Rahman, Zaid Abdel

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.

Introduction Novel high-risk groups have been identified in adult ALL, including secondary (sALL) and Philadelphia-like ALL (Ph-like, based on CRLF2, IgH, ABL2, JAK2 and other tyrosine kinase translocations), and those with minimal residual disease >0.1% (MRD+) after induction therapy. Novel targeted therapies are now routinely incorporated into 1st line regimens, including tyrosine kinase inhibitors (BCR-ABL1-pos), rituximab (CD20+) and blinatumomab (Blina) for MRD+. The impact of these novel high risk groups and therapies after alloHCT is unknown; therefore, we evaluated their impact on overall survival (OS), relapse rate (REL), non-relapse mortality (NRM) and acute and chronic GVHD. Methods We evaluated pts receiving 1st Allo-HCT for ALL at Mayo Clinic (Rochester, Phoenix, and Jacksonville) from 2008-2018 for outcomes of interest, specifically the impact of novel therapies and risk groups. Associations of patient factors with outcomes were examined using univariable (UVA) and multivariable (MVA) Cox proportional hazards regression models, where the cause-specific hazard of the given outcome was modeled to account for the competing risk of death. Results We identified 261 consecutive AlloHCT recipients during the study period. Median age at transplant was 48 years (18-72) and 147 (56.3%) were male. The median comorbidity (HCT-CI) score was 2 (0-8). 213 pts (81.6%) had B-lineage ALL, of which 85 (32.6%) were BCR-ABL-pos, 17 (6.5%) Ph-like (identified by FISH), 16 (6.1%) hypoploidy/near triploidy (Hy/Tri), and 67 (25.7%) pre-B ALL NOS. The remaining 48 (18.4%) had T-ALL. 30 pts (11.5%) had sALL (i.e. prior chemo/radiotherapy for another malignancy). HyperCVAD was the most common 1st line regimen (68.2%). 243 (93.1%) pts achieved Complete Remission (CR1) after induction therapy, and 203 (77.8%) were in CR1 at the time of alloHCT. Blina was administered for MRD+ in 14 pts (5.4%), and for relapsed/refractory ALL (R/R) in 13 (27% of R/R pts), 7 of whom received Blina as initial therapy for R/R. Donors were matched unrelated in 149 (57.1%), matched related in 98 (37.5%), and haploidentical in 14 (5.4%). Peripheral blood (PB) grafts were used in 233 (89.3%). 103 (54.5%) were donor:recipient (D:R) sex-matched, and 86 D:R mismatched [47 (24.9%) M:F; and 39 (20.6%) F:M]. Myeloablative conditioning was used for the majority (78.5%) mostly with Cy/TBI (60.5%). Standard GVHD prophylaxis regimens were used. Outcomes Median follow-up after transplant was 22.4 months (0.5-135), and 51 (19.5%) had REL. The 1, 2 and 5-year survival rates were 71.9%, 64.9%, and 54.1%, respectively (Figure 1). Acute GVHD developed in 144 (55.2%) and chronic GVHD in 100 (38.3%). Ph-like ALL, Blina for MRD+, Blina for R/R, sALL and CD20-pos had no independent impact on OS. In contrast, age>60, Hy/Tri, and >CR1 at alloHCT were associated with worse OS in UVA, however, in MVA only pre-B ALL NOS was associated with better OS. Female:male D:R status was associated with inferior OS. Blina for R/R disease was associated with increased risk of REL in UVA [HR 5.26 95% CI (1.33, 20.00), p=0.017], whereas other novel high risk groups had no impact on REL. In contrast, T-ALL, Hy/Tri and >CR1 at AlloHCT were associated with increased REL in UVA, but only T-ALL and Hy/Tri continued to predict for increased REL in MVA. Secondary ALL was associated with increased NRM in UVA [HR 1.96 95% CI (1.07, 3.57), p=0.028], whereas other novel high risk groups had no impact on NRM. In contrast, age>60, >CR1 at AlloHCT and D:R sex mismatch were associated with higher NRM in UVA, but only sex mismatch and >CR1 at AlloHCT were associated with higher NRM in MVA. TBI use was associated with higher risk of acute GvHD (p=0.008) and ATG use with lower risk chronic GVHD (p<0.001). Similarly non-PB grafts were associated with a lower risk of chronic GVHD (p=0.005). Results for OS, REL, NRM, acute and chronic GVHD analysis are shown in Table 1. Conclusion Novel high risk groups (CD20+, Ph-like and sALL) do not appear to adversely impact OS after alloHCT, although sALL was associated with increased risk of NRM. Interestingly, pre-B-ALL NOS appear to be associated with favorable OS. Novel targeted therapies also do not independently predict outcome, with the exception of Blina for R/R ALL which may be associated with REL after subsequent alloHCT (a subgroup for whom novel maintenance strategies should be explored). Our analysis highlights the importance of allo-HCT for novel high risk ALL subgroups. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Foran:Agios: Honoraria, Research Funding.

