Higher Complete Response Research Articles

S1187 Clinical and Economic Burden of Patients With HRS-AKI Treated With Current Standard of Care: Retrospective Analysis of Real World Data

Introduction: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a serious complication in cirrhotic patients, leading to significant morbidity and mortality. The purpose of this study was to evaluate clinical characteristics and treatment (Tx) response of HRS-AKI patients receiving currently available standard of care (SOC) treatment. Methods: Cerner Real World Data (from 113 U.S. health systems) was used to identify adult HRS-AKI (ICD-10, K76.7) patients hospitalized between 2016 and 2020. Patients with baseline serum creatinine (SCr) >1.5mg/dL treated with midodrine (MID), octreotide (OCT), or norepinephrine (NOR) were included. Tx response was assessed based on baseline SCr and post-Tx SCr readings (Day 14 or Tx discontinuation, whichever came first). Complete response was achieved if post-Tx SCr improved to ≤1.5 mg/dL; partial if decreased by ≥30% but remained >1.5 mg/dL; and no response if decreased by < 30%. Tx response by AKI stage using KDIGO guidelines and several comorbidities during hospitalization were also evaluated, including mechanical ventilation (MV), respiratory failure (RF), and fluid overload. Results: A total of 3,918 patients with HRS-AKI (64.5% male, mean age: 59.4±12.7 years) were identified. Most common precipitant included diuretic treatment (79.2%), paracentesis (55.7%), and gastrointestinal bleeding (29.7%). Majority of patients received MID or OCT (n=2,013, 51.4%) or MID+OCT without NOR (n=1,168, 29.8%) and 982 (25.1%) received NOR, regardless of other vasopressors. During hospitalization, 658 (16.8%) patients received MV, of whom 454 (11.6%) had RF. Additionally, 363 patients had RF without MV. Other common comorbid conditions included fluid overload (20.6%), pleural effusion (14.1%), and abdominal pain (9.6%). Complete response was observed in 683 patients overall (17.4%) and patients with AKI stage 1 or 2 (n=2,302) had a higher rate of complete response (13.0% vs 7.6%) and partial response (11.0% vs 8.0%) than patients with AKI stage 3. Additional patient and clinical characteristics are shown in Table. Conclusion: At least one in six HRS-AKI patients required mechanical ventilation, had RF and/or fluid overload during hospitalization. Current SOC for HRS-AKI was ineffective. The results also suggest an inverse relationship between KDIGO-staged AKI and rate of complete response, indicating a benefit for earlier diagnosis and treatment initiation. Table 1. - Additional Patient and Clinical Characteristics Characteristic N=3,918 Patient Demographics Age, years, mean ± SD 59.4 ± 12.7 Male, n (%) 2,528 (64.5) Ethnicity, n (%) White or Caucasian 3,243 (68.2) Black or African American 325 (6.8) Other 1,036 (21.8) Unknown 151 (3.2) Clinical Characteristics Baseline SCr*, mg/dL, mean ± SD 3.0 ± 1.7 Selected treatments, n (%) Midodrine or Octreotide without norepinephrine 2,013 (51.4) Midodrine and Octreotide without norepinephrine 1,168 (29.8) Norepinephrine (regardless of any other vasopressor) 982 (25.1) Etiology of liver disease*, n (%) Alcoholic cirrhosis/hepatitis 1,779 (45.4) Viral hepatitis 560 (14.3) NASH/NAFLD 1,728 (44.1) Precipitants of HRS-AKI*, n (%) Diuretic treatment 3,104 (79.2) Paracentesis 2,183 (55.7) Gastrointestinal bleeding 1,163 (29.7) Other infections 1,101 (28.1) Spontaneous bacterial peritonitis 690 (17.6) Hepatocellular carcinoma 374 (9.5) Use of mechanical ventilation and rate of respiratory failure, n (%) Mechanical ventilation 658 (16.8) Respiratory failure 454 (11.6) No respiratory failure 204 (5.2) No mechanical ventilation 3,260 (83.2) Respiratory failure 363 (9.3) No respiratory failure 2,897 (73.9) Response type by KDIGO-staged AKI No AKI, n (%) 1,103 (28.2) Complete response, n (% of no AKI) 345 (31.3) Partial response, n (% of no AKI) 146 (13.2) No response, n (% of no AKI) 612 (55.5) Stage 1 or 2 AKI, n (%) 2,302 (58.8) Complete response, n (% of Stage 1 or 2 AKI) 299 (13.0) Partial response, n (% of Stage 1 or 2 AKI) 244 (10.6) No response, n (% of Stage 1 or 2 AKI) 1,759 (76.4) Stage 3 AKI, n (%) 513 (13.1) Complete response, n (% of Stage 3 AKI) 39 (7.6) Partial response, n (% of Stage 3 AKI) 41 (8.0) No response, n (% of Stage 3 AKI) 433 (84.4) Comorbid conditions during hospitalization, n (%) Sepsis 846 (21.6) Respiratory failure 817 (20.9) Fluid overload 807 (20.6) Pleural effusion 553 (14.1) Abdominal pain 354 (9.0) Diarrhea 199 (5.1) Bradycardia 123 (3.1) Dyspnea 89 (2.3) Nausea 54 (1.4) *not mutually exclusive. Abbreviations: AKI, acute kidney injury; HRS, hepatorenal syndrome; KDIGO, Kidney Disease Improving Global Outcomes; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; SCr, serum creatinine; SD, standard deviation.

