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PURPOSE To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

PURPOSE Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months ( P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.

PURPOSE Patients with locally advanced breast cancer (LABC) typically undergo staging tests at presentation. If staging does not detect metastases, treatment consists of curative intent combined modality therapy (neoadjuvant chemotherapy, surgery, and regional radiation). Positron emission tomography-computed tomography (PET-CT) may detect more asymptomatic distant metastases, but the evidence is based on uncontrolled studies. METHODS For inclusion, patients had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1). Consenting patients from six regional cancer centers in Ontario were randomly assigned to 18F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of the chest/abdomen and pelvis). The primary end point was upstaging to stage IV. A key secondary outcome was receiving curative intent combined modality therapy (ClinicalTrials.gov identifier: NCT02751710 ). RESULTS Between December 2016 and April 2022, 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging. Forty-three (23%) PET-CT patients were upstaged to stage IV compared with 21 (11%) conventional staged patients (absolute difference, 12.3%; 95% CI, 3.9 to 19.9; P = .002). Consequently, treatment was changed in 35 (81.3%) of 43 upstaged PET-CT patients and 20 (95.2%) of the 21 upstaged conventional patients. Subsequently, 149 (81%) patients in the PET-CT group received combined modality treatment versus 165 (89.2%) patients in the conventional staging group (absolute difference, 8.2%; 95% CI, 0.1 to 15.4; P = .03). CONCLUSION In patients with LABC, PET-CT detected more distant metastases than conventional staging, and fewer PET-CT patients received combined modality therapy. Our randomized trial demonstrates the utility of the PET-CT staging strategy.

PURPOSE The Pediatric Oncology COVID-19 Case Report registry supplies pediatric oncologists with data surrounding the clinical course and outcomes in children with cancer and SARS-CoV-2. METHODS This observational study captured clinical and sociodemographic characteristics for children (≤ 21 years) receiving cancer therapy and infected with SARS-CoV-2 from the pandemic onset through February 19, 2021. The demographic and clinical characteristics of the cohort were compared with population-level pediatric oncology data (SEER). Multivariable binomial regression models evaluated patient characteristics associated with hospitalization, intensive care unit (ICU) admission, and changes in cancer therapy. RESULTS Ninety-four institutions contributed details on 917 children with cancer and SARS-CoV-2. Median age at SARS-CoV-2 infection was 11 years (range, 0-21 years). Compared with SEER, there was an over-representation of Hispanics (43.6% v 29.7%, P < .01), publicly insured (59.3% v 33.5%, P < .01), and patients with hematologic malignancies (65.8% v 38.3%, P < .01) in our cohort. The majority (64.1%) were symptomatic; 31.2% were hospitalized, 10.9% required respiratory support, 9.2% were admitted to the ICU, and 1.6% died because of SARS-CoV-2. Cancer therapy was modified in 44.9%. Hispanic ethnicity was associated with changes in cancer-directed therapy (adjusted risk ratio [aRR] = 1.3; 95% CI, 1.1 to 1.6]). Presence of comorbidities was associated with hospitalization (aRR = 1.3; 95% CI, 1.1 to 1.6) and ICU admission (aRR = 2.3; 95% CI, 1.5 to 3.6). Hematologic malignancies were associated with hospitalization (aRR = 1.6; 95% CI, 1.3 to 2.1). CONCLUSION These findings provide critical information for decision making among pediatric oncologists, including inpatient versus outpatient management, cancer therapy modifications, consideration of monoclonal antibody therapy, and counseling families on infection risks in the setting of the SARS-CoV-2 pandemic. The over-representation of Hispanic and publicly insured patients in this national cohort suggests disparities that require attention.

