Term Progression Free Survival Research Articles

Ixazomib-Based Consolidation and Maintenance Prolongs Progression-Free Survival after Salvage Autologous Stem Cell Transplantation (sASCT): Results from Interim Analysis of UK-MRA Myeloma XII (ACCoRD)

Introduction: sASCT in multiple myeloma (MM) induces superior durability of response over non-transplant consolidation 1. Currently there is no prospective evidence for post-sASCT consolidation and maintenance. This is important given that most patients relapsing after first ASCT (ASCT1) are lenalidomide refractory (Len-Ref) following maintenance. The role of a proteasome inhibitor (PI) containing post-sASCT consolidation and maintenance strategy is explored in UK-MRA Myeloma XII (ACCoRD) trial using the second-generation oral PI, ixazomib. The results of a planned interim analysis (IA) of efficacy and safety are presented here. Patients and Methods: ACCoRD enrolled patients who relapsed, requiring treatment more than 12m after ASCT1, delivering an oral PI/IMID re-induction regimen (ixazomib, thalidomide and dexamethasone; ITD) prior to randomization between sASCT conditioned with high-dose melphalan (HDM) vs. ixazomib-augmented ( iMel). The second randomization between observation (standard of care in sASCT; OBS) and post-transplant ITD consolidation and ixazomib maintenance (CON/MAINT), was conducted at D100 post-sASCT. The primary endpoint was progression-free survival (PFS). Responses were assessed in accordance with IMWG criteria with MRD defined by the limit of the multi-parameter flow assay (<10 -5). All patients underwent genetic risk categorization by a central laboratory with high-risk (HiR) classified as presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra-high risk (UHiR) the presence of more than one lesion. Pre-planned subgroup analysis included: genetic risk status (SR/HiR/UHiR) and previous treatment received (PI exposure/Len-Ref). Results: ACCoRD recruited between March 2017 and June 2022, with database lock for IA in May 2023. 496 patients were enrolled and 206 patients randomized in this comparison (103 CON/MAINT, 103 OBS). Median age was 62.5y (range 34, 78) with 35.7% patients >65y. The median observed TTP from ASCT1 was 32m (range 2, 212), with 12.5% patients relapsing after lenalidomide maintenance (Len-Ref). The proportion of patients with an ASCT1 TTP <18m, 18-24m and >24m was 13.5%, 15.1% and 71.5%, respectively. Of those with complete genetic results at trial entry, 58.3% had standard risk, 31.1% had HiR and 10.7% had UHiR disease. 61.5% of patients were PI-exposed. The median time from sASCT to CON/MAINT was 4.3m (3.4, 6.7). The ORR following sASCT was 83.3%, with ³VGPR in 50.5% and MRD negative in 19.5%. After median follow-up of 27.3m (IQR 13.1, 38.4), 139 patients had progressed or died (CON/MAINT 62, OBS 77). ITT analysis showed CON/MAINT was associated with longer PFS than OBS (HR 0.54, 95% CI 0.38, 0.76, median PFS CON/MAINT 21m vs. OBS 13m, p=0.0004, Figure 1A). Subgroup analyses (Figure 1B) suggested that there were similar benefits for PFS in terms of baseline characteristics: age, sex, ISS and performance status. There was similar benefit for patients by previous treatment received (PI/Len). However, patients with the shortest remission after ASCT1 achieved the greatest benefit with CON/MAINT (p=0.023). Patients achieving poor response (<VGPR) after ITD re-induction benefitted most from CON/MAINT (P=0.008). 45 patients had a PFS2 event (18 CON/MAINT, 27 OBS). CON/MAINT showed a non-significant improvement with longer PFS2 than OBS (HR 0.56, 95%CI 0.30, 1.01, median PFS2 CON/MAINT NR vs. OBS 44m, p=0.055). 25 patients have died (9 CON/MAINT, 16 OBS). Similarly, CON/MAINT showed a non-significant improvement with longer overall survival (OS) than OBS (HR 0.48, 95%CI 0.21, 1.09, 3y OS: CON/MAINT 81.9% vs. OBS 70.4%). Interpretation of PFS2 and OS are limited by short follow-up and will be updated at final analysis. CON/MAINT was well tolerated with no significant additional toxicity. 87.4% of patients on the CON/MAINT arm completed CON treatment. For those who completed CON, MAINT was administered for median 15 cycles (range 1, 57). The most common grade 3+ adverse events in CON/MAINT were upper respiratory infection (6.8% of patients) thrombocytopenia (5.8%), lung infections (2.9%), lymphopenia (2.9%) and neutropenia (2.9%). Conclusion: This IA demonstrates a clear advantage in durability of response when sASCT is followed by consolidation and maintenance which is consistent across subgroups. The impact on PFS2, OS and quality of life remains to be clarified. 1.Cook G, et al The Lancet Oncology 15(8), 874-885.

