scholarly journals Front-Line Treatment with Obinutuzumab ± Chlorambucil for Chronic Lymphocytic Leukemia in Real-World Clinical Practice: Results of a Multinational, Multicenter Study By Eric and Icllsg

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1766-1766
Author(s):  
Yair Herishanu ◽  
Adir Shaulov ◽  
Riva Fineman ◽  
Sandra Bašić-Kinda ◽  
Ariel Aviv ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Real World Setting ◽  
High Risk Disease ◽  
Frontline Treatment

Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS. In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a "real-world" setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy. Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P<0.001), del(13q) (29.9m, P<0.001) and trisomy12 (not reached, P=0.027). Patients with IGHV-unmutated had a trend for shorter PFS compared to those with IGHV-mutated gene (median PFS 25.3m vs. not reached, respectively. p=0.06). In a multivariate analysis, older age, high risk-disease, lymph nodes >5cm, G-monotherapy, reduced cumulative dose of obinutuzumab and status less than CR, were independently associated with shorter PFS. Seventy patients (16%) received a second-line treatment. The median OS for the entire cohort has not been reached yet and 2-year OS estimate is 88%. In conclusion, in a "real-world" setting, frontline treatment with G-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were observed in patients with high-risk disease [del(11q) and/or IGHV-unmutated] and those treated with G-monotherapy. Thus, even today in the era of novel drugs, G-Clb can be considered a legitimate frontline treatment in unfit CLL patients with low-risk disease [non-del(11q) and IGHV-mutated]. Disclosures Herishanu: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Research Funding. Scarfo:AstraZeneca: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Tedeschi:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Levato:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Rigolin:Gilead: Speakers Bureau; Gilead: Research Funding; AbbVie: Speakers Bureau. Loscertales:Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Gilead: Honoraria. Ghia:Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding.

scholarly journals Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Brian T. Hill ◽  
Deepa Jagadeesh ◽  
Alex V. Mejia Garcia ◽  
Robert M. Dean ◽  
Omer N. Koc ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Proteasome Inhibitors ◽  
Marginal Zone Lymphoma ◽  
Aggressive Lymphoma ◽  
Advisory Committees ◽  
Frontline Treatment

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

scholarly journals Size Matters: Identification of Larger Size CD19 Positive Extracellular Vesicles in Chronic Lymphocytic Leukemia That Inhibit Chimeric Antigen Receptor T Cell Functions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1865-1865
Author(s):  
Cynthia L. Forsman ◽  
Reona Sakemura ◽  
Fabrice Lucien-Matteoni ◽  
Elizabeth Juarez-Diaz ◽  
Nan Yang ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Risk Profile ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Effector Functions ◽  
Cell Functions ◽  
Cd19 Expression

Abstract Introduction: Unprecedented clinical outcomes were reported after CD19 chimeric antigen receptor T cell (CART19) therapy and led to their FDA approval in diffuse large B cell lymphoma and in acute lymphoblastic leukemia. However, the complete response rate in chronic lymphocytic leukemia (CLL) after CART19 therapy is much lower, at approximately 20-30%, and the mechanism(s) for this relative lack of success is unclear. The dominant known mechanism(s) that prevent successful CART cell therapy in CLL have been limited to CART expansion and poor persistence. However, potential mechanisms are not limited to the CLL T-cell. Several immune defects have been identified in CLL that result from the complex bi-directional interaction between B-CLL cells and their microenvironment. In CLL the leukemic microenvironment is rich with extracellular vesicles (EVs) secreted by B-CLL cells. There is growing evidence that these vesicles play an important role in intracellular communication by the delivery of growth factors, genetic material and microenvironmentally relevant molecules. Therefore, we aimed to investigate the role and interactions of EVs in the diminished or absent CART response seen in some CLL patients. Methods: EVs were isolated from peripheral blood of 16 patients with untreated CLL at different Rai stages (8 patients had early and 8 had advanced stage disease) and risk profile by FISH (8 patients had low risk and 8 patients had high risk disease, based on the presence of 17p deletion). Cytometry was used to determine size, number of particles per µl, Annexin V and CD19 expression. These variables were correlated to the Rai stage and risk category of the disease. To investigate the impact of EVs on CART cell functions, CART19 cells were stimulated with either CLL EVs alone or in combination with the CD19 positive cell line JeKo1. After coincubation different effector functions were analysed. Results: Two patterns of EVs in CLL patients were identified; a single versus two distinct EV size populations (small [EVssmall]; 50-240nm, median=110nm) and large [EVslarge]; 180-560nm, median = 360nm Fig 1.A). In 25% of patients, EVs were CD19 positive (EVCD19+). CD19 positivity was detected only in patients with the EVslarge (Fig 1.B). The EVs concentration, CD19 expression (EVsCD19+ vs EVsCD19-), or the size (EVssmall vs EVslarge) did not correlate with disease stage (early vs advanced Rai stage) or risk profile of CLL (low vs high risk) although some variation could be seen (Fig 1.C). To investigate our hypothesis that EVs could modulate CART19 function, CART19 cell effector functions were examined in the presence of EVsCD19+, EVsCD19-, EVssmall, or EVslarge. EVs, 1.5x10e5 particles, alone were insufficient to stimulate CART19 cells. However when CART19 cells were stimulated with the CD19 positive cell line JeKo1, their effector functions were reduced only in the presence of EVsCD19+, 50,000 particles, 2.5 x 10e3/ µl, but not EVsCD19- at the same concentration. This included a significant reduction in CART specific killing (Fig 1.D) and a reduction in cytokine production. The impairment of CART cell functions was independent of the size of EVs, i.e. there was no impairment of CART functions with large or small size EVCD19- in co-culture. Summary: We identify CD19 positive large size EVs from patients with CLL and demonstrate that these EVs play a role in the leukemic microenvironment by reducing CART cell activity. Studies are ongoing to define the mechanism(s). Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; MorphoSys: Research Funding; Abbvie: Honoraria, Research Funding. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Kenderian:Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding; Novartis: Patents & Royalties.