Accurate and reproducible methods to diagnose, grade and report acute graft vs. host disease (GVHD) are critical for evaluation of new treatments and biomarkers. BMTCTN 1202 created a biorepository and clinical data bank for the study of GVHD biomarkers and other transplant outcomes. To create a representative study population any pt >10 kg undergoing alloHCT was eligible (Table 1). Symptoms suggestive of GVHD, biopsy results, immunosuppressive medications, and possible etiologies were reported weekly until day 100. An end-point review committee (ERC) performed a near real time adjudication of reported symptoms at their onset and assigned a confidence level (Confirmed, Probable, Possible or Negative) for each organ according to Harris, BBMT, 2016. The final repository included 41,468 annotated biospecimens from 1709 alloHCT patients (pts) transplanted at U.S. centers from 2012-2016. Although 90% of pts developed symptoms at least once, physicians suspected GVHD in only 23% of cases and GVHD was considered the only etiology in 12%. Biopsies (bx) were performed in 40% of pts, most often for upper or lower GI symptoms. Bx results were equivocal in 11% although the range among centers was broad (0-45%). Equivocal results were most likely for skin bx and during the 2nd week after transplant. Systemic steroids were administered to 70% of pts at least once, often for non-GVHD reasons (41% of steroid courses). When GVHD was in the differential diagnosis, systemic steroids were started 81% of the time. The ERC adjudicated 2,008 cases with symptoms suggestive of GVHD onset. In 12.3% of cases the ERC modified either the center reported diagnosis of GVHD (4.6%) or the automated generated severity grade (7.7%). GVHD was diagnosed in 1025 pts and categorized as confirmed (31%), probable (50%), or possible (19%). The proportion of definitive diagnoses (Confirmed or Negative) increased with longer time post-transplant (Fig 1). ERC adjudication substantially lowered the incidence of GVHD grade 2-4 from 30% as reported by centers to 23% (confirmed or probable) by ERC. An adjudicated diagnosis of GVHD strongly associated with 6 month NRM, adjusted for patient age, gender and HLA matching (HR = 2.0, p In summary, the largest prospective observational study of GVHD outcomes demonstrated that symptoms in GVHD target organs are almost universal after transplant, their differential diagnosis is broad, tissue biopsies are infrequently done and their results are often equivocal, and steroids are often prescribed for reasons other than acute GVHD. These limitations undermine the current methods of diagnosis and reporting of acute GVHD on clinical trials. A robust reporting and adjudication system has significant value and may improve the chances of success of prospective clinical trials.

460 Background: Muscle invasive bladder cancer (MIBC) is an aggressive local disease where initial staging with conventional CT imaging is often suboptimal. To explore the role of PET-CT in both staging MIBC and assessing response to neoadjuvant chemotherapy (NAC), we conducted a prospective multicentre, randomized trial known as PETMUSE. We report here the first results from the neoadjuvant substudy which assessed interim PET-CT response after 2-3 cycles of NAC and how this correlated with disease free survival (DFS) and overall survival (OS). Methods: Patients with MIBC (T2a-4a, N0-3, M0) based on transurethral resection of their bladder tumor and CT staging were randomized 2:1 to PET-CT or no PET-CT. All PET-CT patients, receiving cisplatin-based NAC underwent a second PET-CT after 2 cycles of gemcitabine and cisplatin (GC) or 3 cycles of dose dense methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) to assess for interim response. Patients were scored (1-5) by 2 independent reviewers according to the extent of metabolic response on PET-CT. Disease-free survival (DFS) and overall survival (OS) were collected. Results: Between 2016 and 2021, 291 patients were enrolled on PETMUSE of which 46 participated in the neoadjuvant substudy. Median age was 68 (51-86); 36 (78%) were male; 26 were ECOG 0 (57%); 31 (68%) were T2, 13 (28%) were T3/T4; and 35 (76%) were node negative. In terms of NAC regimens: 22 (48%) received GC, 17 (37%) split dose GC, 6 (13%) ddMVAC, and 1 (2%) MVAC. On PET-CT, 23 (50%) had a complete metabolic response, 14 (30%) had a partial metabolic response, 5 (11%) had no change or mixed response and 4 (9%) had progressive disease or new lesion on PET scan. Metabolic response on PET-CT was a statistically significant prognostic factor for both DFS and OS (see Table). Conclusions: In MIBC patients receiving cisplatin-based NAC, metabolic response seen on interim PET-CT was correlated with DFS and OS. PET-CT warrants further study in this setting as a potential early indicator of response to NAC. Clinical trial information: NCT02462239 . [Table: see text][Table: see text]

