scholarly journals Propensity Score Matching Analysis Comparing Ruxolitinib Vs Historical Controls in 2 nd Line or Beyond Treatment for Chronic Gvhd after Therapy Failure

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1805-1805
Author(s):  
Igor Novitzky-Basso ◽  
Swe Mar Linn ◽  
Jennifer White ◽  
Mohamed Elemary ◽  
Anargyros Xenocostas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Propensity Score ◽  
Propensity Score Matching ◽  
Board Of Directors ◽  
Research Funding ◽  
Therapy Failure ◽  
Advisory Committees ◽  
Line Therapy ◽  
Heavily Pretreated ◽  
Severe Grade

Abstract Background The REACH3 study has reported greater overall response and failure-free survival (FFS) with Ruxolitinib (RUX) as 2 nd line therapy for steroid-refractory chronic graft versus host disease (cGVHD) in comparison to best available therapy (BAT; NEJM 2021). In addition, our Canadian retrospective study as a real-world experience has reported a promising activity of 64.6% FFS and 83.3% overall survival (OS) at 12 months in 115 patients (pts) treated with RUX from 2016 to 2021 for heavily pretreated cGVHD (ASH 2021). Also, 47.6% pts could reduce corticosteroid dose below 0.1mg/kg/day within 6 months. The present study compared treatment outcomes using a propensity-score matching (PSM) analysis between RUX pts ("RUX group", n=115) and a historical cohort of cGVHD pts treated with BAT as 2 nd line therapy or beyond from 2005 to 2013 ("BAT group", n=311). Statistical endpoints such as FFS, OS and steroid dose reduction were evaluated instead of overall response due to limited response assessment available from retrospective chart reviews. Patients and methods BAT included mycophenolate (43%), prednisone (29%), prednisone/cyclosporine (12%), extracorporeal photopheresis (6%), rituximab (3%), and others (7%). The pts and disease characteristics between the RUX vs BAT groups were not well balanced, as expected: RUX group showed a higher number of pts with severe grade GVHD (59.1% in RUX vs. 20.3% in BAT; p<0.0001), and more heavily pretreated with 4 th line or beyond (84.3% in RUX vs. 17.0% in BAT; p<0.0001). FFS and OS were calculated from the day of starting RUX or BAT therapy, while daily prednisone doses at months 0, 3 and 6 were calculated divided by body weight (kg). PSM analysis was applied to adjust risk factors that were unbalanced between the 2 groups, including GVHD severity at therapy start (mild/moderate vs severe grade), HCT-CI score (0-2 vs 3 or beyond), and treatment line (2nd vs 3rd vs 4th line or beyond). A total of 100 patients (i.e. 50 case-control pairs) were finally extracted through PSM process within 0.2 of calliper difference. PSM analysis balanced out the risk factors between the 2 groups: GVHD severity (p=1.0), HCT-CI score (p=1.0) and treatment line (p=1.0). The FFS and OS rate at 12 months were compared using Cox's proportional hazard model. Results In the overall population (n=426), with a median 19 months follow-up duration, 244 failures (57.3%) were noted. While both groups showed similar failure rates due to non-relapse mortality (NRM), the RUX group showed significantly lower failure rate from cGvHD resistance requiring therapy switch. Failure was noted in 40 pts (33.4%) in RUX due to resistance requiring a switch of therapy (n=23; 20.0%), NRM (n=14, 12.2%) and relapse (n=3; 2.6%), while failure occurred in 204 pts (65.6%) in BAT due to resistance requiring a switch of therapy (n=142; 45.7%), NRM (n=36; 11.6%) and relapse (n=26; 12.7%). The 12 months' FFS rate were 64.7% and 40.1% in RUX vs. BAT group (p<0.0001; Fig 1A), while the 12 months' OS rate were 83.4% and 83.7% in RUX vs. BAT group (p=0.913; Fig 1B). In the propensity score matched (PSM) cohort (n=100), the RUX group showed a survival benefit over the BAT group: the 12 months' FFS rate was 74.0% and 29.7% in RUX vs. BAT group (p<0.0001; Fig 2A), while the 12 months' OS rate were 90.5% and 80.2% in RUX vs. BAT group (p=0.109; Fig 2B). Multivariate analysis in the PSM cohort confirmed that RUX is superior to BAT for FFS (p<0.001, HR 0.267 [0.139-0.516]) together with HCT-CI score 0-2 vs ≥3 (p=0.037, HR 0.490 [0.251-0.959]) with a trend to better survival in RUX over BAT (p=0.110, HR 0.402 [0.131-1.228]). The prednisone dose was gradually reduced over time: the median doses of prednisone at months 0, 3, and 6 were 0.34, 0.16 and 0.02 mg/kg/day in the RUX group, and 0.95, 0.24 and 0.15 mg/kg/day at months 0, 3 and 6 in the BAT group. RUX facilitates the discontinuation of prednisone. The proportions of patients who discontinued prednisone at months 0, 3 and 6 were 8.7%, 15.9% and 24.1% in RUX, and 0.7%, 0% and 2.0% in BAT group. The differences in proportions of pts that discontinued prednisone between the RUX vs BAT groups at months 0, 3, and 6 were 8.0%, 15.9% and 22.1% (Fig 3). Conclusion: The current PSM analysis study suggests that RUX showed a superior FFS to BAT as 2nd line therapy or beyond in cGVHD patients after therapy failure. RUX showed better steroid tapering compared to BAT. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Elemary: Pfizer, Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz, BMS, Abbvie, Novartis, Pfiz: Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Paladin: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding.