scholarly journals A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2872-2872 ◽  
Author(s):  
Farheen Mir ◽  
Andrew Grigg ◽  
Michael Herold ◽  
Wolfgang Hiddemann ◽  
Robert Marcus ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Model ◽  
Low Risk ◽  
Prognostic Variables ◽  
Advisory Committees ◽  
High Risk Disease ◽  
Risk Patients ◽  
Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

Carfilzomib: High Single Agent Response Rate with Minimal Neuropathy Even In High-Risk Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1938-1938 ◽  
Author(s):  
Ravi Vij ◽  
Jonathan L. Kaufman ◽  
Andrzej J Jakubowiak ◽  
A. Keith Stewart ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Impaired Renal Function ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Committees ◽  
High Risk Disease ◽  
All Treatment

Abstract Abstract 1938 Background: Carfilzomib (CFZ), a selective, epoxyketone proteasome inhibitor, produces potent, sustained proteasome inhibition and lacks many of the off-target activities associated with bortezomib (BTZ). Durable single-agent activity with CFZ has been observed in patients (pts) with relapsed/refractory multiple myeloma (R/R MM) who have received multiple prior therapies as well as in pts with advanced stage disease or significant comorbidities (Jagannath et al. ASCO 2009 Meeting. Abstract 8504). PX-171-004, is an ongoing Phase 2 study of single-agent CFZ in pts with relapsed or refractory MM following 1–3 prior therapies. Here we present updated data on the BTZ-naïve pts and report on activity observed in pts with significant comorbidities or poor-risk cytogenetic or FISH markers for myeloma. Methods: Enrolled pts received either 20 mg/m2 for all treatment cycles, or a stepped-up, dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter. CFZ was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days (one cycle), for a maximum of 12 cycles. Dexamethasone, 4mg, was administered prior to CFZ in Cycle 1 only. For the present analyses, pts were stratified according to several baseline criteria including ECOG performance score, cytogenetic or FISH markers of high-risk disease per mSMART criteria [del17p, t(4;14), t(14;16), del13 by karyotype and hypodiploidy] and serum ß2-microglobulin. The primary endpoint was overall response rate (ORR) per International Uniform Response Criteria for Multiple Myeloma. Results: Data are available for 110 BTZ-naïve pts. Baseline pt characteristics included: 60% of ECOG PS ≥1; 53% baseline neuropathy Grade 1/2; 30% moderately impaired renal function (CrCl <60 mL/min), and 17% diabetes. Approximately 13% of pts had cytogenetic or FISH markers of poor prognosis. The ORR for the entire BTZ-naïve population was 48%; the ORR for BTZ-naïve pts receiving 20–27 mg/m2 was 54%. The ORRs stratified according to dose and baseline measurements are detailed in the following table. The most common treatment-emergent AEs, regardless of relationship to study drug, were fatigue (61%), nausea (43%), anemia (39%), dyspnea (36%), cough (34%), headache (31%), thrombocytopenia and upper respiratory infections (30% each) and were primarily ≤ Grade 2 in severity. Grade 3/4 AEs occurring in >5% of pts included lymphopenia, neutropenia, pneumonia, thrombocytopenia, anemia and fatigue. Of note, there were no discontinuations for peripheral neuropathy and only 1 pt with impaired renal function at baseline was discontinued for creatinine increases. Twenty-four pts remain on study and 23% have completed the protocol-specified 12 cycles of therapy. Seventeen pts (20%) elected to continue CFZ on an extended treatment protocol (PX-171-010); no cumulative toxicities have been noted. Conclusions: Single-agent CFZ achieves high response rates in BTZ-naïve pts with relapsed myeloma, with minimal neuropathy, even in the setting of high-risk disease. In addition, single-agent CFZ continues to demonstrate long-term tolerability even in pts with comorbid conditions, including renal insufficiency and diabetes, who may benefit from a steroid-sparing treatment regimen. The data from this ongoing trial show that CFZ is a promising new treatment for multiple myeloma in the relapsed or refractory setting. Disclosures: Vij: Onyx: Honoraria. Kaufman:Celgene: Consultancy, Research Funding; Millenium: Consultancy; Merck: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Gabrail:Millenium: Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau. Le:Onyx Pharmaceuticals: Employment. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

