20 abstracts accepted (Tisagenlecleucel – 16 abstracts [6 Oral, 9 Posters, 1 Publication Only]; Pipeline CAR-T: 4 abstracts [1 Oral, 3 Posters])

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Clinical Trial and Real-World Evidence – r/r DLBCL and pALL

ABSTRACT 429 – December 12th, 2021 10:00 am EST 

Daniel J Landsburg, Matthew J. Frigault, Zhen-Huan Hu, Samantha Jaglowski, Frederick L. Locke, Christine Ho, Miguel-Angel Perales, Caron Jacobson, Brian T. Hill, Stephen Ronan Foley, Peter A. Riedell, Ranjan Tiwari, Aisha Masood, Stephen Lim, Marta Majdan, Marcelo C Pasquini, and Cameron J. Turtle

 

Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy that provides high rates of durable response, with a manageable safety profile, in adult patients with R/R diffuse large B-cell lymphoma (DLBCL). An overall response (OR) rate of 53% and progression-free survival (PFS)rate of ~35% at 12 months were observed in the pivotal Phase II trial, JULIET (NCT02445248) [Jaeger et al. Blood 2020; Schuster et al. NEJM 2019]. Early data from the CIBMTR registry indicate similar efficacy and a more favorable safety profile in the commercial setting [Pasquini et al. Blood Adv 2020].Outcomes are reported here for a larger group of patients with aBNHL who received commercial tisagenlecleucel with longer follow-up, including those considered ineligible for JULIET.
 
Methods: This non-interventional prospective study used data from the CIBMTR registry and included adult patients with R/R aBNHL in the USA and Canada. Patients who received commercial tisagenlecleucel after were included, stratified by eligibility for JULIET based on patient characteristics reported in the registry (eg disease histology, treatment history, ECOG performance status, organ function). The safety and efficacy sets included those with completed Day 100 safety and efficacy forms, respectively, with ≥6 months’ follow-up. Patients who died or discontinued prior to data cut-off were also included. Center-reported efficacy outcomes included OR rate, complete response (CR) rate, partial response (PR) rate, PFS, duration of response (DOR) and overall survival (OS). Adverse events of interest, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were reported using the ASTCT grading criteria.
 
Results: As of October 30, 2020, data were collected from 405 patients who received commercial tisagenlecleucel ≥6 months prior to data cut-off, with 365 patients included in the safety set and 362 in the efficacy set. In the full cohort, DLBCL was the histologic subtype in 79.5% of patients. Median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25–33). At infusion, median age was 66 years, with 54.3% of patients aged ≥65 years. Patients had received a median of 3 (range: 0–11) prior lines of therapy and 34.3% had primary refractory disease. ECOG performance status at screening was <2 in 80.2% of patients. Based on the above criteria, 263 patients (64.9%) were considered JULIET-ineligible. 
In the efficacy set (median follow-up 15.8 months), the OR rate was 59.4% (95% CI 54.1–64.5), and 39.5% achieved a CR. Six patients with a 100-day best overall response of PR converted to CR. The 12-month PFS rate was 33.5% (95% CI 27.9–39.3), 12-month OS rate was 60.3% (95% CI 53.7–66.2) and median DOR was not reached. Overall, efficacy outcomes in the JULIET-ineligible subgroup reflected those of the wider study population (Table 1). 
In the safety set, any-grade CRS within 100 days of infusion was observed in 47.7% (n=174) patients, with Grade ≥3 CRS in 4.9% (n=18). Median time to CRS onset from infusion was 4 days (range: 1–15) and median duration was 5 days (95% CI 5–6). Any-grade ICANS within 100 days of infusion was observed in 17.0% (n=62) patients, with Grade ≥3 in 6.0% (n=22). Median time to onset from infusion was 7 days (range: 1–33) and median duration was 9 days (95% CI 6–12). The safety profile of tisagenlecleucel in the JULIET-ineligible subgroup reflected that of the wider study population (Table 1).
 
Conclusions: Updated registry data confirm that aBNHL patients receiving commercial tisagenlecleucel experience similar efficacy outcomes and more favorable safety outcomes than those enrolled in JULIET, even though approximately two-thirds of patients did not appear to meet JULIET eligibility criteria. The CIBMTR registry remains an important source of safety and efficacy outcomes for a large population of aBNHL patients treated with commercial tisagenlecleucel. Updated data will be presented at the meeting.

ABSTRACT 428 – December 12th, 2021 9:45 am EST

Samuel John, Michael A. Pulsipher, Amy Moskop, Zhen-Huan Hu, Christine L. Phillips, Erin Marie Hall, Steven P.Margossian, Sarah Nikiforow, Paul L. Martin, Benjamin Oshrine, Amy K. Keating, Rayne H. Rouce, Ranjan Tiwari, Santiago Redondo, Jennifer Willert, Abhijit Agarwal, Marcelo C Pasquini, and Stephan A. Grupp

 

Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months’ (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age (<18y and ≥18y) [Riveset al. HemaSphere 2018]. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to ELIANA with no new safety signals [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for patients who received tisagenlecleucel in the real-world setting, stratified by age(<18y and ≥18y).
 
Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged <18y and ≥18y at the time of infusion. Efficacy was assessed in patients with ≥12mo follow-up at each reporting center and included best overall response (BOR) of complete remission (CR), duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). Safety was evaluated in all patients who completed the first (100-day) assessment. Adverse events (AEs) of interest – including cytokine release syndrome (CRS) and neurotoxicity – were monitored throughout the reporting period. CRS and neurotoxicity were graded using the ASTCT criteria. 
 
Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25–34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged <18y, indicated by lower rates of morphologic CR and minimal residual disease (MRD) negativity prior to infusion. Older patients were also more heavily pre-treated before infusion. All other patient characteristics at baseline were comparable between the two groups (Table 1). 
In the efficacy set (median follow-up 21.5mo; range 11.9–37.2; N=322), BOR of CR was 87.3% (95% CI 83.1–90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3–not estimable [NE]), median EFS was 14.0mo (9.8–24.8) and median RFS was 23.9mo (13.0–NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). 
In the safety set (median follow-up 20.0mo; range 2.6–37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). 
 
Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged <18y. The overall efficacy and safety profiles of commercial tisagenlecleucel reflected those observed in the clinical trial setting [Grupp et al. Blood 2018; Rives et al. HemaSphere 2018] and were broadly consistent across age groups. Some important differences between the <18y and ≥18y groups were identified, which may point to challenges in timely identification and/or referral of older patients for CAR-T cell therapy.

ABSTRACT 885 – December 13th, 2021 6:45 pm EST

Roberta Di Blasi, Steven Le Gouill, Emmanuel Bachy, Guillaume Cartron, David Beauvais, Fabien LeBras, Francois Xavier Gros, Sylvain Choquet, Pierre Bories, Pierre Feugier, Rene-Olivier Casasnovas, Jacques-Olivier Bay, Mohamad Mohty, Magalie Joris, Thomas Gastinne, Pierre Sesques, Jean Jacques Tudesq, LaetitiaVercellino, Franck Morschhauser, Elodie Gat, Florence Broussais, Roch Houot, and Catherine Thieblemont

 

Background: AntiCD19 Chimeric Antigen Receptor (CAR) T cells are a major therapeutic advance in the management of patients (pts) with relapsed/refractory aggressive B-cell lymphoma (R/R aggressive BCL) with reported overall response rates between 40% and 83% in the pivotal trials(ZUMA1, JULIET, TRANSCEND) as well as in the real-life cohorts with either axicabtagene ciloleucel (axi-cel, Yescarta) or tisagenlecleucel (tisa-cel,Kymriah). However, a significant number of pts will experience progression or relapse after infusion with an estimated 24-month progression-free survival (PFS) of between 33% and 42%. DESCAR-T is a nationwide registry that aims to collect real-life data for all pts treated with commercialized CART-cells in France. It represents a unique opportunity to investigate the outcome of pts who relapse after CAR T-cell therapy.
 
Patients and Methods: In all, 680 pts with R/R aggressive BCL were registered in DESCAR-T from August 2018 and 550 were infused at the time of the present analysis (April 12, 2021) with either axi-cel (n=350) or tisa-cel, n=200). All pts gave informed informed consent before DESCAR-T registration. Progression and relapse after CAR T-cells were defined based on the Cheson 2014 response assessment criteria.
 