225 Background: Metastatic, castration-resistant prostate cancer (mCRPC) is commonly the deadly form of PC. Among these, a subset of tumors are androgen-indifferent with the most aggressive often manifesting variant histology, including neuroendocrine or small cell changes. Neuroendocrine PC can be de novo (NEPC) or develop in response to therapy as treatment emergent (CRPC-NE). Currently effective durable treatments for NEPC are lacking. Hence, we sought to identify additional targets in CRPC/NEPC using an integrative platform of whole genome (WGS) and transcriptome sequencing (RNAseq). Methods: WGS was performed on55 tumor/normal pairs (CRPC-Ad, n= 32; CRPC-NE, n=13; de novo NEPC, n=7; metastatic hormone naïve, PC n=3) from 48 patients. RNAseq data was available in a subset of 21 samples. We employed the Isabl GxT analytic platform and manually curated single base substitution (SBS, COSMIC v3) molecular signatures and structural variants (SV) that involved tumor suppressor genes and oncogenes. Results: We observed 184 events in cancer-associated genes and targets in 38 cases. Non-canonical ETS fusions were identified in 2 CRPC-Ad patients ( MSMB-ERG and YWHAE-ETV4). Other rare events included SVs affecting ALK ( SLC45A3-ALK) and FGFR1 amplification in 1 patient each. Pathogenic germline alterations in 15% of patients with equal frequency in each clinicopathological state. These variants included genes such as BRCA1, BRCA2, and ATM, and other genes of uncertain relevance for prostate cancer ( e.g., PPM1D and MUTYH). SBS genomic signatures associated with homologous recombination deficiency (HRD) were observed in 15% of the patients (7 cases): 3 harbored germline BRCA1/2mutations, 2 with somatic BRCA2 mutations, and 2 without alteration in BRCA1/2 (1 of these CRPC-Ad had a complex SV disrupting RAD51B) without apparent enrichment for any histology, and a majority of both histologies were enriched in Mismatch repair (MMR)-associated SBS. One subject CRPC-NE and amphicrine character, which displayed a complete response to immune checkpoint blockade, harbored driver mutations in AR and CTNNB1, and homozygous loss of MSH2/6. Further, molecular signatures of potential clinical relevance were detected at varying contributions and included CDK12-type genomic instability (CRPC-Ad, n=2) (4%) and MMR deficiency with POLD1 proofreading (CRPC-Ad) who also experienced a durable response to pembrolizumab. Conclusions: WGS/RNAseq in CRPC and NEPC elucidates genomic signatures associated with HRD and MMR, complex SVs in oncogenes, and non-canonical ETS fusions. Expansion of our analysis is underway with enhanced integration of clinical metadata and RNAseq for rational trial design for aggressive variant CRPC and NEPC.

TPS406 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP.1 We reported the association between high intratumoral CD8+ T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI).2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue.3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation.4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants.3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy.7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8+ T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 . References: 1) Scolieri MJ, J Urol 2000, 2) Clin Oncol 36, 2018: suppl; abstr 5068, 3) Muthuswamy R, Prostate 2016, 4) Sfanos KS, Prostate 2009, 5) Gupta S, Prostate 2000, 6) NCT01545141, 7) NCT02151448, 8) NCT02432378.

113 Background: The prognosis of refractory mCRPC remains poor despite advancements in therapeutic options. KeyNote-199 demonstrated modest activity of Pem in mCRPC with expected safety profile. We present our real-world experience with Pem in mCRPC. Methods: We conducted a retrospective review of mCRPC patients treated with Pem at our institution from 1/1/2017 to 10/1/22. Baseline demographic, clinicopathologic, and genomic characteristics were recorded. PSA and radiographic responses were assessed by the study team, and survival distributions estimated using the Kaplan-Meier method. Results: A total of 39 patients were identified – 97% (37) were White, median age was 71 years, 4% (19/35) had a Gleason Score ≥8; 80% (31) had skeletal and 74% (29) had soft tissue metastases at Pem initiation. Overall, patients were heavily pre-treated (median of 7 prior therapies, range 0-8) - 87% (34) had received taxanes, 82% (32) novel antiandrogens, 23% (9) Ra-223, 21% (8) Sipuleucel-T, and 2% (1) Olaparib. Median duration on Pem was 7 months (range = 1-29). Among the 34 evaluable patients, 2 (6%) achieved CR, 2 (6%) had PR, 5 (15%) had stable disease (SD), and 25 (73%) had progressive disease (PD) on radiographic assessment. PSA reduction ≥ 50% was noted in 7/32 (22%) patients. The 4 patients who had radiographic CR/PR had positive predictive biomarkers – Patient 1: CR – MSI-H, high TMB (17.5/Mb); Patient 2: CR – MSI-indeterminate, germline MSH6 mutation; Patient 3: PR – MSI-H, high TMB (28.8/Mb), germline MSH2 mutation; and Patient 4: PR – MSI-S, high TMB (18.3/Mb), PDL1 TPS 100%, positive neuroendocrine markers. Interestingly, patient 3 was switched to ipilimumab + nivolumab after PD on Pem, and subsequently had a CR. None of the evaluated patients with SD or PD had high MSI, TMB, or PDL1 levels. The median overall survival from Pem initiation was 4.4 months (95% CI 3.0-10.2 months). Three (8%) patients discontinued Pem due to immune-related adverse effects (IRAEs); no treatment-related deaths were reported. The most frequent Gr 3 IRAEs are shown. Conclusions: Single-agent Pem demonstrated modest overall efficacy in mCRPC, restricted only to patients with predictive biomarkers. Given the non-trivial risk of IRAEs, financial toxicity, and potential QoL implications, we suggest using checkpoint inhibitors only in appropriately biomarker-selected patients with mCRPC. [Table: see text]

