Abstract: 6064 Background: Targeting the immune checkpoint CTLA-4 in addition to PD-1/PD-L1 alone did not increase efficacy in HNSCC, whereas this has not been studied in combination with chemotherapy. Induction chemo-immunotherapy followed by pathologic response-based patient selection for chemotherapy-free radioimmunotherapy was efficient in locally advanced HNSCC (J Immunother Cancer. 2022 Jan;10(1):e003747). The expansion cohorts of the CheckRad-CD8 trial studied safety and efficacy of induction chemo-immunotherapy with increased dose or without CTLA-4 inhibition. Methods: Patients with previously untreated stage III-IVB (AJCC 8 th edition) HNSCC were eligible for this multicenter phase II trial. Induction chemo-immunotherapy of the main cohort (MC) consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients in expansion cohort 1 (EC1) received this combination with high dose tremelimumab 300mg fix dose d5 and patients in expansion cohort 2 (EC2) received no tremelimumab. In EC1 and EC2 prophylactic G-CSF was recommended. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy entered chemotherapy-free radioimmunotherapy up to a total dose of 70Gy. The current analysis focuses on toxicity and pathologic response after induction chemo-immunotherapy. Results: Between Sep 2018 and Sep 2021, 80 patients were enrolled in the MC (one excluded), 20 in EC1 and 20 in EC2 (one excluded) subsequently. In the MC, EC1 and EC2 a total of 56%, 50%, 58% were stage IV and 29%, 30%, 26% had p16 positive oropharyngeal tumors. Baseline median intratumoral CD8+ immune cell density was 395/mm², 505/mm² and 763/mm² in MC, EC1 and EC2. After induction chemo-immunotherapy 41 (52%), 12 (60%) and 11 (58%) of the patients had pCR in the re-biopsy in MC, EC1 and EC2. Patients with residual tumor after induction therapy had a median intratumoral CD8+ immune cell density of 670/mm², 781/mm² and 1605/mm², which was a median increase by factor 3.0, 2.1 and 4.8 in the corresponding patients’ tissue samples. In the cohorts MC, EC1 and EC2 the overall rate of grade 3-4 adverse events per patient was 1.38, 1.35 and 0.58. The corresponding rate of non-hematologic adverse events per patient was 0.84, 0.95 and 0.37, respectively. Conclusions: Neither increase of tremelimumab dosage nor its omission did significantly affect pathologic response to induction chemo-immunotherapy with cisplatin/ docetaxel/ durvalumab. Non-hematologic toxicity was slightly increased for high dose tremelimumab and clearly decreased without tremelimumab. The role of concomitant administration of tremelimumab with radiotherapy cannot be assessed until the final study analysis. Clinical trial information: NCT03426657.

Abstract: Abstract 1484 Introduction: Acute Myeloid Leukemia (AML) is more common among patients over the age of 60, who also historically have a poorer prognosis. It is unclear which patients will benefit most from intensive chemotherapy; prognostic factors have been identified to risk-stratify these patients, but tend to consider characteristics specific to the disease such as cytogenetics [Lancet 2010; 376: 2000–08], and may not account for patient comorbidities that preceded the diagnosis of AML. Increased body mass index (BMI) has been associated with an increased incidence of various malignancies, including AML [The Oncologist 2010; 15: 1083–1101] , and is increasingly prevalent among the general population. We sought to determine whether patient BMI at time of AML diagnosis is related to overall survival among patients older than age 60. Methods: We performed a retrospective chart review of all patients diagnosed at Massachusetts General Hospital with records available in the electronic medical record between January 1, 1992 and May 1, 2011. Patients were identified using billing codes and pathology records and underwent chart review to confirm a diagnosis of AML. Patients were included in this review if they had a pathologically-confirmed new diagnosis of AML, were older than age 60 at the time of diagnosis, and were given cytarabine-based induction chemotherapy. We collected past medical history, presenting labs, patient