Results: With a median follow-up (F-up) of 7.9 months, 238 pts (43.3%) out of 550 treated pts relapsed, after axi-cel in 136 pts (F-up = 9.0 months [5.1– 9.7]) and after tisa-cel in 102 pts (F-up = 7.8 months [5.9 – 10.4]). Histological subtypes were DLBCL (n 178, 74.8%), PMBL (n=11, 4.6%), HGBCL (n= 3,1.3%), transformed follicular lymphoma (tr FL) (n=31, 13%), or other histologies (FL n=2, PCNSL n=1, tr MZL n=3, unclassifiable hodgkin/DLBCL n=9). At time of registration, median age was 62 years (range 18;77), 43.6% were aged >65 yrs, and 67.2% were male; 184 (79.7%) presented with advanced disease (stage III or IV), and 13 (5.9%) with low age-adjusted International Prognostic Index (aaIPI), 82 (37.1%) with low-intermediate aaIPI, 110 (49.8%)with high-intermediate aaIPI, and 16 (7.2%) with high aaIPI. At time of CAR T-cell infusion, 36 (18.9%) pts presented with ECOG PS >=2 and 72 (38.9%)with an elevated LDH level. The median number of lines prior to CAR T-cell infusion was 3 (range 2-9), including 48 (20.1%) transplant (46 auto-HSCT and 2 allo-HSCT). Median time between order and infusion was 50 days (IQR 43; 59). Bridging therapy was administered to 87.8% of the pts, with a high-dose regimen including combined immunochemotherapy for 84.5% of the pts. Failure after CAR T-cells occurred after a median time of 2.71 months(range 0.2; 21.5), 54 (22.7%) being during the first month after infusion (< M1) and 156 (65.5%) during the first-three months after infusion (<M3). At failure, 154 (64%) patients received treatments that maybe combined and described as followed : 70 (45.5%) lenalidomide, 70 (45.5%) various immunotherapies (rituximab, daratumomab, polatuzumab), 31 (20.1%) a combined immunochemotherapy with various regimens (R-DHAX, RICE, Pola-R-Benda,...), 21 (13.6%) an anti-PD1 immune checkpoint inhibitor (Nivolumab, pembrolizumab), 11 (7.1%) bi-specific T-cell engagers (TCE), 18 (11.7%)radiotherapy, and 3 a transplant (1 an auto-HSCT and 2 an allo-HSCT). The overall response rate to the salvage therapy after CAR T-cells was 11%(complete response rate 5.2%). The median PFS was 2.8 months (95% CL, 2.4 -3.1). The median overall survival (OS) was 5.2 months (95% CL, 4.1- 6.6)(Figure 1A). The median OS was even shorter in pts who failed during the first month (1.9 months [95% CL, 1.1- 3.2] vs 6.7 months [95 CL 5.5 : 9.3]p<0.0001) (Figure 1B). 26.9% of the pts in the overall cohort were alive at 6 months, but only 18.9% were alive in the group of pts relapsing during the first month. In multivariate analysis, predictors of OS were high LDH level at time of infusion, time to failure < 1 month after CAR T-cells, no access to immuno-oncology treatment such as TCE or lenalidomide.
 
Conclusion: This study is the first analysis reporting the outcome of patients with R/R aggressive BCL relapsing after anti-CD19 CAR T-cells. These results demonstrate the poor outcome of these pts and identifies the need for further innovative treatment strategies.

ABSTRACT 92 – December 11th, 2021 9:45 am EST 

Emmanuel Bachy, Steven Le Gouill, Roberta Di Blasi, Pierre Sesques, Guillaume Cartron,, David Beauvais, Louise Roulin, Francois Xavier Gros, Choquet Sylvain, Pierre Bories, Marie Thérèse Rubio, Rene-Olivier Casasnovas, Jacques-Olivier Bay, Mohamad Mohty, Magalie Joris, Thomas Gastinne, Jean Jacques Tudesq, Isabelle Chaillol, Florence Broussais, Catherine Thieblemont, Roch Houot and Franck Morschhauser

 

Background: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the pivotal JULIET trial, tisa-cel led to a best overall response rate (ORR) of 52% with a 40% complete response rate (CRR) and a median overall survival (OS) of 12 months. In the ZUMA-1 trial, axi-cel was associated with an 83% ORR, a 58% CRR and a median OS of 26 months. In the absence of a randomized comparison and given the large differences in trial design precluding a robust matched-adjusted indirect comparison, controversy exists as to whether there are significant differences regarding both efficacy and safety between the two products. 
 
Methods: We conducted a propensity score (PS)-matched comparison of axi-cel and tisa-cel in a large cohort of R/R DLBCL patients treated outside of clinical trials. All data were collected through the French DESCAR-T registry designed by the LYSA/LYSARC which aims to collect real-life data. The PS was calculated for each patient by using multiple logistic regression analysis against treatment category (axi-cel v tisa-cel) entering the following variables (assessed at time of lymphodepletion for most): age, ferritin, time from last treatment to CAR T-cell infusion, sex, histological diagnosis, LDH level, CRP, ECOG status, stage, number of previous treatment lines, use of a bridging therapy, response to bridging therapy if any, previous stem cell transplant, diameter of the largest tumor involved (with a cut-off set up at 5 cm), time from first commercial CAR T-cell order (of any type) of the center to CAR T-cell order for the patient (as a correlate for center experience for CAR T-cell practice), and treatment center. For all categorical variables, missing values (which were marginal for most parameters and balanced between CAR T-cell subtypes) were considered as a category to reduce the number of patients not included in the analysis. Of note, patients with primary mediastinal B-cell lymphoma were not included since approval has been granted for axi-cel only. The primary endpoint was OS. The following secondary endpoints were analyzed: best ORR and CRR (according to Lugano 2014 classification), progression-free survival (PFS) and duration of response (DoR). All time-to-event analyses used time of CAR T-cell infusion as the origin. PS-matching of the two patient cohorts was then conducted using PS rounded to one decimal place. 
 
Results: An initial cohort of 504 patients with DLBCL (NOS, high grade or transformed from indolent lymphoma) and treated with axi-cel (n=321) or tisa-cel (n=183) was considered. Among others, patient characteristics were imbalanced regarding ECOG, and prior transplant rate with worse prognosis for patients receiving tisa-cel. After a 1:1 ratio PS-matching, outcome was compared between 144 patients treated with axi-cel and 144 patients treated with tisa-cel with no residual significant difference in baseline patient characteristics according to CAR T-cell type. After a median follow-up of 6.6 months (95% CI, 6.1-10.4 months), OS was not significantly different between axi-cel and tisa-cel (78% v 70% at 6 months respectively, P=0.44). Best ORR and CRR were significantly higher with axi-cel compared with tisa-cel (73% v 60%, P=0.02 and 56% v 36%, P<0.001, respectively). There was no difference in DoR. PFS was significantly longer with axi-cel than tisa-cel (53% v 32% at 6 months respectively, P=0.011). 
Regarding toxicity, there was no significant difference in incidence of cytokine release syndrome (CRS) but axi-cel was associated with significantly more frequent and higher-grade immune effector cell-associated neurotoxicity syndrome (ICANS) (30.6% v 18.1% for grade 1-2 and 10.4% v 2.1% for grade ≥3 for axi-cel compared with tisa-cel, respectively, P< 0.001). 
 
Conclusion: In this study, after stringent PS-matching on a large patient population treated with CAR T-cell in real-life, there was no OS difference between axi-cel and tisa-cel. Axi-cel yielded higher ORR and CRR and significantly prolonged PFS compared with tisa-cel. However, greater efficacy came at the cost of higher neurotoxicity with axi-cel. These data could help in refining CAR T-cell subtype choice for different patient populations, with young and/or fit patients benefiting most from axi-cel while tisa-cel being most advantageous to elderly and/or unfit patients.

 ABSTRACT 4105 – December 13th, 2021 6:00 - 8:00 pm EST 

Adriana Seber, Mecneide Mendes Lins, Nicolle Queiroz Hazarbassanov, and Maria Lucia De Martino Lee

 

Introduction: Despite the achievement of progressively higher cure rates, acute lymphoblastic leukemia (ALL) remains the main cause of cancer-related deaths in children, adolescents, and young adults, particularly in low- and middle-income countries. According to SEER data, the 3-year survival for ALL ages <20 in 2015 in the US was 90.4%-92.5%. Since new immunotherapy strategies are approved up to the age of 25 years, these young adults should also be included in outcomes analyses. It is important to determine outcomes and the gap between the overall survival observed in developing and in high-income countries to guide policies and priorities regarding specific healthcare needs and, ultimately, to improve the outcomes of ALL treatments worldwide. 
 
Objectives: To describe the treatment lines, protocols and fatality rates in children, adolescents and young adults up to the age of 25 years diagnosed with ALL (PedALL) in Brazil, based on a public healthcare national database.  
 
Methods: The “DataSUS” is an anonymized open-access database of all patients treated in Brazilian public healthcare centers, divided in three datasets: outpatient, inpatient, and death reports. Citizens have a unique number and all diagnoses, diagnostic procedures and medical interventions are included. This national registry is used to track public expenses. DataSUS has information regarding ALL (ICD-10, C91.0) including protocols, treatment lines, and survival. We performed a descriptive cross-sectional study of PedALL included in the database between Jan/2013 and Dec/2018 to understand the burden of the disease in the public healthcare system. Then, we selected a cohort of patients with PedALL included in DataSUS as “First-line chemotherapy for pediatric leukemia” between Jan/2014 and Dec/2015, and followed these patients until Dec/2018, to describe the management and outcomes of PedALL in our country. 
 
Results: Between 2013 and 2018, 17,658 patients ages 0-25 years (86% < 18 years) had the underlying diagnosis of ALL, a mean of 6,045 patients per year: 2,725 newly diagnosed, and the remaining, continuation therapy. The male/female ratio was 1.40. The patients underwent a total of 86,332 procedures in this timeframe including diagnostic procedures, chemotherapy, multiple treatment lines, hematopoietic stem cell transplant, transplant-related exams, and the management of disease and treatment-related complications. Treatment protocols most frequently reported were BFM and two national protocols, GBTLI-LLA and RE-LLA. A total of 1,266 patients died between 2013-2018, a mean of 211 patients each year, 79.3% of them younger than 18 years of age. In the cohort diagnosed between Jan/2014 and Dec/2015, 2,368 patients 0-18 years of age and 91 ages 19-25 years were first included in DataSUS system as “First-line chemotherapy for pediatric leukemia”. The male:female ratio was 1.44 and 1.84 for the 0-18 and 19-25 years of age, respectively. The median time from diagnosis to treatment initiation was 2.3 months. Within the three year-follow-up, a 2 line chemotherapy was registered in 142 patients (6%), 3 line in 11 patients (0.46%) and a 4 line in a single patient (0.04%). The mean duration of each treatment line was 16.4, 8.3, and 4 months, respectively, for the 1 , 2 , and 3 line. Patients were hospitalized for a mean total of 65.3 days: 9.7 admissions per patient, for a mean of 6.7 days each. The absolute death count was 303 (0-18) and 13 (19-25) patients, which would represent a 3-year fatality rate of 12.8% (0- 18) to 14.3% (19-25); 61% of the deaths occurred in the first year of treatment. 
 