scholarly journals Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3339-3339 ◽  
Author(s):  
Ciara Louise Freeman ◽  
Mark Dixon ◽  
Richard Houghton ◽  
Kathryn Humphrey ◽  
Gunter Fingerle-Rowson ◽  
...  
Keyword(s):  
Risk Factors ◽  
Monoclonal Antibodies ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukaemia ◽  
Signs And Symptoms ◽  
Leukemic Cells ◽  
Tumour Burden ◽  
Advisory Committees ◽  
Anti Cd20

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 301-301 ◽  
Author(s):  
Paul Richardson ◽  
David Siegel ◽  
Rachid Baz ◽  
Susan L. Kelley ◽  
Nikhil C. Munshi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Dose Dependent Increase

Abstract Abstract 301 Background: Pomalidomide (POM) is an IMiD® derived from thalidomide with a modified chemical structure with improved potency in vitro and potential efficacy and safety benefits in vivo. Two phase (Ph) 1b, single-center, ascending dose, open-label studies in pts with relapsed/refractory multiple myeloma (MM; Schey et al, 2004, Streetly et al, 2008) identified maximum tolerated dose (MTD) as 2mg QD or 5mg on alternate days (28 of each 28-day cycle). High response rates of POM alone in heavily pretreated pts were encouraging. To evaluate the MTD, safety and efficacy of POM alone or with Dexamathasone (dex) on a 21/28 day schedule, a Ph 1/2, multicenter, randomized, open-label, 3×3 dose-escalation study was initiated in pts with relapsed/refractory MM after at least 2 prior regimens, including bortezomib and lenalidomide. Methods: The study has a Ph 1 POM MTD (n=32) portion, followed by Ph 2 open-label randomized POM+ dex vs POM alone (192 pts planned). Eligible pts had documented relapsed/refractory MM. All pts received low-dose prophylactic aspirin QD and monitored for venous thromboembolic events (VTE). In Ph 1, POM was given QD on Days 1–21 of 28-day cycle: 4 dose levels of POM (2, 3, 4, 5mg) were studied with option to add dex at 40 mg/wk after 4 cycles for lack of response or progressive disease (PD). Pts enrolled in Ph 1 and discontinued either for intolerance or PD could not be enrolled in Ph 2. Toxicities and responses were assessed using CTCAE v3 and modified European Group for Blood and Marrow Transplantation (EBMT) criteria. Results: Results from Ph 1 of the study are reported with 32 pts enrolled to date. Fifteen pts discontinued therapy and 17 pts are ongoing for both safety and efficacy analyses. Mean age is 66.6 yrs (range 38–84), with median number of prior regimens 7 (range 2–18). MTD has not yet been reached. There were 4 dose reductions due to POM (5mg [2-neutropenia, 1-rash]; 3mg [1-neutropenia]) after 108 completed cycles. Neutropenia and thrombocytopenia were the most common grade 3/4 toxicities, with no dose-dependent increase apparent so far: 12 serious adverse events (SAEs) occurred in 10 pts; drug related events included POM (VTE, syncope, 3rd degree AV block, asthenia, diarrhea, neutropenia, anemia, rash); dex (lung infection with neutropenia); POM + dex (sepsis with pharyngeal abscess). AEs such as somnolence (1) VTE (1) neuropathy (2), and constipation (4) were uncommon. There were 3 deaths on study not attributed to POM; 2 pts died of rapid PD, 1 pt died of gastrointestinal perforation due to amyloidosis. Responses were seen at each dose level (Table 1). In 20/21 (95%) evaluable pts, clinical activity (SD or better) was reported. During treatment with POM alone, overall response rate (ORR; 1 CR, 2 PR, 5 MR) was 38% (8/21), mean duration of response (DOR) was 11.1 (range 4–32) wks, mean time to progression (TTP) was 8.3 (range 2–36) wks. Median completed cycles of POM +/− dex overall was 4 (range 1–12), with 13/21 evaluable pts (62%) having dex added to their regimens at various different cycles (median cycle 3, range 2–9) for PD or lack of response. During treatment with POM+dex, ORR (2 PR, 3 MR) was 38%, mean DOR of 14.2 (range 4–32) wks, and mean TTP of 20 (range 4–52) wks. In addition, there were 9 stable diseases (SD) on POM alone with mean DOR of 7.1 (range 4–16) wks, and 6 SD on POM + dex with mean DOR of 10.7 (range 8–16) wks. In 5/13 pts (38%), responses improved after dex was added (2 PR, 2 MR, 1 SD). Conclusions: These preliminary results indicate that POM alone or in combination with dex is associated with 38% MR or better, while SD was achieved in 43% (POM alone) and 46% (POM + dex), amongst heavily pretreated pts with relapsed/refractory MM. The incidence of SAEs and discontinuations decreased with increased dose of POM with no dose-dependent increase in grade 3/4 hematological toxicities. The MTD has not been reached to date. Overall, these data indicate that POM has an acceptable safety profile and is a clinically active therapeutic option for advanced refractory MM, warranting further investigation in this patient population. Disclosures: Richardson: Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an anti-proliferative and immunomodulatory agent that is in clinical development for relapsed/refractory MM. Siegel:Celgene: Speakers Bureau; Millenium Pharmaceuticals: Speakers Bureau. Baz:Celgene: Research Funding. Munshi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Sullivan:Merck: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Merrion: Membership on an entity's Board of Directors or advisory committees. Doss:Celgene: Speakers Bureau. Larkins:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment. Donaldson:Celgene: Employment. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

3G8 and GMA161, Anti FcγRIII Inhibitory Monoclonal Antibodies in the Treatment of Chronic Refractory ITP. (Summary of 2 Pilot Studies).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2404-2404 ◽  
Author(s):  
Charles T Nakar ◽  
James B. Bussel
Keyword(s):  
Monoclonal Antibodies ◽  
Board Of Directors ◽  
Research Funding ◽  
Therapeutic Modality ◽  
Fab Fragment ◽  
Advisory Committees ◽  
Pilot Studies ◽  
Heavily Pretreated ◽  
Moderate Nausea ◽  
Refractory Itp