AML-465 Tagraxofusp, an Anti-CD123 Therapy, in Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm: Sub-Analysis of a Pivotal Trial by Age and Baseline Disease Involvement

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy characterized by plasmacytoid dendritic cells that aberrantly express IL-3 receptor alpha (CD123). Tagraxofusp (TAG), a first-in-class CD123-targeted therapy, is the only approved treatment for BPDCN. In the pivotal trial TAG demonstrated a 57% complete response (CR) or clinical CR (CRc) and 75% objective response rate (ORR) in first-line patients. To determine CR+CRc, ORR, survival, and safety by age and baseline disease site involvement (skin-only, systemic-only, and skin+systemic). Sub-analysis of a 4-stage, single-arm phase 1/2 trial (NCT02113982) Setting: Eight US institutions Patients: 65 BPDCN patients receiving first-line therapy. TAG 12 mcg/kg on days 1-5 of a 21-day cycle. Response criteria for BPDCN and CTCAE criteria. CR/CRc and ORR were similar among age groups: <60y (n=17): 59% and 77%; >/=60-</=75y (n=39): 59% and 74%; and >75y (n=9): 44% and 78%, respectively. Patients with skin+systemic baseline disease (65%) had CR/CRc and ORRs of 50% and 76%, respectively. Twenty-one patients were bridged to hematopoietic stem cell transplantation (HSCT); 58% had baseline disease in ≥2 sites, with probability of survival at 12 and 24 months of 81% and 69%, respectively. In 44 patients not transplanted, four had prolonged responses >6 months; probability of survival at 12 and 24 months was 42% and 24%, respectively. Most common treatment-emergent adverse events (TEAEs) across all age cohorts were increased ALT (67%) and increased AST (61%). Most common TEAEs in the skin-only group were increased ALT and pyrexia (53% each); increased ALT, increased AST, fatigue, and nausea (75% each) in systemic-only group; increased ALT (71%) and increased AST (64%) in the skin+systemic group. Thirteen patients experienced capillary leak syndrome (3 grade 3, 1 grade 4, 2 grade 5). TAG as a first-line treatment for BPDCN was efficacious across all cohorts including older and patients with significant baseline disease. High rates of durable CRs enabled over half of patients in CR to be bridged to HSCT. Safety events were manageable and similar for older vs younger patients. Baseline disease involvement did not appear to predispose patients to different TEAEs.

IBCL-271 Primary Efficacy and Safety Analysis of a Global Phase II Study of Zandelisib Administered by Intermittent Dosing (ID) in Patients With Relapsed or Refractory (R/R) Follicular Lymphoma (FL): The TIDAL Study

Zandelisib is a selective PI3Kδ inhibitor administered orally at 60 mg once daily (QD) for 2 cycles (response induction), then intermittent dosing (ID) on days 1-7 of subsequent 28-day cycles for maintenance, while potentially enabling regulatory T-cell recovery to reduce risk of immune adverse events (irAEs) seen with continuous PI3Kδ inhibition. In a phase Ib study of zandelisib in 37 R/R FL patients, the overall response rate (ORR) was 87% (78% single agent; 95% with rituximab), with only 8% discontinuations due to irAEs (Pagel ICML 2021). Topline results from the fully enrolled FL population from TIDAL, a global phase II study evaluating zandelisib in R/R indolent lymphomas (NCT03768505). Age ≥18y with FL Grade I-IIIA, progressive disease after ≥2 prior therapies, and no prior PI3K inhibitor. Consent required. FL sample size (planned): 120 patients. Primary efficacy population (PEP): first 91 patients treated. Zandelisib 60 mg QD for 2 cycles, followed by ID during cycle 3+. IRC-assessed ORR (Lugano criteria) after a minimum 6-month follow-up. 91 FL patients in PEP (of 121 enrolled): median 3 prior therapies (range, 2-8), 21 (23%) prior stem cell transplant, 42 (46%) refractory to last therapy, 31 (34%) tumors ≥5 cm, 51 (56%) POD24. ORR was 70.3% (64/91; 95% CI: 59.8%, 79.5%) and complete response (CR) rate was 35.2% (32/91; 95% CI: 25.4%, 45.9%). Responses occurred early: 87.5% (56/91) occurred at end of Cycle 2, 75% (24/91) of CRs at end of Cycle 4. Data still immature for accurate duration of response (DOR) estimation. With median follow-up of 9.4 months (range, 0.8-24) for all 121 patients, 12 (9.9%) discontinued due to any treatment-related AE. Grade 3 AEs of special interest (AESI) included diarrhea (6/121; 5%), colitis (2/121; 1.7%), rash (4/121; 3.3%), stomatitis (3/121; 2.5%), and AST and ALT elevation and non-infectious pneumonitis (1/121 each; 0.8%). Most Grade 3 AESIs (15 [83%]) occurred during daily dosing (cycles 1-3). Zandelisib on ID led to high ORR and CR rates in heavily pretreated FL patients and was associated with a low rate of grade 3 AESI and discontinuations due to treatment-related AEs.

