Brandes, Eva

AbstractIntroductionHypoalbuminemia is a known adverse prognostic factor in lymphomas. Yet, it is unknown if axicabtagene ciloleucel (axi‐cel) overcomes the adverse prognostic impact of hypoalbuminemia in relapsed/refractory large B‐cell lymphoma.MethodsWe conducted a retrospective analysis across three Mayo Clinic centers to assess the relationship of hypoalbuminemia (defined as a serum albumin (SA) levels ≤ 3.5 g/dL) on outcomes of patients treated with axi‐cel.ResultsThis analysis included 81 patients. Two patients had no available SA levels preceding axi‐cel infusion. Eighteen patients (22.8%) had hypoalbuminemia with a median SA of 3.3 g/dL. Patients with normal SA had a statistically higher ORR than those without hypoalbuminemia (P = .018). There was no difference in 1‐year PFS and OS between the group with hypoalbuminemia and the group with normal SA levels (48% vs 49%, P = .81) and (74% vs 73%, P = .97), respectively. There was no difference in the severity or median duration of cytokine release syndrome or neurotoxicity between the two groups.ConclusionNotwithstanding the limitations related to the relatively small sample size, axi‐cel therapy appears to overcome the adverse effect of hypoalbuminemia on OS and PFS. Large multicenter clinical studies are certainly needed to validate these findings.

e15020 Background: Durable responses were seen in registration trials for CAR-T in NHL across poor prognostic groups including early relapse post stem cell transplant (ASCT). Multi-center reports of real-world practice noted patients who received BT prior to CAR-T had decreased survival. The impact of last ST and response to BT on clinical outcome are examined here. Methods: Retrospective chart review was performed on 47 patients who received axicabtagene ciloleucel from June 2016 – September 2019 at Mayo Clinic, Rochester. ST was defined as last therapy prior to leukapheresis and grouped into categories – non-ASCT (chemotherapy, and immunotherapy), and ASCT. BT was defined as therapy given between leukapheresis and CAR-T. Response to therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from CAR-T infusion to progression, next treatment, or death. Results: The ST distribution was 77% non-ASCT [chemo 66% (31), and immunotherapy 11% (5)], and 23% (11) ASCT. EFS was significantly prolonged for the ASCT (median not reached) vs non-ASCT (median 3.8 months, p = 0.03) despite no difference in median prior lines of therapy. This may reflect more aggressive disease in the non-ASCT arm, as time from start of ST to leukapheresis was shorter (median non-ASCT 2.2 months vs. ASCT 4.4 months, p = 0.0008). Patients received BT if there were concerns for symptomatic progression during CAR-T manufacturing that would reduce the likelihood to receive CAR-T. Sixty-two percent (29) patients received BT (11 chemo, and 18 immunotherapy). The EFS did not differ between the type of BT. However, patients who progressed after BT had worse EFS than those who achieved stable disease or partial response (median 2.8 vs 8.7 months, p = 0.03). Conclusions: Patients who received CAR-T as the next treatment after ASCT had better EFS than those after other types of ST. While patients who received BT have worse survival than those who didn’t, having some control of lymphoma progression with BT was associated with better EFS than those who continued to have progressive disease.

3028 Background: Chimeric antigen receptor T-cell (CAR-T) therapy induces complete remission (CR) in 30-40% of patients with non-Hodgkin lymphoma (NHL). However, for patients who do not achieve CR as their first response, predictors for achieving CR as best response can guide management between careful observation or early intervention. Increased absolute lymphocyte count to absolute monocyte count ratio (ALC/AMC) predicts better response rates and survival in NHL patients receiving chemotherapy and/or autologous stem cell transplant. We evaluated the prognostic impact of ALC/AMC in CAR-T therapy for NHL. Methods: This was a retrospective review of patients who received CAR-T for NHL from June 2016-August 2019. ALC/AMC was assessed at the start of lymphodepletion (LD) chemotherapy. The receiver operator curve (ROC) was used to determine the best cutoff for ALC/AMC in predicting CR at 3 months. Event-free survival (EFS) was defined from time of CAR-T infusion to relapse or death, whichever occurred first. Overall survival (OS) was defined from time of infusion to death of any cause. Results: Forty-seven patients received axicabtagene ciloleucel, with a median follow-up of 14 months. By ROC, ALC/AMC > 0.8 before LD chemotherapy was predictive of achieving CR at 3 months. Baseline characteristics were similar between the high (n = 30) and low (n = 17) ALC/AMC groups. Patients with an ALC/AMC > 0.8 at the time of LD chemotherapy were more likely to achieve CR at 3 months (46% vs. 12%, p = 0.01), 6 months (52% vs. 0%, p < 0.0005), and 12 months (42% vs. 0%, p = 0.01). Correspondingly, the EFS and OS were significantly shorter in patients with ALC/AMC≤0.8 vs. those > 0.8 (median EFS: 2 vs. 13 months, P < 0.0001) and (median OS: 15 months vs. not reached, P = 0.03), respectively. Association between ALC/AMC ratio and EFS and OS remained consistent in multivariate Cox models after adjusting for other prognostic variables, including abnormal lactate dehydrogenase and increased ferritin level at infusion day. Conclusions: ALC/AMC > 0.8 before lymphodepletion chemotherapy is a strong predictor for complete remission as well as improved event-free and overall survival for axicabtagene ciloleucel in NHL.

