Clinical data, physician choices, patient-reported health-related quality of life, response and survival are to be collected approximately every 3 months during participation. Results: A total of 607 patients have been enrolled (4% from academic sites) with a median age of 70 years. 198 were < 65 years old (age group 1), 187 were between 65–75 years old (age group 2), and 222 were ≥ 75 years old (age group 3). ECOG status varied across the three age groups, with an ECOG status score of ≥ 1 for 39%, 52%, and 70% of patients respectively. Treatment patterns varied across the age groups and by ECOG status in the 496 patients reporting therapies. The most commonly recorded first-line regimens independent of age included fludarabine (F) cyclophosphamide (C) and rituximab (R) (33%), bendamustine (B) +/− R (19%), F +/− R (15%), or investigational therapy (15%). For second-line regimens and beyond, the most frequently recorded regimen was B +/− R (30%), FCR (23%), other F-based regimens (13%), or investigational therapy (8%). The use of FCR for first-line treatment decreased significantly with increasing age group, (45%, 32%, 20%, for age group 1, 2, 3 respectively, p=0.04, spearman correlation) while use of F +/− R remained level across the age groups (14%, 15%, 15%, respectively). Compared to age group 1, first-line therapy with B +/− R in age groups 2 and 3 (15%, 22%, 21%, respectively) was higher but did not achieve statistical significance. B +/− R represented the most common treatment for all age groups (37%, 26%, 29%, respectively) as second line therapy but did not vary by age (P=0.35). The use of chlorambucil was infrequent in all age groups, but was more common in age group 3 patients compared to the others (P=0.01), in both first-line (2%, 4%, 12%, respectively) and subsequent lines of therapy (0%, 1%, 8%, respectively). Treatment assignments did not vary by ECOG PS score for patients in age group 1. First-line therapy for patients with an ECOG PS score of 0 in age groups 2 and 3 consisted of FCR (32% and 15%, respectively), F +/− R (19% and 15%, respectively), B +/− R (16% and 15%, respectively), and alkylating agents (3% and 23%, respectively). Patients in age groups 2 and 3 with ECOG PS score ≥ 1 received B +/− R regimen (33% and 22%, respectively), FCR (23% and 21%, respectively), F +/− R (14% and 10%, respectively) and alkylating agents (7% and 9%, respectively) as first-line therapy. Further description and clarification on the various treatment regimens based on the three age groups and by ECOG PS score will be presented at the meeting. Conclusion: The Connect® CLL Registry is the largest prospective, multicenter registry in the United States evaluating management for patients with CLL. With the currently available data, we characterize the extent to which age and performance status are associated with treatment selection in both first-line and subsequent lines of therapy in routine practice. As enrollment increases and additional follow-up is completed, the data will provide more extensive and real world overview of the current treatment strategies used in CLL patients. Disclosures: Sharman: Celgene - consulting: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. Flowers:Consultancy: Celgene, Prescription Solutions, Spectrum (future), Seattle Genetics, Millennium (future), Genentech (unpaid): Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kay:Genenetech, Celgene, Hospira,: Research Funding. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Research Funding; Amgen: Research Funding. Lamanna:Celgene Corporation: Advisory board. Pashos:United BioSource Corporation: Research Funding. Flinn:Celgene: Research Funding. Kozloff:Celgene: Consultancy. Lerner:Celgene Connect: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene: Employment. Sullivan:Celgene: Employment. Street:Celgene: Employment. Keating:Celgene Connect: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Carfilzomib-Associated Renal Toxicity Is Common and Unpredictable: An Analysis of 114 Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1966-1966 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Charikleia Gakiopoulou ◽  
Erasmia Psimenou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Renal Toxicity ◽  
Steering Committee ◽  
Light Chains ◽  
Advisory Committees ◽  
Renal Complications ◽  
History Of ◽  
Travel Grant

