Tam, Constantine S.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Abstract Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton’s tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

SummaryThe phase I/II AU‐003 study in patients with treatment‐naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow‐up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2‐ and 3‐year progression‐free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow‐up of ~4 years, responses remain clinically meaningful and durable and long‐term tolerability to zanubrutinib therapy continues.

Abstract The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

TPS7570 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL), and although > 50% of pts achieve long-term remission with first-line therapy, pts with R/R disease as well as those with R/R grade 3b follicular lymphoma (FL), double-, or triple-hit high-grade lymphomas have poor long-term outcomes (Crump 2017; Kahl 2016; Jain 2012). Autologous (auto) chimeric antigen receptor (CAR) T cell therapy has provided additional options for pts with R/R disease, but only when leukapheresis and manufacturing prove feasible (Jacobson 2020). Allogeneic (allo) CAR-T cells were designed specifically to address these unmet needs by using healthy donor T cells to produce a readily available product and remove the need for bridging chemotherapy. We are currently investigating the safety and efficacy of CTX110, an allo anti-CD19 CAR-T cell product modified by using CRISPR/Cas9-editing to disrupt the endogenous T-cell receptor (TCR) alpha constant (TRAC) locus in order to remove TCR expression and disrupt β2-microglobulin, which eliminates major histocompatibility complex (MHC) class I expression. Disruption of the TCR should significantly reduce or eliminate risks of graft-versus-host disease and elimination of MHC class I expression may increase CAR-T cell persistence by mitigating CTX110 rejection. In addition, the anti-CD19 CAR transgene construct is precisely inserted into the TRAC locus. Methods: The Phase 1 CARBON trial (NCT04035434) is an open-label, multicenter, global study evaluating the safety and efficacy of CTX110 in pts ≥18 y with R/R DLBCL NOS, double- or triple-hit DLBCL, or transformed or grade 3b FL with ≥2 prior lines of therapy or who are ineligible for/refused prior auto hematopoietic stem cell transplant (HSCT). Pts who received prior auto CAR-T or allo HSCT are excluded. Pts will receive lymphodepleting chemotherapy with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 for 3 days, followed by CTX110 infusion. In part A, dose escalation will be performed using a 3+3 design. Upon completion of dose finding, the cohort will be expanded to further assess safety signals and efficacy including the primary efficacy endpoint of overall response rate. Key secondary efficacy endpoints include duration of response, progression-free survival, and overall survival. The trial is currently open and enrolling. Clinical trial information: NCT04035434.

7502 Background: The BCL-2i venetoclax is active in certain HMs but can increase the risk of tumor lysis syndrome (TLS), requiring a 5-week dose ramp-up for CLL patients. Cases of severe neutropenia with venetoclax treatment have also been reported. Lisaftoclax is a novel, potent, selective BCL-2i that is active against HMs and is under clinical development. Methods: This first-in-human global phase I dose study assessed the safety, PK, PD, efficacy, and MTD/RP2D of lisaftoclax in patients with R/R CLL and other HMs. Lisaftoclax was orally administered daily in a 28-day cycle. Patients with CLL or intermediate-high TLS risk were initiated on a daily ramp-up schedule until the assigned dose before the study cycles. Results: On January 7, 2021, 35 pts had been enrolled and treated with lisaftoclax at doses ranging from 20 to 1,200 mg, with a median (range) of 2 (1-13) prior lines of treatment, and had diagnoses of R/R CLL or SLL (n = 15), MM (n = 6), FL (n = 5), WM (n = 4), and either AML, MCL, DLBCL, MDS, or HCL (n = 1 each). No DLT has been observed, even though 1,200 mg was considered as the highest dose treated. The MTD has not been reached, and no laboratory or clinical TLS has been reported. Any grade TRAEs in > 10% of pts included neutropenia (22.9%) and anemia (17.1%; hematologic), and fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%; nonhematologic). Grade >3 TRAEs were neutropenia (14.3%) and thrombocytopenia, leukopenia, lymphopenia, fatigue, and nausea (2.9% of pts each). In CLL/SLL pts, grade 3-4 TRAEs included neutropenia (13.3%) and thrombocytopenia (6.7%), which did not cause treatment-related discontinuation. In all, 12 of 35 pts (34.3%) had non-treatment-related SAEs, and only two pts experienced > 1 SAE. With a median (range) treatment of 7 (3-20) cycles, 12 of 14 evaluable R/R CLL/SLL pts achieved PR, for an ORR of 85.7% and a median (range) time to response of 3 (2-7) cycles. Absolute lymphocyte counts (ALCs) were reduced at lisaftoclax doses as low as 20 mg/day. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 20 to 1,200 mg (average half-life: 4-5 hours). On BH3 profiling, lisaftoclax rapidly triggered changes in BCL-2 complex in CLL/SLL pt samples, which were consistent with rapid clinical reductions in ALCs. Conclusions: Lisaftoclax was well tolerated up to 1,200 mg/day. No TLS was observed, even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings, and the ORR in R/R CLL/SLL pts was 85.7%. Grade 3-4 TRAEs were infrequent, even at dose levels of 800 mg and above. BCL-2i lisaftoclax offers a treatment alternative for patients with R/R CLL/SLL and other HMs, with a daily ramp-up schedule that may be more pt “user friendly” and a favorable preliminary safety profile. Internal study identifier APG2575-001. Clinical trial information: NCT03537482.