Conclusion: The burden of ALL for the public health care system is large, with over 80 thousand procedures every year. This has a high emotional and socio-economic impact to the families and to the society. More than 200 children and young adults with ALL die every year in Brazil, but fatality rate is very similar to SEER data. The two-month delay between diagnosis and treatment initiation can be an explanation for the early mortality observed in our database and must certainly be appointed as a great opportunity for improvement. Standardization of the national PedALL protocol and new treatment modalities may greatly improve this scenario.


Clinical Trial and Real-World Evidence – r/r Follicular Lymphoma

ABSTRACT 131 – December 11th, 2021 1:00 pm EST

Catherine Thieblemont, Michael Dickinson, Joaquin Martinez-Lopez, Arne Kolstad, Jason P Butler, Monalisa Ghosh, Leslie L. Popplewell, Julio C. Chavez, Emmanuel Bachy, Koji Kato, Hideo Harigae, Marie Jose Kersten, Charalambos Andreadis, Peter A. Riedell, P. Joy Ho, Jose Pérez-Simón, Andy Chen, Loretta Nastoupil, Bastian Von Tresckow, Andres JM Ferreri, Takanori Teshima, Piers EM Patten, Joseph P. McGuirk, Andreas Petzer, Fritz Offner, Andreas Viardot, Pier Luigi Zinzani, Ram Malladi, Aiesha Zia, C Lobetti Bodoni, Aisha Masood, Stephen J. Schuster, Nathan H. Fowler, and Martin H. Dreyling

 

Background: Follicular lymphoma is an indolent disease with a continuous relapsing pattern and typically requires multiple lines of therapy. Novel therapies such as tisagenlecleucel are being investigated to improve outcomes. Primary analysis of the single-arm, multicenter, Phase II ELARA trial in r/rFL demonstrated that tisagenlecleucel resulted in high overall (ORR) and complete response rates (CRR), and prolonged progression-free survival (PFS) at a median follow-up of 11 months (mo). Here, we report updated efficacy results from the overall population at a median follow-up of 17 mo, and a subgroup analysis of pts with high-risk disease from the ELARA trial (NCT03568461).
 
Methods: Eligible adult pts had histologically confirmed r/r FL (grades 1-3A) after ≥2 lines of therapy or had relapsed after autologous stem cell transplant. Bridging therapy was allowed and was followed by disease evaluation before tisagenlecleucel infusion. Pts received tisagenlecleucel (0.6-6×10 CAR+ viable T cells) after lymphodepleting chemotherapy (fludarabine [25 mg/m] + cyclophosphamide [250 mg/m] QD for 3 d or bendamustine [90 mg/m] QD for 2 d). Endpoints included ORR, CRR, PFS, and duration of response (DOR). Descriptive efficacy sub-analyses were performed for 9 high-risk subgroups, including prior hematopoietic stem cell transplant (HSCT), ≥5 prior lines of therapy, progression of disease within 24 mo from first immunochemotherapy (POD24), double-refractory disease, high Follicular Lymphoma International Prognostic Index (FLIPI) at study entry, high lactate dehydrogenase at baseline, high C-reactive protein (CRP) prior to infusion, radiological bulky disease (by GELF criteria), and high total metabolic tumor volume (TMTV; >510 cm) at baseline (median 155.32 cm; range 0.1-2470.4 cm). Descriptive subgroup analysis was supported by multivariate analysis to identify factors predictive of worse outcomes.
 
Results: As of March 29, 2021, 97 pts received tisagenlecleucel and 94 were evaluable for primary efficacy analysis (median follow-up 17 mo). High and durable responses were seen in the overall ELARA population (ORR 86.2%, CRR 69.1%, 9-mo DOR 76.0%, and 12-mo PFS 67.0%). In CR pts at 9 mo, PFS was 85.5% and estimated probability of remaining in response was 86.5%. Safety reflected known tisagenlecleucel profile; 48% of pts had CRS (majority were grade 1/2) and 11.3% had neurological events (3% grade ≥3). In the subgroup analysis, pts were stratified into risk groups. Efficacy (ORR, CRR) and durability of response were well maintained in all high-risk subgroups, except for POD24 (n=35), high TMTV (n=20), and ≥5 prior lines of therapy(n=27). Compared with corresponding low-risk subgroups, there was a numerical reduction in CRR for high-risk subgroups (POD24 59.0% vs 87.9%; high TMTV 40.0% vs 76.4%; ≥5 prior lines of therapy 59.3% vs 73.1%) (Figure). A reduction in 12-mo PFS was also identified for pts in these subgroups: POD24(60.8% vs 77.9%), high baseline TMTV (54.5% vs 68.5%), and ≥5 prior lines of therapy (59.6% vs 69.7%). Evaluating the disease characteristics of the high TMTV subgroup compared with low TMTV, high TMTV was associated with a higher incidence of bulky disease (58.3% vs 90.0%), high FLIPI (54.2% vs85.0%), and high CRP (45.8% vs 70.0%). In the multivariate analysis of high-risk factors, only POD24 (hazard ratio [HR] 2.34; 95% CI, 1.02- 5.34) and high TMTV (HR 2.53; 95% CI, 1.14-5.65) were associated with shorter PFS. For pts with both POD24 and high TMTV (n=12), the CRR was 16.7% with a 12-moPFS of 36.0%. These analyses of high-risk subgroups are exploratory in nature and should be validated in a larger study cohort.
 
Conclusions: With 17-mo median follow-up, tisagenlecleucel produced high ORR and CRR and was associated with durable response and promising 12-mo PFS in pts with r/r FL and 2+ prior lines of therapy. Safety was consistent with known tisagenlecleucel profile. POD24 and high TMTV were independently associated with PFS. These results suggest that tisagenlecleucel can induce high rates of durable response, including most pts in the high-risk disease subgroups, who have poor prognosis with current non-CAR-T cell therapies.

ABSTRACT 3533 – December 13th, 2021 6:00 - 8:00 pm EST

Nathan H. Fowler, Michael Dickinson, Monalisa Ghosh, Andy Chen, Charalambos Andreadis, Ranjan Tiwari, Aisha Masood, Roberto Ramos, Vamsi Bollu, Etienne Jousseaume, Catherine Thieblemont, Martin H. Dreyling, and Stephen J. Schuster

 

Background: Follicular lymphoma (FL) is the second most frequently diagnosed Non-Hodgkin lymphoma subtype in Western countries. Patients often undergo multiple lines of therapy over many years throughout the course of their disease with worse survival after each successive line of therapy. Recent findings from the ELARA trial showed that tisagenlecleucel, a chimeric antigen receptor (CAR)-T cell therapy, had durable complete response rate of 66.0%, with a probability of 79% (95% CI, 66%-87%) to remain in response ≥6 months (overall response rate 86.2%) in patients with relapsed or refractory(r/r) FL. Prior evidence in patients with r/r diffuse large B-cell lymphoma demonstrated that tisagenlecleucel can be safely infused in an outpatient setting and may reduce healthcare resource utilization (HCRU) (Lyman et al, 2020). we present the first HCRU among patients with r/r FL who received tisagenlecleucel in the ELARA trial.
 
Methods: ELARA is a Phase II, single-arm, multicenter study of tisagenlecleucel in adult patients with r/r FL. All patients underwent lymphodepleting chemotherapy with fludarabine and cyclophosphamide or bendamustine, before receiving a single IV infusion of tisagenlecleucel (0.66×10 CAR positive viable T cells) that was administered at the investigator’s discretion in either the inpatient or outpatient setting. Patients were followed for a median of 11 months, and HCRU was characterized using hospitalization data collected from the first day of infusion up to the second month after treatment, the time period wherein occurrence of CAR-T cell-related adverse events (AEs) such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are most frequent. Information on the length of stay (dates of admission), hospital facilities used, and discharge information were assessed. Healthcare costs associated with hospitalizations and intensive care unit (ICU) admissions were estimated by applying unit costs obtained from published literature. All costs were from healthcare system perspective and were inflated to 2020 US Dollars.
 