Abstract Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed or refractory myeloma (RRMM), either in combination with dexamethasone (Kd) or with lenalidomide and dexamethasone (KRd). CFZ has been associated with a risk of cardiovascular toxicity but although a signal of clinically significant renal complications has also been identified, renal toxicity is less extensively investigated. Thus, we analyzed the data of 114 consecutive patients who received CFZ for RRMM in our center (Department of Clinical Therapeutics, Athens, Greece) for renal outcomes and complications. Detailed baseline characteristics and medical history (demographics, history of renal and cardiovascular diseases, diabetes, medication use) and detailed data on myeloma status, proteinuria and urine electrophoresis, serum free light chains (sFLC), serum creatinine and cardiovascular complications were available in all patients for the duration of CFZ therapy. Median age was 70 years (range 36-86, 25% were ≥75) and 60.5% were men. Median number of prior therapies was 2 (range 1-7): 78% had prior bortezomib, 73% prior IMiDs, 27% prior anthracyclines and 46.5% prior ASCT. CFZ dose was 20/27 in 30%, 20/36 in 11% and 20/56 in 59%; 75% received Kd, 14% received KRd and 11% other CFZ-based combinations. Median follow up from start of CFZ is 27 months, median duration of CFZ therapy is 5.5 months (IQR 3.2 to 11.5) and 28 (24.5%) patients continue on CFZ therapy at the time of analysis. During CFZ therapy, 19 (17%) patients developed renal complications, not related to MM progression: 6 (5%) developed thrombotic microangiopathy (TMA), 7 (6%) developed albuminuria > 1gr/day (in all with very low amounts of light chains or with negative urine immunofixation) and 6 (5%) developed acute kidney injury/ acute renal failure (AKI/ARF) at least grade 3, which was not otherwise explained. Median time to development of renal complications was 62 days (~2 months) (IQR 35 to 272) and in 15/19 patients CFZ was discontinued due to renal complications. Median time from CFZ start to TMA was 3 months (0.3-19.5). At diagnosis of TMA, median platelet counts were 20x109/L (range 11-30), median hemoglobin 8 gr/dl, median LDH 449 IU/L (ULN<225, range 371-619) and median blood schistocytes were 2.5% (range 2%-6.5%). All received plasmapheresis: 5 recovered renal function and platelet counts while one died of sepsis. In 2 patients in whom ADAMTS13 was measured, no deficiency was found. No patient was re-exposed to CFZ after TMA. Median time to proteinuria >1 gr/d was 6 months (range 2-59 months), median proteinuria was 3.7 gr/d (range 1 - 4.5) and in all cases >90% of urine protein was albumin; all patients were in disease remission (VGPR or CR); median eGFR was 53 ml/min/1.73 m2 (range 41-92). Only one patient had proteinuria before CFZ which was mainly Bence Jones proteinuria. Following interruption of CFZ, proteinuria decreased in 2/7 patients and in one patient CFZ was resumed at a reduced dose. A renal biopsy was performed in 5/6 patients with albuminuria and one with AKI: none had immunoglobulin mediated pathology (cast nephropathy, MIDD or amyloidosis) or pathology related to the alternative complement activation pathway. The most constant finding (in all patients with albuminuria), was a pattern of focal segmental glomerulosclerosis (FSGS) of various subtypes. Coexistent with the previous lesions, a pattern of TMA with intraglomerular and/or arteriolar fibrin microthrombi and/or mucoid degeneration of arteriolar/arterial wall and/or reduplication of glomerular basement membranes with endothelial cells' swelling, was seen in 4 biopsies. We found no association between CFZ dose with renal complications or of baseline proteinuria (immunoglobulin or albumin), sFLC or myeloma type, age, prior history of cardiovascular disease or hypertension or baseline eGFR. Among 33 patients with baseline eGFR < 60 ml/min, 18 (54.5%) patients improved their eGFR to >60 ml/minafter CFZ therapy. We conclude that renal complications during CFZ therapy are common, occur mostly early and are essentially unpredictable. Albuminuria associated with FSGS and TMA developed in 6% and 5% of our patients respectively and warrant further investigation. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ. Figure. Figure. Disclosures Kastritis: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

scholarly journals Impact of Therapy Choice on Fatigue in Adults with Immune Thrombocytopenia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Jennifer Diraimo ◽  
Caroline Kruse ◽  
Michele P. Lambert ◽  
Alexandra Kruse
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Advisory Committees ◽  
Treatment History ◽  
First Line Therapy ◽  
Line Therapy