The Clinical Complexity of Langherans Cell Histiocytosis in Adult Patients: Experience of the Institute of Hematology of Bologna

Langerhans cell histiocytosis (LCH) in adult patients is a rare disease with protean manifestations, including single system unifocal (SSU) or multifocal (SSM) presentation or multisystemic (MS) involvement. Clinical care of adult patients is based on case series and reports. Regimens applied in pediatric patients show unacceptable toxicity in the adult setting. Our single-center experience with LCH is presented. Data on 30 patients diagnosed between 1997 and 2022 have been reviewed. Patients with isolated pulmonary histiocytosis were excluded. Responses to any treatment were classified according to the acknowledged criteria. Progression-free survival (PFS) after frontline treatment was calculated on all treated patients. Overall survival (OS) was determined on the whole cohort irrespective of any treatment received. Eighteen male and 12 female patients received a diagnosis of LCH at a median age of 46 years (range 20-75). Sixteen patients had single system (SS) disease, with SSU involvement in 12 cases and SSM involvement in 4 cases. The skeleton was the mostly involved system (Figure), while SSU extra-skeletal disease was detected in 25% of cases. Fourteen patients had MS disease: axial skeleton, lungs, hypophysis, skull, skin and appendicular skeleton were the predominantly involved sites, in this order. Ten patients with SS disease received chemotherapy because of symptoms (mostly bone pain) or due to multifocal dissemination. Two patients underwent radiotherapy (RT), 2 had their disease completely excised and 1 received systemic steroids. One patient was observed. A complete response (CR) was obtained in 60% of treated cases, while a partial response (PR) in 27%. Four patients relapsed after frontline therapy and were rescued with RT or autologous transplant. Among patients with MS disease, chemotherapy (MACOP/VNCOP-B, cladribine, vinblastine) was applied in 6 cases; 2 patients received RT and 1 systemic steroids. One patient underwent surgery and 4 were observed because of asymptomatic disease. A CR was obtained in 70% of treated patients and a PR in 10%. Five patients relapsed, with symptomatic disease requiring treatment (chemotherapy and RT) in 3 cases. Median PFS among all treated patients was 177 months. OS was 91% at 20 years. Appropriate treatment based on disease extension, site involvement and clinical manifestations yields high remission rates and long term PFS and OS. The optimal approach to relapsed patients remains undefined.

Real-World Outcomes of Immunotherapy in Second- or Later-Line Non-Small Cell Lung Cancer with Actionable Genetic Alterations.

While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with diverse AGAs and verify the predictive biomarkers of ICI efficacy. From January 2018 to July 2022, this study compared the progression-free survival (PFS) of NSCLC patients with different AGAs treated with ICI monotherapy as second- or later-line therapy at Samsung Medical Center. To ascertain the predictors of ICIs efficacy, we adjusted ICIs' effects on PFS in terms of clinical and molecular biomarkers. EGFR (46.0%) was the most prevalent mutation in 324 patients. In multivariate analysis, PD-L1 positivity (tumor proportion score (TPS) ≥ 1%) (HR = 0.41) and the use of steroids for immune-related adverse events (HR = 0.46) were positive factors for ICI therapy in the AGAs group. Co-existing mutation of STK11 with KRAS mutation (HR = 4.53) and TP53 with MET mutation (HR = 9.78) was negatively associated with survival. The efficacy of ICI treatment varied across AGA subtypes, but patients with KRAS, MET, and BRAF mutations demonstrated relatively long-duration benefits of ICI therapy. PD-L1 was a significant positive predictive biomarker in all AGA groups.

