scholarly journals Survival Trends in Young Patients with Waldenstrom Macroglobulinemia: Over 5 Decades of Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1810-1810
Author(s):  
Jonas Paludo ◽  
Nishanth Vallumsetla ◽  
Stephen Ansell ◽  
Abhisek Swaika ◽  
Tania Jain ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Young Patients ◽  
Age At Diagnosis ◽  
Control Population ◽  
Control Group ◽  
Advisory Committees ◽  
Younger Patients ◽  
The Past ◽  
Frontline Therapy

Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

scholarly journals Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
David Iberri ◽  
Erik Eckhert ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Control Group ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Interval ◽  
Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

scholarly journals BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Austin Kulasekararaj ◽  
Jacques Le Roux Malherbe ◽  
Andrew McDonald ◽  
Melanie Cornpropst ◽  
Phil Collis ◽  
...  
Keyword(s):  
South Africa ◽  
Board Of Directors ◽  
Research Funding ◽  
Total Bilirubin ◽  
Proof Of Concept ◽  
Advisory Committees ◽  
Clone Size ◽  
The Past ◽  
History Of ◽  
Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in < 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion:Membership on an entity's Board of Directors or advisory committees;Apellis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

scholarly journals Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1357-1357 ◽  
Author(s):  
Hannah Asghari ◽  
Dasom Lee ◽  
Yehuda E. Deutsch ◽  
Onyee Chan ◽  
Najla Al Ali ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Groups ◽  
Initial Therapy ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Significant Difference ◽  
Frontline Therapy ◽  
Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

The Introduction of Novel Agents Improves Outcomes of Young Patients with Myeloma (MM) Treated with Autologous Stem Cell Transplant (ASCT)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1348-1348
Author(s):  
Radovan Saso ◽  
Kevin D Boyd ◽  
Kabir Mohammed ◽  
Ping Wu ◽  
Jennifer Treleaven ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Survival Rates ◽  
Young Patients ◽  
Novel Agents ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Younger Patients ◽  
Response To Chemotherapy ◽  
The Impact

Abstract Abstract 1348 Background: There has been an improvement in the population based survival of patients with MM in the UK (Office of National Statistics), however, because of the way the data is collected it is uncertain what has happened to the outcome of younger patients. High dose melphalan with ASCT has formed an integral part of the treatment of younger patients with myeloma for more than 20 years. During this time the context within which this treatment has been delivered has changed. Peripheral blood stem cell harvesting has replaced bone marrow harvesting, and importantly, novel agents have become available at induction and at relapse. It is not known how these changes have affected patient outcome. We analysed the survival of patients undergoing ASCT for MM in a single referral centre over an 18 year period to assess the impact of these changes. Patients: 1291 patients with myeloma were registered on the Royal Marsden Hospital Database in the period between 1981–2009, of which 875 patients underwent autologous transplantation. Bone marrow transplant (BMT) was performed in 191 patient, while 684 patients had peripheral blood stem cell transplant (SCT). Prognostic Factors: The following factors were found to be associated with improved overall survival (OS) in univariate analysis: Salmon Durie Stage A vs Stage B (p<0.004), ISS Stage I vs II vs III (p<0.001), response to chemotherapy CR vs PR vs Other (p<0.007), Platelets >130 vs <130 × 109/L (p<0.001), Hb >10 vs <10 g/dl (p<0.001), Calcium <10 vs >10mg/dl, Albumin >35 vs <35g/L (p<0.034), B-2M >3.5 vs <3.5 mg/l (p<0.001), IgG vs IgA vs BJ (p<0.038). Variables significant in multivariate testing were: Response to chemotherapy CR vs <CR (HR 1.4; 95% CI 1.0–2.0), Platelets >130 (HR 0.52; 95% CI 0.3–0.9), Calcium (HR1.7; 95% CI 1.2–2.5) and B2M (HR2.1; 95% CI 1.5–2.9). These variables were significantly associated with OS in the overall dataset, and in the subgroup of younger patients under the age of 60. Response and Survival: The overall response (OR) rate following induction chemotherapy was 84%, including 22% complete responses (CR). Following autologous SCT, CR rates improved to 42%, with an OR of 91%. Analysis of actuarial survival for the whole group of patients who had SCT showed that young patients had significantly longer survival (Median survival: <60yrs vs. >60yrs; 8.7yrs vs 6.2yrs, p<0.009). In order to assess the impact of the introduction of new therapeutic agents in, we defined groups of patients treated in five year periods: 1991–1996, 1997–2003, 2004–2009. 5 year OS was unchanged when comparing the first two cohorts. However, the cohort of patients treated from 2004–2009 were associated with significant improvement in 5 year survival rates, from 61% for the earlier quinquennia to 82% for those treated in 2004-9 (p<0.001). We also assessed the impact of the introduction of SCT compared to BMT. SCT entered routine use at this centre in 2002, and patient outcomes did not improve from 2002–2004. The improved survival after 2004 is therefore unlikely to be due to the introduction of SCT. Summary: We found that patient survival following ASCT did not change significantly during the period 1991–2004. However, since 2004 survival rates have improved significantly, and the group that benefitted most were patients under the age of 60. This time period corresponds to the incorporation of novel agents such as thalidomide, bortezomib and lenalidomide into induction and relapse regimens, and suggests that novel agents have significantly improved the outcome of younger patients with myeloma in the context of treatment with ASCT. Disclosures: Boyd: celgene: Honoraria. Davies:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Clinical and Economic Burden Of Peripheral T-Cell Lymphoma In The United States