Results: Among 97 patients with r/r FL who received tisagenlecleucel infusion, 17 patients (18%) were infused in an outpatient setting and 80 patients(82%) were admitted for inpatient infusion and monitoring. Of the 30 clinical trial sites, 4 sites in US and 1 site in Australia used out patient administration; at these sites, 68% (17 of 25) of the patients were treated in an outpatient setting. Patients treated in the outpatient setting were more likely to have ECOG performance status of 0 and a more favorable FLIPI score, but more frequently had grade 3A FL, primary refractory disease, and >5 lines of prior antineoplastic therapy than in the inpatient setting (Table). In the outpatient setting, 6 of 17 patients (35%) did not require any hospitalization during the first 2 months post-infusion, whereas 11 of 17 patients (65%) were hospitalized for AEs at a median of 3 days (range 1-25) post-infusion. Patients treated in the inpatient setting had longer total hospitalization days (mean ± SD: 14.3 ± 8.42 vs 5.0 ± 2.16 days) and longer average length of stay (mean ± SD: 13.8 ± 8.54 vs 4.3 ± 1.4 days) compared with the outpatient group. None of the outpatients required ICU admission during the 2 months post-infusion, whereas 7 patients (9%) in the inpatient setting were admitted to the ICU, for a total mean ± SD duration of 5.6 ±4.47 days (Table). Mean overall hospitalization costs for inpatients were $40,054 per patient, which included $36,351 for inpatient stays and $3,703 for ICU, and $7,477 per patient for outpatients, which are only for inpatient stays as there were no ICU stays.
 
Conclusions: In the ELARA trial, hospitalization and ICU patterns varied substantially between inpatient and outpatient settings and favored HCRU in the outpatient setting. Among patients treated in the outpatient setting, one third of patients did not require hospitalization during the post-infusion period; those who did had a lower average length of stay than the patients infused in an inpatient setting. The mean hospitalization costs in the post-infusion period were substantially lower in the outpatient versus inpatient setting due to the lack of ICU admissions. These data suggest that tisagenlecleucel can be safely administered in the outpatient setting, which may reduce HCRU for patients with r/r FL.

ABSTRACT 1360 – December 11th, 2021 5:30 - 7:30 pm EST 

Dong Dai, Ji Haeng Heo, Andrew Rava, Etienne Jousseaume, Roberto Ramos, MD and Vamsi Bollu

 

Objective: To determine treatment regimens used in clinical practice and the associated clinical outcomes among third line (3L) follicular lymphoma (FL) patients in the United States (US).
 
Methods: This non-interventional, retrospective study used Optum electronic health records (EHR) database for FL patients in the US between 1 Jan 2007 and 31 Dec 2020. The start of this period was selected to align with the Morrison et al. 2019, with 5 years of additional data. The identification period was 1 Jan 2008 to 31 Dec 2019, to ensure at least 1 year of baseline before and 60 days of follow-up (unless death happens before) after the index date, defined as start date of 3L treatment. Adult patients (≥18 years) treated in integrated delivery networks with at least one of the 3L treatments of interest (rituximab, bendamustine and rituximab, phosphatidylinositol 3-kinase [PI3K] inhibitors [copanlisib, duvelisib, idelalisib], lenalidomide and rituximab[R2], tazemetostat, and stem cell transplant) were included. Patients with Diffuse Large B-cell Lymphoma (DLBCL) diagnosis or clinical trial enrollment on or before the index date or any other cancer diagnosis before the first FL diagnosis were excluded. All agents initiated within 90 days after the index diagnosis constituted the 1L treatment. A subsequent line of therapy (LOT) was defined as treatment initiated after ≥180 days following the runout date of all agents, or addition or substitution of a new agent in the prior LOT after 90 days. The primary endpoints were time to progression (DLBCL transformation, new LOT initiation, or supportive care), overall survival (OS) and progression-free survival (PFS), while time to next treatment (TTNT) and treatment patterns were the key secondary endpoints. The analyses were conducted for the overall cohort, patients with early progression within 24 months (POD24) after 1L treatment, patients with index date after and including year 2014, as well as for different 3L treatment regimens. The sub-group with 2014 as index date was selected based on idelalisib approval in 2014.
 
Results: The final cohort of patients (used one of the 3L treatments of interest and met inclusion/exclusion criteria) consisted of 687 patients: mean age 62.9 years (range 18 – 86), female (46.9%), Caucasians (87.3%), non-Hispanics (92.1%), and median Charlson Comorbidity Index (CCI) 3 (range 1 – 18). Rituximab-based regimens (73.7%) were the most common 3L treatments (mono 38.4%, combo 35.2%). Obinutuzumab was used as combination 3Ltherapy by 6 (0.87%) patients. Bendamustine, PI3K and lenalidomide monotherapies were administered to 3.1%, 2.2% and 1.9% patients, respectively(Figure 1). Rituximab-based regimens were also the most frequently used 1L, 2L, and 4L treatment options (50.8% moved to 4L and 33.6% had rituximab-based regimens).
The median time to progression, PFS, and TTNT for 3L in the overall cohort were 16.6 (95% CI 14.4, 18.1), 12.5 (95% CI 11.3, 14.4), and 18 (95% CI 15.8, 19.9) months, respectively. The 1-, 2-and 5-year OS were 83.1%, 74.8% and 61.4%, respectively. The outcomes of 3L among POD24 , non-POD24, as well as patients with index date after and including year 2014 were similar to that of the overall cohort. The median time to progression, PFS, and TTNT with rituximab treatment were 19.1 (95% CI 16.7, 21.7), 15.7 (95% CI 14.2, 17.5), and 18.8 (95% CI 17, 21.7) months respectively. The median OS with rituximab therapy was not reached while the 5-year OS was 67% (Table 1). 
Moreover, we did not observe statistically significant differences in time to progression, OS, PFS, and TTNT for the 3L treatment between POD24 and non- POD24 patients using a Cox regression model with adjustment for baseline characteristics (age, gender, region, and CCI). The median time to progression, PFS, and TTNT among POD24 vs. non-POD24 were 15.7 vs. 17.9, 11.6 vs. 15.2, and 18 vs. 17.9 months, respectively. 
 
Conclusion: Rituximab-based regimens were the most common 3L treatment options for FL patients. Bendamustine, PI3K, and lenalidomide monotherapies were used by a smaller proportion of patients. R2 was used by a small number of patients for 3L treatment, but it is becoming an important option for FL treatment since its approval in 2019. The majority of outcomes observed could be considered poor, newer agents undergoing clinical trials could provide additional treatment choices to physicians to balance treatment effectiveness with safety and patients’ quality of life.

ABSTRACT 2419 – December 12th, 2021 6:00 - 8:00 pm EST 

Yanni Hao, Wei-Chun Hsu, Craig S Parzynski, C Lobetti Bodoni, Evgeny Degtyarev, Lisa Hampson, Aisha Masood, and Wen-Hsing Wu

 

Introduction: In the single-arm phase 2 ELARA trial (NCT03568461), tisagenlecleucel demonstrated efficacy and favorable safety profile in patients with relapsed/refractory (r/r) follicular lymphoma (FL) after ≥ 2 lines of prior therapy, including in high-risk sub-populations (Schuster, et al. ASCO 2021). To contextualize these results, we performed a retrospective non-interventional study to compare the efficacy of tisagenlecleucel seen in the single-arm ELARA trial with the standard-of-care (SoC) using individual patient-level data from the US Flatiron Health Research Database (FHRD). FHRD is a database derived from electronic health records from over 280 cancer clinics. The objective was to assess the effect of prescribing tisagenlecleucel vs SoC inpatients who participated in ELARA.
 
Methods: Individual patient-level data from FHRD were used to create an external control arm to carry out an indirect comparison with the ELARA trial. Eligible inclusion and exclusion criteria from ELARA were applied to the external control arm. A single eligible line was selected using propensity scores when patients were qualified at multiple lines.
Key prognostic factors including age, race, gender, number of prior treatment lines, group stage at initial FL diagnosis, number of months between initial FL diagnosis and indication of index treatment, double refractoriness, and disease progression within 24 months were included in a propensity score model to reduce confounding due to systematic differences in ELARA patients from FHRD patients at baseline for the selected line. Weighting by odds of receiving tisagenlecleucel was used to estimate the average treatment effect on progression-free survival (PFS), overall survival (OS), time to next treatment (TTNT), overall response rate (ORR), and complete response rate (CRR).
The rates and difference in rates were calculated for CRR and ORR. Kaplan-Meier (KM) analysis and Cox proportional hazards model were used to analyze all time-to-event endpoints. 95% confidence interval (CI) was calculated using bootstrapping. Data from the first 24 months after enrollment in ELARA or after treatment in FHRD were used for the follow-up period in the time to event endpoints, as few patients in ELARA trial had > 24 month data (Figure).Results were reported based on the post-weighting sample by incorporating a weight factor in the above analyses. A series of sensitivity analyses were conducted to assess the robustness of the primary analysis.
 
Results: As of Mar 29, 2021, 98 patients were enrolled in the ELARA trial, of which 97 were included in this indirect comparison (median follow-up, 15 months). In the FHRD cohort (data cut-off, Jun 30, 2020), 98 patients with ≥ 3 treatment lines who met the ELARA eligibility were included (median follow-up, 14 months in the post-weighted sample) (Table 1).
In the ELARA vs FHRD cohorts, after applying weighting by odds, the ORR was 85.6% vs 58.1%, and the CRR was 69.1% vs 17.7%. The difference in CRR (51.4%; 95% CI: 21.2, 68.8) was clinically meaningful (Table 2).
The median TTNT or death was not reached in the ELARA cohort and was 19.0 months in the FHRD cohort after weighting (HR = 0.34 [95% CI: 0.15,0.78]) (Table 2).
The median OS was not reached for both ELARA and FHRD cohorts in the first 24-month period. KM estimate of OS at 12 months was 96.6% in the ELARA cohort and 84.5% in the FHRD cohort, post weighting. The estimated 59% risk reduction was in favor of tisagenlecleucel over SoC (hazard ratio [HR] =0.41 [95% CI: 0.11, 1.47]) (Table 2).
The median PFS was not reached in the ELARA cohort and was 9.9 months in the FHRD cohort, after weighting. In the ELARA vs FHRD cohorts, the 12-month PFS was 73.2% vs 41.8%, with a HR of 0.45 indicating a 55% reduction in the risk of progression and death with tisagenlecleucel vs SoC. The median PFS considering new anti-cancer therapy as an event was not reached for ELARA and was 9.9 months for FHRD; the estimated probability of being progression-free at 12 months was 70.5% in the ELARA cohort and 39.4% in the FHRD cohort (Table 2). Sensitivity analyses results were consistent with that of primary analysis.
 