Abstract Abstract 2404 Poster Board II-381 Immune thrombocytopenia (ITP) is mediated by anti-platelet antibodies causing accelerated destruction and impaired production of platelets (PLTs). The clearance of IgG- coated PLTs is by Fcγ receptor- bearing macrophages in the spleen and liver. Patients (pts) with ITP, who despite splenectomy maintain low PLT counts, exhibit significant morbidity and mortality. For these pts inhibition of the mononuclear phagocytic system was targeted as a therapeutic modality. The clinical and immunological results of 15 pts treated with mouse and humanized versions of anti FcγRIII (anti-CD16) inhibitory monoclonal antibodies (mAbs), 3G8 and GMA161, are reported here. Pts were adults with chronic refractory ITP. Baseline PLT counts were <20K/ul and <30K/ul for pts treated with 3G8 and GMA16 respectively, and all had significant bleeding histories. All pts had limited or no response to splenectomy, steroids, IVIG and multiple other treatments. 3G8, a mouse mAb was infused at an initial dose of 25mg (0.25–0.5mg/kg). Subsequent infusions of 50mg on day 3-4 and 75mg on day 6-7 were administered if no response was seen. Two pts treated with Fab fragment of 3G8 with no response received a single infusion of 25mg of intact 3G8 on day 7-8. GMA161 is a humanized version of 3G8 which also has the Fc piece denuded of carbohydrates. In the 1st 4 pts, it was infused once at 0.1mg/kg. Response was defined as a PLT increase >20K. 6/11 (55%) pts treated with 25mg of 3G8 responded. The mean peak PLT increase was 93K for all 11 pts and 160K for the 6 responders (median PLT increases were 32 and 147, respectively). The peak PLT count was seen on day 3 and was significantly above baseline on days 1-6 in responders and remained above baseline for a median of 14 days following the initial treatment. Three responders were treated again. 2/3 pts had high HAMA titers and failed to respond. Two pts (a responder and a non-responder) were treated again 4 years later, after their HAMA titer had decreased to almost baseline. Both had short-lived PLT responses >30K after re-challenge. Two pts remained stable for more than 3 years; one after receiving a 2nd infusion 4 years following the first, and the second after 3 infusions of 3G8 at 3-month intervals. There was marked transient neutropenia and decrease in NK cells activity following infusion in all pts. Pts developed significant fever-chill-vomiting reactions. Prevention required a cocktail of methylprednisolone, diphenhydramine, acetaminophen and metaclopramide. One patient who suffered from significant pre-existing pulmonary disease including heart failure, bronchopneumonia and (silent) lung cancer, developed ARDS at the time of the second 3G8 infusion and unfortunately died the following day. Another patient developed GI bleeding following a methylprednisolone infusion. No abnormalities in liver, renal function tests or coagulation studies were detected. 2/4 pts treated with GMA161 responded with peak PLT counts of 108K/ul and 45K/ul. The responses to GMA161 were short-lived, lasting between 7 and 10 days. A dramatic, transient decrease in the WBC was seen with GMA161 as with 3G8. The first patient had marked chills, fever, and vomiting 2 hours after infusion which resolved with methylprednisolone. The second patient had mild-moderate nausea. The third and fourth patients received acetaminophen, diphenhydramine and ondansetron premedication and had no adverse events. Six additional patients were treated; their data is being analyzed. FcγRIII is the primary receptor implicated in the destruction of immune complexes. 3G8 an anti FcγRIII blocking antibody resulted in dramatic but transient responses in approximately 50% of heavily-pretreated, very refractory ITP pts. Certain pts did not respond which may be due to decreased PLT production or the use of other FcγR's to achieve PLT phagocytosis. However acute reactions occurred and infusions could not be repeated because of HAMA so GMA161 was created to overcome both of these issues via humanizing the antibody and denuding the Fc piece of carbohydrates. Unfortunately this was not an entirely successful approach; complete results are being collated. In summary, the redundancy of the FcγR system may limit the utility of blocking specific FcγR's; alternatively impaired PLT production may be of paramount importance in refractory patients. Disclosures: Off Label Use: 3G8 and GMA161 are Anti FcγRIII Inhibitory Monoclonal Antibodies used to treat refractory patients. The abstract presents the results of two pilot trials. . Bussel:Immunomedics: Research Funding; Sysmex: Research Funding; Cangene: Research Funding; Scienta: Speakers Bureau; Genzyme: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, My family owns stocks, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, My family owns stocks, Research Funding; Inc: Research Funding.

Hypercholesterolemia In Imatinib Intolerant/Resistant CML-CP Patients Treated With Nilotinib: A Retrospective Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1503-1503 ◽  
Author(s):  
Devendra K. Hiwase ◽  
David T Yeung ◽  
Lisa Carne ◽  
David Ross ◽  
Andrew Grigg ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lipid Profile ◽  
Retrospective Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Lipid Profiles ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Advisory Committees ◽  
Before And After