TPS398 Background: Randomized data from the interferon era demonstrated survival benefits of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN in most IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in mRCC now includes multiple first-line combination immunotherapy approvals. Five-year follow-up from the Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and durable objective responses with ipilimumab and nivolumab (I/N) compared to sunitinib. However, patients with a primary kidney lesion in situ appeared to have less benefit than patients with prior nephrectomy. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. We hypothesize that SBRT to the primary kidney mass will enhance the efficacy of I/N compared to standard of care I/N alone in this unique subset of de novo mRCC patients. We also hypothesize that the combination of SBRT and I/N will lead to upregulation of key components of immune modulation as well as unique perturbation of the host gut microbiome compared to I/N alone. Methods: This phase II trial randomizes untreated mRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven mRCC (any histology) and IMDC intermediate/poor risk disease. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include: (1) immune and genomic profiling of liquid biopsies; (2) transcriptional profiling of baseline tumor biopsies; and (3) interrogation of the gut microbiome and bacterial functionality. Blood and fecal samples will be prospectively collected at baseline, prior to cycle 2 of each arm, and at time of disease progression or the 12-month mark, whichever comes first. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α = 0.1, power = 80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Trial is enrolling in Canada and Australia. Clinical trial information: NCT04090710.

182 Background: Androgen receptor (AR) signaling is critical to prostate cancer (PCa) cell survival and proliferation. Androgen ablation leads to expansion of both AR−/lo and AR+/hi resistant clones in CRPC xenografts. Most current therapies for mCRPC are directed towards AR+/hi cells. BCL-2 is highly up-regulated in CRPC xenografts and human tumors post-Enza. Ven, a selective BCL-2 inhibitor, inhibits Enza resistance in AR−/lo and CRPC models. We hypothesize that co-targeting AR−/lo and AR+/hi clones with Ven and Enza may inhibit Enza resistance in human mCRPC. Methods: This is a phase 1b single center, single arm trial of fixed dose Enza (160mg/d) with escalating doses of Ven in patients with mCRPC that has progressed on multiple lines of prior therapies including antiandrogens to evaluate pharmacokinetics, safety and recommended phase 2 dose. A total of 10 patients were enrolled in the study. Three dose levels of Ven (400mg (DL1), 600mg (DL2), and 800mg (DL3)/d q28d) were evaluated using a 3+3 study design. Kaplan Meier method was used to estimate median overall survival (OS) and time to next systemic therapy (TNST). Results: Median age was 71.3 years and mean duration on treatment was 28.7 weeks (range: 8-140 weeks). On an average, each patient received 3 lines of treatment prior to enrollment(range:1-8). The most frequent treatment related adverse events (TRAEs) (>10%) were mostly grade 1-2 as listed. Grade 3 TRAEs included hypertension (20%), fatigue (10%), and thrombocytopenia (10%). Grade 3 fatigue as DLT was reported in one patient in DL3. Only 1/10 (10%) attained PSA50 response; 4/10 (40%) patients had stable disease and 6/10 (60%) had disease progression as their best radiographic response. Median OS for the study population was 18.8 months (95% CI 5.3-28.2 months) and median TNST was 5.4 months (95% CI 0.9-34.6 months). Conclusions: This phase 1b trial demonstrates an acceptable toxicity profile for the combination of Enza and Ven in refractory mCRPC. PK evaluations and correlative biomarker studies are currently ongoing. Clinical trial information: NCT03751436 . [Table: see text]

PURPOSE To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups ( P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not ( P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR ( P < .0001). Toxicity was comparable in both dose groups. CONCLUSION In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

PURPOSE The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.

PURPOSE We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy ( P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy ( P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.