Results of the Astral Study: A Prospective Phase II Clinical Study of the German Lymphoma Alliance to Assess the Efficacy and Toxicity of High-Dose Chemotherapy Followed By Allogeneic Stem Cell Transplantation As Treatment of Primary Progressive and Relapsed Aggressive Non-Hodgkin Lymphoma

Introduction Patients with relapsed and refractory (r/r) aggressive B- or T-cell lymphoma have a dismal prognosis. Registry analyses as well as one preceding prospective clinical study demonstrated durable disease control through graft-versus-lymphoma activity conferred by allogeneic stem cell transplantation (alloSCT) in this population and suggests this modality being a preferred treatment option after failing of less toxic approaches. Recently, allogeneic SCT has been shown to result in long term PFS in r/r large B-cell lymphoma (LBCL) with preceding CAR-T treatment. Despite the current achievements in treatment of r/r LBCL by introducing anti CD19 CAR-T as a treatment modality appproximately 60% need further approaches to achieve long term progression free survival (PFS). Here we represent the results of a prospective clinical trial of allogeneic SCT in r/r aggressive B- and T-cell lymphoma using a thiotepa based conditioning regimen. Methods ASTRAL is a national, multicenter, prospective phase II study of the German Lymphoma Alliance (GLA). Eligible were patients aged 18 or older with relapsed or primary progressive aggressive B- or T-cell lymphoma who had a fully matched (10/10) related or unrelated donor available. Patients underwent myeloablative conditioning regimen with Fludarabine 125 mg/m², Thiotepa 15 mg/kg and Cyclophosphamide 120 mg/kg (FTC). GVHD prophylaxis and posttransplant immunosuppression was done by local standards. The primary objective was to determine the efficacy and toxicity of the defined conditioning therapy followed by allogeneic stem cell transplantation. The primary endpoint was progression free survival at 1 year. Key secondary efficacy endpoints included rate of complete remissions (CR), rate of partial remissions (PR), overall response rate (OR), rate of progressive disease (PD), relapse rate, event free survival (EFS) and overall survival (OS) at 1 year and non-relapse mortality (NRM). Results From June 2019 until December 2021 in total 60 patients were enrolled. The demographic data are presented in table 1. The majority of patients (70%) had B-cell lymphomas. Patients had received a median of 3 prior lines (range 1-6), including autoSCT in 42% of all patients and CAR-T in 29% of the B-cell patients. The rate of primary progressive disease before salvage therapy was 27% (29% B-cell and 22% T-cell). 83% (50/60) still had measurable disease (no CR) prior to FTC, thereof 81% with B-cell (34/42) and 89% with T-cell lymphoma (16/18) and 13 (22%) had high intermediate and high IPI. After alloSCT, CR was achieved in 45% of patients with B-cell and in 67% with T-cell lymphoma, respectively. The overall response rate was 53%, 48% for B-cell lymphoma and 67% T-cell lymphoma. After a median observation time of 30 months, 1-year PFS was 40% [95%-CI: 28%-52%] (38% [23%-53%] (B-cell) vs. 44% [21%-67%] (T-cell) (figure 1). EFS was identical to PFS. After one year 15 patients (25%) had progressive disease or relapse, thereof 13 patients (29%) with B-cell lymphoma and two with T-cell lymphoma (11%). Thirty-seven patients died. Main cause of death was treatment related 19/37 (51%), including 8/19 deaths due to toxicity of the conditioning therapy (6 infections, 1 respiratory failure and 1 neurotoxicity). 12/37 (32%) patients died lymphoma related, 4/37 (11%) patients died of a SARS-Cov-2 infection, and two causes of death were unknown. 1-year OS was 43% [31%-56%] (40% [26%-55%] (B-cell) vs. 50% [27%-73%] (T-cell)). 1-year NRM was 35% [23%-47%] (31% [17%-45%] (B-cell) vs. 44% [20%-68%] (T-cell)). Most of the patients with grade 3-5 adverse events had infections 40/60 (67%), renal disorders 17/60 (28%) and oral mucositis 14/60 (23%). Conclusions This is the second prospective trial on alloSCT for r/r aggressive lymphoma ever performed, demonstrating that alloSCT can provide sustained disease control in heavily pretreated patients. Also in the modern era, including patients who failed CARTs the strong anti-lymphoma activity of allogeneic SCT is shown in the low relapse/progression rate and the long term PFS. FTC conditioning avoids the toxicities of busulfan-based regimens but fosters neuro- and other toxicities, especially when given at 15mg/kg. Still, NRM remains a challenge and warrants exploration of novel transplant strategies, such as modulation of conditioning intensity and GVHD prophylaxis, e. g. post-transplant cyclophosphamide.