cytopathology, weight, and height at diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method, with 95% confidence intervals calculated using Greenwood's formula. We then performed a stepwise multivariable Cox regression analysis, pre-specifying that a variable had to be significant at the 0.3 level before it could be entered into the model, while a variable in the model had to be significant at the 0.05 level for it to remain in the model. Results: We identified 152 patients with AML diagnosed after the age of 60. The median age was 68 years (range 60–87); 54% of patients were male, and 86% were white. Patient disease was identified as de novo in 50%, and secondary in 50%. Cytogenetics, when available (86.2% of patients), were most commonly normal (37.5%) or poor risk (34.2%); only 1.3% of patients were good risk. The median OS for all patients was 269 days (95% CI 217–323). The 60 day OS for all patients was 83% (95% CI 77–89%). Using the log-rank test to perform a univariate analysis, worsened OS was associated with increased age (P=0.024); body mass index (BMI) 〈 27, the median BMI in our cohort, (P=0.011); presence of coronary artery disease (CAD) (P=0.042); and with cytogenetics (P=0.013). The multivariable analysis of the Cox proportional-hazards model found that the hazard rate for death was increased with older age (HR 1.53, P=0.027, 95% CI 1.05–2.24), lower BMI 〈 27 (HR 1.93, P=0.002, 95% CI 1.28–2.92) and cytogenetics (P 〈 0.05). After multivariable analysis we did not find a significant association between OS and CAD, diabetes, gender, race, de novo vs. secondary disease, or presenting hematocrit, sodium, or total bilirubin. Conclusions: Patients over the age of 60 with a new diagnosis of AML carry a poor prognosis; comorbid disease at the time of presentation may assist a clinician in risk stratification of this age group. Intriguingly, BMI greater than or equal to 27 was associated with improved OS among patients older than 60 treated at our institution. Additional studies will be necessary to determine the causal factors of worse survival in patients older than age 60 who have normal BMI compared to obese patients and to identify approaches that will ameliorate these poorer outcomes in this population. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 3772 Introduction: Clinical outcomes for patients with chronic myeloid leukemia (CML) have dramatically improved over the course of the past ten years, following the advent of tyrosine kinase inhibitors (TKIs) that target BCR/ABL. Nonetheless, survival differences persist between age groups. Prior analyses suggested that this difference occurs in part due to treatment variation; in Sweden, patients older than age 79 had poorer relative survival, and more typically were treated with hydroxyurea rather than a TKI [Bjorkholm, J Clin Oncol 29:2514]. Other studies have noted gains made in relative survival up to the year 2004 [Brenner, Haematologica93:1544] , but longer-term overall survival following the widespread use of TKI therapy is less well described among older patients in the U.S. We performed an epidemiologic study of patients registered in the Surveillance, Epidemiology, and End Results (SEER) database to estimate the 5 year overall survival (OS) of patients treated for CML in the era of TKI therapy to assess for differences in survival outcomes among patients within different age groups. Methods: Patients with a diagnosis of CML were identified using the SEER 19 registries database [www.seer.cancer.gov, 1973–2009, November 2011 submission]. We included patients with a diagnosis code of CML NOS (Code 9863) and BCR/ABL+ CML (Code 9875) diagnosed between January 2000 and December 2005. This interval brackets the FDA approval of imatinibin 2001, and its incorporation into NCCN guidelines in 2003. To reflect the evolution of CML treatment during this interval, we trended 5-year overall survival by the year of initial diagnosis. To evaluate the effect of age on survival, patients were divided into cohorts based on age at diagnosis: 15–44 years old, 45–64 years old, 65–74 years old, and 75–84 years old. Overall survival was estimated