Introduction There have been few recent therapeutic advances in T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), a rare and aggressive malignancy. Intensive chemotherapy +/- allogeneic transplantation (AlloHCT) can effect cure, realized by only a minority of adults. In distinction to B-ALL, there have been no safe/effective targeted therapies developed in T-ALL/LBL. We therefore performed a focused tissue array to identify novel tumor proteins, including CCR4; evaluated together with established immunophenotypic (IP) T-ALL/LBL subtypes [early-T-precursor (ETP), early non-ETP (Pre/Pro-T), common & late thymocyte]. We evaluated the clinical phenotype and outcome together with clinical and epidemiologic data in patients diagnosed at the 3-site Mayo Clinic Cancer Center (MCCC: Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Methods Following IRB approval, we identified 50 consecutive T-ALL/LBL patients from 1997 -2019 diagnosed at the 3-site MCCC. Available remnant leukemia/lymphoma paraffin blocks were identified (n=28). Using immunohistochemistry (IHC) we evaluated expression of leukemic antigens of interest (CCR4, CD47, BCL2, BCL6, PD-L1, CD38 and CD123); these were selected based on clinical availability of novel targeted agents, approved or in development for other indications. Tissue array studies were performed and interpreted by a single hematopathologist (L.J) blinded to clinical data, using positive and negative controls, according to standard techniques. We also evaluated the clinical and epidemiological parameters, including different IP subtypes [ETP: CD1a-, sCD3- & CD8-, Pre/Pro-T: CD1a-, sCD3- & CD8+ or CD8- (11 marker T-ALL IP score was used to distinguish CD8- ETP vs. Pre/Pro-T), thymic: CD1a+ and mature: CD1a- & sCD3+] (Khogeer et al., Br J Haematol., 2019) & the presence of the unique MLLT10-PICALM fusion (n=6), as well as therapy and outcome. Comparisons of characteristics and outcomes of interest were made using a Wilcoxon rank sum test (continuous characteristics) or Fisher's exact test (categorical characteristics), unadjusted Cox proportional hazards regression models (overall survival), or unadjusted logistic regression models (complete remission after first line treatment). Results We identified the expression of novel targetable tissue proteins in all adult T-ALL/LBL cases [Table 1]. BCL2, CD38 & CD47 were expressed in majority of the cases, and CCR4 [Fig. 1] was expressed in 11/28 (39.3%) cases. CCR4 expression was significantly more common in the Pre/Pro-T (75%) vs. other IP subtypes (19%) (p=0.011); there was no other association of CCR4 expression with clinical characteristics/outcomes. We also observed differences in T-ALL vs. T-LBL, specifically T-ALL patients were more likely to be male (71% vs. LBL 38.9%, p=0.038). Surprisingly, T-LBL patients were more likely to have a family history of leukemia/lymphoma (41.2% vs. T-ALL 0%, p<0.001). In addition, a significantly different distribution of IP subtype in T-LBL was noted [Table 2]. Not surprisingly, T-LBL patients were more likely to receive 1st line Hyper-CVAD therapy (88.2% v. T-ALL 43.3%, p=0.005), & had a longer delay from diagnosis to initiation of therapy (median 14 vs. 4 days, p=0.012), however this did not appear to impact clinical outcome. In contrast, we observed an important association of IP subtype with outcome after therapy, including complete remission (p=0.035), & a trend suggesting differences in survival (p=0.069) [Table 3]. However, MLLT10-PICALM was not associated with any unique clinical features or with outcome (death, p=0.85; CR, p=0.98), although 4/6 patients underwent AlloHCT, suggesting an important role of AlloHCT in this subgroup. No other significant association of epidemiologic risk factors with phenotype or outcome was noted. Conclusion Using focused tissue array we have identified expression of tumor associated proteins in T-ALL/LBL including CCR4 (Pre/Pro-T IP) & others, which may be targets of therapeutic agents like mogamulizumab. Furthermore, our analysis demonstrates an important clinical impact of IP subtype in T-ALL/LBL, as well as important clinical & therapeutic differences in T-ALL vs. LBL. This study will help guide development of targeted clinical trials in T-ALL/LBL (CCR4 trial already in development). Further analyses are planned to determine the clinical & epidemiologic association of genetic lesions in this cohort. Disclosures Foran: Agios: Honoraria, Research Funding.