Abstract Background CML patients (pts) enjoy prolonged leukaemia-free survival with tyrosine kinase inhibitor (TKI) treatment. Addressing common non-CML causes of morbidity and mortality such as cardiovascular disease (CVD) and its associated risk factors is therefore increasingly important. Anecdotal evidence suggests a possible association between nilotinib (NIL) therapy and vascular events though there is little good quality evidence in this regard. The incidence of hyperlipidaemia and hyperglycaemia is higher in NIL-treated pts compared to imatinib- (IM) treated pts; conversely IM treatment may retard development of dyslipidaemia and hyperglycaemia. This retrospective analysis assessed the lipid profile of CML-CP pts before and after changing from IM to NIL therapy. Method Plasma lipid profile (total cholesterol, LDL, HDL and triglycerides), TKI exposure, and CVD risk factors before and after switchover to NIL of chronic phase CML pts were analysed. Baseline measurements were done during IM treatment or within 2 weeks of changing from IM to NIL. Follow-up results were obtained at least 1 month after starting NIL. Results Thirty-one CML pts were switched to NIL (median dose 400mg bd) after a median of 27 (1-96) months of IM therapy, predominantly for intolerance (16/31, 52%) or for failure to achieve deep molecular responses (13/31, 42%). Median age at NIL start was 51 (17-80) years (Table I). After switching to NIL, three pts had new onset PVD/IHD and one patient had multiple recurrences of PVD. Antihypertensive and hypoglycaemic medications were started in one additional patient each after switching over to NIL. Three pts were excluded from further analysis because of lack of data (n=2) or pre-existing dyslipidemia (n=1). The remaining pts had 90 TC assays, 72 of which were full lipid profiles whilst on NIL. Observations were censored at the time of statin commencement. Median time to 1st lipid measurement on NIL was 108 days (28-633) after switching. Median TC on IM was 4.7mM (2.1-6.4), compared to 6.1mM on NIL (3.1-8.5). Median peak TC on NIL was 6.8mM. Full fasting lipid profiles available for 11 pts before and after switching showed significantly increased LDL to be the major contributor to the increase in TC (Fig. 2). Thirteen pts had a fasting TC >5.5 mM (210 mg/dL) whilst on NIL, peaking at 312 days (medians). Eight of 13 pts started statins treatment for dyslipidemia whilst on NIL; (all retrospectively confirmed to be appropriate according to Australian National Heart Foundation guidelines, using a composite measure of CVD risk); whilst the other 5 were offered lifestyle modifications only. Of note, 2 pts had dyslipidaemia prior to starting IM treatment, discontinued statins whilst on IM, and had recurrence of dyslipidaemia after switching to NIL necessitating resumption of statin treatment. In addition, the 2 pts with PVD were also offered statins (total starting statin n=10) Discussion This retrospective analysis showed a high incidence of dyslipidemia in a cohort of CML pts treated with second-line NIL after IM therapy; 10/31 pts required lipid lowering agent. While the epidemiological association between nilotinib and CVD remains controversial, the increase in TC may have a contributing effect. Monitoring lipid levels in NIL-treated pts is prudent, along with screening for and minimisation of concomitant CVD risk factors, especially in pts previous treated with IM which may mask underlying metabolic syndromes. # DKH DTY and LC contributed equally to this work. Disclosures: Hiwase: Novartis Pharmaceuticals: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria. Hughes:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2016-2016
Author(s):  
Tomer M Mark ◽  
Peter Forsberg ◽  
Ihsane Ouansafi ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Selinexor Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4773-4773 ◽  
Author(s):  
Christine I. Chen ◽  
Martin Gutierrez ◽  
David S. Siegel ◽  
Joshua R. Richter ◽  
Nina Wagner-Johnston ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Transcriptional Activation ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Heavily Pretreated ◽  
Equity Ownership