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Background: Two-year follow-up from ZUMA-1 trial for axicabtagene ciloleucel (axi-cel) CD19 chimeric antigen receptor T-cell (CART) in aggressive non-Hodgkin lymphoma (NHL) demonstrated that patients (pts) achieving complete remission (CR) as their best response have the longest progression free survival (PFS), while PFS remained poor for others. Majority of the best response are achieved by month 3 post-infusion. Moreover, a subset of pts who do not achieve CR by month 1 may still achieve CR while others will progress within months. Having a clinically available test to predict for durable response can assist clinicians in selecting pts who can be observed for continued response vs. those who may need intervention earlier. Peak CAR-T expansion has been correlated with best clinical response to axi-cel. However there is no clinically available test to quantify CART cells post treatment. Given the prolonged lymphotoxic effect of the lymphodepletion (LD) chemotherapy administered before CART infusion, we hypothesize that the peak expansion of absolute lymphocyte count (ALC, ALCpeak) after infusion likely corresponds to CART expansion. We examined for correlation between ALCpeak and clinical response at month 3 post-infusion for pts who received axi-cel. Methods: Data was collected from pts who received axi-cel between June 2016 and March 2019 at Mayo Clinic Rochester (NCT02348216, NCT03153462, and standard of care). All infused pts were included in the intention to treat analysis for response and event-free survival (EFS). Lugano 2014 criteria were used for clinical response. EFS was defined as the date of infusion until progression or death due to any cause and evaluated using Kaplan Meier curves with log-rank test. Comparison between subgroups was investigated using Fisher's exact test and Wilcoxon test for categorical and continuous variables, respectively. Statistical analysis performed using JMP Pro 14.1. Results: Of the thirty-six NHL pts treated with axi-cel, the median age was 56 yrs (range 26-65); 78% (28) were male; 44% (16) had DLBCL; the median number of prior therapies was 3 (2-6), 47% (17) had stem cell transplant. Nineteen (53%) pts received bridging therapy after leukapheresis. All pts received fludarabine and cyclophosphamide for LD chemotherapy and achieved ALC nadir by the day of CART infusion (median 0.03 x 10^9/L, range 0.01-0.11). As CART expansion were found to peak within the first two weeks in ZUMA-1 trial, we examined ALC trend over 15 days post infusion and found that ALCpeak generally happened within the same timeframe (median ALCpeak day: 9, range 6-15). At 3 months post infusion, 33.3% (12/36) of pts achieved CR, 8.3% (3/36) pts were in partial remission (PR). No correlation was found between CR response and clinical characteristics: age >60 years, stage III/IV, B symptoms, elevated LDH, IPI score 3-4, number of previous treatments, use of bridging therapy, peak CRP and ferritin. However, the ALCpeak was significantly different between CR and non-CR pts (median, range: 1.09, 0.35-2.55; 0.67, 0.15-1.03; p=0.04). Using receiver operator curve (ROC)-derived area under the curve (AUC) estimates, ALCpeak 1.08 x 10^9/L was identified as the best threshold to discriminate patients at different likelihood to achieve CR at month 3. Pts achieving ALCpeak ≥ 1.08 showed a strong increased likelihood of achieving CR at month 3 (OR 2.8; 95% CI, 1.12-6.99; P=0.02). There was no statistical difference between the ALCpeak high and low groups in terms of use of bridging therapy, occurrence of any grade or higher grade cytokine release syndrome or neurotoxicity, or the use of tocilizumab or steroid. Interestingly, for pts who had changes in clinical response from month 1 to month 3, all 3 pts who converted to CR by month 3 had ALCpeak≥1.08, while the 13 of the 15 pts who had progressed by month 3 had ALCpeak<1.08. In addition, EFS was significantly different between pts who had ALCpeak above and below 1.08 (6 months EFS rate 75% vs. 25%, respectively, Figure 1). Conclusions: We found that the ALC expansion occurred in the first 15 days post axi-cel infusion, consistent with the known time frame for CART expansion. Higher ALCpeak level in this timeframe correlated with higher likelihood of achieving CR, and is associated with conversion to CR. This study is limited by the small sample size and limited follow-up, but the results are promising for further prospective investigation in a larger cohort of patients. Disclosures Paludo: Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding; Celgene: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Bennani:Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Karyopharm: Research Funding; Rigel: Consultancy. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Background: Autologous stem cell transplantation is an integral part of myeloma therapy for patients who are able to undergo the treatment. While high dose melphalan has remained the typical conditioning regimen for ASCT in MM, recently there have been efforts to enhance the conditioning therapy by adding newer drugs to melphalan. Addition of bortezomib as well as carfilzomib have been attempted in phase 2 trials. Previous studies have shown that the combination of melphalan and total body irradiation (TBI) is an effective conditioning regimen. Pre-clinical studies have shown that bortezomib can sensitize MM cells to radiation, and based on this finding, we designed a clinical trial to examine the feasibility of combining low dose TBI with a combination of melphalan and bortezomib. Patients and Methods: The primary goal of the phase 1 study was to determine the maximally tolerated dose (MTD) of bortezomib that can be added to high dose melphalan and low dose TBI as part of conditioning chemotherapy in patients undergoing an ASCT for MM. The secondary goals were to examine the toxicities associated with addition of bortezomib to high dose melphalan and TBI in patients with MM and to determine the progression free rate at 1 and 2 years. Patients eligible to receive full dose melphalan conditioning regimen for ASCT were included as long as they had no more than 2 prior regimens and had not received a prior transplant. An accelerated design that was later converted to a standard 3+3 cohort design was used for dose escalation. Three patients were treated at a given dose level combination and observed for at least 36 days to assess toxicity. Melphalan 80 mg/m2 was given days -4, -3, with bortezomib at increasing doses given on day -5, -2 along with TBI of 200 cGY given on the same days of bortezomib, timed after bortezomib administration. Stem cells were infused day 0. Results: Eleven patients were enrolled; 6 were males, and the median age was 60 years. Median time from diagnosis was 5.4 months (range 3.4-7.0). Four dose levels were explored with increasing doses of bortezomib (0.7 mg/m2 to 1.6 mg/m2). No dose limiting toxicities were observed. The dose levels and the best response after ASCT are as shown in the Table. The overall response rate was 100%, including 7/11 with a CR or sCR. With a median follow-up of 12.5 months, two patients have progressed; median OS was not reached. Toxicity was mostly hematologic, with other AEs being grade 3 or less and attributable to the conditioning therapy. All patients engrafted their counts adequately. Conclusion: The combination of melphalan, bortezomib, and low dose TBI is a safe conditioning regimen in patients with MM with good efficacy. The regimen should be further examined in the phase 2 setting. Table Table. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Noxxon: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