scholarly journals Real-World Outcomes with Bortezomib-Containing Regimens and Lenalidomide Plus Dexamethasone for the Treatment of Transplant Ineligible MM Patients: A Multi-Institutional Report from the National Myeloma Canada Research Network (MCRN) Database

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2008-2008 ◽  
Author(s):  
Victor Jimenez-Zepeda ◽  
Donna E Reece ◽  
McCurdy R Arleigh ◽  
Esther Masih-Khan ◽  
Eshetu G Atenafu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Small Sample ◽  
Research Network ◽  
National Database ◽  
Categorical Variables ◽  
Advisory Committees ◽  
Entire Cohort

Abstract Introduction: Bortezomib-containing regimens (BCRs) have been the standard frontline approach for the treatment of transplant ineligible multiple myeloma (TIMM) patients in Canada for many years. Based on recent randomized clinical trial results lenalidomide and dexamethasone (Ld) has become another provincially funded option in Canada in the same therapeutic space. We aimed to compare the effect of BCRs and Ld for the treatment of TIMM using the newly-formed Myeloma Canada Research Network Multiple Myeloma Database (MCRN-MM-DB) project. This web-based centralized platform can track and characterize real-world outcomes of patients treated at major Canadian institutions and includes both legacy data dating back to 2007 (from 4 centres) as well as ongoing prospective data collection (from 11 centres) analyzed up to 01/07/18. Patients and Methods: The primary objective was to assess the ORR, PFS and OS for TIMM patients treated with CyBorD/CyBorP, Ld, VMP or VD/VP, each given as reported previously but with dose-adjustments at the discretion of the treating physician to maintain patients on therapy. The two-sided Fisher exact test was used to test for differences between categorical variables. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test; a p value of <0.05 was considered significant. Results: 842 TIMM patients were evaluated. Clinical characteristics are shown in Table 1. Median OS and PFS for the entire cohort were 54.1 and 20.4 months, respectively. ORR and ≥VGPR better rates were 83% and 52% for the entire cohort. A ≥VGPR rate of 53%, 46%, 56% and 51% were observed for patients treated with CyBorD/P, VMP, Ld and VD/VP, respectively (p=0.3). The median PFS was longer for Ld patients (25 months) compared to CyBorD/CyBorP, VMP and Vd/VP (19.3, 20.5 and 13.7 months, respectively), (p=0.03, Fig 1a); there was no significant difference in PFS between the 2 different alkylating-agent containing regimens when combined with bortezomib + steroids (CyBorD/P vs VMP, p =0.9). Median OS was 51, 59.5, 29.4 and 66.5 months for those patients treated with CyBorD/CyBorP, VMP, VD/VP and Ld, respectively (p=0.07, Fig 1b). When the OS and PFS for CyBorD/P (typically given for a fixed duration of 9 cycles) were compared with Ld in a subset analysis, the p-values were 0.08 and 0.008, respectively. Conclusions: 1) OS was not significantly different in patients treated with either a bortezomib-containing triplet that includes an alkylator + steroid or continuous Ld. 2) The BCR triplets and Ld were more efficacious than the bortezomib + steroid doublet (VD/VP) for both OS and PFS although, the small sample size and adverse factors, such as frailty and comorbidities, may have influenced the findings. 3) The results in the real-world setting, i.e., a median PFS in the range of 1.5-2 years and median OS of 4.5-5.5 years, confirm triplet-based BCRs and Ld as current valid standards of care for frontline therapy in TIMM. 5) This study confirms the utility of a large comprehensive national database to benchmark current results for comparison with newer regimens as they are introduced into the Canadian therapeutic landscape. Disclosures Arleigh: Celgene: Honoraria; Janssen: Honoraria. Sebag:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Leblanc:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Louzada:Janssen: Honoraria; Celgene: Honoraria; amgen: Honoraria; pfizer: Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria.