Conclusion: In the weighted analyses with adjustment for baseline prognostic factors, there was a consistent trend towards greater CRR, TTNT, OS and PFS in favor of tisagenlecleucel vs SoC in patients with r/r FL. These results support the clinically meaningful treatment benefit of tisagenlecleucel observed in the ELARA trial.

ABSTRACT 1349 – December 11th, 2021 5:30 - 7:30 pm EST

Gilles Salles, Stephen J. Schuster, Luca Fischer, John Kuruvilla, Piers EM Patten, Bastian vonTresckow, Sonali M. Smith, Ana Isabel Jiminez Ubieto, Keith L. Davis, Saurabh P Nagar, Jie Zhang, Vamsi Bollu, Etienne Jousseaume, Roberto Ramos, Yucai Wang, and Brian K. Link

 

Background: Novel therapies for multiply relapsed follicular lymphoma (FL) are often evaluated in single arm trials with no comparative data on patients receiving usual care. This study (ReCORD-FL) therefore sought to construct a historical control cohort to augment current and future single arm trials in relapsed/refractory (r/r) FL. The analytic aims were to document patient characteristics, treatment patterns and clinical outcomes in a r/r FL population treated with standard therapies in routine practice.
 
Methods: This was a retrospective cohort study via medical record review in 10 oncology centers across North America and Europe. Adult patients were required to meet several criteria defining multiply r/r FL (i.e., r/r after ≥2 lines of therapy, or relapsed during or within 6 months after completion of anti-CD20 antibody maintenance or relapsed after autologous HSCT). Patients were also required to have ≥ 1 line of systemic therapy (ie first qualifying salvage therapy) after first meeting the r/r FL criteria; the date of first qualifying salvage therapy defined the study index date. At index, patients were required to have grade 1-3A FL, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and no evidence of prior histological transformation. Outcomes were observed from the index date and from the start of each therapy line until the earliest of death, last follow-up, or December 31, 2020 (data cutoff). Endpoints were complete response (CR) rate, overall response rate (ORR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). In a subgroup analysis, endpoints were examined by double refractoriness (r/r to both an anti-CD20 mAb and an alkylator) and POD24 status at index (best response of stable/progressive disease or relapsed within 24 months of front-line anti-CD20 mAb-containing therapy). Time to event outcomes were analyzed using the Kaplan-Meier method.
 
Results: A total of 187 patients were identified for inclusion (Table 1). Most patients’ (80.2%) first qualifying salvage (index) therapy occurred in third line(3L) (range: 3L – 6L). Anti-CD20 mAb plus chemotherapy (including alkylating and/or non-alkylating agents) was the most common index regimen (64.2%of patients); 8% received anti-CD20 mAb monotherapy, 11.2% received alkylator-based chemotherapy alone (i.e., an alkylator-containing regimen withoutanti-CD20 mAb), and 16.6% received other therapies (i.e., other regimens containing neither anti-CD20 mAb nor alkylator). Median follow-up from FL diagnosis was 9 years (range: 1 – 21 years), over which a median of 5 (range: 3 – 11) lines of therapy were observed per patient. CR rate and ORR to the index treatment were 39.0% and 70.6%, respectively (Table 2). Median (95% confidence interval [CI]) TTNT and PFS from index were 14.4 (11.8 – 18.6) and 14.6 (11.0 – 18.0) months, respectively; median OS from index was 128 months (10.6 years). Compared with non-double refractory, those with double refractory disease at index had numerically lower CR (34.3% vs. 45.1%) and ORR (67.6% vs. 74.4%) and substantially shorter median (95% CI) TTNT (11.8[9.0 – 15.2] vs. 20.9 [14.4 – 26.2] months), PFS (10.7 [7.7 – 14.5] vs. 20.1 [14.4 – 25.4] months), and OS (78.1 [45.8 – 146.7] vs. [Not Reached] months).Outcomes were similarly less favorable for patients who were POD24 at index. All outcomes steadily worsened across successive treatment lines (Table 2,Figures 1a-c). ORR, for example, decreased from 69.5% in 3L (n = 187) to 45.8% in 5L (n = 96) and 41.2% in ≥8L (n = 51), while median (95% CI) PFS decreased from 11.8 (10.1 – 16.6) months in 3L to 9.4 (6.8 – 13.1) months in 5L and 4.4 (1.7 – 5.9) months in ≥8L; median (95% CI) OS had a similar trend: 133.7 (78.1 – 232.4), 46.3 (31.7 – 76.5), and 11.4 (5.9 – 21.2) months in 3L, 5L, and ≥8L, respectively.
 
Conclusions: Our findings further demonstrate the poor outcomes and limited survival in FL patients with multiply r/r, double refractory, or POD24disease. In assessing response rates and PFS, it is important to consider that response assessment criteria and schedules were more heterogenous in the routine practice settings of ReCORD-FL than in clinical trials. Based on comparability of results with another similar study (SCHOLAR-5), the robustness of data collected, and continued low likelihood of randomized trials in this area, ReCORD-FL provides valuable historical control data for new r/r FL therapies in development.

ABSTRACT 3528 – December 13th, 2021 6:00 - 8:00 pm EST 

Gilles Salles, Stephen J. Schuster, Martin H. Dreyling, Luca Fischer, John Kuruvilla, Piers EM Patten, Bastian Von Tresckow, Sonali M. Smith, Ana Isabel Jiminez Ubieto, Keith L. Davis, Carla Anjos, Jufen Chu, Jie Zhang, C Lobetti Bodoni, Catherine Thieblemont, Nathan H. Fowler, Michael Dickinson, Joaquin Martinez-Lopez, Yucai Wang, and Brian K. Link

 

Background: In the ELARA (E2202) trial (NCT03568461), tisagenlecleucel (tisa-cel) demonstrated high response rates in patients with relapsed/refractory follicular lymphoma (r/r FL), including those with high-risk disease, with an overall response rate (ORR) of 86% and complete response rate (CRR) of 66%.As ELARA did not include a comparator arm, an adjusted indirect treatment comparison (ITC) using patient-level data from a global retrospective cohort study was conducted. This study aimed to provide comparative, contextual evidence to the efficacy outcomes of tisa-cel from ELARA relative to standard of care (SoC) in routine practice.
 
Methods: ELARA is an ongoing, single-arm, global, multicenter, phase II trial which evaluates the efficacy and safety of tisa-cel in adult patients with r/r FL. As of March 29, 2021, 98 patients were enrolled with a median follow-up of 15 months. SOC data were obtained from ReCORD-FL, a global retrospective cohort study of clinical outcomes in patients with r/r FL meeting the ELARA eligibility criteria who were treated per routine practice at 10 academic centers across North America and Europe; 7 ReCORD-FL sites are also participating in ELARA, but no patients are enrolled in both studies. In ReCORD-FL, with a data cutoff date of December 31, 2020, a total of 187 patients with ≥2 lines of previous treatment were identified for inclusion, with a median follow-up from third-line of 57 months. A complete-case comparison analysis was performed for 97 ELARA apheresed patients and 143ReCORD-FL patients with complete data on all baseline variables and prognostic factors used for adjustment. For the comparative analysis, one line of therapy (LoT) per patient was selected using a propensity score model to identify the LoT which had the highest chance of being enrolled in ELARA conditional on baseline characteristics and prognostic factors available at the start of the LoT (i.e., the selected LoT was the one with the highest propensity score to be in ELARA). After selection of LoT, an adjusted ITC was performed to assess the effect of tisa-cel versus SOC by measuring CRR,ORR, progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT). A subgroup analysis of SOC patients with ≥1 eligible LoT initiated from 2014 on (coinciding with the introduction of the Lugano response criteria as well as regulatory approval of idelalisib) was performed for all endpoints.
 
Results: Baseline characteristics for the tisa-cel and SOC cohorts are described in Table 1; after weighting, baseline variables, including number of previous lines of systemic therapy (median: 4 lines) were well balanced between the tisa-cel and SOC cohorts. Treatment regimens observed for ReCORD-FL patients at LoT selection were: anti-CD20 antibody plus alkylator (31.5% of patients), anti-CD20 antibody without alkylator (25.9%), alkylator without anti-CD20 antibody (17.5%), and regimens other than anti-CD20 antibody and alkylator (25.2%). After LoT selection and adjusting for differences in baseline variables, tisa-cel was associated with improvement over SOC in CRR (69.1% vs. 37.3%), ORR (85.6% vs. 63.6%), as well as PFS, TTNT and OS(Table 2, Figures 1-2), with a numerically higher 6-month PFS rate vs. SOC (85.3% vs. 66.5%), as well as higher 24-month OS rate (87.8% vs. 64.8%).Further, there was an estimated 80% reduction in death risk in favor of tisa-cel over SOC, a 40% reduction in risk of progression in favor of tisa-cel over SOC and a 69% reduction in risk of death or requiring a new anticancer therapy (Table 1). In the sub-analysis of SOC patients with lines of therapy initiated in or after 2014, the superiority of tisa-cel over SOC was confirmed in all the efficacy outcomes (CRR: 69.1% vs. 30.5%; ORR: 85.6% vs. 58.8%; hazard ratios substantially < 1 for OS, PFS, TTNT).
 