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2963-2963
Author(s):  
Michele H. Potashman ◽  
Chakkarin Burudpakdee ◽  
Weiying Wang ◽  
Yanyan Zhu ◽  
Kenneth R. Carson
Keyword(s):  
Board Of Directors ◽  
Economic Burden ◽  
Research Funding ◽  
Index Date ◽  
The United States ◽  
Control Group ◽  
Pharmacy Services ◽  
Office Visits ◽  
Peripheral T Cell Lymphoma ◽  
Advisory Committees

Abstract Background Peripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma (NHL). PTCL has a poor prognosis due to advanced stage at presentation, and generally poor response to standard chemotherapy. According to recent SEER estimates, PTCL accounts for about 4% of all NHL cases in the United States each year. To date, few studies have assessed the clinical and economic burden of PTCL. Methods MarketScan data for commercially insured and Medicare supplemental patients were used to retrospectively identify unique PTCL patients. Patients were identified by ICD-9-CM diagnosis codes between October 1, 2007 and June 30, 2011. The time of first PTCL diagnosis code served as the index date, and a second PTCL diagnosis date was used for confirmation. All patients were required to have at least 6 months of continuous enrollment before and 12 months of continuous enrollment after their index date. Patients were excluded if aged <18 years, date of birth or gender were missing, or if they had received a stem cell transplant (SCT) prior to PTCL diagnosis. The control group includes patients that may have any other malignant (excluding PTCL) or non-malignant condition and are considered to represent an average insured patient population from the payer perspective. The control group was matched based on age, sex, region, plan type, payer type, and length of enrollment. Mean cost per month was measured and annualized to provide average yearly costs. Healthcare costs included hospitalizations, pharmacy services, office visits, emergency room visits, hospice stays, SCT, and other patient-related costs (lab procedures, radiology procedures, blood transfusions, and other ancillary procedures). Results Of 2820 patients with ≥1 PTCL diagnosis, 1000 patients were identified that met all inclusion criteria (mean age 56 years, 58% male), and were matched to the control group. On an average annual basis, PTCL patients were hospitalized more often (0.9 vs 0.1 hospitalizations), and experienced a longer length of stay (6.4 vs 4 days) compared with matched controls. In addition, PTCL patients had a higher utilization of office visits (16.2 vs 4.1 visits), pharmacy services (34.2 vs 11.6 prescriptions), emergency room visits (0.8 vs 0.2 visits), and hospice care (0.6 vs 0.1 stays). PTCL patients also experienced higher comorbidities (mean Charlson Comorbidity Index of 1.72 vs 0.39, as determined at index date). Overall, PTCL patients incurred much higher average annual costs compared with matched patients ($75,934.08 vs $4660.64; Table), driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). Conclusions PTCL is associated with high resource utilization rates and high overall costs. The development of efficacious treatments for PTCL may offer better disease management and may reduce the clinical and economic burden of PTCL. Disclosures: Potashman: Millennium: The Takeda Oncology Company: Employment. Burudpakdee:Millennium: The Takeda Oncology Company: Consulting researcher Other. Wang:Millennium: The Takeda Oncology Company: Consulting researcher Other, Research Funding. Zhu:Millennium: The Takeda Oncology Company: Employment. Carson:Millennium: The Takeda Oncology Company: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Spectrum, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Research Funding.