585. INDIAN SINGLE CENTRE EXPERIENCE USING CROSS PROTOL IN CARCINOMA ESOPHAGUS AND GASTROESOPHAGEAL JUNCTION (GEJ)

Abstract Last decade has changed the treatment modality in esophageal cancer. Neoadjuvant chemoradiation followed by surgery is proven to be highly effective in locally advanced esophageal and GEJ tumors by Dutch CROSS protocol. The aim of neoadjuvant treatment is to increase R0 resection, down staging and pathological complete response which eventually increases disease free and overall survival. This is a prospective observational single arm study of 51 patients who were treated with neoadjuvant chemoradiation with radiation therapy (RT) to 41.4 Gy/23 Fr/4.5 weeks and weekly paclitaxel and carboplatin, followed by surgery at our institute between 2013 and 2021. Eligibility for the use of CROSS protocol was expanded beyond the clinical stage T1N1 or T2-3N0-1, which includes T4aN0-1, T3N2-3. The median age of this cohort was 58 years. 37/51 (72%) had T3 disease, 8/51 (15%) had T4a and 14/51 (27%) had N2/N3 disease. 90% patients had squamous cell carcinoma. All patients completed the intended dose of radiation; 11/51 (22%) patients had a treatment delay due to haematological toxicity; one patient died. 42 (82%) successfully completed esophagectomy with R0; one patient had inoperable disease, four defaulted and three refused surgery; 26 (62%) had pCR, 12 (28.57%) PR and one had SD. At last follow up 35 patients were alive, 12 died of disease and 7 had recurrent disease. Our experience of neoadjuvant chemo radiation therapy (CROSS protocol) is in line with published data. Surgery post induction therapy was not associated with increased morbidity. It was associated with high complete resections and pathological complete response.

Improving outcomes for high-risk DLBCL: a pilot study looking at the role of fractionated cyclophosphamide with RCHOP chemo-immunotherapy (SCUBA-1 trial).

The outcomes for patients with high-risk DLBCL are suboptimal, especially in Low-middle income countries in comparison to published data from the western world. Most newer therapies aimed at improving outcomes are either unavailable or out of reach for the majority of patients in low-middle income countries. Cyclophosphamide is an easily available and accessible drug that forms the backbone for therapy for DLBCL. We conducted a single-center, open-label randomized pilot study comparing standard RCHOP to RCHOP with fractionated cyclophosphamide (RfCHOP) in patients with newly diagnosed, high-risk DLBCL. Fifty-five patients were randomized- 28 to RfCHOP and 27 to the RCHOP arm. RfCHOP was associated with a higher complete response rate than RCHOP at the end of 6 cycles of therapy (81.2% vs. 59.3%; p-0.062). Grade III/IV adverse events were comparable in both arms with the use of prophylactic GCSF in the RfCHOP arm. At a median follow-up of 22 months, the Median EFS and OS was not reached in either arm. RfCHOP may represent a therapeutic option for patients with newly-diagnosed, high-risk DLBCL, especially in Low-middle income countries. Larger studies are required to confirm these findings.

Prognostic variables and 4-year survival outcomes in CD20 Positive AIDS-Related Lymphoma in the Anti-retroviral treatment era: A Retrospective Review from a Single Centre in KwaZulu-Natal, South Africa.

To describe 4-year survival outcomes and assess the value of established and additional relevant variables to predict complete response (CR), four-year progression-free survival (PFS) and overall survival (OS) of CD20 positive AIDS-Related Lymphoma (ARL) treated with standard combination chemotherapy. We performed a retrospective review of patients diagnosed with CD20 positive ARL between 2006 and 2016. All patients over 12 years of age who received at least one cycle of combination chemotherapy with curative intent were included in the analysis. Variables assessed included the International Prognostic Index (IPI), age-adjusted-IPI, age, gender, B symptoms, extent of disease, functional performance status, CD4 cell count, viral load, concurrent ART with chemotherapy, rituximab inclusion, and number of chemotherapy cycles used. Kaplan-Meier survival curves for OS and PFS at 4 years were compared for IPI and aaIPI using the log-rank test. A Cox proportional hazards model was used to investigate the effects of prognostic variables for patients achieving OS and PFS at 4 years and logistic regression for patients achieving CR. A total of 102 patients were included in the analysis. At year four of follow-up, the OS was 50% (n = 51) and PFS was 43% (n = 44). Attaining a CR and male gender were significantly associated with improved 4-year OS (p<0.001 and p = 0.028 respectively) and PFS (p<0.001 and 0.048 respectively). A viral load of < 50 copies/ml was associated with a higher complete response rate (aOR 6.10 [95% CI 1.15, 24.04], p = 0.01). Six or more cycles of chemotherapy was superior to fewer cycles for both PFS (aHR 0.17 [95% CI 0.10, 0.29]) and OS (aHR 0.12 [95% CI 0.07, 0.22]) with p-value < 0.001 for both PFS and OS. The Kaplan-Meier survival estimates demonstrated the prognostic utility of the IPI and aaIP for OS (p = 0.002 and 0.030 respectively) and the IPI for PFS (p = 0.002). This study is a first from a high prevalence HIV area in KwaZulu-Natal, South Africa, and confirms the utility of the internationally accepted prognostic scoring systems in predicting survival in CD20 positive ARL in the local population.