Conclusion: The ITC results suggest that tisa-cel has superior efficacy over SOC in r/r FL for all evaluated endpoints. A key limitation of this study is that response assessment criteria and schedule was more heterogeneous in ReCORD-FL than in ELARA. However, the sub-analysis on SOC patients assessed with a LoT selected in 2014 or later (when more patients could have been assessed using the Lugano response criteria) showed similar favorability for tisa-cel over SOC in all the efficacy outcomes. Moreover, outcome parameters independent of response criteria, namely OS and TTNT, were also significantly better for tisa-cel vs. SOC.


CAR-T Pipeline

ABSTRACT 2848 – December 12th, 2021 6:00 - 8:00 pm EST 

Boris Engels, Xu Zhu, Jennifer Yang, Andrew Price , Akash Sohoni , Andrew M Stein, Lana Parent , Michael Greene,, Matthew Niederst, Jeanne Whalen , Elena J Orlando, Louise M Treanor, and Jennifer L Brogdon

 

Background: Extended T-cell culture periods in vitro deplete the CAR-T final product of naive and stem cell memory T-cell (Tscm) subpopulations that are associated with improved antitumor efficacy. YTB323 is an autologous CD19-directed CAR-T cell therapy with dramatically simplified manufacturing, which eliminates complexities such as long culture periods. This improved T-ChargeTM process preserves T-cell stemness, an important characteristic closely tied to therapeutic potential, which leads to enhanced expansion ability and greater antitumor activity of CAR-T cells.  
 
Methods: The new T-ChargeTM manufacturing platform, which reduces ex vivo culture time to about 24 hours and takes <2 days to manufacture the final product, was evaluated in a preclinical setting. T cells were enriched from healthy donor leukapheresis, followed by activation and transduction with a lentiviral vector encoding for the same CAR used for tisagenlecleucel. After ≈24 hours of culture, cells were harvested, washed, and formulated (YTB323). In parallel, CAR-T cells (CTL*019) were generated using a traditional ex vivo expansion CAR-T manufacturing protocol (TM process) from the same healthy donor T cells and identical lentiviral vector. Post manufacturing, CAR-T products were assessed in T-cell functional assays in vitro and in vivo, in immunodeficient NSG mice (NOD-scid IL2Rg-null) inoculated with a pre–B-ALL cell line (NALM6) or a DLBCL cell line (TMD-8) to evaluate antitumor activity and CAR-T expansion. Initial data from the dose escalation portion of the Phase 1 study will be reported separately. 
 
Results: YTB323 CAR-T products, generated via this novel expansionless manufacturing process, retained the immunophenotype of the input leukapheresis; specifically, naive/Tscm cells (CD45RO/CCR7+) were retained as shown by flow cytometry. In contrast, the TM process with ex vivo expansion generated a final product consisting mainly of central memory T cells (Tcm) (CD45RO+/CCR7+) (Fig A). Further evidence to support the preservation of the initial phenotype is illustrated by bulk and single-cell RNA sequencing experiments, comparing leukapheresis and final products from CAR-Ts generated using the T-Charge™ and TM protocols. YTB323 CAR-T cell potency was assessed in vitro using a cytokine secretion assay and a tumor repeat stimulation assay, designed to test the persistence and exhaustion of the cell product. YTB323 T cells exhibited 10- to 17-fold higher levels of IL-2 and IFN-γ secretion upon CD19-specific activation compared with CTL*019. Moreover, YTB323 cells were able to control the tumor at a 30-fold lower Effector: Tumor cell ratio and for a minimum of 7 more stimulations in the repeat stimulation assay. Both assays clearly demonstrated enhanced potency of the YTB323 CAR-T cells in vitro. The ultimate preclinical assessment of the YTB323 cell potency was through comparison with CTL*019 regarding in vivo expansion and antitumor efficacy against B-cell tumors in immunodeficient NSG mouse models at multiple doses. Expansion of CD3+/CAR+ T-cells in blood was analyzed weekly by flow cytometry for up to 4 weeks post infusion. Dose-dependent expansion (Cmax and AUC0-21d) was observed for both YTB323 and CTL*019. Cmax was ≈40-times higher and AUC0-21d was ≈33-times higher for YTB323 compared with CTL*019 across multiple doses Delayed peak expansion (Tmax) of YTB323 by at least 1 week compared with CTL*019 was observed supporting that increased expansion was driven by the less differentiated T-cell phenotype of YTB323. YTB323 controlled NALM6 B-ALL tumor growth at a lower dose of 0.1×106 CAR+ cells compared to 0.5×106 CAR+ cells required for CTL*019 (Fig B). In the DLBCL model TMD-8, only YTB323 was able to control the tumors while CTL*019 led to tumor progression at the respective dose groups. This ability of YTB323 cells to control the tumor at lower doses confirms their robustness and potency. 
 
Conclusions: The novel manufacturing platform T-Charge™ used for YTB323 is simplified, shortened, and expansionless. It thereby preserves T-cell stemness, associated with improved in vivo CAR-T expansion and antitumor efficacy. Compared to approved CAR-T therapies, YTB323 has the potential to achieve higher clinical efficacy at its respective lower doses. T-Charge™ is aiming to substantially revolutionize CAR-T manufacturing, with concomitant higher likelihood of long-term deep responses.

ABSTRACT 740 – December 12th, 2021 6:00 - 8:00 pm EST 

Ian W. Flinn, Ulrich Jaeger, Nirav N. Shah, Didier Blaise, Javier Briones, Leyla Shune, Nicolas Boissel, Attilio Bondanza, Darlene Lu, Xu Zhu, Boris Engels, Jennifer L Brogdon, Jennifer Mataraza, Jaclyn Davis, Anne Laure Marchal, Luisa Mariconti, Michele Moschetta, Laure Moutouh-de Parseval, Pere Barba, and Michael Dickinson

 

Background: Despite unprecedented efficacy of existing CAR-T cell therapy, many pts fail to respond to the therapy, or relapse after initial response. YTB323 is an autologous CD19-directed CAR-T cell therapy utilizing the FMC63 domain for CD19 recognition and 4-1BB costimulatory domain. YTB323 is manufactured with an innovative simplified process, called T-Charge, which reduces the ex vivo culture time to about 24 hours and takes <2 d to manufacture the final product. The T-Charge platform preserves naive and stem cell memory T (T) cells in the final product (preclinical data will be reported separately), which is expected to result in longer CAR-T cell persistence, and in turn higher response rates and longer durability of response.
 
Methods: This Phase I, multicenter, dose-escalation study (NCT03960840) is evaluating safety and preliminary efficacy of YTB323 in pts with B-cell malignancies. Results presented here focus on the DLBCL cohort. Eligible pts are adults with measurable disease at enrollment, ECOG 0-1, and r/r DLBCL after ≥2 lines of prior therapies, including autologous hematopoietic stem cell transplantation (aHSCT). Pts received single-dose YTB323 at dose level 1 (DL1; 1-2.5×106 CAR+ cells), DL2 (5-12.5×106 CAR+ cells), or DL3 (25-40×106 CAR+ cells). Bridging therapy prior to YTB323 was optional. Primary endpoints are rate of dose-limiting toxicities (DLTs) in the first 28 d and safety to determine a recommended Phase II dose (RP2D). Secondary endpoints are cellular kinetics, overall response rate (ORR) by local investigator assessment, duration of response, and overall survival.
 
Results: As of April 16, 2021, 15 pts with r/r DLBCL were infused with YTB323: 4 at DL1, 10 at DL2, and 1 at DL3 (Fig, n=14 for DL1 and DL2). Median age was 65 years; most (60%) received 2 prior lines of therapy and 4 (27%) had prior aHSCT. All adverse events were reported regardless of study drug relationship. Of the 15 pts evaluable for safety, 4 pts (27%) reported at least one Grade (Gr) 3 AE, 6 (40%) at least one Gr 4 AE, and 2 (13%) at least one Gr 5 AE. Most commonly reported Gr 3/4 AEs were thrombocytopenia (n=2, 13%), neutropenia (n=3, 20%), and decreased neutrophil count (n=3, 20%). Seven pts (47%) had neurological AEs, of which 2 events (13%) were considered serious—1 event each of Gr 3 peripheral neuropathy (unrelated) and Gr 2 seizure (immune effector cell-associated neurotoxicity syndrome Grade 3, related to treatment). Four pts (27%) experienced cytokine release syndrome (CRS), including 3 (20%) Gr 1/2 and 1 (7%) Gr 4 (Lee et al, 2014), which met DLT criteria. Tocilizumab and corticosteroids were administered for CRS management in 2 (13%) and 1 (7%) pts, respectively. There have been 4 deaths on trial, all unrelated to YTB323: 2 due to disease progression and 2 to sepsis (1 at DL1 and 1 at DL3). Median time to onset of CRS was 9 d (range, 9-9 d) for DL1 and 11 d (range, 8-17 d) for DL2. Preliminary dose-dependent response was observed. At DL1, 4 pts were evaluable for efficacy at Mo 3 and the ORR and CR rates were both 25% (95% CI, 0.6%-80.6%). At DL2, 8 pts were evaluable for efficacy at Mo 3, including 2 pts in CR prior to YTB323 infusion; ORR and CR rates were both 75% (95% CI, 34.9%-96.8%). Dose-dependent expansion (Cmax and AUC0-28d) was observed following infusion with mean peak expansion (Cmax) at DL2 of 13.6% CAR+ in CD3+ cells or 32,100 copies/μg DNA. Although long-term persistence cannot be evaluated yet, of the 8 pts at DL2 with 3-mo follow-up, 3 had detectable CAR expression by flow cytometry (≥1%). Time of peak expansion (Tscm) coincided with peak cytokine levels (~16 d post infusion). The novel manufacturing methodology of YTB323 allowed preservation of CD4 and CD8 naive/T cells in the final product as ascertained by flow cytometry. Bulk and single-cell RNAseq analysis demonstrated that YTB323 retained a naive stem-like phenotype. 
 
