Imaging Biomarkers to Predict Outcomes in Patients with Large B-Cell Lymphoma with a Day 28 Partial Response By PET/CT Imaging Following CAR-T Therapy

Abstract Introduction: CD19 Chimeric Antigen Receptor T-cell (CAR-T) therapy is now a commonly used treatment for relapsed/refractory (R/R) Large B-cell Lymphoma (LBCL). However, predictors of long-term response remain poorly defined. In particular, partial response (PR) at first tumor assessment at Day 28 (D28) is a source of uncertainty both for clinicians and patients. In the pivotal CAR-T trials for LBCL, approximately half of these patients eventually achieved a complete remission (CR), while the other half experienced progressive disease (PD) (Neelapu et al, NEJM 2017). Herein, we present real-world data on 24 patients achieving a PR on D28 by PET/CT imaging following CAR-T therapy for R/R LBCL. We explore whether differences between baseline and D28 PET/CT imaging might predict progression free survival (PFS), overall survival (OS), best overall response rate (B-ORR), or last overall response rate (L-ORR). Methods: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 24 (32%) as achieving a PR on D28. Two independent radiologists collected baseline (pre-CAR-T therapy) and D28 PET/CT Standard Uptake Value (SUV) max and Total Tumor Metabolic Volume (TMV, in cm 3) using ROVER software. The Intraclass Correlation Coefficients (ICC) as a measure of absolute agreement between two readers was 0.99 for SUV the 0.97 for TMV. There was a strong absolute agreement between the two radiologists. For simplicity of data interpretation and given this concordance we present the results of one reviewer. Univariable Cox regression model was used to calculate PFS and OS. All statistical tests were 2-sided and conducted at the 0.05 level of significance. Results: Of the 24 patients with PR on D28 PET/CT, median follow-up time was 1.9 years with 17 patients (71%) still alive at last follow-up (see Fig 1a). Median age was 51 years-old, 46% were female, 66.7% had stage III/IV disease, all patients had ECOG ≤2, 58% received bridging therapy, and half had ≥3 lines of prior therapy (see Table 1A). Results of the univariable Cox regression model revealed that a lower D28 SUV max (p=0.004), lower TMV at both baseline (p=0.03), and at D28 (p=0.01) may be predictive of better OS. Longer PFS was found with lower D28 SUV max (p=0.002) and lower TMV at both baseline (p=0.01), and D28 (p=0.04). In analysis of B-ORR achieved by PET/CT, half of patients in PR at D28 ultimately achieved a CR (see Table 1B). OS was significantly lower in those with a B-ORR of PR vs CR (p<0.004) (see Fig 1b). The median SUV max at baseline was 14 in those with B-ORR of CR vs 15 in PR (Not Significant (NS)); at D28 median SUV max was 5 in CR vs 7 in PR (p=0.04). The median TMV at baseline was 210 in those with CR vs 861 with PR (p=0.07); at D28 median TMV was 12 in CR vs 26 in PR (NS). There was no significant difference in absolute or percent change between baseline and D28 in either SUV max or TMV; however, the absolute difference in TMV was notably greater in those with B-ORR of PR than CR (793 vs 201) (p=0.08). In analysis of outcome by L-ORR by PET/CT, 11 patients were in CR, while 13 had PD (see Table 1C). The median SUV max at baseline was 14 in those in CR vs 15 in PD (NS); at D28 median SUV max was 5 in those with CR vs 6 in PD (NS). The median baseline TMV was 298 in those with CR vs 591 in PD (NS); the median TMV at D28 was 15 in those with CR vs 21 in PD (NS). There was no significant difference in absolute or percent change between baseline and D28 of either SUV max or TMV based on L-ORR. Conclusion: In this analysis of patients in PR at D28 following CD19-directed CAR-T therapy, D28 but not baseline SUV max was significantly higher in those with a B-ORR of PR; and, in our modeling, lower D28 SUV max may predict favorable PFS and OS. Lower TMV, both at baseline and D28, may also be predictive of longer PFS and OS. Collectively, these findings suggest that for patients achieving a PR at D28, the best predictive factor by imaging for ultimately achieving a CR is lower SUV max at D28 and lower TMV at baseline and D28. These characteristics were also associated with longer PFS and OS. These findings indicate that there may be an intrinsic quality to the tumor itself (e.g. FDG-avidity and metabolic volume) that determines the ultimate outcome from a D28 PR. While further study is warranted, we demonstrate that patients with such characteristics should be identified, monitored closely for relapse, and perhaps be considered for further early intervention. Figure 1 Figure 1. Disclosures Hardy: InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees.