789O Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): Primary analysis of a phase II study

CSCC is highly immune-responsive; a prior pilot study demonstrated a high rate of pathologic complete response (pCR) or major pathologic response (MPR, ≤10% viable tumor), using cemiplimab anti-programmed death 1 (PD-1) therapy in the neoadjuvant setting. Here, we present the primary analysis of a confirmatory, open-label, multicenter, Phase 2, single-arm trial of neoadjuvant cemiplimab in pts with resectable Stage II–IV (M0) CSCC.

Neoadjuvant treatment in non-small-cell lung cancer—the earlier, the better

SummaryNeoadjuvant checkpoint inhibition in resectable non-small-cell lung cancer (NSCLC) is safe and high major pathologic response (MPR) and pathologic complete response (pCR) rates can be achieved in combination with chemotherapy. The Checkmate 816 trial gives evidence that pathologic response also leads to EFS benefit. This opens new opportunities in the curative setting but also raises questions: What is the value of adjuvant treatment with checkpoint inhibitors? Or should we treat our patients peri-operatively? Which biomarkers can we use for treatment decisions and monitoring of curative patients? Targeted therapies in the neoadjuvant setting lead to promising response rates and data for EFS and overall survival are eagerly awaited.

Efficacy of Large Use of Combined Hypofractionated Radiotherapy in a Cohort of Anti-PD-1 Monotherapy-Treated Melanoma Patients.

Simple SummaryMelanoma patients who failed anti-PD-1 therapy have limited therapeutic options. Some studies suggested the efficacy of radiotherapy combined with anti-PD-1 monoclonal antibodies. We previously reported in small-sized studies that hypofractionated radiotherapy combined with an unmodified anti-PD-1 monotherapy regimen induced long-lasting efficacy. This study shows that the large use of hypofractionated radiotherapy combined with anti-PD-1 induced high rates of complete response (32.5% [95% CI: 26.1–38.9]) in a cohort of 206 melanoma patients. Radiated patients who had confirmed failure to anti-PD-1 monotherapy had longer progression-free and overall survival than non-radiated ones. No unexpected safety concern was observed. Although no clinical predictive factors have been identified in our study, a synergy between anti-PD1 and radiotherapy is likely. Adding hypofractionated radiotherapy in metastatic melanoma patients treated with anti-PD-1 is a safe option, which may increase the response rate and could be offered in patients with lesions threatening or not responding to anti-PD1.To assess the role of radiotherapy in anti-PD-1-treated melanoma patients, we studied retrospectively a cohort of 206 consecutive anti-PD-1 monotherapy-treated advanced melanoma patients (59% M1c/d, 50% ≥ 3 metastasis sites, 33% ECOG PS ≥ 1, 33% > 1st line, 32% elevated serum LDH) having widely (49%) received concurrent radiotherapy, with RECIST 1.1 evaluation of radiated and non-radiated lesions. Overall (OS) and progression-free (PFS) survivals were calculated using Kaplan–Meier. Radiotherapy was performed early (39 patients) or after 3 months (61 patients with confirmed anti-PD-1 failure). The first radiotherapy was hypofractionated extracranial radiotherapy to 1–2 targets (26 Gy-4 weekly sessions, 68 patients), intracranial radiosurgery (25 patients), or palliative. Globally, 67 (32.5% [95% CI: 26.1–38.9]) patients achieved complete response (CR), with 25 CR patients having been radiated. In patients failing anti-PD-1, PFS and OS from anti-PD-1 initiation were 16.8 [13.4–26.6] and 37.0 months [24.6–NA], respectively, in radiated patients, and 2.2 [1.5–2.6] and 4.3 months [2.6–7.1], respectively, in non-radiated patients (p < 0.001). Abscopal response was observed in 31.5% of evaluable patients who radiated late. No factors associated with response in radiated patients were found. No unusual adverse event was seen. High-dose radiotherapy may enhance CR rate above the 6–25% reported in anti-PD-1 monotherapy or ipilimumab + nivolumab combo studies in melanoma patients.

Efficacy comparison of tisagenlecleucel vs usual care in patients with relapsed or refractory follicular lymphoma

AbstractThe ELARA trial indicates tisagenlecleucel (tisa-cel) is an effective anti-CD19 chimeric antigen receptor T-cell therapy for relapsed or refractory follicular lymphoma (r/r FL). As ELARA is a single-arm trial, this study compares tisa-cel outcomes from the ELARA trial with usual care from a real-world cohort. ELARA enrolled 98 patients as of 29 March 2021 (median follow-up: 15 months from enrollment). Usual care data were obtained from ReCORD-FL, a global retrospective study of patients with r/r FL, who met similar eligibility criteria to ELARA. With a data cutoff date of 31 December 2020, 187 patients with ≥2 preceding treatment lines were included in the ReCORD-FL (median follow-up: 57 months from third-line) study. An indirect treatment comparison was performed for 97 patients from the ELARA trial and 143 patients from the ReCORD-FL study with no missing data on baseline factors. The line of therapy for which outcomes were assessed was selected or matched between cohorts using propensity score modeling. After baseline factor adjustment via weighting by odds, complete response rate (CRR; 95% confidence interval) was 69.1% (59.8%-78.3%) for tisa-cel vs. 37.3% (26.4%-48.3%) for usual care; overall response rate was 85.6% (78.7%-92.5%) vs. 63.6% (52.5%-74.7%). Kaplan-Meier probability of being progression/event-free at 12 months was 70.5% (61.4%-79.7%) for tisa-cel vs. 51.9% (40.6%-63.3%) for usual care, with hazard ratio (HR)=0.60 (0.34-0.86); 12-month overall survival was 96.6% (92.9%-100%) vs. 71.7% (61.2%-82.2%), with HR=0.2 (0.02-0.38). In conclusion, tisa-cel was associated with a 1.9-fold higher complete response rate and a 1.4-fold higher rate of being progression or event free at 12 months vs usual care, as well as a death risk reduction of 80%. The findings provide additional evidence on the benefit of tisa-cel in patients with r/r FL after ≥2 treatment lines. This trial was registered at www.clinicaltrials.gov as NCT03568461