scholarly journals Connect MM®—the Multiple Myeloma (MM) Disease Registry: Interim Analysis of Overall Survival and Outcomes in Patients with High-Risk Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2106-2106 ◽  
Author(s):  
Jatin J. Shah ◽  
Rafat Abonour ◽  
Brian G M Durie ◽  
Jayesh Mehta ◽  
Mohit Narang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
African American ◽  
High Risk ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
High Risk Disease

Abstract Background: MM treatment (Tx) advances have greatly improved clinical outcomes for patients (pts). A recent study demonstrated improved survival in MM through the past decade attributable to the impact of initial therapy with lenalidomide, bortezomib, and thalidomide. The greatest impact was observed in older pts (Kumar, et al. Leukemia, 2014). Connect MM, the first and largest prospective, observational, US-based, multicenter registry was designed to characterize pts, Tx patterns, and outcomes in newly diagnosed MM (NDMM). Methods: This ongoing registry was initiated in September 2009. Eligible pts with NDMM (diagnosis must have occurred within 2 mos of study entry) were enrolled at 234 US sites. Data were collected at baseline and each subsequent quarter using an electronic case report form. The initial enrollment includes all pts who had provided informed consent as of November 1, 2012 (N = 1493). The data cutoff for this analysis was Dec 10, 2013. A total of 1444 pts were treated and were included in overall survival (OS) analyses. Survival was examined for all treated pts adjusting for pt and Tx characteristics including age, autologous stem cell transplant (ASCT) status, gender, race, disease risk factors (International Myeloma Working Group [IMWG] high risk vs. non-high risk), and therapy received (triplet vs. non-triplet) among others. Triplet therapy was defined as any combination of 3 or more drugs during the first Tx regimen. OS was estimated using Kaplan-Meier methods and comparisons across groups were assessed used the log-rank test. Results: At the time of data cutoff, 1493 pts were enrolled with 1444 having received Tx. Of the treated pts 253 pts (18%) had IMWG high-risk disease and 108 pts (7%) had del(17p) at baseline. Median age was 67 y (range, 24-94 y), 57.2% were male, and 81.9% were white. Median follow-up was 29 mos (0-49.4 mos). The median OS for all treated pts was 44.4 mos. When assessed by age group, OS was significantly different (log-rank P < .0001) with a median of 47.6 mos for pts aged < 65 y (n = 632), 45.0 mos for those aged 65 to < 75 y (n = 443), and 33.7 mos for those aged ≥ 75 y (n = 369). OS was significantly longer for pts with ASCT vs. no ASCT (P < .0001), but not different by gender (P = .962) or race (Caucasian vs. African American vs. other; P = .250). Three-year OS probabilities by subgroup are listed in Table 1. When considering risk factors, IMWG risk was borderline significant (high vs. non-high; P = .106), and presence of del(17p) by cytogenetics and FISH was associated with significantly shortened OS (P = .005; Figure 1A). Interestingly, use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk (non-high: P < .0001; high: P = .003; Figure 1B). However, no improvement was noted for triplet vs. non-triplet therapy in pts with del(17p). By multivariate analysis, the significant (P < .05) factors impacting OS were age (in 10-yr increments), International Staging System (ISS) disease stage, ECOG performance status, history of diabetes, anemia, renal function, and platelet count. Conclusions: This interim analysis based on initially treated pts demonstrated that age, ISS stage, and co-morbidities impact OS irrespective of IMWG cytogenetic risk. Triplet Tx was associated with significantly longer OS in pts regardless of IMWG risk status. This is the largest prospective pt cohort with high-risk disease including del(17p). Pts with high-risk disease did not have significantly lower OS vs. pts without high-risk features. Pts with del(17p) (p53 deletion) continue to have shorter OS approaching 3 y and increased survival with use of triplet therapy. Table 1. Kaplan-Meier Estimated 3-Y OS Probability Patients 3-y OS Probability (%) (95% CI) All (N = 1444) 62.6 (59.5-65.8) < 65 y (n = 632) 69.8 (65.2-74.3) 65 to < 75 y (n = 443) 65.0 (59.4-70.6) ≥ 75 y (n = 369) 47.2 (40.7-53.8) Gender Male (n = 831) 62.1 (57.9-66.3) Female (n = 613) 63.4 (58.7-68.2) Race Caucasian (n = 1191) 61.8 (58.3-65.3) African American (n = 183) 64.4 (55.4-73.5) Other (n = 27) 77.6 (57.3-98.0) ASCT Yes (n = 494) 77.1 (72.5-81.7) No (n = 950) 54.2 (50.0-58.3) Triplet therapy Yes (n = 778) 69.3 (65.3-73.3) No (n = 666) 54.8 (49.9-59.6) IMWG risk High (n = 253) 59.0 (51.6-66.4) Standard (n = 566) 66.3 (61.4-71.2) Low (n = 86) 75.7 (63.6-87.8) del(17p) Present (n = 108) 52.7 (41.8-63.6) Absent (n = 1336) 63.4 (60.1-66.7) Figure 1 Figure 1. Disclosures Shah: Celgene Corp: Consultancy, Research Funding. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Durie:Celgene Corp: Export Board Committee Other, Membership on an entity's Board of Directors or advisory committees; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Rifkin:Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy.

