ALBERT

Description: Introduction Both blinatumomab and lenalidomide have proven, but limited, efficacy in relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). Failure of blinatumomab to mediate durable responses is due to its inability to recruit competent cytotoxic T cells which leads to eventual T cell exhaustion. Lenalidomide has been shown to improve efficacy of rituximab through T and NK cell activation even in patients who have previously failed rituximab containing regimens. Based on this, we hypothesized that lenalidomide, when combined with blinatumomab, will enhance its efficacy. We report safety, efficacy and correlative analysis of blinatumomab and lenalidomide in R/R NHL. Methods We conducted a phase I, open-label trial involving patients 18 years and older with R/R CD19+ NHL who have received at least two prior chemotherapeutic or biologic regimens and were not eligible for standard curative options at time of enrollment. Previous CD19-targeted therapy was allowed. Study consisted of a dose escalation followed by a dose expansion phase once the maximum tolerated dose (MTD)/ recommended phase II dose (RP2D) was established using a Phase I Queue modified 3+3 design. The escalation phase has been completed and consisted of blinatumomab continuous infusion (level 1 and 2: 9 mcg/day to 112 mcg/day) from days 1-56 and lenalidomide (level 1: 10 mg and level 2: 20 mg daily) days 29-49 of a 56-day induction cycle. Patients who responded underwent consolidation with blinatumomab continuous infusion days 1-7 and lenalidomide days 1-21 of a 28-day cycle for a maximum of 6 cycles followed by lenalidomide maintenance for 2 years or until unacceptable toxicity or disease progression. Dose limiting toxicities (DLT) included any grade 3/4 drug related adverse events (AE) observed during and up to 7 days after blinatumomab/lenalidomide simultaneous administration. Additional patients were accrued to replace patients who had grade 3/4 AE or progressed before receiving lenalidomide for dose-finding purposes. Primary endpoints included toxicity and determination of the MTD/RP2D during the first 8 weeks of blinatumomab/ lenalidomide induction. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, progression free survival (PFS) which was censored at time of transplant and immune response biomarkers. Results As of July 17, 2019, 18 patients initiated therapy; 7 with diffuse large B cell lymphoma, 3 with mantle cell lymphoma, 3 with follicular lymphoma, 2 with nonspecified B cell lymphoma and 1 each with marginal zone lymphoma, Burkitt's lymphoma and small lymphocytic lymphoma. Median age was 58 (range 30-84) years and the median number of prior regimens was 2.5 (range 2-5); 5 patients had previous stem cell transplant (SCT). 6 patients had disease progression prior to starting lenalidomide. 3 patients received blinatumomab/lenalidomide at dose level 1 with no DLT noted. 9 patients received blinatumomab/lenalidomide at dose level 2 with 4 requiring blinatumomab dose reduction prior to starting lenalidomide. Due to favorable safety profiles with the combination using the MTD/RP2D of lenalidomide 20 daily, upfront doublet therapy was initiated as part of the planned expansion phase. Most common grade 3/4 adverse events were lymphopenia (39%), hypophosphatemia (22%) and hyponatremia (11%). 1 patient (5.5%) experienced grade 3 neurotoxicity. No grade 3/4 cytokine release syndrome or treatment related deaths were seen. At time of data cutoff, three patients remain on active treatment. At a median follow-up time of 14.3 months, ORR was 56% for all patients and 83% (50% CR) for those who received blinatumomab/lenalidomide combination therapy. Median PFS was 3.8 months (95% CI, 1.1 to NR) for all patients and 8.3 months (95% CI, 2.2 to NR) for those who received blinatumomab/lenalidomide combination therapy. 3 patients who achieved response underwent allogeneic SCT and remained in remission for 14.2 to 22.3 months thereafter. Correlative studies are pending and will be reported at time of presentation. Conclusions The combination of blinatumomab and lenalidomide, given at the RP2D dose of 20 mg daily, is safe and well tolerated. This regimen demonstrates encouraging efficacy in this heavily pretreated patient population and is a promising alternative treatment option for R/R NHL patients who are not candidates for aggressive cytotoxic chemotherapy or as a bridge to allogeneic SCT. Disclosures Abedi: Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zain:Seattle Genetics: Consultancy; Spectrum: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. William:Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; miRagen: Consultancy; Eisai: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Rosenberg:Amgen: Consultancy, Research Funding. Tuscano:Seattle Genetics: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Spectrum: Research Funding; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: The use of blinatumomab and lenalidomide in patients with aggressive lymphoma