Efficacy and prognosis of newly diagnosed multiple myeloma patients treated with bortezomib, lenalidomide and dexamethasone

Objective: To evaluate the efficacy of VRD (bortezomib+lenalidomide+dexamethasone) in newly diagnosed multiple myeloma (NDMM) patients as well as the effect of the regimen on the long-term prognosis. Methods: The clinical characteristics, survival rates, response rates and minimal residual disease (MRD) of patients with NDMM at Institute of Hematology & Blood Diseases Hospital from January 1, 2013 to January 1, 2020 were retrospectively analyzed. Subgroup analysis was also performed among groups according to the cytogenetics and autologous stem cell transplantation (ASCT) of patients. Results: A total of 87 patients were retrospectively analyzed. The age[M(Q1,Q3)] of all patients was 56 (51, 61) years and males and females accounted for 58.6% (51/87) and 41.4% (36/87), respectively. The overall response rate (ORR) was 95.9% (71/74) after 2 courses of induction therapy, with 13.5% (10/74) achieving the deep response [complete response (CR) or better] and 51.3% (38/74) of patients achieving a very good partial response (VGPR) or better. After 4 courses of induction therapy, the ORR achieved 95.2% (60/63), and the proportions of the deep response and VGPR or better grew up to 46.0% (29/63) and 77.7% (49/63). According to the treatment, the patients (≤65 years old) were divided into transplantation group and non-transplantation group. After the induction therapy, 88.8% (32/36) of patients in the transplantation group achieved VGPR or better, and 55.5% (20/36) reached the deep response. After the transplantation, the proportion increased to 97.1% (34/35) and 77.2% (27/35), respectively(88.8% vs 97.1%,P=0.174;55.5% vs 77.2%,P=0.055), with the rate of undetectable MRD increasing from 44.4% (16/36) to 77.8% (28/36) (P=0.004). In the non-transplantation group, 74.2% (23/31) of patients achieved VGPR or better after 4 courses of induction therapy, 35.5% (11/31) of the patients achieved deep response and the rate of undetectable MRD was 37.0% (10/27). Compared with the non-transplantation group, transplantation was associated with a higher rate of complete response (89.5% vs 53.1%, P<0.001) and a lower rate of MRD detection(78.4% vs 55.2%, P=0.045). The median follow-up time of all patients was 26.3 months (20.8, 33.8). The median progression-free survival and overall survival were not reached. The three-year PFS and OS rates were 78.4% and 87.2%, respectively. None of the standard-risk group, the high-risk group, the transplantation group and non-transplantation group achieved the median PFS and OS. Conclusions: VRD regimen has a promising efficacy and results in a substantial survival benefit. ASCT after VRD induction therapy is associated with higher rate of deep response, higher rate of undetectable MRD and longer survival.

Immune phenotypes and checkpoint molecule expression of clonally expanded lymph node-infiltrating T cells in classical Hodgkin lymphoma

Lymph node-infiltrating T cells have been of particular interest in classical Hodgkin lymphoma (cHL). High rates of complete therapeutic responses to antibody-mediated immune checkpoint blockade, even in relapsed/refractory patients, suggest the existence of a T cell-dominated, antigen-experienced, functionally inhibited and lymphoma-directed immune microenvironment. We asked whether clonally expanded T cells (1) were detectable in cHL lymph nodes, (2) showed characteristic immune phenotypes, and (3) were inhibited by immune checkpoint molecule expression. We applied high-dimensional FACS index sorting and single cell T cell receptor αβ sequencing to lymph node-infiltrating T cells from 10 treatment-naïve patients. T cells were predominantly CD4+ and showed memory differentiation. Expression of classical immune checkpoint molecules (CTLA-4, PD-1, TIM-3) was generally low (< 12.0% of T cells) and not different between CD4+ and CD8+ T cells. Degrees of clonal T cell expansion varied between patients (range: 1–18 expanded clones per patient) and was almost exclusively restricted to CD8+ T cells. Clonally expanded T cells showed non-naïve phenotypes and low checkpoint molecule expression similar to non-expanded T cells. Our data suggest that the therapeutic effects of immune checkpoint blockade require mechanisms in addition to dis-inhibition of pre-existing lymphoma-directed T cell responses. Future studies on immune checkpoint blockade-associated effects will identify molecular T cell targets, address dynamic aspects of cell compositions over time, and extend their focus beyond lymph node-infiltrating T cells.

Volumetric modulated arc therapy versus tomotherapy for late T-stage nasopharyngeal carcinoma.