scholarly journals Very Few Interventions after Tumor Lysis Monitoring in Patients with Chronic Lymphocytic Leukemia Who Are Started on Venetoclax in the Real-World Setting- Suggests Less Intensive Monitoring Maybe Safe for Low-Risk Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1557-1557
Author(s):  
Ashley Matuszfisher ◽  
Rupali Bose ◽  
Danielle Boselli ◽  
Gray Magee ◽  
Tommy Chen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Calcium Supplementation ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Phosphate Binders ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Unplanned Hospitalizations

Abstract Background: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in adults. Venetoclax, an orally administered B-cell lymphoma 2 (BCL2) inhibitor, is a FDA approved therapy offering durable responses. Due to risk of tumor lysis syndrome (TLS) upon venetoclax initiation, a strict dose escalation schedule with frequent laboratory monitoring is recommended in the package insert (PI). Real world data reflecting adherence to this schedule and frequency of interventions resulting from intense monitoring are not described. Methods: Retrospective review of the Levine Cancer Institute database identified 73 consecutive patients with CLL who were initiated on venetoclax between July 2017 and March 2021. This included those initiated at the central academic site and regional academic-hybrid community sites. In the first two weeks of venetoclax, ramp up dosing and TLS labs (creatinine, potassium, calcium, phosphorous and uric acid) were evaluated for compliance consistent with the PI. Compliance required labs to be performed pre-dose, and at 6-8 hours and 24 hours after the initial 20 mg and 50 mg doses on weeks 1 and 2. The consequent interventions within these first 2 weeks, based on TLS labs, were then recorded. Patients who strictly adhered to all these laboratory checks at the various timepoints were considered compliant. Those who missed even a single lab or time point were considered non-compliant. Tumor lysis was measured by standard criteria using the Cairo-Bishop definition. The following Interventions were recorded: rasburicase administration, renal replacement therapy, ED visits, unplanned hospitalizations, ICU admissions, unplanned administration of IV fluids, the use of calcium supplementation, phosphate binders, treatment for hyperkalemia, dose reduction or holding of venetoclax. Baseline patient, disease, and treatment characteristics were summarized and described; rates of compliance were compared between tumor burden categories using Fisher's Exact test. Results : Baseline characteristics of the 73 identified patients were: 64% male, 79% white and 19% black, median age at venetoclax initiation was 67 (44 - 84). There were 49% of patients in the low tumor burden category, 44% in the medium tumor burden category and 6% in the high tumor burden category. Compliance with TLS labs during the first 2 weeks was 66% overall (n=48), with compliance between the tumor burden categories being 75% in high, 66% in medium and 67% in low (P&gt;0.99). Interventions occurred in 6 (8%) of the patients, with all interventions occurring in the medium or high tumor burden group. These interventions included administration of IV fluids (n=2), calcium supplementation (n=1), phosphate binders (n=2) and holding of venetoclax (n=1). None of these 6 patients requiring an intervention had clinical or laboratory TLS. None of the 73 patients required rasburicase administration, renal replacement therapy, ED visits, unplanned hospitalizations, or ICU admissions during this 2 week ramp up period. Of the 6 patients requiring interventions, 4 patients had TLS labs performed by the PI versus 2 patients who did not. Clinical and laboratory TLS in the PI-compliant group was recorded. None of these patients had clinical TLS and 1 patient met the criteria for laboratory criteria TLS based on a 25% change from baseline in phosphorus and uric acid, however, labs remained in normal range. There were no deaths during the venetoclax ramp up. Conclusion: Compliance with the strict TLS lab monitoring during venetoclax initiation is not universal, likely due to real world patient and institutional barriers. The intervention rates during the first 2 weeks were low, with no patients in the low tumor burden category requiring an intervention. These results suggest that a less strict laboratory monitoring schedule may be safe in patients with low tumor burden CLL. If the safety is confirmed prospectively, it would make the venetoclax initiation less cumbersome and result in increased access to venetoclax for patients with low burden CLL. Disclosures Hu: Kite: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Cellectar: Membership on an entity's Board of Directors or advisory committees. Moyo: Seattle Genetics: Consultancy. Park: Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; G1 Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Takeda: Research Funding. Copelan: Amgen: Consultancy. Avalos: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMJ Best Practice: Patents & Royalties: Royalties from a co-authored article on evaluation of neutropenia. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Jacobs: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; Verastem: Consultancy; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; MEI Pharma: Research Funding; TeneoBio: Research Funding; SecuraBio: Consultancy, Speakers Bureau; Genentech: Consultancy; Jannsen: Speakers Bureau. Ghosh: Genmab: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding.

