Search

e19537 Background: Tisa-cel showed durable responses and manageable safety in pts with r/r DLBCL in the phase 2 JULIET trial. High baseline programmed cell death 1 (PD-1) expression associated with higher probability of no response (Schuster et al. NEJM 2019). Here we report an updated analysis of PORTIA, a phase 1b, multicenter, open-label study of tisa-cel plus pembro in pts with r/r DLBCL. Methods: Eligible pts (≥18 y) had r/r DLBCL after ≥2 lines of therapy and relapsed after or were not candidates for autologous stem cell transplant (autoSCT). Patients received a single tisa-cel infusion on Day 1 and were enrolled in 1 of 3 cohorts that initiated pembro (200 mg q 21 days, for up to 6 doses) on either Days +15, +8, or –1. Primary endpoints were incidence of dose-limiting toxicities (DLTs) and overall response rate (ORR; complete response [CR] and partial response [PR]). Secondary endpoints included duration of response, progression-free survival, overall survival, safety, and cellular kinetics. Results: As of November 9, 2020, 15 pts were enrolled and 12 received tisa-cel (n = 4 pts for each Days +15, +8, and –1 cohorts; median follow-up, 4 mo). At study entry, the median age among treated pts was 62 y (range, 35-79), 100% had an International Prognostic Index score ≥2, 67% had ≥3 prior lines of therapy, 58% had stage IV disease, 58% had lactate dehydrogenase > ULN, and 42% had prior autoSCT. All 12 pts had ≥1 AE. Grade ≥3 AEs suspected to be related to tisa-cel and/or pembro were neutropenia (n = 4); neutrophil count decreased (n = 3); febrile neutropenia, lymphocyte count decreased, malnutrition (each n = 2); anemia, leukopenia, diarrhea, white blood count decreased, liver function tests increased, thrombocytopenia, hepatitis, and cytokine release syndrome (CRS; each n = 1). No neurotoxicity or DLTs were observed. Among the Day +15, +8, and –1 cohorts (each n = 4), the ORR was 50% (2/4; CR n = 0, PR n = 2), 25% (1/4; CR n = 1, PR n = 0), and 25% (1/4; CR n = 1, PR n = 0; longer follow-up is needed for n = 2 pts), respectively. Tisa-cel exposure and peak expansion were consistent with JULIET, with a trend toward delayed expansion in the Day –1 cohort (n = 4). There was no sign of secondary expansion following pembro administration regardless of the number of doses. Compared with JULIET, lower CRS severity and frequency and lower cytokine profiles were observed for all 3 cohorts. Conclusions: The combination of tisa-cel plus pembro was feasible and showed manageable safety. The lack of improved efficacy in PORTIA with the addition of pembro compared with tisa-cel alone may be related to more pts with ≥3 prior lines of therapy (67% vs 51%, respectively), and/or pts with more advanced disease in PORTIA. Additional studies with larger patient cohorts are needed to determine the value of adding PD-1 inhibitors to CAR-T cell therapy in pts with r/r DLBCL. Clinical trial information: NCT03630159.

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.