OA-15 Serial MRD assessments as a surrogate for long term progression free survival

OA-15 Serial MRD assessments as a surrogate for long term progression free survival

2/1 dose schedule of sunitinib is superior than the 4/2 regimen for the first-line therapy of clear cell metastatic renal cell carcinoma - An Indian experience.

Sunitinib remains the first-line treatment for favorable risk metastatic clear cell renal cell cancer (mccRCC). It was conventionally given in the 4/2 schedule; however, toxicity necessitated trying the 2/1 regimen. Regional variations in treatment response and toxicity are known, and there is no data from the Indian subcontinent about the outcomes of the alternative dosing schedule. Clinical records of all consecutive adult patients who received sunitinib as first-line therapy for histologically proven mccRCC following cytoreductive nephrectomy from 2010-2018 were reviewed. The primary objective was to determine the progression-free survival (PFS), and the secondary objectives were to evaluate the response rate (objective response rate and clinical benefit rate), toxicity, and overall survival. A list of variables having a biologically plausible association with outcome was drawn and multivariate inverse probability treatment weights (IPTW) analysis was done to determine the absolute effect size of dosing schedules on PFS in terms of "average treatment effect on the treated" and "potential outcome mean." We found 2/1 schedule to be independently associated with higher PFS on IPTW analysis such that if every patient in the subpopulation received sunitinib by the 2/1 schedule, the average time to progression was estimated to be higher by 6.1 months than the 4/2 schedule. We also found 2/1 group to have a lower incidence than the 4/2 group for nearly all ≥ grade 3 adverse effects. Other secondary outcomes were comparable between both treatment groups. Sunitinib should be given via the 2/1 schedule in Indian patients.

Addressing the Impact of the COVID-19 Pandemic on Survival Outcomes in Randomized Phase III Oncology Trials

We assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on the statistical analysis of time-to-event outcomes in late-phase oncology trials. Using a simulated case study that mimics a Phase III ongoing trial during the pandemic, we evaluated the impact of COVID-19-related deaths, time off-treatment and missed clinical visits due to the pandemic, on overall survival and/or progression-free survival in terms of test size (also referred to as Type 1 error rate or alpha level), power, and hazard ratio (HR) estimates. We found that COVID-19-related deaths would impact both size and power, and lead to biased HR estimates; the impact would be more severe if there was an imbalance in COVID-19-related deaths between the study arms. Approaches censoring COVID-19-related deaths may mitigate the impact on power and HR estimation, especially if study data cut-off was extended to recover censoring-related event loss. The impact of COVID-19-related time off-treatment would be modest for power, and moderate for size and HR estimation. Different rules of censoring cancer progression times result in a slight difference in the power for the analysis of progression-free survival. The simulations provided valuable information for determining whether clinical-trial modifications should be required for ongoing trials during the COVID-19 pandemic.

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma

BackgroundWe previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of...

Analysis of circulating tumor DNA in the phase 2 BTCRC LUN 16-081 trial of consolidation nivolumab with or without ipilimumab after chemoradiation in stage III non–small cell lung cancer.