scholarly journals An Open-Label, Phase 2 Study of KRT-232, a First-in-Class, Oral Small Molecule Inhibitor of MDM2, for the Treatment of Patients with Myelofibrosis (MF) Who Have Previously Received Treatment with a JAK Inhibitor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2945-2945 ◽  
Author(s):  
Regina Garcia-Delgado ◽  
Donal P. McLornan ◽  
László Rejtő ◽  
Eric Jourdan ◽  
Haifa Kathrin Al-Ali ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Small Molecule ◽  
Research Funding ◽  
Jak Inhibitor ◽  
Open Label ◽  
Advisory Committees ◽  
Cycle Arrest ◽  
High Risk Disease ◽  
Open Label Phase

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis, ineffective erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. MF includes primary MF (PMF), post-polycythemia vera MF (post-PV-MF), and post-essential thrombocythemia MF (post-ET-MF). Clinical presentation is heterogeneous, marked by splenomegaly, progressive anemia, and constitutional symptoms. The median survival in patients with high-risk disease is approximately 2 years. Hematopoietic Stem Cell Transplant (HSCT) is a potentially curative therapy, however due to considerable morbidity and mortality rates, HSCT is not appropriate for most patients, including elderly patients with intermediate-II and high-risk disease. The Janus kinase (JAK) inhibitor ruxolitinib is approved in the US and EU for the treatment of patients with intermediate or high-risk MF, including PMF, post-PV-MF, and post-ET-MF. In clinical studies, treatment with ruxolitinib has been shown to reduce spleen volume by International Working Group (IWG) criteria in approximately 28% to 42% of patients and improve constitutional symptoms of MF in approximately 46% of patients (Verstovsek, J Hematol Oncol. 2017). Ruxolitinib provides symptomatic improvement, however, does not target the malignant clone or appreciably reduce the degree of fibrosis; some patients experience disease progression and leukemic transformation while on therapy (Versotvsek, NEJM. 2010; Harrison, NEJM. 2012; Kremyanskaya, Br J Hem. 2014). Moreover, ruxolitinib is associated with AEs including anemia and thrombocytopenia, which can lead to discontinuation. Approximately 50% of patients treated with ruxolitinib discontinued treatment within 3 years and 73% at 5 years (Verstovsek, Haematologica. 2015; Verstovsek, J Hematol Oncol. 2017; Cervantes, Blood. 2013; Harrison, Leukemia. 2016). Median overall survival in patients who discontinue ruxolitinib is 14-16 months, highlighting the need for novel therapies targeting alternative pathways in the setting of failure or intolerance of JAK inhibitor therapy (Newberry, Blood. 2017). The tumor suppressor protein p53 is the master regulator of cell-cycle arrest and apoptosis in response to cellular stress or DNA damage. Murine double minute 2 (MDM2) is a key regulator of p53, inhibiting its activity via ubiquitination, nuclear export, and direct inhibition of transcriptional activity. Increased MDM2 protein expression has been observed in MF CD34+ cells, suggesting that MF might be sensitive to MDM2 inhibition (Lu M, Blood. 2017). KRT-232 is a potent and selective, oral, small molecule drug that targets MDM2 and prevents MDM2-mediated p53 inhibition, allowing p53 to mediate tumor cell-cycle arrest and apoptosis. In MF, TP53 is observed to be wild-type in 96% of MF patients, suggesting MDM2 inhibition could be a successful therapeutic strategy in this disease (Raza, Am J Hematol. 2012). KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue. The majority of TRAEs were grade 1 or 2. Methods: KRT-232 is being evaluated in an open-label phase 2 study in patients with MF who relapsed on or are refractory to JAK inhibitors (Figure). Up to 247 patients ≥ 18 years of age, with ECOG performance status ≤ 2, with high-, intermediate-2, or intermediate-1 risk disease by Dynamic International Prognostic System (DIPSS), and failure of prior treatment with JAK inhibitors will be enrolled. The study will be conducted in 2 parts. Part A will identify the recommended dose and schedule by testing varying doses and schedules across 7 treatment cohorts. Part B will evaluate safety and efficacy using the recommended dose and schedule from Part A. The primary endpoint of the study is to determine spleen response at week 24; secondary endpoints include improvement in MPN-SAF Total Symptom Score (weeks 24 and 48), red blood cell (RBC) transfusion independence, and rates of complete remission and partial remission (IWG-ERT and ELN) at week 24. This trial is enrolling at multiple sites in the United States and Europe (NCT03662126, EudraCT: 2018-001671-21). Disclosures Garcia-Delgado: Hospital Virgen De La Victoria Malaga: Employment; Novartis: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Jourdan:Novartis: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria. Pluta:Freelight Poland: Honoraria; Sandoz: Honoraria; Servier: Honoraria; Jansen-Cilag: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria; Specialistic Hospital in Brzozow,Dept of Haematooncology Ks.Bielawskiego 18 36-200 Brzozow, Poland: Employment; Teva: Honoraria; Roche Poland: Membership on an entity's Board of Directors or advisory committees; Jansen Cilag Poland: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . Khan:Amgen: Consultancy; Celgene: Consultancy; Incyte: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. Jost:Novartis: Research Funding; Celgene: Other: Travel Support; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Patents & Royalties: Royalty payments for the drug compound ABT-199, Research Funding; Bohringer: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Rothbaum:Kartos Therapeutics: Employment, Patents & Royalties: Pending; Quogue Bioventures LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. McGreivy:Kartos Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a registered clinical trial that will evaluate the safety and efficacy of KRT-232 for patients with myelofibrosis.