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed/refractory B-cell lymphoid malignancies. Axicabtagene ciloleucel (axi-cel), an anti-CD19 CAR-T not only targets the malignant B-cell, but can potentially also target and eliminate normal B-cells. This can interfere with the normal B-cell repertoire, compromising host humoral immunity such as decreased titers of common vaccines (DTaP, MMR). To assess if this was a clinically significant problem, we evaluated all recipients of axi-cel at our center between 6/2018 through 7/2019. Patients and methods: For patients who received commercial axi-cel, humoral immunity was evaluated both quantitatively [absolute lymphocyte count (ALC)] as well as qualitatively by serology titers [IgG antibodies (Abs)] for diphtheria, tetanus, pertussis, measles, mumps, and rubella, and total Immunoglobulin G (IgG) levels. Data was collected within 30 days prior to CAR-T infusion, then at day +30 and between days +60 and +100 after CAR-T infusion. Results: We identified 10 patients (males = 5, 50%), with a median age of 49.9 years (range 30-65) who received commercial axi-cel during the study period. Patient characteristics and indications for CAR-T therapy are shown in Table 1; the cohort represented a heavily pre-treated aggressive B-cell lymphoma patient population. Baseline information on antibody (Ab) titers was available in 8 patients. At baseline, all patients had positive tetanus IgG Abs (≥0.01 IU/mL), 7 had positive diphtheria IgG Abs (≥0.01 IU/mL), 6 had positive measles IgG Abs (≥ 1.1 AI), 5 had positive rubella IgG Abs (≥ 1.0 AI), 3 had positive mumps IgG Abs (≥ 1.1 AI). None of the patients had a positive pertussis IgG Abs (≥100 IU/mL). At follow-up, all patients with positive Ab at baseline maintained titers in the positive range at day +30 and between days +60 and +100 (Figure 1). None of the patients demonstrated a clinically meaningful decrease in Abs titers, despite a drop in ALC and IgG levels (table 2). Conclusions: Albeit a small sample size, IgG Ab titers for diphtheria, tetanus, measles, mumps, and rubella did not appear to be affected by axi-cel at a short interval follow-up after infusion (up to day +100). We plan to extend this analysis in a larger cohort with a longer-term prospective follow-up to validate our findings, especially in light of dropping absolute lymphocyte counts and IgG levels. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding. Foran:Agios: Honoraria, Research Funding. Tun:Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding; Xencor: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

e17500 Background: Metastatic head and neck cancer is a diagnosis with poor prognosis and very little in terms of available active therapy. Until recently the mainstay of therapy was chemotherapy with or without cetuximab. The regimen of cetuximab (C), platinum (P) and 5FU has a response rate(RR) of 36% in the first line setting, and a PFS of 5.6 months and OS of 10.1 months. In the setting of post first line therapy immunotherapeutic agents (IO) have average RR of 15% and median OS of 8 months. Methods: We studied all patients with metastatic or recurrent head and neck cancer who were treated with an IO at our institution between May 2016 and July 2018 evaluating their entire history of therapy. 19 patient were treated with IO at our institution in the designated period of whom 9 received nivolumab (N) and 10 received pembrolizumab ( P ). Patients treated on trials were excluded. Patients who received less than 1 cycle of therapy were also excluded. 7 of the 19 patients received an IO in the first line setting after being refractory or resistant to platinum containing definitive therapy, 7 received the IO after a cetuximab (C) containing first line regimen, 1 patient received IO in second line but was naïve to C and 4 received IO in the third line setting. Results: 3 of 19 patients treated with IO had partial response, there were no complete responses, 6 patients had stable disease as their best response and 10 patients progressed at the time of their first evaluation. 11 of 19 patients received additional therapy post IO. 10 patients received taxane based therapy 5 of whom the taxane was combined with C. Of the 5 patients who received a taxane and C combination 2 had CR, 2 had PR and one had PD. Of the 5 who received other taxane regimens, 1 had PR 1 had SD and 1 had PD, 2 expired prior to their first evaluation. The patient who received a non taxane regimen all had progressive disease. Of the 4 responding patients to C regimens 1 had SD during IO therapy and 3 had PD. The longest response duration to a C regimen post IO was 628 days. Conclusions: We observe an unusual response rate among patients treated with a combination of taxanes and cetuximab after IO therapy. This finding may relate to a modifying effect of IO on sensitivity to subsequent therapy. This observation merits further investigation.