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Metabolic PET/CT Analysis of Aggressive Non-Hodgkin Lymphoma Prior to Axicabtagene Ciloleucel CAR-T Infusion: Predictors of Progressive Disease, Survival, and Toxicity

Blood ◽

10.1182/blood-2021-153739 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2518-2518

Author(s):

William Breen ◽

Jason R. Young ◽

Matthew Hathcock ◽

Roman O. Kowalchuk ◽

Radhika Bansal ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Increased Risk ◽

Pet Ct ◽

Car T ◽

Grade 3

Abstract Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion. Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use. Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD. Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each). While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2). Additional patients and follow-up will be presented. Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

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Outcomes and Factors Impacting Use of Axicabtagene Ciloleucel in Refractory and Relapsed Large B-Cell Lymphoma: An Intent-to-Treat Analysis

Blood ◽

10.1182/blood-2019-127087 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4452-4452 ◽

Cited By ~ 2

Author(s):

Agrima Mian ◽

Wei Wei ◽

Allison M. Winter ◽

Jack Khouri ◽

Deepa Jagadeesh ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Car T ◽

Ecog Ps ◽

Aggressive B Cell Lymphoma

Background: Axicabtagene Ciloleucel (Axi-cel), the first chimeric antigen receptor T-cell therapy (CAR-T), is approved for refractory/relapsed (R/R) aggressive B-cell lymphoma with the ZUMA-1 trial reporting an objective response in 83% and complete response in 58% patients at a median duration of 27 months (Locke et al. 2019). The availability to successfully deliver CAR-T therapy may be restricted by socio-economic, technical/manufacturing challenges and comorbidities related to aggressive B-cell lymphoma and its treatment. In this intent-to treat (ITT) analysis, we compared the outcomes of patients at our center with R/R B-cell lymphoma who received Axi-cel with those for whom Axi-cel therapy was intended but not administered, in order to identify factors that may limit its use in this population. Methods: We reviewed medical records of consecutive adult patients with R/R diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) and primary mediastinal B-cell lymphoma (PMBCL) for whom letters of medical necessity (LMN) were sent to request approval for Axi-cel, from March 2018 to May 2019 at our center. Patients were grouped according to whether or not they ultimately received Axi-cel. Baseline characteristics between Axi-cel and Non-Axi-cel group were compared using Fischer's exact test for categorical and Wilcoxon rank sum test for continuous variables. Comorbidities were assessed using the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror 2013). Time-dependent outcomes were calculated from the date of LMN. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: LMNs were sent for a total of 38 patients, 27 male (71%) with a median age of 63 (range, 25-77) years. 24 patients (63%) had an ECOG PS of 0 or 1 at study entry, while median IPI at diagnosis was 2 (range, 0-5). The most common histology was DLBCL in 25 patients (66%) and 18 (47%) had a germinal center B-cell (GCB) subtype. Four patients had double/triple hit lymphoma. The median number of prior therapies was 4 (range, 2-6) and 21 patients (55%) underwent prior autologous transplant. Forty-seven percent had relapsed and 53% had refractory disease. Patient characteristics are shown in Table 1. Twenty seven (71%) patients received Axi-cel, while 11 patients (29%) were considered candidates for but could not receive Axi-cel. The median time from LMN to cell infusion was 62 (range, 33-248) days. A higher HCT-CI score was observed in the Non-Axi-cel group as compared to the Axi-cel group (median score of 4 vs 2, P=0.04). The two groups did not differ with respect to age, ECOG PS, IPI, number of prior therapies or transplant status. Median follow- up was 5 (range, 2-16) months. At the time of last follow-up, 8 out of 27 patients (30%) in the Axi-cel and 10 out of 11 (91%) in the Non-Axi-cel group had died. The median OS for the entire cohort was 10 months (95% CI, 3.7 to 13), Axi-cel group was 13 months (95% CI, 7.7 to N.R.) and Non-Axi-cel group was 1 month (95% CI, 0.4 to 3.7) (Figure 1). In the Non-Axi-cel group, 3 patients underwent leukapheresis but died prior to infusion (including 1 manufacturing failure and 2 patients with rapid systemic progression). The other 7 deaths in this group were prior to leukapheresis (3 due to sepsis, 3 due to rapid progression including 1 case of active CNS disease and 1 patient could not receive therapy due to caregiver and financial barriers). The one surviving patient in the Non-Axi-cel group had refractory CNS relapse at the time of last follow-up. Conclusions: In this retrospective ITT analysis, approximately one third of patients with R/R aggressive B-cell lymphoma for whom CAR-T therapy was intended were unable to receive it and had extremely short median OS. Patients who could not receive Axi-cel had a higher comorbidity index at the time of decision to proceed with CAR-T therapy; the majority of them died before leukapheresis from disease progression or complications of prior treatment. Improved strategies are needed to safely bridge patients with aggressive B-cell lymphoma intended to receive Axi-cel. New targeted agents such as polatuzumab vedotin and tafasitamab (formerly MOR208) may increase the proportion of patients with aggressive B-cell lymphoma who ultimately receive and benefit from CAR-T therapy. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Gerds:Incyte: Consultancy, Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pfizer: Consultancy; Roche: Research Funding. Majhail:Anthem, Inc.: Consultancy; Incyte: Consultancy; Atara Bio: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding.

