ALBERT

Beschreibung: Introduction: Blinatumomab is a bispecific, CD19-directed CD3 T-cell engager (BiTE®) that activates endogenous cytotoxic T cells to kill target B cells and is FDA-approved for the treatment of relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL). Subgroup analyses of pivotal trials revealed lower response rates and higher risk of cytokine release syndrome (CRS) in blinatumomab recipients with high pre-treatment tumor (B-ALL) burden. It has therefore been hypothesized that cytoreduction prior to blinatumomab initiation may improve response and reduce risk of severe CRS in patients (pts) with high baseline B-ALL burden. We therefore sought to describe pt and disease characteristics at diagnosis, patterns of pre-blinatumomab cytoreduction, and treatment outcomes in pts with high burden of R/R B-ALL treated with blinatumomab at our institution. Methods: We retrospectively reviewed medical records of adult (≥ 18 years-old) pts with morphologic R/R B-cell ALL (i.e. ≥5% BM blasts and/or radiographically evident EM disease) treated with blinatumomab at Memorial Sloan Kettering Cancer Center (MSKCC) between January 2011 and March 2019 and characterized pts with ≥ 50% bone marrow (BM) blasts by morphology or ≥ 15,000 peripheral blood blasts/µL as having "high-burden" B-ALL. CRS and neurologic toxicity (NTX) were graded per Common Terminology Criteria for Adverse Events v5.0. Objectives included describing cytoreductive therapy given pre-blinatumomab and determining rates of NTX and CRS (any grade and grade ≥3) and morphologic complete response (CR) following 1-2 cycles of blinatumomab. Results: We identified 14 pts with high-burden R/R B-ALL prior to blinatumomab. These pts had a median age of 52 years (range, 23 - 69 years) and median BM blasts of 73% (range, 52 - 〉95%, n=12 pts with evaluable BM). Of these 14 pts, 8 received cytoreductive therapy prior to blinatumomab initiation. Cytoreductive regimens included dexamethasone alone (n=4), cyclophosphamide + dexamethasone (n=2), dexamethasone and vincristine (n=1), or cyclophosphamide + vincristine + dexamethasone (n=1). One pt transitioned to hospice care prior to completing cycle 1 (C1) of blinatumomab and was considered non-evaluable for response. CR was achieved in 6 of the 13 evaluable pts, including 4 of 7 evaluable pts who received cytoreductive therapy and 2 of 6 pts who did not receive cytoreductive therapy. One pt achieved CR in BM but exhibited refractory extramedullary disease. CRS was observed during C1 of blinatumomab in 11/14 pts (grade 1, n=7; grade 2, n=3; grade 3, n=1). The pt with grade 3 CRS had received blinatumomab without cytoreductive therapy. In 4 pts, blinatumomab was temporarily discontinued for management of CRS. NTX of any grade occurred in 4/13 pts during C1, including 1 pt w/grade 3 NTX (depressed level of consciousness), and was reversible in all cases; the pt with grade 3 NTX had full resolution of symptoms following brief interruption of blinatumomab and administration of dexamethasone. Conclusions: Real-world clinical experience with blinatumomab in pts with high-burden B-ALL at a single institution suggested an efficacy and safety profile comparable to what has been reported in the overall population in clinical trials. Compared to published clinical trial experience, rates and severity of CRS following blinatumomab were similar and rates of NTX appeared slightly higher in this small series. Administration of cytoreductive therapy prior to blinatumomab for pts with high-burden B-ALL appears safe, with no additional toxicities. Larger studies will be required to assess whether pts with high-burden B-ALL treated (vs not treated) with cytoreductive therapy prior to blinatumomab exhibit significantly higher rates of CR. Disclosures King: Incyte: Other: Advisory Board; Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board. Bolanos:Amgen Inc.: Employment. Velasco:Amgen Inc.: Employment. Tu:Amgen Inc.: Employment. Zaman:Amgen Inc.: Employment. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

Beschreibung: Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a 〉10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p