PurposeTo compare the dosimetric parameters and clinical outcomes between volumetric modulated arc therapy (VMAT) and tomotherapy for treating late T-stage nasopharyngeal carcinoma (NPC).MethodsPatients with non-metastatic late T-stage NPC who received definitive radiotherapy with tomotherapy or VMAT were selected. 1:1 propensity score matching (PSM) was used to control the balance of confounding factors. The dosimetric parameters and clinical outcomes were compared.ResultsA total of 171 patients were enrolled before matching, with 61 patients in the VMAT group and 110 patients in the tomotherapy group. In the post-PSM cohort, 54 sub-pairs of 108 patients were included after matching. Tomotherapy was superior to VMAT in the dosimetric parameters of planning target volumes, brainstem, spinal cord, lenses, and parotid glands but inferior in the optic nerves and optic chiasm. The tomotherapy group had a lower incidence of grade ≥ 3 acute mucositis (22.2% vs. 40.7%, p = 0.038) and a higher rate of complete response (83.3% vs. 66.7%, p = 0.046) after radiotherapy. However, there were no significant differences in locoregional failure-free survival (p = 0.375), distant metastasis-free survival (p = 0.529), or overall survival (p = 0.975) between the two groups.ConclusionTomotherapy is superior to VMAT in terms of most dosimetric parameters, with less acute mucositis and better short-term efficacy. There are no significant differences in the survival outcomes between the VMAT and tomotherapy groups.

Long-Term Disease Control After locoregional Pelvic Chemoradiation in Patients with Advanced Anal Squamous Cell Carcinoma.

IntroductionThe incidence of metastatic squamous cell carcinoma of the anus (SCCA) is increasing. Even if systemic docetaxel, cisplatin, and 5-Fluorouracil (DCF) provide a high rate of long-term remission, the role of pelvic chemoradiation (CRT) is unknown in this setting. We reported the safety and efficacy of local CRT in patients with synchronous metastatic SCCA who achieved objective response after upfront DCF.MethodsPatients included in Epitopes HPV01 or Epitopes HPV02 or SCARCE trials and treated with DCF followed by pelvic CRT were included. Concurrent chemotherapy was based on mitomycin (MMC) (10 mg/m² for two cycles) and fluoropyrimidine (capecitabine 825 mg/m² twice a day at each RT treatment day or two cycles of intra-venous 5FU 1000 mg/m² from day 1 to day 4). Primary endpoints were safety, local complete response rate, and local progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and metastasis-free survival (MFS).ResultsFrom 2013 to 2018, 16 patients received DCF followed by a complementary pelvic CRT for advanced SCCA. Median follow-up was 42 months [range, 11-71]. All patients received the complete radiation dose. Compliance to concurrent CT was poor. Overall, 13/15 of the patients (87%) had at least one grade 1-2 acute toxicity and 11/15 of the patients (73%) had at least one grade 3-4 toxicity. There was no treatment-related death. The most frequent grade 3-4 adverse effects were neutropenia (36%), dermatitis (40%), and anitis (47%). Eleven patients (73%) had at least one chronic grade 1 or 2 toxicity. One patient had a grade 4 chronic rectitis (7%). Complete local response rate was 81% at first evaluation and 62.5% at the end of the follow-up. Median local PFS was not reached and the 3-year local PFS was 77% (95%CI 76.8-77).ConclusionsIn patients with metastatic SCCA who had a significant objective response after upfront DCF, local CRT was feasible with high complete local response rate. The good local control rate, despite interruptions due to toxicities and low CT compliance, underline the role of pelvic RT. The high rate of toxicity prompts the need to adapt CRT regimen in the metastatic setting.

Breast cancer. De-Escalating Breast Cancer Surgery

The high rates of pathologic complete response (pCR) after modern systemic therapy observed in patients with HER2-positive and triple-negative breast cancer led to the fact that there was a tendency to reduce surgical activity up to the complete refusal of breast surgery subject to the assessment of complete pathological regression using both radiation diagnostic methods and methods of morphological verification of the tumor bed, such as vacuum-assisted biopsy , and accurate core needle biopsy. This review article summarizes all available data on how to morphologically assess complete pathomorphological response (p CR) after neoadjuvant systemic therapy using core needle biopsies and vacuum-assisted biopsy .

Intentional Watch and Wait or Organ Preservation Surgery Following Neoadjuvant Chemoradiotherapy Plus Consolidation CAPEOX for MRI-defined Low-risk Rectal Cancer: Findings From a Prospective Phase 2 Trial (PKUCH-R01 Trial, NCT02860234).

To assess the efficacy and safety of intentional watch and wait (W&W) and organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX in magnetic resonance imaging (MRI)-defined low-risk rectal cancer. Clinical T2/early T3 rectal cancers can achieve high yield pathological complete response (ypCR) rates after chemoradiotherapy; thus, an intentional W&W or organ preservation strategy for good clinical responders in these subgroups can be further tested. This prospective, single-arm, phase 2 trial enrolled patients with low-risk MRI prestaged rectal cancers, who concurrently received chemoradiation, followed by four 3-weekly cycles of CAPEOX regimen. Following reassessment, clinical complete response (cCR) or near-cCR patients underwent W&W/organ preservation surgery; the primary endpoint was a 3-year organ preservation rate. Of the 64 participants, 58 completed treatment, with 6.4% and 33.9% grade 3 to 4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median 39.5-month follow-up. Initial cCR, and non-cCR occurred in 33, 13, and 18 patients, respectively. Of the 31 cCR and 7 near-cCR cases managed by W&W, local regrowth occurred in 7; of these, 6 received salvage surgery. The estimated 2-year local regrowth rates were 12.9% [95% confidence interval (CI): 1.1%-24.7%] in cCR and 42.9% (95% CI: 6.2%-79.6%) in near-cCR cases, respectively. Eight patients received local excision, including 2 with regrowth salvage. Lung metastases occurred in 3 patients and multiple metastasis occurred in 1 patient; no local recurrence occurred. The estimated 3-year organ preservation rate was 67.2% (95% CI: 55.6%-78.8%). The estimated 3-year cancer-specific survival, non-regrowth disease-free survival, and stoma-free survival were 96.6% (95% CI: 92.1%-100%), 92.2% (95% CI: 85.5%-98.9%), and 82.7% (95% CI: 73.5%-91.9%), respectively. Chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer can lead to high rates of organ preservation through intentional W&W or local excision. The oncologic safety of this strategy should be further tested.