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Response to Bridging Therapy As a Predictor of Outcomes for Chimeric Antigen Receptor Therapy in Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-154186 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3841-3841

Author(s):

Arushi Khurana ◽

Matthew Hathcock ◽

Radhika Bansal ◽

Yucai Wang ◽

Jonas Paludo ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Board ◽

Bridging Therapy ◽

Advisory Committees ◽

Pet Ct ◽

Car T

Abstract Background: Bridging therapy (BT) was not allowed in the ZUMA-1 pivotal trial for axicabtagene ciloleucel (axi-cel) chimeric antigen receptor T-cell therapy (CAR-T) . Since then, several real-world studies have shown the use of bridging therapy to be associated with worse overall survival, duration of response, and complete remission rates. In addition, patients requiring BT during CAR-T manufacturing have a more aggressive and higher tumor burden of disease, also factors associated with poor outcomes. Therefore, factors that can predict outcomes in this high-risk patient cohort are required. We herein examine the impact of response to BT on CAR-T outcomes in large B-cell lymphoma (LBCL). Methods: A retrospective review of patients who received axi-cel for NHL from June 2016 - July 2020 at Mayo Clinic, Rochester, was performed. BT was defined as any lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing, reducing the likelihood of eligibility to receive CAR-T. The decision and choice of BT were at the discretion of the treating physician. Response to all lymphoma-directed therapy was evaluated using the 2014 Lugano criteria. Response to BT included patients with a partial response (PR) or stable disease (SD) on PET-CT before initiating lymphodepletion chemotherapy. Event-free survival (EFS) was defined as the time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as the time from axi-cel infusion to death. Survival curves were calculated using Kaplan-Meier estimates and were compared between subgroups using the log-rank test. Cox regression was used for univariate and multivariate analysis (MVA). Results: A total of 73 patients underwent car T therapy during this period. Of these, 67% (49/73) received BT therapy. Table 1 shows baseline characteristics of the total BT cohort (n = 49). The median age at CAR-T infusion was 59 years (IQR 46-64); 57% were males and comprised of 47% (23/49) DLBCL followed by 31% (15/49) high-grade B-cell lymphoma types. Based on the Lugano criteria on PET-CT, 22/49 (45%) patients responded to BT. The baseline characteristics were comparable between the responders and non-responders to BT except for a higher proportion (73%) of patients receiving systemic chemotherapy as BT in the responders (Table 1). At a median follow-up of 24 months, 75% had either progressed, died, or started the next treatment (event), and 59% (29/49) had died. The median EFS was significantly longer in the responders as compared to the non-responders to BT, figure 1 (13.04 months (95%CI, 3.54-not reached [NR]) vs. 2.56 months (95%CI, 1.18-3.02), p = 0.002). The OS also trended in favor of the responders (median OS 18.4 months (95% CI, 13.44-NR) vs. 11.84 months (95% CI, 5.05-NR), p = 0.092). The responder group also had a higher 6-month CR rate of 50% than 11.1% in the non-responder group (p = 0.004). There were no differences in any grade or grade ≥ 3 cytokine release syndrome and neurotoxicity rates in the two groups. On univariate analysis within the bridging group (n = 49), type of bridge (non-chemo) and response to bridge (PR+SD) were associated with a better EFS. In the MVA, only response to BT maintained significance for EFS (HR 0.34, p = 0.025). Conclusions: Having some control of lymphoma after BT was associated with better EFS and 6-month CR rate. Future studies need to prospectively evaluate the type and response to BT as a prognostic factor for improving outcomes in patients receiving CAR-T. Figure 1 Figure 1. Disclosures Wang: InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Takeda: Research Funding.