Conclusions: YTB323 recruitment is ongoing at DL3; RP2D remains to be identified. At DL2, YTB323 showed promising efficacy and a favorable safety profile. Current data support continued development of YTB323 in r/r DLBCL pts.

ABSTRACT 2770 – December 12th, 2021 6:00 - 8:00 pm EST 

Dexiu Bu, Paul Bennett, Nathaniel Barton, Laura Bradshaw, Maria Pinon-Ortiz, Xiangen Li, Poonam Vaidya, Xu Zhu, Keith Mansfield, Brian Granda, Carla P Guimaraes, Louise M Treanor, and Jennifer L Brogdon

 

Background: Chimeric antigen receptor T cell (CAR-T) therapies for multiple myeloma (MM) targeting B cell maturation antigen (BCMA) have demonstrated promising efficacy; however, many patients with relapsed/refractory (r/r) MM will ultimately relapse. To improve on existing BCMA CAR-Ts, two critical attributes of the CAR-T product were investigated: 1) the potency of the BCMA CAR construct, and 2) a rapid manufacturing process that would both preserve the stemness of T cells to ensure longer duration of response and provide timely access for patients with rapidly progressing, aggressive disease. Through extensive panning and discriminating CAR-T functional assays to assess performance, we have identified a superior anti-BCMA CAR construct that when combined with an innovative T-Charge™ manufacturing platform, produces a highly potent product.
 
Methods and Results: We have developed a novel anti-BCMA CAR-T product for the treatment of MM. Our anti-BCMA CAR consists of an extracellular single chain variable fragment (scFv) targeting BCMA, fused to the CD8α hinge and transmembrane domains, followed by CD137 (4-1BB) co-stimulatory and CD3ζ chain signaling domains. Selection of our development candidate was based on a screening of seventeen anti-BCMA CARs, each comprising a distinct scFv derived from phage display libraries and hybridoma with a wide range of affinities and epitopes. One candidate clone from the fully human B cell library was identified after rigorous assessment of transduction efficiency, CAR expression, antigen specificity/selectivity and CAR-T cell function against a MM cell line, both in vitro and in vivo. This scFv also demonstrates high specificity to human BCMA by Retrogenix platform using a commercial human plasma membrane protein array assay. CAR expression and functionality of the CAR constructs were compared in the CAR-T cells generated with two different cell processes: a traditional manufacturing (TM) in which CAR-T cells are expanded in vitro for 9–10 days and a novel T-Charge process, which is an expansion less CAR-T manufacturing process that takes <2 days to generate functional CAR-Ts.
PHE885 generated with the novel T-Charge manufacturing platform, retains naïve/ stem cell memory T cell (T) (CD45RO/CCR7) while the traditionally manufactured cell product carrying the same scFv (TM_PHE885) mainly contains central-memory T cells (CD45RO/CCR7). In addition to its unique phenotype, PHE885 secretes up to 25 fold more target specific IL-2 and ~7 fold more IFN gamma in vitro, when comparing to the TM products either using the same lentiviral vector (TM_PHE885) or a clinically validated anti-BCMA vector (MCM998). In an immunodeficient NOD-scid IL2R gammanull (NSG) mouse model of MM, PHE885 induced tumor regression at a very low dose in a dose-dependent manner, and was up to 5 fold more efficacious in eradicating tumors compared to the two TM products. This enhanced efficacy was accompanied by higher cellular expansion in vivo (up to 3 fold higher Cmax and AUC0-21d). The ability of PHE885 to control the tumor at lower doses with a greater expansion profile confirms the robustness and potency of the PHE885 cells. Furthermore, unlike the TM products, PHE885 induced earlier graft-versus-host disease at medium and high tested doses in this mouse model suggesting the stemness of the product is most likely the driver of stronger T cell expansion.
 
Conclusions: PHE885 was discovered and designed to enhance potency and drive persistence of CAR-T through the combination of a novel CAR construct carrying a fully human anti-BCMA scFv fused with 4-1BB/CD3ζ signaling domains and a novel T-Charge manufacturing platform, which enables rapid and reliable patient access. The novel T-Charge platform allows PHE885 to preserve a significantly higher proportion of naïve/ T cells, enabling PHE885 to effectively engraft, expand and reject tumors at a dose of 5 fold lower than TM CAR-T cells. Based on these results, a Phase 1, open-label trial assessing PHE885 in patients with r/r MM (NCT04318327) was initiated. Initial data from the dose escalation portion of the Phase 1 study will be presented separately.

ABSTRACT 3864 – December 13th, 2021 6:00 - 8:00 pm EST 

Adam S. Sperling, Sarah Nikiforow, Omar Nadeem, Clifton C Mo, Jacob P. Laubach, Kenneth C. Anderson, Alejandro Alonso, Shuntaro Ikegawa, Rao Prabhala, Diego Hernandez Rodriguez, Heather Daley, Kit L. Shaw, Yohei Arihara, Soudeh Ansari, David S Quinn, David Pearson, Anniesha Hack, Louise M Treanor, Dexiu Bu, Jennifer Mataraza, Lawrence Rispoli, Marc Credi, Jerome Ritz, Serena De Vita, and Nikhil C. Munshi

 

Background: Chimeric antigen receptor (CAR)-T cells are highly effective in patients (pts) with multiple myeloma (MM), but duration of response can be limited, and pts with rapidly progressing disease require a fast and reliable CAR-T cell manufacturing process. Here, we report initial clinical data from a Phase I trial assessing PHE885 manufactured using the T-ChargeTM process and characterization of in vivo expansion, suggesting a preserved T-cell stemness (Tscm) phenotype in pts with relapsed/refractory (r/r) MM (NCT04318327).
 
Methods: PHE885 is a unique and fully human BCMA CAR-T cell product manufactured using the novel T-ChargeTM platform, which reduces ex vivo culture time to about 24 hours and takes <2 days to manufacture the final product, thereby relying entirely on in vivo expansion after CAR-T cell infusion. Pts with MM r/r to ≥2 prior lines of treatment (tx), including an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody, were eligible. Pts received fludarabine and cyclophosphamide for lymphodepletion prior to a single PHE885 intravenous injection. Primary objectives were safety, including dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary objectives were clinical responses, evaluation of theT-Charge process, and pharmacokinetic properties.
 
Results: As of data cut (April 1, 2021), 7 pts were enrolled in the dose escalation portion; 1 pt failed screening (prolonged QTc), and 6 pts were successfully infused with PHE885. All pts were heavily pretreated, penta-refractory, and refractory to the last line of tx. Fixed doses received were 5×106 (n=5) and 14.3×106 CAR+ T cells (n=1). All 6 pts were eligible for safety and efficacy. Two DLTs were reported: asymptomatic grade 3 transaminitis in the pt infused with 14.3×106 CAR+ T cells, and asymptomatic grade 4 lipase increased in 1 pt infused with 5×106 CAR+ T cells. Treatment-related grade ≥3 AEs included anemia and neutropenia in all pts; thrombocytopenia (n=4, 67%); and leukopenia, cytokine release syndrome (CRS), ALT and AST increase, and decreased blood fibrinogen (each n=2, 33%). All pts experienced grade ≤3 CRS per Lee 2014 criteria; median times to CRS onset and resolution were 7 d (range, 4-9 d) and 22 d (range, 10-27 d), respectively. All pts received at least 1 dose each of steroids and tocilizumab; 3 pts received anakinra to manage CRS. Two pts experienced grade 2 neurotoxicity related to PHE885. Both events were nonserious and temporally associated with grade 3 CRS. No deaths occurred on study. At 1 mo after tx, all pts had achieved at least a partial response (PR), with complete response (CR) in 1 pt (17%) and very good PR in 2 pts (33%). Of 4 pts evaluable at 3 mo after tx, 2 had stringent CR, 1 had PR and 1 pt in PR experienced progressive disease presumed to be due to loss of BCMA. Of 3 pts evaluable for minimal residual disease (MRD) at 1 mo after tx, all were MRD negative: 2 at sensitivity of 10-6 and 1 at 10-5.
Robust cellular expansion was observed in all pts via qPCR and flow cytometry; maximum expansion (geometric mean Cmax) was 283000 copies/μg by qPCR and 69.3% of circulating T cells by flow cytometry. Maximum expansion was reached by 30 d, with median Tmax of 21.1 d by qPCR (16.4 d by flowcytometry). PHE885 was detectable in peripheral blood up to the latest measured sample for each pt (6 mo for the longest followed pt; range of follow-up, 1-6 mo). A naïve-like T-cell phenotype (Tnaive +Tscm) was preserved during manufacturing of all PHE885 products.
 