Analysis of Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated in Randomized Clinical Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4000-4000 ◽  
Author(s):  
Raffi Tchekmedyian ◽  
Paul Elson ◽  
Aaron T. Gerds ◽  
Navneet Majhail ◽  
Hetty E. Carraway ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Phase Iii ◽  
Advisory Committees ◽  
The Past ◽  
American Society ◽  
Over Time

Abstract Introduction The major reasons for failure to achieve cure in the majority of AML patients (pts) are primary refractoriness of disease to initial chemotherapy or failure to maintain complete remission (CR) that has been achieved (relapse). There is no uniformly accepted standard treatment for relapsed or refractory (RR) AML, with most available therapies regarded as palliative or as a bridge to allogeneic transplantation. While the past two decades have witnessed trials of several investigational therapies in RR AML, data regarding the effectiveness of these interventions remains unclear. We studied the impact of experimental drugs in RR AML pts by undertaking a comprehensive analysis of all phase 2 and 3 randomized clinical trials (RCTs) reported in the past 3 decades. Methods We searched PubMed, Embase, Cochrane Controlled Trials Register electronic databases, ClinicalTrials.gov and conference abstracts from the American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) websites covering a period from 1988 to 2015. Key words used during this search included "refractory" or "relapsed" or "AML" or "phase II" or "phase III" or "randomized". Only double-arm, phase II with a sample size of at least 50 pts and phase III RCTs conducted in RR AML pts were included. Two reviewers independently extracted data on study methods, participants, therapies, and outcomes from all eligible trials: differences in how to classify agents in RCTs were resolved by discussion. The primary outcomes examined in the experimental arms (EAs) and standard arms (SAs) included CR rates, disease-free survival (DFS), refractory disease rates, treatment-related mortality (TRM) rates and overall survival (OS). Odds ratios (OR) were used to summarize differences between EAs and SAs. The DerSimonian and Laird random-effects model was used to compare them and to assess the overall impact of time. Results Of 5500 included pts, 40.5% were treated on 21 double-arm, phase II trials, 51% on 10 phase III trials and 6.6% analyzed through 4 retrospective studies. There was no change in CR rates in either EAs (p=.21) or SAs (p=.15) over time (Figure 1). The CR rates in EAs tended to be higher than in SAs [OR=1.24; 95% CI, 1.02-1.50, p=.03). Rates of disease refractoriness to salvage regimens in both EAs (p=.70) and CAs (p=.31) did not change over time and these rates were not significantly different between treatment arms [OR=0.82; 95% CI, 0.62-1.08, p=.16]. TRM rates tended to decrease over time but the change was not significant in either group [p=.24 for SAs and p=.33 for EAs]. TRM rates were higher in SAs compared to CAs but did not reach statistical significance [OR=1.21; 95% CI, 0.97-1.50, p=.09]. Over time, there was no significant change inDFS in either group (p=.32 for CAs and p=.58 for EAs). DFS rates did not differ between EAs and SAs [OR=1.01; 95% CI, 0.86-1.19, p=.89] (Figure 2). OS tended to remain stable over time in both groups [p=.85 for SAs and p=.66 for EAs]. While OS tended to be higher in SAs, it did not reach statistical significance [OR=0.93; 95% CI, 0.83-1.05, p=.27]. Conclusions: These findings indicate a lack of significant or clinically meaningful improvement in disease outcomes, including OS, in RR AML pts treated within RCTs over the past 3 decades. Greater efforts need to be directed towards designing RCTs using novel statistical approaches and directed agents based on recent discoveries of targetable mutations. Disclosures Carraway: Amgen: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer Inc.: Consultancy, Research Funding; Blinatumomab: Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Cladribine Combined with Idarubicin and High-Dose AraC (CLIA2) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4039-4039 ◽  
Author(s):  
Mansour Alfayez ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Marina Y. Konopleva ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Young Patients ◽  
Multiparameter Flow Cytometry ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Advisory Committees ◽  
Genetics Research ◽  
Equity Ownership