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Portia: A Phase 1b Study Evaluating Safety and Efficacy of Tisagenlecleucel and Pembrolizumab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-129120 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5325-5325 ◽

Cited By ~ 3

Author(s):

Ulrich Jaeger ◽

Nina Worel ◽

Joseph P. McGuirk ◽

Peter A. Riedell ◽

Isabelle Fleury ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell Therapy ◽

Car T ◽

Phase 1B

Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after ≥ 2 prior lines of therapy. T-cell exhaustion due to an immunosuppressive environment has been a hypothesized mechanism for CAR-T cell therapy failure. Subgroup analyses of the JULIET trial suggested an association between programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) interaction in baseline biopsies and lack of response (Agoulnik et al. EHA. 2018). Moreover, the anti-PD-1 monoclonal antibody pembrolizumab has shown clinical activity in r/r DLBCL after failing tisagenlecleucel therapy (Chong et al. Blood. 2017). PORTIA is a phase 1b, multicenter, open-label trial investigating the safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with r/r DLBCL. We report data from a completed cohort of the ongoing study. Methods: Eligible patients must be ≥ 18 years old with a confirmed diagnosis of DLBCL that has relapsed after or is refractory to ≥ 2 prior lines of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients treated with prior allogeneic stem cell transplantation, anti-CD19 therapies, or checkpoint inhibitors are excluded. Lymphodepleting chemotherapy consists of fludarabine-cyclophosphamide. Patients receive a single tisagenlecleucel intravenous infusion (target dose: 0.6-6.0x108 cells) on Day 1. Pembrolizumab is given at 200 mg every 21 days, for up to 6 doses. Pembrolizumab was started on Day 15 post-tisagenlecleucel in Cohort 1, with the option of moving to Day 8 or 22 in subsequent cohorts, based on observed data and guided by a Bayesian Logistic Regression Model with Escalation with Overdose Control principle, evaluating the distribution of dose-limiting toxicities (DLTs) occurring in the 21 days following the first pembrolizumab dose. As per study protocol, a total of 20 patients will be treated at the optimal dose timing. Primary endpoints are the proportion of patients receiving pembrolizumab per protocol schedule, the incidence of DLTs in the dose-timing selection phase, and the overall response rate in the dose-expansion phase. Secondary outcomes include duration of response, progression-free survival, overall survival, safety, cellular kinetics, and immunogenicity. Results: As of 5 March 2019, 5 patients were screened for Cohort 1. Four patients were enrolled and received tisagenlecleucel and pembrolizumab. Median age was 54 (range, 35-79). Median follow-up from time from tisagenlecleucel infusion to data cut-off was 46 days (range, 36-85). Patients received 1.7-3.0x108 CAR-positive T cells, and 1, 2, 2 and 4 pembrolizumab doses, respectively, with no delays. All 4 patients experienced at least 1 adverse event (AE), with no exacerbation or recurrence of tisagenlecleucel-related AEs following pembrolizumab infusion. No pembrolizumab-related AEs were observed. No DLTs or grade 3-4 treatment-related adverse events (TRAEs) were observed. TRAEs and AEs are summarized in Table 1. Two patients discontinued pembrolizumab treatment (after 1 and 2 doses, respectively) due to disease progression. All 4 patients experienced initial expansion between Days 6 and 15 post-tisagenlecleucel infusion, with peak transgene levels ranging from 1,980 to 77,200 copies/µg DNA (Figure 1). No secondary expansion was observed after pembrolizumab administration. The overall exposure is consistent with the observed exposure in r/r DLBCL patients in the JULIET trial. With very limited follow-up, 1 partial response has been observed. Cohort 2 (pembrolizumab starting Day 8) was ongoing at the time of submission. Conclusions: Overall, PD-1 blockade with pembrolizumab on Day 15 after tisagenlecleucel infusion was feasible and showed a manageable safety profile in the first 4 patients. No DLTs and no clinically significant exacerbation of AEs were observed, supporting the initiation of Cohort 2. Efficacy and safety data with an updated cutoff for Cohort 1 and new data from Cohort 2 will be presented at the congress. Clinical trial information: NCT03630159. Disclosures Jaeger: Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Riedell:Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau. Fleury:AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chu:Novartis: Employment. Abdelhady:Novartis: Employment. Forcina:Novartis: Employment. Bubuteishvili Pacaud:Novartis: Employment. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy.