Background: The patient/caregiver experience during CAR-T therapy is stressful, overwhelming, terrifying, and often a patient’s last treatment option. The Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Innovation and Design team has worked with the CAR-T therapy clinical team to develop a patient experience that provides patients with a sense of caring, supportive environment, timely knowledge, and realistic expectations. Using a human-centered design approach, the Innovation and Design team worked with patients and caregivers to understand latent and unspoken needs in order to develop an ideal CAR-T therapy patient journey. Methods: With qualitative interviewing techniques, patient observation, and low fidelity experimentation, 21 patients/caregiver pairs were interviewed throughout their CAR-T therapy experience in 2018. Patients were interviewed at several touch points as well as encouraged to reach out to the Innovation and Design team at any point with reflections on their experiences. Patients were recruited as they began their evaluation phase for CAR-T therapy. The interviews were unscripted to allow for a breadth of discovery by not constraining the conversations to previously developed themes. As themes emerged from patient/caregiver interviews, artifacts and interventions were designed to alleviate pain points and improve the patient/caregiver experience. These artifacts and interventions were integrated into the clinical processes in real time and patient/caregivers were interviewed to understand the impact of these activities. Results: Several themes emerged from qualitative interviews with patients and caregivers. From the themes, interventions were developed. We were able to demonstrate a qualitative improvement in patient/caregiver experience through these interventions (Figure 1). Conclusions: Patients/caregivers undergoing CAR-T therapy have unique issues surrounding the logistics of care, emotional burden, and physical effects of treatment. We implemented processes to address these issues and observed a qualitative improvement via patient interviews/feedback. Ongoing work includes optimizing remote monitoring, digital platforms for patient education, and a quantitative study looking at patient reported outcomes (PROs) in such patients. To our knowledge, this is the first report for care delivery optimization in real-world practice for this new therapy.