Association Between EGFR and ALK Mutation Status on Patient-Reported Symptoms After Palliative Radiation for Bone Pain in NSCLC

IntroductionAfter palliative radiotherapy for bone metastases from NSCLC, up to 30% of patients may derive no symptomatic benefit, and there are a lack of biological predictors for this. The purpose was to investigate whether EGFR and ALK genetic rearrangements were associated with greater rates of pain response to palliative radiotherapy. MethodsPatients were identified from a prospectively collected patient-reported outcomes database for all patients with lung cancer treated with conventional palliative radiotherapy for bone metastases from 2013 to 2016 in the province of British Columbia. Patients were divided on the basis of mutational status into the following: EGFR and ALK wild type (WT), EGFR mutation present (EGFR+), or ALK mutation present (ALK+). Patient-reported outcomes of global pain severity were collected before and after radiotherapy and on an ordinal scale of 0 to 4, with 0 representing no bone pain and 4 representing the maximal possible bone pain. The primary outcome was the rate of partial pain response (any improvement in score), and the secondary outcome was the rate of complete pain response (final pain score of 0). Stepwise, multivariable logistic analysis was used to compare response rates between treatment courses for different mutational statuses. ResultsThe final cohort consisted of 388 treatment courses for 329 unique patients. For the WT, EGFR+, and ALK+ groups, there were 180, 63, and nine treatment courses, respectively. There were 92 patients with no ALK and EGFR testing. The most common treatment fractionations were 8 Gy in one fraction (188 of 388) and 20 Gy in five fractions (160 of 388), and use of multifraction radiotherapy did not differ between mutation status groups (p = 0.3). Partial pain response rates were as follows: WT 63%, EGFR+ 75%, and ALK+ 78%. On multivariable analysis, rates of partial response were higher for EGFR+ (OR = 5.4, p < 0.001) and for ALK+ (OR = 12.8, p = 0.008) in comparison to WT. Complete response rates were as follows: WT 20.5%, EGFR+ 35%, and ALK+ 67%. On multivariable analysis, complete response was not significantly increased in EGFR+ compared with WT (OR = 1.6, p = 0.127). ALK+ mutation status was associated with a higher rate of complete response compared with WT (OR = 5.2, p = 0.031). ConclusionsThere was an association between EGFR+ and ALK+ tumors and increased rates of partial pain response to palliative radiotherapy.

Measurable Residual Disease Assessment in Multiple Myeloma: How Deep Is Enough?

The introduction of new and more effective therapeutic options for Multiple Myeloma (MM) has significantly deepened and prolonged patients’ remission. As currently used treatment protocols induce high rates of complete responses, Measurable Residual Disease (MRD) assessment has become essential to enhance the evaluation of treatment efficacy. Detection of MRD has improved with the development of highly sensitive and standardized techniques such as Next Generation Flow or Next Generation Sequencing, complemented by functional imaging techniques. These advances offer a valuable opportunity to further optimize criteria of response to treatment. Currently, extensive data demonstrate that MRD status is a valuable prognostic factor of survival. Since MRD represents a real measurement of disease burden, its incorporation in clinical trials to guide treatment decisions will certainly translate into clinical benefits. Sustained MRD negativity can be used to consider optimal candidates for treatment discontinuation, whereas MRD positive high-risk patients may have access to novel immunotherapeutic strategies such as bispecific drugs or CAR T cell therapy. In this review, we describe the available techniques to detect MRD, address the current data regarding MRD as a surrogate endpoint within clinical trials, examine how MRD can be introduced into the clinical management of MM patients, and discuss the future of MRD monitoring.

P866: CORRELATIVE ANALYSIS TO DEFINE PATIENT PROFILES ASSOCIATED WITH MANUFACTURING AND CLINICAL ENDPOINTS IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS TREATED WITH IDECABTAGENE VICLEUCEL (BB2121)