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Blinatumomab Consolidation Post Autologous Hematopoietic Stem Cell Transplantation in Patients with Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood-2020-142464 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Armin Ghobadi ◽

Michael P. Rettig ◽

Amanda F Cashen ◽

Leah Gehrs ◽

Stephanie Christ ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Large B Cell Lymphoma ◽

Pet Ct

Introduction: Autologous hematopoietic stem cell transplantation (auto-HCT) is the standard treatment for patients with chemo-sensitive relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, post-auto-HCT outcomes are still poor in this population, with 5-year progression free survival (PFS) of 40%. We hypothesize that in patients with DLBCL, blinatumomab consolidation post auto-HCT will eradicate remaining tumor cells, leading to decreased relapse and increased overall survival. Therefore we conducted a pilot study to test blinatumomab as consolidation therapy post auto-HCT for patients with DLBCL. Methods: Adult patients with chemosensitive DLBCL or transformed FL who underwent auto-HCT were included. All patients received one cycle of blinatumomab consolidation starting 42 days post auto-HCT (9 mcg daily as continuous infusion for 7 days, followed by 28 mcg daily for 21 days). Response evaluation was done at day 100 post auto-HCT. Minimal residual disease (MRD) was quantified by immunoglobulin high-throughput sequencing (Ig-HTS) of plasma cell-free DNA on days 42 post auto-HCT (pre-blinatumomab) and on day 100 post auto-HSCT (one month post completion of blinatumomab). Immunophenotyping of T cells in cryopreserved peripheral blood mononuclear cells collected on day 42 (pre-blinatumomab), day 56 (midpoint of blinatumomab treatment cycle), and day 100 (1 month post blinatumomab) was performed using 18-color flow cytometry panels for extracellular and intracellular antigens. Results: As of August 2020, ten patients have been treated with at least 100 days follow up. Patient characteristics and outcomes are summarized in Table 1. Three out of 10 patients (30%) were in partial remission (PR) as determined by CT or PET/CT imaging before auto-HCT. All subjects completed the planned cycle of blinatumomab consolidation. Blinatumomab was well tolerated. Two patients developed grade 1 CRS, with no grade 2 and higher CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) was not observed. Six patients developed transient tremor (four grade 1, one grade 2, and one grade 3). One subjects developed BCNU pneumonitis and CMV viremia that resolved with steroid and ganciclovir. One hundred days post auto-HCT (one month post blinatumomab consolidation) 10/10 (100%) of patient were in complete remission (CR) as determined by both MRD testing and by CT or PET/CT imaging. Plasma cell free based MRD was positive on day 42 (post auto-HCT and pre-blinatumomab), in two out of ten patients (20%). These two patients achieved MRD negative status after receiving blinatumomab consolidation. With median follow up of 14.5 months (range: 7-34 months), all 10 patients are alive and 6/10 remain in remission.. Interestingly, the 4 patients with disease relapse had lower CD8/CD4 T cell ratio before starting blinatumomab compared with patients who remained in remission (Figure 1A). However, there were no significant differences in the distribution of the major T cell subtypes (naïve, memory, effector and Treg), and expression of markers of T cell activation, proliferation, or exhaustion (Figure 1B-1E). High dimensional analysis with t-stochastic neighbor embedding (tSNE) revealed a cluster of CD8+ and CD4+ T cells characterized by high expression of granzyme B (GB) and perforin that was present in the DLBCL patients before and after blinatumomab treatment but not in a healthy untreated control (Figure 1F-1H). Although further analysis of healthy untreated controls and pre-transplant samples is needed, CD8+ T cells from these DLBCL patients pre-blinatumomab contained very few naïve cells and were enriched for terminally differentiated effector cells. Conclusion: This pilot study shows that blinatumomab consolidation post auto-HCT is safe and well tolerated. MRD response to blinatumomab in all patients with MRD positive disease post auto-HCT is encouraging. Strategies to increase CD8/CD4 ratio and more cycles of consolidation in a larger randomized trial are needed to confirm the efficacy of consolidation with blinatumomab post auto-HCT. Finally, the unusually "high activation" immunophenotype (Teff/GB+) seen in CD8 T cells of DLBCL patients after auto-HCT (compared to those seen in resting peripheral blood) may both impact the response to blinatumomab and provide key insights into optimal timing for administration after auto-HCT. Disclosures Ghobadi: WuGen: Consultancy; Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding; EUSA: Consultancy; Amgen: Consultancy, Research Funding. Mehta-Shah:Bristol Myers-Squibb: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Celgene: Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; AbbVie: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Impact and Safety of Chimeric Antigen Receptor T Cell Therapy in Vulnerable Older Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-125162 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1603-1603 ◽

Cited By ~ 3

Author(s):