8534 Background: The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiation (CRT) followed by up to 1 year of checkpoint inhibitor (CPI) therapy. However, many patients are not able to complete 1 year of treatment and the optimal duration of consolidation therapy remains unknown. Identifying minimal residual disease (MRD) via detection of circulating tumor DNA (ctDNA) may help inform the optimal duration of treatment. Here we report the results of a preplanned correlative study evaluating the association between detectable ctDNA and survival outcomes from the BTCRC LUN 16-081 phase 2 trial of consolidation nivolumab or nivolumab plus ipilimumab following CRT in patients with unresectable Stage III NSCLC (NCT03285321). Methods: Following CRT, patients with unresectable stage IIIA/B NSCLC were randomized 1:1 to receive nivolumab 480 mg IV Q4weeks for up to 6 cycles or nivolumab 240 mg IV Q2weeks plus ipilimumab 1 mg/kg IV Q6weeks for up to 4 cycles. Plasma samples for ctDNA analysis were collected after completion of CRT, prior to C2D1 of CPI, and at the end of treatment or withdrawal from the study. Tumor genotyping and ctDNA analysis were performed using CAPP-Seq with a panel targeting 260 genes recurrently mutated in NSCLC. Patient-specific tumor variants were identified using tumor tissue or baseline plasma and matched leukocyte DNA samples. Tumor variants were then monitored in plasma samples using a tumor mutation-informed bioinformatic strategy. Results: Thirty-nine patients received either nivolumab (n = 25; cycles: median = 6, range 1-6), or nivolumab plus ipilimumab (n = 14; cycles; median = 2, range = 1-6). Patients with detectable ctDNA MRD after completion of CRT demonstrated significantly inferior progression free survival (PFS) than patients who were MRD-negative (12-month 29% vs 76%, 24-month 29% vs 68%, P = 0.003), prior to C2D1 of CPI (12-month 0% vs 85%, 24-month 0% vs 72%, P < 0.0001) and at the end of CPI (12-month 14% vs 90%, 24-month 14% vs 79%, P < 0.0001). Patients with undetectable ctDNA MRD at the end of CPI (median cycles = 5.5; range 1-6) demonstrated 24-month overall survival of 91%. Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 73% vs 0%, P < 0.0001). Progression of disease occurred within 10.8 months of starting CPI in all patients with increasing ctDNA levels at C2D1. Conclusions: Detectable ctDNA before, during, and after consolidation CPI is strongly associated with inferior survival outcomes. Furthermore, less than 12 months of CPI consolidation can result in MRD negativity and high rates of long term PFS. Clinical trial information: NCT03285321.

The insolvable problem; survival effect of lymphadenectomy in advanced stage ovarian cancer.

In this study, we aimed to evaluate the effect of systemic lymphadenectomy on overall and progression free survival in advanced stage of ovarian cancer. The data of ovarian cancer patients who had been admitted to our clinic between March 2008 and December 2019 were collected retrospectively. The patients who had received neo-adjuvant chemotherapy (NACT), those having undergone interval surgery, those who had non-epithelial ovarian cancer, those with residual tumour larger than 1 cm and those with stage I-IIA were excluded from the study. A total of 241 patients with inclusion criteria were included in the study. While 169 patients (70.1%) had undergone systemic lymphadenectomy (SLND), 72 (29.9%) had not. Lymph node involvement was present in 105 out of 169 patients (62.1%) who had undergone SLND. There was no statistically significant difference between the groups in terms of SLND and lymph node involvement for both progression free survival (PFS) and overall survival (OS) (p = 0.577, p = 0.493, p = 0.481, p = 0.849 respectively). When subgroup analysis was performed according to the residual tumor amount, we could not find any statistically significant difference in both PFS and OS in terms of SLND and lymph node involvement in R0 (complete resection) group (p = 0.057, p = 0.917, p = 0.106 and p = 0.980 respectively). We found similar results for patients in the R1 (optimal resection) group. It was found that performing systemic lymphadenectomy had no effect on both progressive and overal survival. It should be kept in mind that the increasing number of malignant lymph nodes removed could have a therapeutic effect in OS. Large numbers of randomized clinical trials are required to enlighten this debatable issue that has been continuing, particularly in the recent two decades.