scholarly journals Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Retrospective, Single-Institution Analysis Based on Risk Features and Debulking Strategy with Anti-CD20 Monoclonal Antibody

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5484-5484 ◽  
Author(s):  
Ariel F Grajales-Cruz ◽  
Julio Chavez ◽  
Virginia Olivia Volpe ◽  
Jose Sandoval-Sus ◽  
Bijal Shah ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
Very High

Background: The treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) has continued to evolve in recent years, offering the patients different therapeutic options. Venetoclax (ven) is a selective, small molecule inhibitor of B-cell receptor-2 (BCL-2) approved by the FDA for patients with newly diagnosed and relapsed/refractory CLL. Stratification based on tumor lysis syndrome (TLS) risk is recommended and may guide debulking strategies. Methods: We retrospectively analyzed 36 patients with relapsed/refractory (RR) CLL who received treatment with ven at the Moffitt Cancer Center between January 2016 and July 2019. Objective response to therapy was determined based on iwCLL. Progression free survival (PFS) and overall survival (OS) were evaluated via Kaplan-Meier method; overall response rate (ORR) and complete response (CR) via Fisher's exact test. Adverse events (AEs) were graded by CTCAEv5. Results: The median age was 58.5 years (28-82). Median follow up was 12.97 months. The vast majority of patients had high risk disease; Chromosomal analysis by Fluorescence In Situ Hybridization (FISH) reported Del17p and Del11q (+/- others, except Del17p) in 18 (50%) patients and 6 (16.7%) patients respectively. Twenty one (58.3%) patients had a TP53 mutation by next generation sequencing. Twenty five (80.6%) patients had unmutated IGHV status, and 24 (79.9%) patients had high or very high CLL-International prognostic Index (CLL-IPI) score. Twenty-four patients (66.7%) had been previously treated with Ibrutinib, 11 of those progressing on it. Further characteristics are described in table 1. Median OS was not reached. Median PFS was 23.93 months, figure 1a. Median duration of response was 25.97 months. The ORR (PR+CR) at the time of analysis was 63.9%, with CR rate of 33.3%, and PR rate of 30.6%. Nine patients (25%) had stable disease (SD), while four patients (11.1%) progressed on treatment. Minimal residual disease (MRD) was evaluated as part of the response assessment in 7 patients (19.4%) by flow cytometry (1 patient) and by clonoSEQ (6 patients), and 4 (11.1%) had achieved undetectable disease. Response rates were also based on risk stratification; OS and PFS were not affected by the presence of TP53 mutation (p=0.1145) as described in figure 1b, IGHV unmutated status, or NOTCH1 mutation. PFS was inferior in patients with high-very high CLL-IPI score (p=0.0414), figure 1c. The presence of bulky lymphadenopathy (≥5 cm) did not affect outcomes (p=0.5772), figure 1d. Reasons for treatment discontinuation were: progressive disease (PD) in 6 (16.7%), MD/patient preference in 5 (13.9%), Richter's transformation in 2 (5.6%), AEs in 1 (2.8%), allogeneic transplant in 1 (2.8%), and death while on treatment in 1 (2.8%) case. Twenty patients (55.6%) were considered to be at intermediate/high risk of developing TLS, of whom 15 (75%) received debulking therapy with rituximab (1), ofatumumab (11), or obinutuzumab (3) prior to ven. Based on the absolute lymphocyte count (ALC), the risk of TLS became low in 12 patients. The use of a debulking monoclonal antibody (MoAb) improved lymphocytosis, but did not impact PFS. Treatment was well tolerated, and was not dependent on the use of debulking MoAb; however, out of the 18 patients (50%) who underwent debulking therapy, 9 (25%) had grade 3/4 toxicities. Neutropenia was the most common grade 3/4 toxicity in all patients, which was seen in 7 (19.4%) patients, and diarrhea was the most common grade 3/4 non-hematologic toxicity, seen in 4 (11.1%) patients; grade 3/4 neutropenia was seen in 4 (57.1%) of those patients who received debulking therapy, while diarrhea was only seen in 1 (25%). No cases of TLS were observed. Ten patients (27.8%) were admitted for ramp up of ven as per physician preference, independent of TLS risk and comorbidities. Conclusion: Venetoclax is a very active agent for R/R CLL with an acceptable toxicity profile. Debulking strategy is a tolerable option for patients with high burden disease and may reduce the incidence of TLS and/or hospitalization. Nonetheless, based on this retrospective study, it does not seem to have a significant impact in outcomes, and it carries a higher risk for potential cumulative toxicity. Disclosures Chavez: Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau.