Richard J Lin ◽

Stephanie M Lobaugh ◽

Martina Pennisi ◽

Jason T Chan ◽

Yakup Batlevi ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

B Cell Lymphoma ◽

Tumor Burden ◽

Advisory Committees ◽

Comorbidity Burden ◽

Car T ◽

Equity Ownership

The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients. We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger (<65yo, n=25) patients. Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure). We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients (<65yo, n=25) who received a CAR T. Baseline characteristics were similar among the two groups including: KPS, the prevalence of functional impairment, prior fall, and weight loss, and pre-treatment tumor burden measured by LDH (Table). The older group had more females (p<0.001) and higher comorbidity burden measured by DCI/CCI (p=0.04) (Table). Numerically more younger patients (84%) received axicabtagene ciloleucel compared to tisagenlecleucel versus older patients (63%; p=0.11). Importantly, the two groups had similar incidences of cytokine release syndrome (CRS) and neurotoxicity (NT) of all grades (Table). We also examined the incidence of grade 3-4 hematologic and non-hematologic toxicities by CTCAE v5.0 and found that numerically, older patients appeared to have less infection and cytopenia, and more metabolic and other toxicities (Table). In addition, the rate of Intensive Care Unit admission was similar. At the time of last follow-up, we observed only 1 treatment-related death, a 69-year-old female with a history of prior allogeneic hematopoietic cell transplantation who died of influenza pneumonia 129 days after CAR T infusion. Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Kite: Consultancy. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Santomasso:Kite/Gilead: Consultancy; Novartis: Consultancy; Juno/Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyte/Gilead: Research Funding; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽

10.1182/blood-2019-122393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2898-2898

Author(s):

Vania Phuoc ◽

Leidy Isenalumhe ◽

Hayder Saeed ◽

Celeste Bello ◽

Bijal Shah ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Improving the Definition of Response Assessment: Prognostic Value of Minimal Residual Disease Combined with PET/CT at Day 100 Post Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood-2020-142845 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Miguel Gonzalez-Velez ◽

Mariano Arribas ◽

Heidi E. Kosiorek ◽

Richard Butterfield ◽

Carlo Guerrero ◽

...

Keyword(s):

Board Of Directors ◽

Prognostic Value ◽

Residual Disease ◽

High Sensitivity ◽

Response Assessment ◽

Advisory Committees ◽

Pet Ct ◽

Definition Of ◽

Minimal Residual

Introduction: Response assessment at day 100 post Autologous Stem Cell Transplant (ASCT) is associated with long-term relapsed free survival (RFS) and overall survival (OS) in multiple myeloma (MM). The International Myeloma Working Group (IMWG) are the preferred criteria to define best response to treatment and define relapse. In the last years, response assessment has incorporated minimal residual disease (MRD) status -associated with improved RFS and OS (Munshi et al); and PET/CT combined with clinical characteristics -also associated with favorable outcomes (Zamagni et al. NCT01910987; MMY3033). The 2016 IMWG MRD criteria, combined imaging (PET/CT) plus next-generation sequencing (NGS) MRD-negative to define complete response (CR). To our knowledge, there is limited data examining the correlation and prognostic value of MRD and FDG-PET/CT at day 100 post ASCT in MM. IN this study, we aimed to determine the prognostic valued of MRD by NGS combined with PET/CT in RFS and OS status after high dose chemotherapy and ASCT in MM. Methods: Patients who underwent ASCT for MM at Mayo Clinic Arizona and had MRD and PET/CT data were included in the study. Clinical data was obtained via retrospective chart review. Cytogenetic risk (CyR) was classified using the mSMART criteria . Disease and ASCT related characteristics were compared by MRD status. MRD was measured by NGS on bone marrow aspirates using the previosly validated clonoSEQ ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) tracking the IgH, IgK and IgL rearrangements at a minimum sensitivity level of 10-5. MRD was defined by residual clonal cells per million nucleated cells as: negative= 0, borderline= 1-5, positive >5. PET/CT scans were performed locally at baseline and at day 100. Comparisons were performed using the chi-square test for categorical variables, Wilcoxon rank-sum test for continuos variables, McNemar's test and Cohens's Kappa for agreement measures. Results: A total of 103 patients had matched MRD and PET/CT assessment around day 100 (+/-9 days) and were included in the analysis. Median age at diagnosis was 62 years (range, 54-66 years), 71 patients (68.9%) were men. CyR was standard risk in 49 (47.6%), high-risk in 39 (37.9%) and unknown in 15 (14.6%) patients. Most 75 (72.8%) patients were MRD positive, 16 (15.5%) were MRD negative, and 12 (11.7%) borderline. The median main MRD clone detected was 64 (range 0-91,874). 70 patients (68%) and 33 (32%) had a negative and positive PET/CT respectively. The median follow-up time was 18 months (range, 13-31 months). At the time of data analysis, 10 patients (9.7%) had relapsed and only 4 (3.9%) had died. There was a high-correlation between MRD status and PET/CT, 31 patients (93.9%) with positive PET/CT were also MRD positive (p=0.0027). There were no statistical differences between PET/CT and CyR (p=0.95). We analyzed the correlation using the FREQ procedure (McNemars's test); there was a strong association between positive PET/CT and positive MRD in 31/33 patients (93.9%, high sensitivity), and low association for negative PET/CT the negative/borderline MRD in 26/70 (37.1%, low specificity; p<0.001). The agreement measure between the PET/CT and MRD using negative/borderline combined had a kappa of 0.23 (95% CI 0.11, 0.35) indicating a fair agreement beyond chance (Figure 1). PET/CT-CT was a statistically significant predictor of worse RFS (HR 3.53, 95%CI: 1.02-12.24, p<0.0337) and OS (HR 11.38, 95%CI: 1.18-109.56, p<0.0078) (Figure 2-3, respectively). MRD was not predictive of neither RFS (HR 1.72, 95%CI: 0.36-8.14, p<0.49) or OS (p<0.16). Conclusions: In conclusion, we demonstrate that the combination of MRD by NGS (clonoSEQ ®) and PET/CT at day 100 are complementary and have a high sensitivity (true positive rate) and fair correlation of agreement but low specificity (true negative rate). PET/CT was the best most sensitive technique to prognosticate RFS and OS. We did not find prognostic correlation of MRD with RFS and OS. However, our findings might be confounded by the low risk of relapse and death, a longer follow-up may demonstrate clinically important differences. Our results add evidence that MRD plus PET/CT improve the definition of CR in MM patients post ASCT. Prospective studies are needed to elucidate the optimal timing and role of combined MRD, PET/CT with other prognostic markers of clinical outcomes. Disclosures Larsen: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fonseca:Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy.