Description: Introduction: Outcomes remain poor for adults with acute lymphoblastic leukemia (ALL). Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) is a high intensity chemotherapy regimen that results in high complete remission (CR) rates and long-term survival in 30-40% of adults with ALL. Approximately 50% of patients achieve measurable/minimal residual disease (MRD) negativity after Hyper-CVAD therapy. Bortezomib, the first proteasome inhibitor, showed potentially synergistic activity in relapsed ALL in combination with chemotherapy. Carfilzomib is a next-generation irreversible proteasome inhibitor with increased specificity and potency compared to bortezomib and with significant activity in multiple myeloma. Therefore, we hypothesized that the addition of carfilzomib to Hyper-CVAD would be safe and could improve outcomes for adults with ALL by increasing the rate of MRD negativity. Methods: The primary objectives of this phase I study (NCT02293109) were to determine safety, tolerability, and recommended phase two dose of carfilzomib added to Hyper-CVAD in patients with newly diagnosed, untreated Philadelphia chromosome negative ALL. The secondary objectives were to determine rate of CR and MRD negativity. Time-to-event analyses were not planned. Patients were aged 18-65 with adequate left ventricular, renal, and liver function and Eastern Cooperative Group Performance Status of 0-2. Patients received four 28-day cycles of standard Hyper-CVAD (i.e. two courses each of Part A and Part B) with the addition of 4 doses of carfilzomib on days 0, 1, 7 and 8 of each of the four cycles. Rituximab was added for patients with CD20 positive disease. After completing study mandated carfilzomib plus Hyper-CVAD, patients continued standard Hyper-CVAD therapy. Dose escalation used a standard 3+3 design with carfilzomib dose levels (DL) of 20mg/m2 (DL1), 27mg/m2 (DL2) and 36mg/m2 (DL3). Dose-limiting toxicities (DTLs) were assessed through completion of one A and one B cycle. Patients not evaluable for DLT were replaced. Adverse events (AEs) were graded using NCI Common Terminology for Adverse Events version 4.03. MRD was tested by multiparameter flow cytometry (MFC) and

Description: Background: While multiple myeloma (MM) comprises only 2% of all cancer diagnoses, the prevalence of the disease in the US has markedly increased from 46,865 patients in 2000 to 124,733 in 2015. New therapeutic classes have led to longer survival, and allowed older patients to undergo life-prolonging therapy. Survivorship issues are now becoming relevant for this population, as ongoing therapy may have as yet unappreciated long term sequelae. MM is a disease of older patients, with a median diagnosis age of 69, and the incidence is greatest among African Americans (AA), populations at higher risk of cardiovascular disease (CVD). We therefore designed a retrospective study to quantify the incidence of new CVD in this population, as well as changes in incidence over time, hypothesizing that CVD incidence would increase due to both longer survival times, and increased utilization of potentially cardiotoxic drugs. Methods: Using the California Cancer Registry linked to the California Patient Discharge Database, we identified 15,404 patients diagnosed with MM between 1991-2012 with follow-up through 2014. CVD was defined as a hospital admission for coronary artery disease (CAD), congestive heart failure (CHF), or stroke (CVA) using ICD9 codes or if the cause of death due to CVD was the first report of CVD. Patients with prior CVD or in whom CVD was diagnosed within 60 days of MM diagnosis were excluded. All patients had a minimum of 60 days of follow up. Changes in CVD rates were assessed by era: 1991-97 (era 1), 1998-2002 (era 2), 2003-07 (era 3) and 2008-12 (era 4). The cumulative incidence of CVD was estimated from date of MM diagnosis to first CVD event, accounting for the competing risk of death. Adjusted hazard ratios (aHR) for developing CVD were estimated accounting for the competing risk of death per the methods by Fine and Grey. Results: Of the 15,404 patients, 8,056 (52%) were male, 9154 (59%) were non-Hispanic white (NHW), 1890 (12%) were African American, 2839 (18%) were Hispanic, and 1360 (9%) were Asian. Median age at diagnosis was 65, with 12% of patients 80. Stem cell transplant was utilized by 2989 (19%) patients. The most common insurers were private/military (42%), followed by Medicare (31%), Medicaid/other public (7%), and unknown (19%) insurance. The median age of patients who developed CVD was 68 vs 63 who were never admitted for CVD (p