PURPOSE Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab. METHODS A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review. RESULTS A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively. CONCLUSION Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

LBA501 Background: Adjuvant breast RT is usually prescribed following BCS to reduce the risk of local recurrence (LR). However, this treatment is inconvenient, costly, and associated with acute and late toxicity. Traditional clinical pathological factors (CPFs) alone are limited in their ability to identify women with a low enough risk of LR to omit RT. Molecular defined intrinsic subtypes of BC provide additional prognostic information with luminal A having the lowest risk of recurrence. A retrospective analysis of a previous trial suggested that women >60 years with luminal A grade 1-2 T1N0 BC treated by BCS and endocrine therapy alone had a low rate of LR ( JCO 2015; 33:2035). The utility of identifying luminal A subtype combined with CPFs has not been prospectively evaluated for its ability to guide RT decision-making. Methods: A prospective multicenter cohort study was performed. Eligibility criteria were: women ≥ 55 years; having undergone BCS for grade 1-2 T1N0 BC; ≥ 1mm margins of excision; luminal A subtype (defined as: ER ≥ 1%, PR>20%, HER2 negative and Ki67 ≤ 13.25%); and treated with adjuvant endocrine therapy. ER, PR and HER2 were performed locally as per ASCO guidelines. Patients meeting clinical eligibility with ER ≥ 1%, PR>20%, HER2 negative BC were registered and had Ki67 immunohistochemistry performed centrally in one of three Canadian laboratories using International Ki67 Working Group methods. Proficiency testing between laboratories was performed yearly. Patients with Ki67 ≤ 13.25% were enrolled in the trial and were assigned to not receive RT. The primary outcome was LR defined as time from enrollment to any invasive or non-invasive cancer in the ipsilateral breast. Assuming a 5-year LR rate of 3.5%, 500 patients were required to show that the upper bound of a two sided 90% (one-sided 95%) confidence interval (CI) was 1N0 luminal A BC following BCS treated with endocrine therapy alone had very low rates of LR at 5 years and are candidates for omission of RT. Clinical trial information: NCT01791829. [Table: see text]

7570 Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). We recently developed a simplified diagnostic and prognostic index termed the ‘optimized HLH inflammatory’ (OHI) index comprising the combined elevation of sCD25 ( > 3,900 U/mL) and serum ferritin ( > 1,000 ng/mL), which in HM patients both identifies HLH and predicts mortality more accurately than conventional criteria for HLH. In this study, we examined whether mortality in our cohort is directly related to progressive malignancy vs. HLH-associated causes in OHI+ and OHI- patients. Methods: We performed a multicenter, retrospective study of patients with newly diagnosed lymphoma from Israel, the USA, and Japan for whom sCD25 and ferritin levels were measured either as routine surveillance or during investigation for HLH and classified patients by their OHI status. The International Prognostic Index, International Prognostic Score, and Follicular Lymphoma International Prognostic Index were used to estimate the predicted prognosis of T/B cell non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, and follicular lymphoma, respectively. Predicted five-year overall survival was calculated based on the relevant prognostic index and was compared between OHI+ and OHI- patients using the unpaired t-test. The actual survival at five years/last follow-up was recorded, as was the cause of death. The odds ratios (ORs) for observed vs. predicted mortality, and for HLH- vs. malignancy-related death were calculated using the Chi-square test. Results: 100 lymphoma patients were studied: 65% with B cell NHL, 18% with natural killer/ T cell lymphoma, 17% with Hodgkin’s lymphoma; 37 were OHI+, and 63 were OHI-. The disease-relevant international prognostic index-predicted five-year survival did not differ between OHI + and OHI- patients (a mean of 58% n OHI+ and 57% in OHI- p = 0.62). However, the observed five-year survival in OHI+ patients was lower (12%) than predicted, reflecting a mortality incidence that was four times higher than predicted by the relevant prognostic score (OR 3.9; CI 1.3-12.1). By contrast, OHI- patients had better survival (79%) than predicted by their prognostic scores (OR 0.15; CI 0.07-0.34). More than half of the OHI+ patients died from non-malignant causes (39% multi-organ dysfunction or HLH, 18% infection), while most OHI- patients (92%) died from progressive malignancy. The likelihood of dying from multi-organ dysfunction or HLH was 26 times higher in OHI+ vs. OHI- patients (OR 26.2; CI 4.1-286.7). Conclusions: OHI index status strongly correlated with mortality in patients with lymphoma within our cohort, and death in OHI+ patients was largely due to causes other than progressive malignancy. The OHI index appears to identify a harmful inflammatory state and deserves further prospective study.