Abstract Background Nucleoside analogues such as cladribine can increase the efficacy of cytarabine (araC) by modulating deoxycytidine kinase. The addition of cladribine to standard 7+3 chemotherapy has been shown to improve survival in pts with AML (Holowiecki JCO 2012). Results of our part-1 phase-2 clinical trial (cladribine combined with intermediate dose araC and idarubicin (CLIA1)) reported promising results that exceeded pretreatment expectations for response and tolerability (Jain, et. al. ASH 2016). Based on that, and the benefit of higher doses of cytarabine in younger patients (UK-MRC AML, Willemze JCO 2014), we investigated a higher dose of araC in combination with cladribine and idarubicin (CLIA2). Methods Non-APL, non-core binding factor AML pts 18-65 yrs of age with adequate organ function were enrolled in 1 of 3 cohorts: de novo AML, secondary AML (s-AML), or relapsed/refractory AML (R/R). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5, followed by araC 2g/m2 IV on days 1-5, and idarubicin 10 mg/m2 IV days 1-3. Consolidation consisted of up to 5 more cycles of CLIA2 for 3 days instead of 5. Dose-adjustments were allowed for age and PS. Sorafenib or midostaurin was added for pts with FLT3 mutations which occurred in 35% of pts on this study. Prophylactic intrathecal therapy was offered to higher risk pts at count nadir during cycle 1. Mutation profiling was performed using next generation sequencing prior to starting therapy. Results 65 patients were enrolled, with a median age of 47 yrs (range, 24-65): 37 pts (57%) in the frontline, 12 (19%) pts in the s-AML, and 16 (25%) in the R/R cohorts. Pt characteristics and outcomes by cohort are outlined in Table 1. The most commonly detected mutations at baseline were TET2 (45%), DNMT3a (37%), FLT3 (35%), ASXL1 (28%), and NPM1 (28%). Of 35 evaluable pts in the frontline cohort, 31 responded (ORR=89%) with 27 CR (77%) and 4 CRi (11%). Among the responders, 61% were negative for minimal residual disease (MRD [-]) by multiparameter flow cytometry. In the s-AML cohort, 10 pts were evaluable with an ORR of 60% (6/10) with 5 CR (50%) and 1 CRp (10%); 4 (67%) were MRD [-]. In the R/R cohort, 14 pts, previously treated with a median of 1 (1-4) prior therapy were evaluable for response. There were 7 CR (50%), 1 CRi (7%), for ORR of 57%; and 63% were MRD [-]. The median OS was not reached in the frontline and s-AML cohorts with median follow up of 5.2 and 11.5, months, respectively. In the R/R cohort, the median follow up was 4.7 months and median OS was 6.7 months [Figure.1]. Relapse-free survival was not reached in frontline and salvage cohort, and was 9.1 months in s-AML with median follow up of 5.2, 3.9, and 3.5 months in frontline, s-AML, and salvage cohorts, respectively [Figure.2]. The regimen was well tolerated. The most common ≥ grade 3 possibly-related non-hematologic adverse events were fever/infection (38), bleeding (2), and abnormal liver function test (3). Conclusion The 3-drug combination with a higher dose of araC, CLIA2, is safe and effective in younger pts with AML. Compared to our prior experience in pts with s-AML, using higher dose of cytarabine in CLIA2 for this cohort seems to have the highest impact. This trend however was also seen in the salvage and frontline cohorts when compared to the results from CLIA1. Response rates for pts in the newly-diagnosed AML, s-AML, and in the salvage settings are promising and should be explored further in larger studies and compared to current standard regimens. Disclosures Ravandi: Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Abbvie: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Daver:Otsuka: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Sunesis: Research Funding; BMS: Research Funding; ARIAD: Research Funding; Karyopharm: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Medimmune: Honoraria; Agios: Consultancy. Bose:Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Pfizer, Inc.: Research Funding. Andreeff:SentiBio: Equity Ownership; Jazz Pharma: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Astra Zeneca: Research Funding; Oncolyze: Equity Ownership; Celgene: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer . Pemmaraju:abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; celgene: Consultancy, Honoraria. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding. Kadia:Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding.

scholarly journals The Impact of Myeloproliferative Neoplasms (MPNs) on Patients' Quality of Life and Productivity: Results from the International MPN Landmark Survey

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4267-4267
Author(s):  
Claire N. Harrison ◽  
Steffen Koschmieder ◽  
Lynda Foltz ◽  
Paola Guglielmelli ◽  
Tina Flindt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Well Being ◽  
Ability To Work ◽  
Advisory Committees ◽  
The Past ◽  
Night Sweats ◽  
The Impact