using the method of Kaplan and Meier. Cox proportional hazards regression was used to model OS to estimate the effects of year of diagnosis within each age group. All analyses were performed using SAS statistical software. Results: We identified 5,138 patients registered in the SEER database with a new diagnosis of CML between January 2000 and December 2005. The patients were 57.6% male; this was the first recorded primary malignancy for 88.4% of the cohort. The 5-year OS improved among patients in every age group between the years 2000 and 2005 (Table 1, Figure 1). Compared to patients diagnosed in the year 2000, patients between the ages of 15 and 44 years had the greatest improvement in 5 year OS (Figure 1; hazard ratio (HR) for dying 0.427, 95% CI: [0.278;0.655], P 〈 0.0001). Patients between ages 75 and 84 also had significant survival gains; the OS estimate at 5 years increased from 19.2% in 2000 to 36.4% in 2005 (HR for dying 0.571, 95% CI: [0.443;0.736], P 〈 0.0001). Discussion: Tyrosine kinase inhibitors targeting BCR/ABL have been FDA-approved for the treatment of CML since 2001 and are highly effective therapy for this disease. Since their advent, patient survival has improved among all age groups; intriguingly, this is also seen among older patients. Indeed, we found marked improvements in OS at 5 years among patients between the ages of 75 and 84, a group which historically has had very poor outcomes. Our data suggests that the advent of BCR/ABL tyrosine kinaseinhibitors has had a significant impact on the outcomes of older patients with CML, likely by providing them with tolerable and effective treatment options not previously available. Further study is needed to determine specific factors that contribute to this improvement in survival. In the future, older age groups are likely to experience ongoing benefit from novel and effective therapeutics with tolerable side effect profiles. Disclosures: Fathi: Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 1041 Introduction Granulocytic Sarcoma (GS), also known as chloroma or myeloblastoma, is a rare neoplasm composed of immature myeloid cells occurring in any extramedullary organ, most commonly in the lymph node and soft tissue. It can occur as an isolated lesion, or in conjunction with a diagnosis of acute myeloid leukemia (AML), myeloproliferative disorder (MPD) or myelodysplastic syndrome (MDS). GS has been generally associated with more aggressive disease and a poor prognosis. Although it has been described in the literature in small case series, the clinical characteristics and prognosis of patients with GS associated with AML, MDS, MPD or as an isolated lesion have not been thoroughly described. We therefore studied our institutional experience of granulocytic sarcoma to gain further insight into the clinical features and associations of this disease. Methods We conducted a retrospective medical record review of patients who presented with GS to Massachusetts General Hospital from 1994 through 2011. In total, 35 patients with GS were identified. Kaplan Meier method was used to estimate overall survival (OS). OS was defined as the duration from the time of diagnosis of GS to date of death; patients still alive at the time of analysis were censored. Patients were categorized into three groups for analysis depending on the presence of bone marrow disease: primary (isolated) GS, GS associated with AML, and GS associated with MDS or MPD. Result Of 35 patients with GS, 20 (57%) were associated with a diagnosis of AML, 10 (29%) presented with either MDS or MPD, and 5 (14%) presented with primary GS. Of the AML-associated GS, 13 occurred concurrently with AML at diagnosis and 7 presented as AML relapse. Of the 10 cases of GS with either MDS or MPD, one patient presented with MDS and 9 with MPD. The median age of all patients was 57 years old; 19 of 35 patients were female. Median white blood count (WBC) was 4.6 (th/cmm) (IQR 3.5–8.8) for patients with AML-associated GS and 20.2 (th/cmm) (IQR 9.7–61) for those with MDS/MPD-associated GS. One year survival was 10% (95% CI 0.5 – 35.8%) in MDS/MPD associated GS, 49.5% (95% CI 26.5 – 68.9%) in AML associated GS, and 60% (95% CI 12.6 to 88.2%) in primary GS. The most common area of involvement in patients with AML-associated GS was the nervous system (22%). In contrast, among patients with MPD/MDS-associated GS, the most commonly involved site was bone (45%) (Table 1). 