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Easix As Prediction Score before CAR-T Cells Vs Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Relapsed/Refractory (r/r) Large B Cell Lymphoma (LBCL)

Blood ◽

10.1182/blood-2020-139615 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Felix Korell ◽

Thomas Luft ◽

Michael Schmitt ◽

Sascha Dietrich ◽

Anita Schmitt ◽

...

Keyword(s):

T Cells ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Tumor Board ◽

Advisory Committees ◽

Educational Activities ◽

Bulky Disease ◽

Car T Cells ◽

Car T

BACKGROUND: In a previous study we have shown that CD19-directed chimeric antigen receptor (CAR)-T cells do not appear to be inferior to alloHCT when used as standard cellular immunotherapy (CI) for patients with multiply r/r LBCL (EBMT 2020). The purpose of the present follow-up analysis was to further compare the risk profile of the 2 cohorts by applying the EASIX score (lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (109 cells per L)), and to assess if EASIX could be used as outcome predictor in patients with r/r LBCL undergoing CAR-T and alloHCT, respectively. METHODS: Eligible were all patients referred to our institution with relapsed/refractory (R/R) DLBCL and a tumor board decision recommending treatment with CAR-T cells between 07/2018 and 02/2020 and those recommending allogeneic donor search between 2004 and 2019. Patients with DLBCL transformed from CLL were excluded. EASIX was evaluated retrospectively using uni- and multivariable analyses (with regards to age, gender and number of failed therapy lines) and mortality using Cox regression analyses. RESULTS: 41 patients intended for CAR-T cells and 60 patients intended for alloHCT were included. In both cohorts nearly all patients had active disease at indication. Cohorts were comparable for sex, time from diagnosis, ZUMA1 eligibility, and PS, but CAR-T patients tended to be older (median 56 vs 51 years, p=0.093), and had more often primary refractory and bulky disease (p=0.004 and p=0.04, respectively). Median EASIX score across both cohorts was 1.50 (0.27-70.5), with significantly higher scores in the CART group both at indication (EASIX-ind; median 1.79 and 1.22 for CAR-T and alloHCT, respectively, p=0.031) and at conditioning for CI (EASIX-pre, median 2.24 vs 1.26, p=0.005). Median OS from indication was 475d for the CAR-T cohort vs 285d for the alloHCT cohort (p=0.88). On multivariate analysis, EASIX-ind was significantly associated with adverse OS if alloHCT was intended (HR per 2fold increase 1.43, 95%CI 1.08-1.90, p=0.013), but not if CAR-T was intended (HR per 2fold increase 1.16, 95%CI 0.88-1.53, p=0.3). After CI, 12-month estimates for NRM, relapse incidence, PFS, and OS for CAR-T vs alloHCT were 3% vs 21% (p=0.04), 59% vs 44% (p=0.12), 39% vs 33% (p=0.97), and 68% vs 54% (p=0.32). EASIX-pre predicted overall survival (OS) in both CAR-T (HR per 2fold increase 2.11, 95%CI 1.21-3.7, p=0.009) and alloHCT (HR per 2fold increase 3.69, 95%CI 1.54-8.31, p=0.003) cohorts. In the alloHCT group, the EASIX effect was largely driven by higher NRM risk with increasing EASIX-pre, while in the CAR-T group poorer OS with increasing EASIX-pre was largely relapse-related. CONCLUSIONS: In patients undergoing CI for r/r LBCL, EASIX measured prior to conditioning can predict mortality after both CAR-T and alloHCT. If applied already at indication for CI, the predictive capacity of EASIX is weaker and no longer significant if CAR-T is intended. Further studies for validation of this data appear to be warrantable. Disclosures Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder; Hexal: Other: Travel grants , Research Funding; Apogenix: Research Funding; Kite: Other: Travel grants, educational activities and conferences; Novartis: Other: educational activities and conferences, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Schmitt:Hexal: Other: Travel grants ; TolerogenixX LtD: Other: Co-founder, Part-time employee ; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grants . Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau.