Beschreibung: The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) is active in pts w/ relapsed/refractory B-ALL or persistent minimal residual disease. Notable toxicities include cytokine release syndrome (CRS), a constellation of symptoms related to brisk systemic inflammatory response, and a spectrum of neurologic toxicities (NTX). BLIN prescribing information provides basic CRS/NTX management guidance, but limited reports describe "real-world" toxicity management strategies (TMS) and outcomes. We further previously reported association between higher baseline and peak levels of acute phase reactants (APR; C-reactive protein [CRP]/ferritin), time to APR peak, and incidence of CRS/NTX post-BLIN (King et al. ASH Annual Meeting, 2017). While CRS is also mediated in part by IL-6, routine monitoring of IL-6 levels during BLIN is not currently standard. As such, we sought to determine rates/severity of CRS/NTX at our institution, efficacy of TMS, and utility of APR/IL-6 in predicting CRS/NTX post-BLIN. We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated B-ALL receiving BLIN between 1/1/2011 and 3/31/19 at Memorial Sloan Kettering Cancer Center (MSK). NTX was classified/graded w/ CTCAEv5.0 (Common Terminology Criteria for Adverse Events). CRS was graded per CTCAEv5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) criteria. The primary objective was to characterize rates/clinical features of CRS/NTX. Secondary objectives included assessing the nature/efficacy of TMS, and association of APR/IL-6 levels w/ CRS. Maximal (max) fold increase in APR/IL-6 was measured from pre-BLIN baseline to peak value during BLIN cycle 1 (C1). APR/IL-6 levels/fold changes were compared between groups using the Wilcoxon-Mann-Whitney test w/o adjustment for multiple comparisons. 59 pts were identified, including 31 male pts (52%). Median age at start of BLIN was 57 yrs (range, 20-76). Median number of prior therapies was 1, including 8 pts w/ previous allogeneic hematopoietic cell transplant (alloHCT) and 5 w/ prior chimeric antigen receptor T-cell therapy (CAR-T). No pt had baseline organ dysfunction or central nervous system (CNS) disease. All pts were admitted for initiation of BLIN C1. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for R/R ALL) in 52 pts and at 28 mcg/day IVCI in 7 pts for MRD (per Gökbuget et al., Blood, 2018). During BLIN C1, 34/59 pts experienced CRS (57%), w/ max grade (G) 1 (n=24), G2 (n=9) or G3 (n=1). CTCAEv5.0/ASTCT grading was concordant in all cases. Eight of 34 (23%) were managed w/ brief interruption of blinatumomab (BIB) for G1 (n=3) and G2 (n=5) CRS. Median duration of BIB was 39 hours (h) (range, 21-91h). Three pts had concomitant NTX and received brief courses of dexamethasone (DEX, daily dose of 24 mg). One pt w/ grade 2 CRS received tocilizumab for hypotension suboptimally responsive to fluid boluses (FB) w/ IL-6 level = 25754 pg/mL. Remaining pts w/ BIB (5/8) received FBs for hypotension. One pt permanently discontinued BLIN during C1 due to rapidly progressive B-ALL. All pts managed w/ BIB were successfully re-challenged w/ BLIN and finished C1 w/o recurrence of CRS. Of the 25/34 (74%) pts w/ CRS not managed w/ BIB, 5 received FBs, w/ 1 pt receiving a FB and a single dose of DEX. Five pts developed recurrent CRS (≥24 hours after resolution); 4/5 recurrences occurred in pts not managed w/ BIB. NTX, excluding isolated headache, was observed in 8/59 pts (14%) during BLIN C1 (Table 1) w/ max G1 (n=4), G2 (n=3), or G3 (n=1). Four pts w/ NTX were managed w/ BIB and a brief course DEX; 3/4 had concomitant CRS. Median time to onset of CRS and NTX were 1 day (d) (range 0-15) and 2 d (range 0-10), respectively. Non-significant trend toward higher peak IL-6 was noted in pts w/ G1 vs. G0 CRS (p=0.07; Fig 1A, note log scale); median peak levels of CRP were higher in pts w/ G1 vs G0 CRS (p=0.01, Fig 1B); median peak ferritin levels were higher in pts w/ G2 vs. G0 CRS (p=0.01, Fig 1C). While CRS was common during C1 of BLIN, supportive management was sufficient in most pts; BIB was an effective strategy and allowed successful BLIN re-challenge. The incidence of ≥G2 NTX was low and all cases of NTX were reversible w/ supportive care or BIB ± DEX. Peak APR levels correlated w/ CRS severity. Authors noted concordance of CRS grading between CTCAE and ASTCT, suggesting the feasibility of a single, BITE-specific grading system. Disclosures King: Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Park:Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Allogene: Consultancy. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria.

Beschreibung: Background: The treatment indications for venetoclax in CLL are broadening quickly. While the initial approval was for relapsed patients with del 17p (Stilgenbauer S, et al. JCO 2018), it has subsequently been extended to all patients (Seymour J, et al. NEJM 2018, Fischer K, et al. NEJM 2019). The duration of therapy with each approval has evolved as well, from continuing therapy until progression/toxicity to 1 year in front-line CLL. The limited durations of therapy were applied to all patients based on trial design and were not dependent on response to treatment. Undetectable minimal residual disease (U-MRD) with venetoclax is associated with improved progression-free survival (PFS), both as a single agent and in combination with rituximab (Stilgenbauer S, et al. JCO 2018, Seymour J, et al. NEJM 2018). Early phase data suggest that patients who discontinue venetoclax after achieving MRD negativity can be monitored off therapy and successfully retreated upon relapse (Seymour J, et al, Lancet Onc 2017). However, patients who discontinue therapy with persistent residual disease have a higher incidence of relapse (Kater A, et al. JCO 2019). Together, these data suggest that the duration of venetoclax therapy should be individualized, based on the depth of response one achieves and not a fixed duration schedule. Therefore, we propose a prospective clinical trial, utilizing MRD assessment with a next generation sequencing (clonoSEQ®) assay to guide clinical decision making in patients with CLL receiving venetoclax-based regimens. Methods: This is a multicenter, phase II clinical stopping trial for 80 venetoclax-treated CLL patients. The clonoSEQ® assay is used to assess MRD, and patients who achieve U-MRD (defined as