63% of all patients had one site of involvement with GS at presentation. The most common presenting symptom was pain either caused by a mass or lymphadenopathy. Cytogenetics were normal for the majority of patients. Interestingly, however, one AML patient and one patient with primary GS presented with a 9;22 translocation, two AML presented with other cytogenetic abnormalities involving chromosome 9 (t(9;11)(p22;q23) & add(9)(q34)), and three others, including one with primary GS, displayed abnormalities at chromosome 11, specifically 11q23 (Table 2). Conclusions With this study, we provide a single institution experience of granulocytic sarcoma, a rare manifestation of myeloid neoplasms. Interestingly, we found variable presentation with different patterns of site involvement and white blood counts in patients with GS associated with AML and in those with GS associated with MPD/MDS. Additionally, certain karyotypic abnormalities were over-represented in patients with GS, including t(9;22) and translocations involving chromosome 11q23. Finally, in our small series, patients with a diagnosis of GS associated with MPD/MDS had worsened outcomes compared to those with AML-associated GS or primary GS. Larger, prospective studies are needed to better and more fully assess outcomes in these patients. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background: Patients (pts) with MDS or AML who relapse after allogeneic transplantation (allo-HCT) have a very poor prognosis. Hypomethylating agents (HMA) and checkpoint blockade with the anti-CTLA4 blocking antibody ipilimumab (IPI) have each induced responses with acceptable toxicity in AML pts who relapse after allo-HCT. We hypothesized that adding decitabine (DAC) would improve response compared with IPI alone by activating and promoting T cell-mediated anti-leukemic immune reactivity. We are conducting a multicenter phase I study (CTEP 10026) of DAC plus IPI in pts with R/R MDS/AML in both post allo-HCT and transplant-naïve settings to assess safety and estimate efficacy. Methods: The primary objective is to determine the maximum tolerated dose (MTD) or RP2D of combination DAC + IPI in pts with R/R MDS/AML who are post allo-HCT (Arm A) or transplant-naïve (Arm B). Cohorts of 3-6 are sequentially enrolled in 3 dose levels (DL) of IPI using a 3+3 design with expansion in each arm; DLs 0-2 are 3, 5 and 10 mg/kg, respectively. Eligibility for both arms: relapsed AML (extramedullary or ≥ 5% blasts) or R/R MDS (≥ 5% blasts) or unfit elderly AML; Arm A only: ≥ 2 wks off systemic immunosuppressive (IS) therapy, T cell chimerism ≥ 20%, and no prior acute GVHD ≥ gr III. DLT is defined as ≥ gr 3 non-heme, ≥ gr 3 acute GVHD or ≥ gr 3 steroid-refractory immune-related adverse events (AEs) occurring within 8 weeks from first IPI dose. Epigenetic priming with DAC lead-in cycle 0 was followed by combination cycles of DAC + IPI. DAC is given at 20 mg/m2 days 1-5 q 28 days. IPI is given on day 1 of cycles 1-4 and every other cycle in cycles 5-12. Pts who discontinued study either in cycle 0 or DLT period without IPI-toxicity were replaced. Arm A opened after safety was confirmed at DL0 in Arm B. Results: As of June 9, 2019, 26 pts (15M, 11 F) have enrolled in this on-going trial. Of the 12 pts (11 AML and 1 MDS) enrolled in Arm A (post allo-HCT), median age was 66.5 (range 29-74) and 9 had previously received HMA. 7 of 8 pts in DL0 (1 progressed in cycle 0) and 3 of 4 pts in DL1 (1 died from pneumonia in cycle 0) received DAC + IPI. DL0 was expanded to 6 to confirm safety without DLT. Median treatment duration after first IPI dose was 5 cycles (range 1-7); 4 pts continue on trial. Common AEs were gr 1-2 dyspnea (n=4), gr 1-3 fatigue (n=4), and gr 1-2 fever (n=4). Gr 3 AEs were febrile neutropenia (n=2), pneumonia (n=1), and candidemia (n=1). Gr 1 immune-related dermatitis (n=1) reversed