Abstract Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, <20 mg DEX and 20 mgs DEX. Results: In MM.1s cells Sel-Dex showed synergy for nuclear retention of the DEX activated GR (Ser211-phosphorylated) and concomitant GR transcriptional activation. Sel-Dex showed highly synergistic cytotoxicity in MM.1s cells in vitro and in vivo, with a corresponding increase in apoptosis. Selinexor alone was potently cytotoxic in the DEX resistant MM cell lines MM.1R and ANBL6, but addition of DEX provided no additional effect. Twenty-eight pts with heavily pretreated refractory MM (16 M, 12 F; median age 62; ECOG PS 0/1: 7/21; median prior regimens: 6) received selinexor at 30 – 60 mg/m2 with either 0, <20, or 20 mgs DEX. All pts have received a proteasome inhibitor and an Imid and the majority of the pts have received pomalidomide (68%) and/or carfilzomib (36%). The most common Grade 1/2 AEs for these three groups were: nausea (82%/86%/70%), fatigue (55%/86%/40%), anorexia (36%/71%/60%), and vomiting (36%/57%/10%). Of the 28 pts treated; 10 heavily pretreated refractory MM pts treated with a combination of selinexor (45 mg/m2 twice weekly) and DEX (20 mg with each selinexor dose) were found to have dramatically improved disease response (n=10, ORR 60%), with one stringent complete response (sCR, 10%), 5 partial responses (PR, 50%) and clinical benefit rate (CBR) rate of 80% (Figure 1). Treatment with ³30mg/m2 selinexor and <20 mg DEX (n=7), resulted in ORR of 14% and CBR of 86%, while treatment with selinexor (30-60 mg/m2) without DEX (n=12) showed best response of stable disease (50%). Sel-Dex was also associated with an increase in time on study relative to selinexor alone, with 7 of out 10 pts in the 20 mg DEX combo group still on study (11-25 weeks). Five additional pts were treated with selinexor at a dose of 60 mg/m2 in combination with 20 mg DEX. Response evaluation is pending. Conclusions: Sel-Dex combination is markedly synergistic in preclinical models, which is supported by the preliminary clinical data presented. One potential mechanism underlying this synergy is the amplification of GR activity due the combined effects of selinexor-induced nuclear retention of activated GR coupled with DEX-mediated GR agonism. These results provide a promising basis for the continuing study of Sel-Dex for treatment of pts with refractory MM. Phase 2 studies of Sel-Dex in pts with MM refractory to both pomalidomide and carfilzomib are planned for early 2015. Disclosures Chen: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

Genes Influencing the Development and Severity of Chronic ITP Identified through Whole Exome Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 73-73 ◽  
Author(s):  
Jenny M. Despotovic ◽  
Linda M. Polfus ◽  
Jonathan M. Flanagan ◽  
Carolyn M. Bennett ◽  
Michele P Lambert ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Second Line ◽  
Second Line Therapy ◽  
Advisory Committees ◽  
Chronic Itp ◽  
Line Therapy ◽  
Whole Exome ◽  
Phenotype Data