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Fludarabine Plus Cyclophosphamide and Rituximab In Waldenström's Macroglobulinemia: Results In 55 Patients

Blood ◽

10.1182/blood.v116.21.1757.1757 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1757-1757

Author(s):

Véronique Leblond ◽

Laetitia Compain ◽

Vincent Levy ◽

Jérôme Tamburini ◽

Alain Delmer ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Progressive Disease ◽

Response Rate ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Best Response ◽

Previously Treated ◽

Delayed Responses

Abstract Abstract 1757 Treatment of Waldenström's Macroglobulinemia relies on alkylator agents, nucleoside analogs and/or monoclonal antibody based therapies. We showed previously that combination of fludarabine and cyclophosphamide yields a 78% response rate (RR). We performed a retrospective study in 55 WM patients (pts) treated with RFC regimen in 10 French centers. The median age was 65 years (range: 34–79), the median IgM level measured by electrophoresis was 27.3 g/L (range: 6.5–64), the median haemoglobin level was 9.7g/dl (range: 3.7–14), the median platelet count was 174 × 109/L (range: 22–500), the median beta 2 microglobulin level was 3.4 mg/l (range: 1.7–9). In all, 40/55 pts had previously been treated with a median of 2 lines of therapy (range: 1–4), including 24 patients with relapsed disease and 16 patients with refractory disease. RFC regimen was given every 4 weeks and consisted in: Rituximab 375 mg/m2 IV Day 1, Fludarabine 40 mg/m2 per os Day 1 to Day 3, Cyclophosphamide 250 mg/m2 per os Day 1 to Day 3. 55 pts received the first cycle of RFC, and 52 received two or more cycles (median of 4 cycles, range 2–6). Main toxicity was hematological. No toxic death was observed.Response was assessed 3 months after the last RFC cycle according to response criteria agreed by the 3rd International Workshop on WM (Kimby, 2006), but delayed responses with improvement of the response occurring more than 3 months after treatment discontinuation were observed in 15 patients. The best response was evaluated in 51 pts (3 early discontinuation treatments, one progressive disease), including 26 partial responses (PR), 5 minor responses (MR), and 2 stable diseases (SD). Of note 18 very good PR/ near RC (VGPR) were observed (> 90% decrease in M-protein) . The overall response rate was 89%. Long lasting cytopenia was observed in 10 patients. In the untreated group one pt in failure had a Burkitt-like lymphoma, the other 14 pts are alive in response. In the previously treated group, 6 pts relapsed, one developed a large B-cell lymphoma. Three ASCT and 4 allogeneic SCT were performed in six patients. With a median follow-up time of 28 months, median time to treatment failure (TTF) was not reached, even in previously treated patients. There was not significant difference in the TTF duration in patients in VGPR compared with those in PR + MR.The median progression free survival time was not reached. Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was observed in two heavily treated patients and 3 pts had a secondary solid cancer. In all, 48 pts are alive, 7 patients died (4 from progressive disease, 2 from secondary cancer, and 1 from Burkitt-like transformation). Conclusion: RFC combination even in heavily treated patients with poor prognostic factors gives a very high response rate (89%) with 33% of patients achieving at least a very good partial response with acceptable toxicity. The toxicity on the hematopoietic stem cell reservoir is a major concern. This combination could be offered to relapsed/refractory patients. In first line, the choice of this combination must be discuss, increased incidence of MDS/ AML after purine analogs, and impairment of stem cell mobilization having previously been reported by us and others. Because frequent delayed responses, a long follow-up with periodic electrophoresis is needed to assess the best response after RFC. Disclosures: Leblond: ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees. Tournilhac:MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees. Choquet:ROCHE : Consultancy.

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