with steroids. Acute GVHD was not observed. Moderate-severe chronic GVHD was noted in 2 pts mainly involving skin, which was responsive to photopheresis and oral IS. Though 1 CR and 1 marrow CR have been observed at DL0, dose-escalation up to DL2 is on-going to determine MTD. Of the 14 pts (11 AML and 3 MDS) enrolled in Arm B (transplant naïve), median age was 75.5 (range 34-82) and 9 had previously received HMA. 4 of 6 pts in DL0 (1 progressed and 1 withdrew in cycle 0), 3 of 5 pts in DL1 (2 withdrew in cycle 0) and 3 of 3 pts in DL2 received DAC + IPI. Median treatment duration after first IPI dose was 4 cycles (range 1-8); 3 pts remain on study. Common AEs were gr 1-3 fatigue (n=9), gr 1-2 anorexia (n=5), and gr 3 febrile neutropenia (n=8). Immune-related gr 2 colitis (n=1) and gr 2/3 (n=4) dermatitis were all steroid-responsive. Of the 10 pts who received at least one IPI dose, 5 (50%) achieved an objective response including 3 CR, 1 CRi and 1 PR. All responses were observed in AML pts, including 1 with only skin involved. Expansion to confirm MTD is underway. No treatment-related deaths or DLTs were observed in either Arm. Reasons for discontinuation after IPI: progression (n=9), proceeding to allo-HCT or DLI (n=2), withdrawal (n=1), stroke due to underlying atrial fibrillation (n=1) and disseminated nocardiosis (n=1). In both Arms, multiplex immunofluorescence (MIF) staining of BM biopsies revealed a higher density of CD3+CD4+ cells after 4 cycles of DAC + IPI in 4 responders (R) compared to 4 non-responders (NR) (p=0.0433). Longitudinal MIF IHC in an Arm B responder identified the increasing presence of a tumor immune infiltrate composed of CD3+CD8+GZMB+ T cells prior to achieving CR (Fig 1). Conclusions: Combination DAC + IPI is tolerable and has encouraging clinical activity in post allo-HCT and transplant naïve pts with R/R MDS/AML. Ongoing studies focus on comparing the immunologic and genetic characteristics of the tumor immune infiltrate in each cohort to understand the contribution of alloimmunity to treatment response. Disclosures Garcia: Abbvie: Research Funding; Genentech: Research Funding. Keng:agios: Membership on an entity's Board of Directors or advisory committees. Brunner:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding. Khaled:Omeros: Consultancy; Alexion: Consultancy, Speakers Bureau; Daiichi Sankyo: Other: Travel support. Steensma:H3 Biosciences: Other: Research funding to institution, not investigator.; Arrowhead: Equity Ownership; Onconova: Consultancy; Stemline: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Summer Road: Consultancy; Astex: Consultancy. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Cutler:Omeros: Consultancy; Kadmon: Consultancy; BiolineRx: Other: DSMB; Cellect: Other: DSMB; Kalytera: Other: DSMB; ElsaLys: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy; Incyte: Consultancy; Jazz: Consultancy; BMS: Consultancy. Ho:Omeros Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy. Neuberg:Madrigal Pharmaceuticals: Equity Ownership; Pharmacyclics: Research Funding; Celgene: Research Funding. Lindsley:Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Research Funding; Medlmmune: Research Funding. Galinsky:ABIM: Other: Member of specialty oncology board; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ritz:TScan Therapeutics: Consultancy; LifeVault Bio: Consultancy; Kite Pharma: Research Funding; Talaris Therapeutics: Consultancy; Draper Labs: Consultancy; Avrobio: Consultancy; Celgene: Consultancy; Merck: Research Funding; Equillium: Research Funding; Aleta Biotherapeutics: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. Wu:Pharmacyclics: Research Funding; Neon Therapeutics: Other: Member, Advisory Board. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. DeAngelo:Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy. Soiffer:Jazz: Consultancy; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Kiadis: Other: supervisory board; Mana therapeutic: Consultancy; Cugene: Consultancy. OffLabel Disclosure: Combination of ipilimumab and decitabine for MDS/AML treatment for patients who are post-transplant or transplant naive