Abstract Background: Chronic immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by antibody mediated platelet destruction and impaired production. Sustained autoimmunity in chronic ITP appears to be due to generalized immune dysregulation including altered T cell balance with a shift toward immune activation (increased Th1/Th2 ratio) as well as decreased number and impaired function of regulatory T cells (Treg). The cause of these abnormalities has not been fully elucidated and is likely multifactorial, but genetic factors may be involved in ITP pathogenesis. Improved understanding of genetic influences could lead to novel therapeutic approaches. Aim: To identify genetic variants that may be involved in chronic ITP susceptibility and severity. Methods: Whole exome sequencing (WES) was performed on 262 samples with robust phenotype data on children with chronic ITP from the North American Chronic ITP Registry (NACIR, n= 173) and the Platelet Disorders Center at the Weill-Cornell Medical Center (n=89). All but three patients were ≤19 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, 7% had other autoimmune disorders. Sequencing data for ITP cases of European American (EA) ancestry were compared to EA controls with platelets >150 x 109/L sequenced in the Atherosclerosis Risk in Communities (ARIC) Study (N=5664) to identify candidate genes associated with ITP susceptibility. Analyses filtered variants on a minor allele frequency (MAF) <0.01 as well as functionality of nonsynonymous, stop gain, splicing, stop loss, and indel variants. Both Fisher-Exact tests of single variants and Firth logistic regression for gene-based tests, accounting for an unequal proportion of cases compared to controls, were used. A Bonferroni corrected threshold based on 16,532 genes was calculated at 3.0x10-6. In a separate analysis, phenotype data for ITP cases were reviewed and cases stratified by disease severity according to second line treatment needed (Yes =139, No=113) and compared to ARIC EA controls with platelet count >150 x 109/L (N=5664). Results: Several damaging variants identified in genes involved in cellular immunity had a significantly increased frequency in the EA ITP cohort (Table). The most significant associations were detected in the IFNA17 gene, which is involved in TGF-β secretion and could affect number and function of the Treg compartment. IFNA17 rs9298814 (9:21227622 A>C) was identified in 26% of cases in the EA ITP cohort compared to <0.01% of EA controls, and other low frequency but presumed deleterious variants were also identified in IFNA17. IFNA17 gene variants remained significant in the most severely affected patients, specifically those requiring second line therapy, providing further evidence for this gene's functional relevance in the pathogenesis and pathophysiology of ITP. Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained variants with increased frequency in the EA ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy. Analysis of this large cohort did not validate any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP. Conclusion: Damaging variants in genes associated with cellular immunity have an increased frequency in children with chronic ITP compared to controls, providing further evidence for the role of T cell abnormalities in the pathophysiology of ITP. The IFNA17 and IFNLR1 genes maintained significance when the ITP cohort was stratified according to disease severity, and may be important candidate genes involved in immune regulation and sustained autoimmunity associated with chronic ITP. Table. Genes identified through WES analysis of children with chronic ITP. Gene Function Relevant to ITP