Abstract Background Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) whose associated disease burden includes a range of debilitating symptoms, thrombosis, hemorrhage, and shortened survival. To enhance patient care, it is important to understand the impact of MPNs in patients' lives; however, little is known regarding how these conditions affect patients' quality of life (QOL), activities of daily living, productivity, and emotional well-being. The US LANDMARK survey (Mesa et al. BMC Cancer 2016) captured data for US patients. Here, we present an interim analysis of results of another MPN LANDMARK survey conducted in the rest of the world. Methodology MPN LANDMARK survey is a cross-sectional survey of MPN patients across 6 countries (Australia, Canada, Germany, Japan, Italy, and UK). Patients completed an online questionnaire to measure MPN related symptoms experienced over the past 12 months and the impact of their condition on their QOL and ability to work. Additional questions related to employment productivity and activity impairment (including absenteeism and loss of productivity over the past 7 days). Patients included in this interim analysis had completed the survey by July 18, 2016, with enrollment continuing in all countries. Results Patients: Overall, 437 patients had completed the survey (98 MF, 121 PV, 218 ET). For MF and PV, the male to female gender split was relatively even (54% male for each), whereas an expected greater proportion of ET patients was female (70%). Patients with MF were significantly older than PV and ET patients (mean ages, 62, 59, and 55 years, respectively) and more had been diagnosed within 2 years of experiencing their symptoms (83% MF, 67% PV, 71% ET). MPN Symptoms (Table): Most patients (94%) experienced MPN-related symptoms in the past 12 months. The most commonly reported symptom among all subtypes was fatigue (69% MF, 62% PV, 73% ET), incidence of other common symptoms varied depending on disease subtype (MF: shortness of breath [38%], bruising [36%], night sweats [35%], early satiety [33%]; PV: night sweats [36%], trouble concentrating [36%], trouble sleeping [34%], dizziness [34%]; ET: trouble sleeping [37%], dizziness [37%], bruising [35%], night sweats [35%]). When asked which symptom patients would most like to have resolved, most patients preferred to have feeling of fatigue/tiredness improved across all disease subtypes (31% MF, 30% PV, 33% ET). Patients experienced an average of 6.4 symptoms at diagnosis but this progressed to an average of 7.6 symptoms since diagnosis after a median time of 6 years. QOL: A majority of patients indicated that they experienced a reduction in QOL due to MPN symptoms (87% MF, 71% PV, 73% ET) with 33% and 26% of MF and ET patients expressing that their condition has caused emotional hardship, and one-third of patients with PV reporting that they have felt worried or anxious about their disease (39%). MPN Impact on Activity/Employment: Patients reported a high impact on their ability to work, 12% reported voluntarily leaving their job, 10% had taken early retirement, 10% had moved onto disability living allowance, 8% moved to a lower paid job, and 2% experienced involuntary loss of work (Table). Of the patients who were in full-time or part-time employment at the time of the survey (MF [n=17]), PV [n=41], ET [n=98]), approximately, 40% had been absent from work within the past 7 days; this was the highest in MF patients (41% MF, 38% PV, 33% ET). On an average, over the past 7 days, MF patients had missed 3.1 hours from work, PV patients 2.3 hours and ET patients 2 hours. Across all subgroups, a substantial proportion of patients reported impairment in work (mean: 34% MF, 33% PV, 31% ET) and overall activity (mean: 46% MF, 42% PV, 39% ET). Conclusions This interim analysis from the MPN LANDMARK survey indicates that MPN patients experience a high burden of disease, including a high prevalence of symptoms, an increase in the number of symptoms from diagnosis and reduction of their emotional well-being, QOL, and ability to work. These results are consistent with those from the previous US LANDMARK survey with the addition of novel data on how MPNs impact work. When treating MPN patients, care should be taken in trying to manage a patient's disease burden, so as to minimize the impact on a patient's daily life. Further results from additional survey responses will be presented at the congress. Disclosures Harrison: Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Koehler:Novartis Inc. (Germany): Consultancy, Other: Training. Komatsu:Shire: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boothroyd:Novartis: Employment, Equity Ownership. Spierer:Novartis: Employment. Ronco:Novartis: Employment. Taylor-Stokes:Adelphi Real World: Employment. Waller:Adelphi Real World: Employment. Mesa:Celgene: Research Funding; Galena: Consultancy; Novartis: Consultancy; CTI: Research Funding; Ariad: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding.

scholarly journals Comparison of Denosumab Versus Intravenous (IV) Bisphosphonate Use for Hypercalcemia in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-16
Author(s):  
Matthew M Lei ◽  
Erica Tavares ◽  
Uvette Lou ◽  
Evan Buzgo ◽  
Noopur S. Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Dysfunction ◽  
Board Of Directors ◽  
Research Funding ◽  
Additional Dose ◽  
Newly Diagnosed ◽  
Median Dose ◽  
Publicly Traded ◽  
Advisory Committees ◽  
The Past