Conclusions: Initial data from this Phase I study demonstrate that low doses of BCMA CAR-T cells manufactured by T-Charge in <2 days have encouraging clinical activity and a manageable safety profile in pts with r/r MM. PHE885 CAR-T cells expand rapidly in vivo, persist at relatively high levels for prolonged periods, and demonstrate a relatively immature T-cell phenotype. The trial is ongoing and updated data will be presented at the annual meeting.


CAR-T Manufacturing

ABSTRACT 1768 – December 11th, 2021 5:30 - 7:30 pm EST 

Margarida Rodrigues, Emmanuel Duran, Bernd Eschgfaeller, David Kuzan, and Karen Habucky

 

Background: Tisagenlecleucel (Kymriah) is an autologous CD19-directed CAR-T-cell therapy, approved in Aug-2017 for treating children and young adults with relapsed/refractory (r/r) acute lymphoblastic leukemia and in May-2018 for treating adults with r/r diffuse large B-cell lymphoma. Post-approval, a key goal has been to upscale and continuously improve manufacturing success and turnaround time in the commercial settings to meet the needs of a global patient population. Here we report accrued experience from our 4-year journey of optimizing the commercial tisagenlecleucel manufacturing process at the US site (Morris Plains, NJ), for faster and successful delivery to patients in the US. 
 
Methods: As reported previously, the tisagenlecleucel manufacturing process includes leukapheresis of the patient’s peripheral blood mononuclear cells, enrichment and activation of T cells, transduction of the lentiviral vector containing the anti-CD19 CAR transgene, activation with anti-CD3/CD28 antibody–coated beads, expansion in cell culture, washing, and formulation of the viable cells into a cryoformulation medium. The final product is then cryopreserved, shipped back to the treatment center and infused to patients (Tyagarajan, 2020). Use of cryopreserved leukapheresis material as the starting point in commercial manufacturing is unique to tisagenlecleucel; this allows flexibility in terms of scheduling leukapheresis when a patient’s health is optimal to provide T cells, and also helps offset logistical challenges (Tyagarajan, 2019). 
 
Results: As of Jun-2021, tisagenlecleucel has been manufactured for >5000 patients worldwide, enabled by Novartis’s significantly increased global manufacturing footprint at six sites strategically located across six countries (US, France, Switzerland, Germany, Japan and Australia) and a global treatment network of >340 certified centers, including 127 centers in the US. 
Specifically for the US manufacturing site, between Dec-2020 and Jun-2021, 376 patients in the US had starting material available for manufacturing. Overall, the manufactured product was available for shipment for 98% of patients (shipping success rate [SSR]). The commercial manufacturing success rate (MSR) was 96%, with an out-of-specification (OOS) rate of <3% and no OOS for viability. All ten OOS batches were released for infusion as benefit:risk assessment was positive. Manufacturing was cancelled for two patients upon physician’s request. 
Immediate manufacturing capability without waiting time was available on receipt of all apheresis starting materials. The median time from start of manufacturing to shipping was 20 days. As is evident, the COVID-19 pandemic did not appear to have significantly affected the success rate or manufacturing turnaround time. 
These latest success metrics, reflecting significant improvements from 2018 to 2021 in MSR (69% to 96%), SSR (93% to 98%), and overall OOS rate (26% to 2%) including viability OOS rate (from 25% to 0%), are a result of upscaling the manufacturing capabilities, enhancements with hospitals focusing on optimizing apheresis collection and cryopreservation procedures, and continuous evaluation and improvement of the manufacturing process since tisagenlecleucel was first launched (Figure). Two key process and analytical improvements that were considered to have improved robustness of manufacturing and testing processes, reduced OOS rates, and minimized variability in turnaround time were introduced towards the end of 2020. Firstly, a simplified sample preparation procedure for final product cell count and viability measurement, which is more reflective of final product at infusion. Secondly, an alternate serum source (5% plasma-derived human AB serum [PD hABs]) which further improves process robustness with a trend towards improved growth and higher peak cell counts. 
 
Conclusions: Tisagenlecleucel’s current global commercial manufacturing footprint and treatment network are well-positioned to meet anticipated future increase in demand for CAR-T therapies. Recent process improvements have significantly increased the MSR (to 96%) and SSR (to 98%), and immediate product availability for patients in need of CAR-T cells. Ongoing and upcoming process improvements are anticipated to further reduce the throughput time, thus allowing more patients faster access to CAR-T therapy.

ABSTRACT 3882 – December 11th, 2021 5:30 - 7:30 pm EST 

Jennifer Willert, David Fong, Lee Clough, Andrea Magley, Ali Shojaee, Ranjan Tiwari and Christopher Acker

 

Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy approved for patients (pts) ≤25 years of age with B-cell acute lymphoblastic leukemia (B-ALL) that is refractory or in second or later relapse. Pts <3 years of age were excluded from tisagenlecleucel clinical trials in relapsed/refractory (r/r) ALL (NCT02435849 [ELIANA]; NCT02228096 [ENSIGN]). We present leukapheresis and tisagenlecleucel manufacturing outcomes in pts <3 years old with r/r B-ALL in the US commercial setting since regulatory approval. 
 
Methods: Qualified pts were <3 years of age at time of request for commercial tisagenlecleucel, with manufacturing data after August 30, 2017 (date of first FDA approval of tisagenlecleucel). Only pts whose tisagenlecleucel was manufactured and administered in the US were included; tisagenlecleucel was manufactured at Morris Plains, NJ, USA. Pt leukapheresis and manufacturing outcome data are presented for all pts and stratified by weight (<10 kg and ≥10 kg) and age (<1 year old and 1-3 years old). These data provide an extended analysis (cut-off March 31, 2021) from the previous report (Eldjerou, 2019). 
 
Results: Among 65 pts, the median age was 15.6 months (range, 3.6-36); median body weight was 10.4 kg (range, 6-20) at leukapheresis; 105 leukaphereses were performed in 65 pts (49 <10 kg and 56 ≥10 kg). A median of 1 leukapheresis day was required to meet adequate cell counts (range, 1-4 <10 kg and 1-6 ≥10 kg). The median total blood volume reported in 53/65 pts was 3.5 L (range, 1.3-14.3). The acceptance criteria for tisagenlecleucel manufacture (total nucleated cells: ≥2.0 × 109, CD3+ count: ≥1.0 × 109, CD3%: ≥3%) were met in 59/66 (26 <10 kg and 33 ≥10 kg) leukapheresis materials; 7/66 did not meet acceptance criteria but proceeded to manufacturing. Following leukapheresis, median percent cell populations were: T cells 55.1% (58% <10 kg and 54.8% ≥10 kg), B-cells 16.9% (20.3% <10 kg and 14.6% ≥10 kg), natural killer cells 4% (3.8% <10 kg and 4.7% ≥10 kg), and monocytes 3.9% (2.6% <10 kg and 4.9% ≥10 kg). 
Manufacturing success is the formulation of a final product within approved specifications. Out of 66 manufacturing batches (23 batches <1 year old and 43 batches 1-3 years old; 29 batches <10 kg and 37 batches ≥10 kg), 55 (83.3%) were successful. Of the 59 manufacturing batches that met acceptance criteria, 50 were within specification, 2 were terminated, and 7 were out-of-specification due to cell viability (n=4), CAR+% expression (n=2), or another reason (n=1). One pt who experienced manufacturing failure was remanufactured successfully with a second attempt. Of the 7 batches that did not meet the acceptance criteria, 5 were within specifications and 2 were terminated. The median manufactured cell dose was 2.3x106 CAR+ viable T cells/kg [range, 0.23-4.6x106 (2.5x106 <10 kg and 2.1x106 ≥10 kg)], median percent cell viability was 90.6% [range, 66.7%-98.3% (91.9% <10 kg and 90% ≥10 kg)], median CAR+ percent expression was 12.0% [range, 2.1%-37.2% (12.2% <10 kg and 11.8% ≥10 kg)]. From 2017 to 2021, the frequency of CD3+ cells present in the leukapheresis material was greatest in 2021 (Figure, left panel). The percentage of in-specification products was 69%-83% in 2017 to 2019 and increased to 89% and 100% in 2020 and 2021, respectively. Additionally, the number of terminations decreased over time (Figure, right panel). 
Measures for successful leukapheresis in low-weight infant/toddler pts include verification of absolute lymphocyte and/or CD3+ counts on the day prior to the leukapheresis procedure, maintenance of hematocrit levels at 40%, adequate venous access, blood prime of the leukapheresis instrument, prevention of hypocalcemia, and consideration for allowing for >1 day of leukapheresis for the pt to meet the acceptance criteria when medically feasible/safe. During leukapheresis, hypothermia must be prevented, and the pt must be monitored for hypocalcemia, hypomagnesemia, and alkalosis. 
 
Conclusions: Leukapheresis and tisagenlecleucel manufacturability in pediatric pts with r/r B-ALL <3 years old and low weight (lowest 6 kg, youngest 3.6 months) continues to be feasible and leukapheresis and manufacturing outcomes show an improvement over time. Communication among cross-functional teams within and between the institution and manufacturer have been key for achieving these advancements. Clinical outcome data for these pts are currently being explored.

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