Pathophysiology Minor Allele Count (MAC)Cases Controls p value EA Chronic ITP vs. EA ARIC (non-ITP) controls N=172 N=5664 IFNA17 Treg, TGF-β signaling 91 17 3.97x10-13 DGCR14 IL-17 induction 14 3 1.27x10-10 SMAD2 TGF-β signaling 1 0 5.62x10-22 CD83 Th17/Treg balance 2 3 1.67x10-6 EA Chronic ITP requiring Second Line Therapy vs. EA ARIC (non-ITP) controls N=139 N=5664 IFNLR1 Class II cytokine receptor 2 1 3.95x10-15 IFNA17 Treg, TGF-β signaling 75 17 3.40x10-7 REL T and B cell function, inflammation 2 0 1.39x10-14 Disclosures Off Label Use: Off-label use of CliniMACS purified CD34+ cells. Lambert:GSK: Consultancy; NovoNordisk: Honoraria; Hardin Kundla McKeon & Poletto: Consultancy. Recht:Baxalta: Research Funding; Kedrion: Consultancy. Bussel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; protalex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3444-3444 ◽  
Author(s):  
Yi L. Hwa ◽  
Rahma Warsame ◽  
Morie A. Gertz ◽  
Francis K Buadi ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Practice Patterns ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Second Line ◽  
Second Line Therapy ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals The Fate of Patients with Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5413-5413
Author(s):  
Pavel Otahal ◽  
Andrea Janikova ◽  
David Belada ◽  
Vit Prochazka ◽  
Heidi Mocikova ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clinical Stage ◽  
B Cell Lymphoma ◽  
Refractory Disease ◽  
First Line ◽  
Advisory Committees ◽  
Advanced Clinical Stage ◽  
Line Therapy

Abstract Background: The outcome of DLBCL patients is improving, it however seems to be very poor for those who are refractory to the therapy. We have decided to analyze this group of patients. Methodology: As part of an observational clinical study NiHiL (GovTrial No NCT03199066) we identified the patients treated in the first line by R-CHOP like immunochemotherapy who met at least one criterium: 1. refractory (stable disease - SD or progression) on 1st line therapy (1st l- R), 2. refractory (SD or progression) on salvage (platinum based regimen) (Salv-R), 3. refractory to or relapse/progression within 12 months after ASCT (ASCT-R/R). There were 210 patients diagnosed in the period 2001-2017 who fulfilled the criteria. Progression-free survival (PSF) and overall survival (OS) were estimated from the time of determination of a refractory disease. Results: The cohort consisted of 163 patients primarily resistant to the first-line therapy, 31 patients were resistant to the salvage therapy and 16 patients progressed within 12 months after ASCT . At the time of the diagnosis, the median age was 65 years (22-91) (the same as at the refractory disease), 54% were males, 74% had advanced clinical stage (III+IV), 68% had IPI >3, 77% had above-normal LDH, and 45% had a tumor mass >10cm. The OS from the time of determination of refractory disease was 0.53 years, median PFS was 0.29 years. Patients under 65 years had median survival 0.8 years compared to 0.4 years in the group of patients above 65 years of age. The median PFS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.3, 0.26 and 0.35 years resp. and 5y survival 22%, 0% and 6% resp. The median OS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.55, 0.39 and 0.65 y resp. and 5y survival was 28%, 0% and 13% resp. Our results demonstrate that resistant DLBCL has an extremely poor prognosis, clearly new effective therapeutic strategies such as CAR-based therapies or others are required. This work was supported by a research program Progres Q28-9. Disclosures Belada: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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