Background: The anti-B-cell maturation antigen (BCMA) autologous chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel; bb2121) has achieved deep and durable responses in relapsed/refractory multiple myeloma (RRMM) patients (Munshi, N Engl J Med 2021). Prior studies have described the correlation between patient characteristics and clinical outcomes from CD19 CAR T cell therapy (Finney, J Clin Invest 2019; Fraietta, Nat Med 2018). Aims: We sought to define patient profiles correlated with manufacturing and clinical endpoints in RRMM patients treated with ide-cel in clinical trials using unsupervised clustering and multivariate machine learning across multiple key variable domains. Methods: Clinical and manufacturing data were harmonized across 164 RRMM patients treated with ide-cel in KarMMa (NCT03361748) and KarMMa-2 cohort 1 (NCT03601078). Based on individual multivariate importance, 10 selected peripheral blood mononuclear cell (PBMC), drug product (DP), and in-process cell growth variables were used to define patient clusters. Random forest classifiers were generated to identify patient characteristics associated with manufacturing and clinical endpoints. Wilcoxon rank sum and Kruskal-Wallis tests were used to compare 2 and 3+ categorical groups; Cox proportional hazards were used to compare groups with time-to-event data. Results: Using an unsupervised method, 4 patient clusters were identified that represented 10%, 57%, 15%, and 18%, respectively, of the total 164 patients. Cluster 4 was the most favorable and was characterized by a higher frequency of T cells in PBMCs; increased T-cell size during manufacturing; higher DP T-cell transduction, potency, and vector copy number; and ultimately a > 3-fold higher CAR T cell yield compared with the least favorable cluster 1. Cluster 2 contained most patients and was associated with intermediate manufacturing endpoints. Patients in cluster 4 had a higher complete response rate, longer progression-free survival, and were defined by lower tumor burden, higher absolute lymphocyte count (ALC), and longer washout period after alkylator treatment, among others (Table). Image:Summary/Conclusion: The current study identified patient profiles in RRMM using accessible laboratory or medical history data that correlated with longitudinal outcomes. These findings may inform patients likely to achieve improved outcomes with CAR T cell therapy.

P651: VENETOCLAX-BASED TREATMENT OF PATIENTS WITH RICHTER SYNDROME: OUTCOMES FROM A MULTICENTER RETROSPECTIVE STUDY

Background: Patients (pts) with chronic lymphocytic leukemia (CLL) who develop Richter Syndrome (RS) have a poor prognosis with median overall survival (OS) often reported as less than 12 months (Tsimberidou JCO 2006; Rogers BJH 2018), using chemoimmunotherapy (CIT) regimens typically administered to de novo large cell lymphoma. Venetoclax (ven) has demonstrated single-agent activity in RS with an overall response rate of 43% (Davids JCO 2017). Ven combined with DA-EPOCH-R achieved a median OS of 19.6 months and the highest complete response (CR) rate (50%) reported in pts with RS (Davids Blood 2022). These results support a synergistic effect when compared to CR rates of 20% and 0% with EPOCH-R and ven monotherapy, respectively. Aims: To evaluate the outcomes of pts with RS treated with ven-based treatment, outside clinical trials, including novel-novel combinations and CIT combinations. Methods: We analyzed pts with RS treated with a ven-based regimen at MDACC (n=37) or Mayo Clinic (n=18) between 12/2013 and 8/2021. Patient and disease characteristics from the time of ven-based treatment start were ascertained. Retrospective response assessment was as per Lugano 2014 guidelines. Toxicity was recorded per iwCLL 2018 guidelines (hematologic toxicity) or CTCAE v5.0 (non-hematologic toxicity). OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method, with and without censoring for allogeneic hematopoietic stem cell transplantation (alloSCT). No formal statistical comparisons were made between different treatment groups. Results: Fifty-five pts were identified with a median age of 66 years (range 43-83 years); 31% were female. High-risk CLL disease characteristics were frequently identified: 92% unmutated IGHV, 42% del(17p), 57% TP53 mutation, and 62% complex karyotype. The median number of prior CLL-directed therapies was 2 (range 0-7), including prior chemotherapy (42%), prior Bruton tyrosine kinase inhibitor (BTKi; 38%), and prior ven (22%); 62% of pts were previously untreated for RS. Median follow-up from the start of ven-based RS treatment was 9 months (mo). The most common ven-based combination regimens achieved overall response and CR rates as follows: 50%/40% with intensive CIT + ven (n=20), 40%/30% with BTKi + ven +/- CD20 antibody (n=20), 60%/50% with R-CHOP + ven (n=10). Among the remaining 5 patients, 2 received ven monotherapy and 3 received varied ven-based combination regimens. Nine pts proceeded to subsequent alloSCT. The median PFS for the total cohort when censored at alloSCT was 4.0 mo; PFS uncensored for alloSCT was 4.4 mo (Figure 1A). Median PFS by treatment group (Figure 1B) was as follows: 3.7 mo for intensive CIT + ven, 3.9 mo with BTKi + ven +/- CD20 antibody, not reached with R-CHOP + ven. The median OS for the total cohort was 9 mo. The estimated median OS by treatment group (Figure 1C) was 8.4 mo with intensive CIT + ven, 10.6 mo with BTKi + ven +/- CD20 antibody and not reached with R-CHOP + ven. Grade 3-4 neutropenia and thrombocytopenia were more common with intensive CIT + ven (71%; 69%) and R-CHOP + ven (77%; 67%) compared to BTKi + ven +/- CD20 antibody (35%; 25%). Febrile neutropenia occurred in 42%, 33%, and 25% of pts in these three groups, respectively, with 37%, 33%, and 30% experiencing a grade 3-4 infection. Image:Summary/Conclusion: In the notoriously difficult-to-treat RS patient population, ven-based combination regimens achieve high response rates, including some with prolonged duration, particularly with the use of R-CHOP + ven. A prospective clinical trial evaluating this combination is ongoing (NCT03054896).