scholarly journals Unifying the Definition of High-Risk in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2714-2714
Author(s):  
Ariel Siegel ◽  
Eileen M Boyle ◽  
Patrick Blaney ◽  
Yubao Wang ◽  
Hussein Ghamlouch ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Risk Scores ◽  
Individual Risk ◽  
Risk Models ◽  
Advisory Committees ◽  
High Risk Disease ◽  
Definition Of ◽  
Standard Risk

Abstract Introduction: There is considerable heterogeneity in the clinical outcome of newly diagnosed multiple-myeloma (NDMM) with some patients having a good prognosis while others fail to respond or relapse quickly after therapy progressing rapidly to death. Using risk scores based on clinical, biochemical and genetic features it is possible to predict some of this variation giving an ability to segment the disease into risk strata. Clinical studies have suggested that patients with standard-risk disease have benefited more from the recent advances in therapy compared to those with high-risk disease. The development of clinical trials specifically recruiting patients with high-risk disease features offers the potential to improve the outcome of a subgroup of patients with a very poor clinical outcome. To perform such studies is it important to have a unifying definition of high-risk including standard parameters, group size and outcome of individual risk strata so that clinical trial rigor can be achieved (e.g., common entry criteria, statistical power). In order to understand the size and feasibility of such studies we analyzed the Myeloma Genome Project (MGP) dataset to assess multiple risk factors and scores to determine and compare how they perform as risk stratifiers with each other. Methods: The MGP dataset is a large set of molecular and clinical data from 1273 patient with NDMM. Data were available on clinical variables (Albumin (Alb), B2-microglobulin (B2M), LDH, age), cytogenetic variables [t(4;14), t(14;16), t(14;20), 17p-, TP53 mutations, 1q+ and 1p-] and gene expression analysis (GEP70). A literature search was used to identify risk models used in clinical studies. Survival analysis was performed in R. The median follow-up at the time of analysis was 54.5 (53.2-56.5) months. Results: The median patient age was 66 years, with 641 (50.4%) patients over age 65. The sex ratio (M:F) was 1:0.66. African American, White, and Asian constituted 17%, 76%, and 2%, of cases respectively. 26.7% received a stem cell transplant. We determined the size of the strata and actual risk (measure by the hazard ratios, HR) compared to standard risk cases for both PFS and OS of the various clinical models available, data are summarized in Figure 1. When looking at individual risk scores, the HR for progression for t(4;14), TP53 inactivation (deletion and mutations), gain(1q), and del(1p) were 1.4, 1.1, 1.3, and 1.1 respectively. When considering overall survival these HR were 1.4, 1.7, 1.5, and 1.4 respectively. We went on to analyze the impact of these events in combination and show that combined, there is increased specificity, especially for OS (HR 2.3-5.1) but they identify small subsets making up &lt;10% of patients. We then analyzed the purely clinical scores (ISS) and combined clinical/genetic scores. We show again, that the more specific risk scores (double hit, Boyd IV, GEP70) identify between 7-13% of cases with HR (2-3.1) for OS. When we looked specifically at the younger patients (=&lt; 65), similar trends were seen with GEP70 by RNA-seq offering one of the most interesting means of identifying HR cases. Conclusion: In this large NDMM dataset, we demonstrate the clear variation in risk groups that occur dependent upon the approach used resulting in heterogeneous levels of risk, strata size, and performance. With the exception of GEP70, none of the single features are sensitive or specific enough to identify all cases. Risk models based on a combination of markers improve the ability to detect true high-risk disease but there remains variability. At a molecular level the inclusion of TP53 inactivation, and 1q+ improve the performance of the ISS. This analysis provides insights into standardizing the definition of high-risk and the generation of consensus definitions for clinical trial entry. Figure 1 Figure 1 Figure 1. Disclosures Braunstein: Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cairns: Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Davies: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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