7510 Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, has redefined treatment paradigms for CLL/SLL. We report final analysis with up to 6 years of follow-up on ibr from the phase 3 RESONATE study of single-agent ibr vs ofatumumab (ofa) in pts with relapsed/refractory (R/R) CLL/SLL. Methods: Pts were randomized to receive oral ibr 420 mg daily until PD or intravenous ofa for up to 24 weeks. Long-term efficacy endpoints were investigator-assessed. Results: Among 391 pts randomized to receive ibr (n=195) or ofa (n=196), 86% and 79%, respectively, were in the genomic high-risk population (del(17p), del(11q), TP53 mutation, and/or unmutated IGHV). At final analysis, median follow-up was 64 mo (range, 0.3-72) on ibr. Of pts randomized to ofa, 68% crossed over to receive ibr. Significant sustained PFS benefit was observed with ibr vs ofa, with median PFS 44.1 vs 8.1 mo (HR 0.15; 95% CI 0.11-0.20; P˂0.0001) and was consistent across baseline subgroups. Median PFS in genomic high-risk population was 44.1 vs 8.0 mo on ibr vs ofa (HR 0.11; 95% CI 0.08-0.15). ORR with ibr was 88% (CR/CRi in 11%). Initial ibr treatment conferred better OS than ofa when censored for crossover (HR 0.64; 95% CI 0.42-0.98). Median duration of ibr was 41 mo (range 0.2-71); 41% of pts received ibr >4 yrs. AE profile with ibr remained consistent with prior reports. Cumulatively during long-term ibr therapy, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of pts, respectively; major hemorrhage occurred in 10%. Most common reasons for ibr discontinuation (DC) prior to study closure were PD (37%) and AEs (16%); DC due to AEs occurred in 6%, 3%, 4%, 4%, 6% and 4% of pts during yrs 0-1, 1-2, 2-3, 3-4, 4-5 and 5-6, respectively. Conclusions: With up to 6 years of follow-up, extended ibr treatment showed sustained efficacy in pts with R/R CLL, including in pts with high-risk genomic features. Safety remained acceptable with low rates of DC due to AEs, and with no new safety signals over long-term therapy. These results establish long-term benefit and tolerability for continuous ibr treatment in pts with R/R CLL. Clinical trial information: NCT01578707.

7533Background: Duvelisib, an oral dual inhibitor of PI3K-δ,γ, is being developed for the treatment of hematologic malignancies, including relapsed/refractory (RR) CLL/SLL. In the Phase 3 DUO study...

e15056Background: Analyses supporting a safe and efficacious dose for CAR therapies are not well defined and vary across CAR-T programs. These analyses present key considerations to support tisagen...

3044Background: Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy, contains a murine single chain variable fragment (mCAR19) binding domain. Humoral immunity to anti-mCAR19 had no ...

7521Background: B2M is often elevated in pts with CLL and correlates with disease stage and burden. Normalization of B2M at 6 mo during ibr treatment was associated with improved progression-free s...

TPS7567 Background: Patients (pts) with R/R CLL who discontinue treatment with the BTKi ibrutinib due to progression have a particularly dismal prognosis. A phase I study showed that the Fc-enhanced, humanized, CD19 antibody MOR208 was well tolerated with encouraging single-agent activity in pts with R/R CLL/SLL. In preclinical models, MOR208 showed synergy with idelalisib (an inhibitor of PI3K delta) and venetoclax (an inhibitor of BCL-2), both approved for the treatment of CLL. Methods: This two-cohort, phase II study will investigate MOR208 combined with idelalisib (cohort A) or venetoclax (cohort B) in pts with R/R CLL or R/R SLL and includes a safety run-in phase for each cohort, to be evaluated by an Independent Data Monitoring Committee. Key inclusion criteria: aged ≥18 years, R/R CLL/SLL while receiving a BTKi therapy or intolerance of such therapy, BTKi administered as a single-agent or in combination for at least 1 month as the most recent prior anticancer therapy, ECOG performance status of 0–2, and adequate organ function. Key exclusion criteria: transformed CLL/SLL or Richter’s syndrome, BTKi treatment within 5 days prior to study drug dosing, prior treatment with a CD19-targeted therapy, a PI3K inhibitor (cohort A) or a BCL-2 inhibitor (cohort B). Pts will be treated for a maximum of 24 (28-day) cycles or until disease progression. Treatment will be MOR208 12 mg/kg IV (weekly for the first 3 months, every second week for the next 3 months, and monthly thereafter) in combination with oral idelalisib 150 mg twice-daily or venetoclax administered on a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Primary endpoint: overall response rate based on independent review; secondary and exploratory endpoints include: progression-free and overall survival, duration of response, safety, pharmacokinetics, MOR208 immunogenicity, quality of life and minimal residual disease negativity. 120 pts per cohort are planned. Clinical trial information: 2015-002915-14.

7510 Background: Ibr, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is FDA-approved for all pts with CLL/SLL. We report updated safety and efficacy results with up to 4 y follow-up from the ph III RESONATE trial of ibr vs ofatumumab (ofa). Methods: Pts had ≥1 prior therapy. Pts received 420 mg ibr PO until PD or ofa up to 24 wks. At interim analysis (median 9 mo follow-up), the DMC declared superiority of ibr vs ofa for PFS and OS, and ibr access was recommended for all ofa pts. Long-term follow-up efficacy endpoints are per investigator assessment. Ofa pts were censored at crossover for OS. Results: 391 pts were randomized to receive ibr (n = 195) or ofa (n = 196). Median age was 67 y (40% ≥70 y); 57% had Rai stage III/IV. With median follow-up of 44 mo (53 mo max) for ibr arm, PFS was significantly longer for ibr vs ofa (median NR vs 8 mo, [HR 0.133; P< 0.0001]; 3-y PFS 59% vs 3%) with significant benefit across subgroups. PFS with ibr for del11q subgroup trended to have the most favorable outcome; however, PFS was not statistically different for pts with del17p or del11q or without these FISH abnormalities. At analysis, with the majority of pts (68%) randomized to ofa crossing over to ibr, OS was longer for ibr vs ofa (median OS NR for either arm). The OS rate for ibr at 3 y was 74%. ORR for ibr was 91% with CR/CRi rates (now 9%) increasing over time. Baseline cytopenias improved with extended ibr therapy for hemoglobin (85%), platelet (95%), and absolute neutrophil counts (95%). AE profile of ibr was consistent with previous reports. Major hemorrhage, Gr ≥3 atrial fibrillation, and Gr ≥3 hypertension occurred in 6%, 6%, and 8% of pts, respectively, over a follow-up of up to 4 y. Incidence of most Gr ≥3 AEs decreased from y 1 vs y 2-3: neutropenia- 18% vs 8%; pneumonia- 11% vs 4%; atrial fibrillation- 4% vs 2%, respectively. Discontinuations were most frequently PD (27%) and AE (12%). At analysis, 90 ibr pts (46%) continue ibr on study. Conclusions: Long-term treatment with ibr in this international ph III RESONATE study is tolerable and continues to show sustained PFS and OS regardless of high-risk cytogenetics. Ph III results in relapsed del17p and del11q pts compare favorably to prior ph II reports. Clinical trial information: NCT01578707.

TPS7572Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), is an important treatment option for patients (pts) with CLL/SLL. Pts who progress early on ibrutinib are difficult to tre...

7012 Background: Ibrutinib (ibr), a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), is rapidly eliminated from plasma after oral administration (Advani, JCO ...

TPS8619 Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with >= 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count

7015 Background: Besides clinical staging, a number of biomarkers predicting OS in CLL have been identified. The multiplicity of markers, limited information on their independent value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We developed an integrated prognostic index using the database of the German CLL Study Group (GCLLSG), which was subsequently validated in a cohort of untreated CLL patients (pts) from the Mayo Clinic. Methods: The analysis was based on a dataset collected between 1997 and 2006 in 3 GCLLSG phase III trials. The external validation was performed on a series of newly diagnosed CLL pts managed at Mayo Clinic. Results: The GCLLSG dataset (1,948 physically fit pts at early and advanced stage; median age: 60 yr (range 30-81); median observation time 63.4 mo) was used as a training dataset. 7 parameters were identified as independent predictors for OS: sex, age, ECOG status, del 17p, del 11q, IGHV mutation status, thymidine kinase and β2-microglobulin. By using a weighted grading a prognostic index was derived separating four different pts groups: low risk (score 0 - 2), intermediate risk (score 3-5), high risk (score 6-10) and very high risk (score 11-14) with significant different OS rates (95.2%, 86.9%, 67.7% and 18.7% OS after 5 yr for the low, intermediate, high and very high risk group respectively (p 0.70) necessary to have utility at the level of the individual.