Background:Immune thrombocytopenia purpura (ITP) is an autoimmune bleeding disorder that is heterogeneous in presentation, disease course, treatment response, and impact on quality of life. Treatments often cause unpleasant side effects, and prolonged use can lead to tolerability issues and toxicity. Both disease symptoms and treatments available impact the health-related quality of life (HRQoL) among patients living with this rare condition. Here, we compare self-reported fatigue and its impact among adult ITP patients and determine whether these fatigue levels differ depending on treatment status. Methods: For this study, we used three of the five surveys from the PDSA Natural History Study Registry including; treatment history and two adult QoL surveys. As of June 2020, 357 adult patients completed the survey assessing treatment history. A total of 310 adult patients completed the adult QoL (part one) survey, and 301 adults completed the adult QoL (part two) survey. Patients were stratified by 1) no treatment received 2) treated in the past 3) on therapy within the last six months; patients currently on therapy were further stratified by first and second-line therapy. Results: Among the 357 completed surveys on treatment history, 11% (n=40) reported they have never received treatment for their ITP, while 46% (n=166) have in the past, and 43% (n=158) currently receive therapy (within the last six months). Among those currently on treatment, 82% receive monotherapy; 47 (26%) use a first-line therapy (corticosteroid, IVIG, or Anti-D), and 78 (43%) are using a second-line therapy (TPO-RA, rituximab, and other second-line options). Therapies reported include TPO-RA's (41%), corticosteroids (24%), IVIG (7%), rituximab (3%), SYK inhibitor (1%), antibiotics (4%), anti-D (1%), other second-line treatments (such as MMF, dapsone etc.), and "other" therapies including complementary treatments (14%). Overall, 93 (23%) reported having had a splenectomy at some point to manage their active ITP. When asked to reflect on general tiredness, 98% of patients (n=310) reported being tired overall, with 55% reporting feeling tired 'almost always/often' regardless of treatment group or type. Those who have never been treated reported they felt tired 94% of the time, and 55% reported feeling tired 'almost always/often'. Among those who are not currently on treatment (but have received therapy in past), 99% reported feeling tired overall, and 50% reported feeling tired 'almost always/often'. Respondents using a first line therapy reported feeling tired overall 100% of the time, and reported feeling tired 53% 'almost always/often'. Respondents using a second line therapy reported feeling tired 99% of the time, and indicated they were tired 59% 'almost always/often'. There were no significant differences between these treatment types and groups identified. When asked to reflect on fatigue levels over the last seven days, collectively, 86% reported fatigue, and 30% reported experiencing it 'very much/quite a bit'. Among those who had never been treated, 85% reported fatigue, and indicated they felt fatigue 27% of the time 'very much/quite a bit'. Respondents who were not receiving treatment reported feeling fatigue 84% of the time, of which 26% was experienced 'very much/quite a bit'. Among those receiving a first line therapy, 90% reported fatigue in the last seven days, and 34% reported they experienced this 'very much/quite a bit'. Those using a second line therapy reported feeling fatigue 91% of the time, and 29% reported this was 'very much/quite a bit'. There were no significant difference among these treatment types and groups. Conclusion: Reported fatigue and overall tiredness are high among those currently on treatment, not on treatment, and those who have never been treated for their ITP. We did not find that fatigue levels were related to treatment type or group, indicating that the underlying causes may not be platelet count, or disease severity, but rather a combination of factors associated with having an unpredictable chronic disease. The multi-faceted effects of ITP often take a significant toll on patients' quality of life. The registry continues to collect data with the intent of understanding the longitudinal impact of ITP and in future with more of a sample size we can learn if these trends continue. Disclosures Kruse: CSL Behring: Other: Grant paid to PDSA; UCB: Other: Grant and consultancy fee, all paid to PDSA; Rigel: Other: Grant paid to PDSA; Principia: Other: Grant paid to PDSA; Pfizer: Other: Grant and consultancy fee, all paid to PDSA; Argenx: Other: Grant paid to PDSA; Amgen: Other: Grant and honorarium, all paid to PDSA; Novartis: Other: PDSA received payment for recruiting patients to I-WISh and for promoting I-WISh on the globalitp.org website. Grant and consultancy fee, all paid to PDSA outside the submitted work. Lambert:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Consultancy; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; Octapharma: Consultancy, Research Funding; Bayer: Consultancy; Argenix: Consultancy; ClinGen: Honoraria; Platelet Disorder Support Association (PDSA): Consultancy; 22qSociety: Consultancy; ITP Australia: Consultancy; CdLS Foundation: Consultancy; RDMD ITP study: Consultancy; Sysmex: Research Funding; AstraZeneca: Research Funding.

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