Abstract Figure Figure In order to characterize the clinical course of patients (pts) with deletion 17p13.1 (17p-) CLL, we identified 100 consecutive treatment-naïve pts with 17p- from the MD Anderson Cancer Center (MDACC, n=61) and Mayo Clinic (n=39) clinical databases. The diagnosis of 17p- was established by FISH with a median time from initial diagnosis to FISH documenting 17p- of 9 months. Median age was 64 yrs (60 for MDACC pts & 70 for Mayo pts) and Rai stage was 0, 1–2 and 3–4 in 34%, 49% and 17% pts respectively. 17p- was the sole FISH abnormality in 29%. Unmutated IgVH and ZAP-70 positivity were present in 30/62 and 54/84 patients respectively. <<<TIME TO FIRST THERAPY>>> 69 asymptomatic pts were followed until they developed progressive disease requiring therapy as defined by the NCIWG 96 criteria. The 2 year actuarial risk of progression to initiation of therapy was 43% (46% for MDACC pts & 36% for Mayo pts). Only 2 of 10 pts with stable disease >2 years progressed on prolonged follow-up of up to 54 months. Two pts with baseline 17p- in 10% and 13% of nuclei lost their 17p- clone after 23 and 41 months. Independent predictors of shorter time to treatment were Rai stage > 0 (hazard ratio 7.2) and unmutated IgVH (HR 5.3). Pts with 0, 1 or 2 of these factors had a 2 year progression rate of 0%, 48% and >75% respectively (p<0.01). Other prognostic parameters such as ZAP-70 and CD38 did not have independent prognostic utility. <<<RESPONSE TO THERAPY>>> 41 pts from MDACC were assessable for response to first therapy. Overall (OR) and complete response (CR) rates were: rituximab without chemotherapy (n=6), OR 67% CR 17%; purine analogue + rituximab combinations (n=20), OR 75% CR 30%; purine analogue, rituximab + alemtuzumab combinations (n=13), OR 85% CR 54%. The pt who achieved CR after rituximab was negative for minimal residual disease assessed by flow cytometry and consensus primer IgH PCR, and has remained in remission at 29 months. At 2 years, 75% of complete responders remained relapse free. <<<SURVIVAL FROM 17P- DIAGNOSIS>>> Two year survival was 78%. Independent predictors of inferior survival were age 60+ (HR 3.4), B-symptoms (HR 3.7) and 17p- in nuclei 70+% (HR 6.0). Considering age 60+ and 17p- in nuclei 70+% in a prognostic model, 2 year survival was 100%, 82% and 55% for pts with 0, 1 and 2 risk factors respectively. Other prognostic parameters such as ZAP-70, IgVH mutation status and CD38 did not have independent prognostic utility. <<<CONCLUSIONS>>> Pts with de novo 17p- CLL exhibit marked clinical heterogeneity, with some pts experiencing an indolent course with prolonged survival. Survival and time to treatment among patients with 17p- can be predicted using clinical and biological characteristics.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Treatments include pharmacologic approaches, phlebotomy, and bone marrow transplant. Outcome studies have historically focused on hematologic improvement and survival benefit. Few prospective studies have evaluated patient-reported symptoms and quality of life outcomes after standard therapy. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard treatments. Here we provide updated results for the prospective MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: The MEASURE trial is a prospective international cohort study evaluating responsiveness of the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) in an anticipated 480 ET, PV, and MF patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF TSS (JCO 2012) for seven consecutive days at enrollment then again for seven days between 90 days and six months later. Patients also complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. Physicians report demographic, laboratory, and clinical data. Results: Demographics To date, 340 patients have enrolled and 270 have completed both study visits. Participants include ET (60%), PV (29%), and MF (12%; including 68% primary MF, 12% post-ET, 20% post-PV) patients. Enrolled patients are 51% male. The most common therapies received prior to enrollment were aspirin (34%), phlebotomy (15%), hydroxyurea (14%), and warfarin/clopidogrel/anticoagulation (6%). The most common current MPN therapies were hydroxyurea (67%), aspirin (24%), phlebotomy (9%), and ruxolitinib (8%). Information on mutational analysis was also collected; 77% of patients have a known JAK2 V617F mutation, 3% have an MPL W515 mutation. Symptom Measures On the MPN-SAF TSS, the majority of individual symptoms assessed did not change significantly between the two assessment time points while on standard therapy. Notable exceptions were a significant decrease in weight loss (mean 2.0 vs. 1.7 on a 0=absent to 10=worst imaginable scale, p=0.005) and a significant worsening in quality of life (mean 3.6 vs. 3.8 on a 0=as good as it can be to 10=as bad as it can be scale, p=0.04). No changes were seen in other symptoms including early satiety, abdominal discomfort, night sweats, fatigue, inactivity, poor concentration, bone pain, itching, or fever. Similarly, the cumulative MPN-SAF TSS score remained stable at a mean of 24.4 over the treatment period. These findings were congruent with those observed using the EORTC QLQ-C30 instrument, with no significant changes seen in emotional, physical, role, cognitive, or social functioning. Finally, the MDASI also revealed a lack of change in either symptom severity (mean 2.7) or symptom distress (mean 3.0) scores, which remained stable over the study period. Discussion: Myeloproliferative neoplasms are associated with burdensome symptoms that significantly compromise quality of life. To date, no studies have quantified symptomatic response to standard-of-care treatments. Overall, results from the MEASURE study suggest that standard treatments have limited systematic impact on patient symptomatology over time, with no improvements in overall quality of life. However, we note the relatively low proportion of patients in this cohort treated with ruxolitinib, which has been shown previously to improve symptom burden, and this may have impacted the symptom responses seen in the group as whole; detailed responses by treatment and MPN subtype will be presented. Figure. Figure. Disclosures Dueck: Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy.