ABSTRACT
Background: Patients with relapsed or refractory (R/R) LBCL after first-line treatment who are unable to undergo high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) hae poor outcomes and limited treatment options. Aims: PILOT (NCT03483103) ealuated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as second-line treatment in patients with R/R LBCL not intended for HSCT. Methods: Eligible patients were adults with R/R LBCL after first-line treatment who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria as follows: age ≥ 70 years, Eastern Cooperatie Oncology Group performance status (ECOG PS) of 2, diffusing capacity for carbon monoxide ≤ 60%, left entricular ejection fraction < 50%, creatinine clearance < 60 mL/min, or alanine aminotransferase/aspartate aminotransferase > 2 × the upper limit of normal. Bridging therapy was allowed. Patients receied lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by liso-cel infusion at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria. Neurological eents (NE) were defined as inestigator-identified neurological aderse eents related to liso-cel and graded using the National Cancer Institute Common Terminology Criteria for Aderse Eents, ersion 4.03. The primary endpoint was objectie response rate (ORR) per independent reiew committee;all patients had ≥ 6 months of follow-up from first response. Results: Of 74 patients who underwent leukapheresis, 61 receied liso-cel and 1 receied nonconforming product (ie, product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered lisocel). Common reasons for preinfusion dropout included death and loss of eligibility (5 each). For liso-cel-treated patients, median age was 74 years (range, 53-84;79% ≥ 70 years) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectiely;26% had ECOG PS of 2 and 44% had Hematopoietic Cell Transplantation-specific Comorbidity Index score ≥ 3. After first-line treatment, 54% were chemotherapy refractory, 21% relapsed within 12 months, and 25% relapsed after 12 months;51% of patients receied bridging chemotherapy. Median (range) onstudy follow-up was 12.3 months (1.2-26.5). ORR and complete response rate were 80% and 54%, respectiely (Table). Median duration of response and progression-free surial were 12.1 months and 9.0 months, respectiely. Median oerall surial has not been reached. The most frequent treatment-emergent aderse eents (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade 3 CRS in 1 patient (2%) and no grade 4/5 CRS eents. Any-grade NEs were seen in 31% (n = 19) of patients;grade 3 NEs occurred in 5% (n = 3) of patients and no grade 4/5 NEs were reported. Seen percent (n = 4) receied tocilizumab only, 3% (n = 2) receied corticosteroids only, and 20% (n = 12) receied both tocilizumab and corticosteroids for treatment of CRS and/or NEs. Oerall, grade ≥ 3 TEAEs occurred in 79% (n = 48) of patients, with grade 5 TEAEs in 2 patients (both due to COVID-19). Two patients (3%) had grade 3/4 infections and 15 (25%) had grade ≥3 neutropenia at Day 29. Summary/Conclusion: In the PILOT study, liso-cel as second-line treatment in patients with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable oerall and complete responses, with no new safety concerns. (Table Presented).
ABSTRACT
Background: Pts with R/R LBCL after first-line (1L) treatment (tx) who are unable to undergo high-dose chemotherapy (HDCT) and HSCT have poor outcomes and limited tx options. PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. Methods: Eligible pts were adults with R/R LBCL after 1L tx who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF < 50%, CrCl < 60 mL/min, or ALT/AST > 2 × ULN. Bridging tx was allowed. Pts received lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by liso-cel at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria and neurological events (NE) per NCI CTCAE, version 4.03. Primary endpoint was ORR per independent review committee (IRC);all pts had ≥ 6 mo followup (f/u) from first response. Results: Of 74 pts leukapheresed, 61 received liso-cel and 1 received nonconforming product. Common reasons for pre-infusion dropout included death and loss of eligibility (5 each). For liso-cel-treated pts, median age was 74 yr (range, 53-84;79% ≥ 70 yr) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectively;26% had ECOG PS = 2 and 44% had HCT-CI score ≥ 3. After 1L tx, 54% were chemotherapy refractory, 21% relapsed ≤ 12 mo, and 25% relapsed > 12 mo;51% of pts received bridging chemotherapy. Median (range) on-study f/u was 12.3 mo (1.2-26.5). ORR and CR rate was 80% and 54%, respectively. Median DOR and PFS was 12.1 mo and 9.0 mo, respectively. Median OS has not been reached (Table). Most frequent tx-emergent AEs (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade (gr) 3 CRS in 1 pt (2%) and no gr 4/5 CRS. Any-grade NEs were seen in 31%, gr 3 in 5% (n = 3), and no gr 4/5 NEs;7% received tocilizumab, 3% corticosteroids, and 20% both for tx of CRS/NEs. Overall, gr ≥ 3 TEAEs occurred in 79%, with gr 5 in 2 pts (both due to COVID-19). Two pts (3%) had gr 3/4 infections and 15 (25%) had gr ≥3 neutropenia at Day 29. Conclusions: In the PILOT study, liso-cel as 2L tx in pts with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable overall and complete responses, with no new safety concerns.
ABSTRACT
Background. The consequences of SARS-CoV2 reinfections for patients, healthcare workers and society are unclear. We reviewed the clinical, laboratory, and epidemiological characteristics of patients re-infected with genetically distinct strains of SARS-CoV2 identified by Whole Virus Genome Sequencing (WvGS). Methods. Cases were selected based on a positive SARS-CoV-2 Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test, clinical resolution, a negative interim test and a subsequent positive nasopharyngeal swab. Positive samples were prepared for sequencing by cDNA synthesis, tiled-PCR following the ARTIC protocol and amplicon sequencing using Illumina MiSeq platform. Raw reads were mapped to the reference sequence using bowtie and Samtools was used for variants calling and to generate the consensus sequences. Comparative sequence analysis was conducted by phylogenetic inference maximum likelihood method with RAxML using the multiple sequence aligned by MAFFT. Clades and variants were assigned respectively using Nextstrain and Pangolin COVID-19 lineage assigner (Figure 1). The clinical, radiological and laboratory data were collected from patient medical notes and laboratory information system. Results. Two cases of SARS-CoV-2 reinfection were detected by RT-PCR (patient 1 and 2). CT values and strain variants are presented in Table 1. The time between detection of the first and second infection was 67 and 270 days respectively. WvGS confirmed that the second episodes were due to a genetically distinct strain of SARS CoV2. These reflected the dominant contemporaneous variants in circulation. Both patients were immunocompromised from co-morbidities and medications. First and subsequent infections were minimally symptomatic. Both cases were associated with known hospital outbreaks. They passed away within 2 weeks of the second infection of unrelated causes. Conclusion. Two patients in this study were diagnosed with a SARS-CoV-2 reinfection confirmed by WvGS. A common factor in these cases was immunocompromise. Where a previously infected patient test shows a new positive or an unexpected reduction in CT value is observed, we recommend individual risk assessment to determine the timing of discontinuation of isolation and infection control precautions.
ABSTRACT
Background: Venetoclax (VEN), an oral B-cell lymphoma 2 inhibitor, is approved for use in adult patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). As a targeted and highly active antitumor agent, VEN induces rapid and profound tumor reduction. Inpatient monitoring for initial doses of VEN is recommended by US Prescribing Information for pts with medium tumor burden and reduced renal function or high tumor burden. Administration of debulking agents, such as obinutuzumab (G), help reduce tumor burden and, consequently, facilitate subsequent administration of VEN in the outpatient setting. However, tumor reduction data are needed to definitively establish the utility of a debulking strategy. This study performed disease restaging after every 2 cycles of debulking to evaluate the safety and efficacy of G ± bendamustine (B) as a debulking regimen before VEN treatment in the outpatient community setting. The safety and efficacy of subsequent VEN+G treatment after debulking was also evaluated. Methods: This open-label, Phase 3b study (NCT03406156) enrolled adult pts with previously untreated CLL/SLL (except those with 17p deletion) who had medium (any lymph node [LN] 5 to <10 cm or absolute lymphocyte count [ALC] ≥25×10 9/L) or high (any LN ≥10 cm or any LN ≥5 cm and ALC ≥25×10 9/L) tumor burden. A maximum of six 28-day cycles of G±B were administered, and disease restaging was performed after every 2 cycles. Once low tumor burden was achieved (all LN <5 cm and ALC <25x10 9/L), VEN+G was administered for 5 cycles followed by VEN monotherapy for a total time on VEN of up to 1 year. Disease assessments were performed at the end of combination therapy (EoCT;5 mo after last dose of G) and at the end of therapy (EoT;3 mo after last dose of VEN), and peripheral blood was collected for assessment of minimal residual disease (MRD) using the clonoSEQ assay (Adaptive Biotechnologies). Undetectable MRD was defined as <1 CLL cell/10 4 leukocytes (<10 -4;uMRD4), <10 -5 (uMRD5), or <10 -6 (uMRD6). The primary endpoints were the percentage of pts achieving low tumor burden after 2, 4, and 6 cycles of G±B debulking and complete remission (CR) and CR with incomplete marrow recovery (CRi) rates among pts receiving VEN. Results: Of 120 pts treated, 81 received G for debulking and 39 received G+B. As of 13 May 2021, 2 pts remained on study treatment, 108 were in posttreatment follow-up, and 10 had discontinued the study for reasons including death (n=7), withdrawn consent (n=2), and COVID-19 infection (n=1). At baseline, 82.5% of pts had ALC ≥25x10 9/L, 33.3% had LN ≥5 cm, and 24.2%/75.0%/0.8% had high/medium/low tumor burden, respectively. Low tumor burden was achieved in 91.6% (109/119) of evaluable pts receiving G±B debulking. In the all-treated population (N=120), the objective response rate (ORR) was 90.0% and the CR/CRi rate was 35.8%. Among pts receiving VEN with disease assessment at EoT (N=76), the ORR was 98.7% and the CR/CRi rate was 44.7% (Table). The best uMRD4 rates in peripheral blood were 89.2% (107/120) for all-treated and 98.2% (107/109) for evaluable pts. Among evaluable pts, the uMRD4 rates were 100% (100/100) and 97.1% (68/70) at EoCT and EoT, respectively. Among pts with MRD assessments at both timepoints (N=67), 19.4% had a deepening of their MRD response from EoCT to EoT, and 67.2% maintained the same MRD level (Figure). At a median follow-up of 24.0 mo, 7 deaths (6 related to COVID-19 infection and 1 from cardiac complication after pancreatic mass resection) and no incidences of disease progression were reported;the estimated 18-mo PFS was 94.1%. In pts treated with G vs G+B debulking, respectively, the incidences of Grade ≥3 TEAEs were 71.6% vs 84.6% (most common was neutropenia at 28.4% vs 41.0%) and serious AEs were 23.5% vs 17.9% (most common were pneumonia and COVID-19 pneumonia, each at 3.7% vs 2.6%). Conclusion: In this study, most (91.6%) pts achieved low tumor burden after debulking. The uMRD4 rate was 98.2% among MRD-evaluable pts (89.2% among al pts), with 100% and 97.1% uMRD4 rates at EoCT and EoT, respectively. Overall, these results highlight the utility of G±B as an effective debulking strategy that can facilitate VEN treatment initiation in the outpatient setting. The efficacy and safety results are consistent with other VEN+G trials. Preventive measures for COVID-19 should be continuously emphasized for pts with CLL. [Formula presented] Disclosures: Flinn: AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding;Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Agios: Other All research funding payments made to Sarah Cannon Research Institute, Research Funding;Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah CannonResearch Institute;Sarah Cannon Research Institute: Current Employment;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding;Johnson & Johnson: Current holder of individual stocks in a privately-held company;Seattle Genetics: Research Funding. Andorsky: AbbVie: Research Funding;Celgene/Bristol Myers Squibb: Consultancy;Celgene/Bristol Myers Squibb: Research Funding;Epizyme: Research Funding;AstraZeneca: Other: served on steering committees;AbbVie: Consultancy. Melear: TG Therapeutics: Speakers Bureau;Astrazeneca: Speakers Bureau;Janssen: Speakers Bureau. Manda: Morphosys: Honoraria;Genmab: Current equity holder in publicly-traded company. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company;Atara Biotechm: Consultancy;McKesson Specialty Health: Consultancy;Sunitomo Dainippon Pharma: Consultancy;Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Yimer: GSK: Speakers Bureau;Beigene: Speakers Bureau;Janssen: Speakers Bureau;Astrazeneca: Speakers Bureau;Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau;Sanofi: Speakers Bureau;Amgen: Speakers Bureau;Pharmacyclics: Speakers Bureau;Texas Oncology: Current Employment. Burke: Kura: Consultancy;Epizyme: Consultancy;Kymera: Consultancy;Adaptive Biotechnologies: Consultancy;Roche/Genentech: Consultancy;Beigene: Consultancy, Speakers Bureau;MorphoSys: Consultancy;Verastem: Consultancy;AstraZeneca: Consultancy;AbbVie: Consultancy;Bristol Myers Squibb: Consultancy;X4 Pharmaceuticals: Consultancy;SeaGen: Consultancy, Speakers Bureau. Fanning: BMS: Speakers Bureau;TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bur au;Genmab: Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees;Sanofi: Speakers Bureau;Takeda: Speakers Bureau;Genentech: Membership on an entity's Board of Directors or advisory committees. Islas-Ohlmayer: OHC/USON: Current Employment;AbbVie: Honoraria;Rigel: Honoraria, Speakers Bureau. Vizkelety: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman: Pharmacyclics LLC, an AbbVie Company: Consultancy;BMS: Consultancy;Lilly: Consultancy;BeiGene: Consultancy;Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Consultancy;TG Therapeutics: Consultancy;AbbVie: Consultancy.