Background Hypercalcemia (HC) is a frequent complication of multiple myeloma (MM) occurring in 20-30% of patients. This is often associated with renal dysfunction and both features are important myeloma defining events resulting in significant morbidity and mortality. Denosumab, a fully human monoclonal antibody that inhibits RANKL, has been evaluated in the prevention of skeletal related events in patients with newly diagnosed MM, as well as the treatment of bisphosphonate-refractory HC of malignancy (HCM). Cases of denosumab for HCM in MM patients with renal dysfunction have been described. Both denosumab and IV bisphosphonates (IVB) represent treatment options for HC in MM. We describe a comparison of patients with MM with HC who received denosumab vs IVBs. Methods We retrospectively identified patients age ≥18 with a diagnosis of MM with HC (corrected serum calcium level [CSC] &gt;10.5 mg/dL). Patients were included if they received either denosumab or IVB (zoledronic acid [ZA] or pamidronate), between April 2016 and June 2020. The primary endpoint was complete response (CR), defined as normalization of CSC to less than 10.5 mg/dL. Secondary endpoints included HC relapse (CSC &gt;10.5 mg/dL) and safety. Hypocalcemia was graded per CTCAE v5. Acute kidney injury (AKI) was defined using KGIDO criteria. Patients were followed-up for 56 days. Bivariate analyses were performed. Results A total of 40 patients were included with 18 in the denosumab group and 22 in the IVB group, of whom 15 (68%) received ZA and 7 (32%) received pamidronate. Baseline characteristics are described in Table 1. Patients with newly diagnosed MM composed 33% and 55% of the denosumab and IVB groups, respectively. All patients in the denosumab group received 120 mg except one who received 60 mg, while in the IVB group, dose reductions occurred in 5/15 patients who received ZA (median dose, 4 mg; range, 3.3-4) and 4/7 patients who received pamidronate (median dose, 60 mg; range, 30-90). Most patients received HC treatment as an inpatient (58% inpatient vs. 42% outpatient). A minority of patients had received IVBs in the past 90 days. The mean CSC was 12.5 mg/dL (standard deviation [SD], 1.40) and 13.3 mg/dL (SD, 2.39) in the denosumab and IVB groups, respectively. Baseline serum creatinine (SCr) was higher and creatinine clearance (CrCl) was lower in the denosumab group (median SCr, 2.06 vs. 1.24 mg/dL, p=0.048; median CrCl, 33 vs. 48 mL/min, p=0.048). The CR rate by day 3-4 was 92% and 94% in the denosumab and IVB groups, respectively (p=NS). HC relapse occurred in 2 (12%) and 6 (29%) patients in the denosumab and IVB groups, respectively (p=0.257). Incidence of grade 1 hypocalcemia was similar between groups; however, incidence of grade ≥2 hypocalcemia was higher in the denosumab group. Incidence of new AKI was 28% (5/18) in the denosumab group 23% (5/22) in the IVB group (p=0.71). No patients in the denosumab group received an additional dose of denosumab within 14 days of initial dose. Three patients in the IVB group received an additional dose of an IVB within 14 days of initial dose. One patient, who was in the denosumab group, had refractory hypercalcemia and had not achieved CR at day 56. Conclusions We describe our experience with denosumab and IVB for the management of HC in patients with MM. The CR rate at 3-4 days was similar with either agent in our MM only population that was not bisphosphonate refractory. A higher incidence of grade 2 hypocalcemia was noted in the denosumab group. Conclusions on renal safety are limited by the small sample size and that patients in the denosumab group had a higher SCr on presentation. Denosumab and IVB represent acceptable agents for the management of HC in MM patients with further investigation necessary in those with renal dysfunction. Disclosures Lei: Fresenius Kabi USA: Consultancy; Trapelo Health: Consultancy; Bluebird Bio: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Clovis Oncology: Current equity holder in publicly-traded company; Blueprint Medicines: Divested equity in a private or publicly-traded company in the past 24 months. Lou:Fresenius Kabi USA: Consultancy. Raje:Bluebird, Bio: Consultancy, Research Funding; Takeda: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Astrazeneca: Consultancy. Yee:Karyopharm: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Denosumab is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. We describe the use of denosumab for hypercalcemia of malignancy in a multiple myeloma only patient population that is not bisphosphonate refractory. The use of denosumab for these patients was part of normal clinical practice in adherence to institutional policies and guidelines.

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.

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