Pirtobrutinib (LOXO-305) Is Active and Overcomes ERK Related Pro-Survival Signaling in Ibrutinib Resistant, BTK Cys481 Mutant Expressing WM and ABC DLBCL Lymphoma Cells Driven By Activating MYD88 Mutations

MYD88 mutations are common in B-cell malignancies including Waldenstrom Macroglobulinemia (WM) and ABC subtype of Diffuse Large B-cell Lymphoma (ABC DLBCL). Mutated MYD88 activates BTK, and triggers downstream pro-survival signaling that includes NF-kB and ERK (Yang et al, Blood 2013; Blood 2016). ERK related signaling triggers inflammatory cytokine production including IL-6 and IL-10 (Chen et al, Blood 2016). Ibrutinib covalently binds to BTK Cys481 and inactivates BTK and downstream NF-kB and ERK signaling. Ibrutinib is approved for the treatment of WM and is associated with high overall response rates (>90%) and long term progression free survival in WM though intolerance to therapy, as well as resistance related to acquired BTK Cys481 mutations frequently leads to treatment discontinuation. We therefore investigated a novel, non-covalent BTK-inhibitor, pirtobrutinib that binds to BTK at non-Cys481 amino acids (G473-K483). Pirtobrutinib showed highly selective anti-proliferative activity against MYD88 mutated WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD-8 and HBL-1) versus MYD88 wild-type (OCI-Ly7, OCI-Ly19, Ramos, and RPMI-8226) cells, with marked apoptotic effect exhibited against primary MYD88 mutated WM cells at pharmacologically achievable levels (100-500 nM). Importantly, pirtobrutinib blocked BTK activity and overcame ibrutinib resistance in BCWM.1 WM and TMD-8 ABC DLBCL cells transduced to express both wild-type and mutated BTK (BTK Cys481Ser) with similar efficacy. The downstream signaling consequences of pirtobrutinib in vector only, wild-type and mutant BTK Cys481 expressing BCWM.1, MWCL-1, TMD-8 and HBL-1 cells was also examined. Treatment of vector only and wild-type BTK Cys481 expressing WM and ABC DLBCL cells with ibrutinib or pirtobrutinib abrogated both p-BTK and p-ERK signaling. In contrast, only pirtobrutinib blocked p-BTK and p-ERK signaling in mutant BTK Cys481 expressing WM and ABC DLBCL cells. In previous studies, we showed that inflammatory cytokine production that included IL-6 and IL-10 driven by ERK triggered ibrutinib resistance in wild-type BTK Cys481 MYD88 mutated lymphoma cells co-cultured with their mutated BTK expressing counterparts (Chen et al, BLOOD 2018). ERK-driven cytokine resistance to ibrutinib was postulated to explain how disease progression occurs in patients with modest variant expression of mutated BTK Cys481 (Woyach et al, JCO 2017; Xu et al, Blood 2017). Co-culture of BTK Cys481 mutated expressing TMD-8 cells with wild-type BTK expressing TMD-8 cells triggered resistance of the latter to ibrutinib. Treatment with pirtobrutinib blocked IL-6 and IL-10 production and overcame the protective effects conferred by BTK Cys481 mutated TMD-8 cells in these experiments. Lastly, oral administration of pirtobrutinib blocked p-BTK and p-ERK in BTK Cys481 mutated TMD-8 tumors xenografted in mice. Our findings therefore show that pirtobrutinib inhibits growth of MYD88 mutated lymphoma cells in a highly selective manner and can trigger apoptosis of primary WM patient BM lymphoplasmacytic cells at levels comparable to ibrutinib. Moreover, pirtobrutinib effectively blocked mutated BTK Cys481 driven BTK and ERK1/2 activation and produced similar cellular efficacy in both BTK wild-type and BTK Cys481 mutated cells. Pirtobrutinib also blocked the protective effect conferred to BTK wild-type cells through paracrine cytokines released by BTK Cys481Ser expressing cells. Lastly, pirtobrutinib blocked BTK and ERK1/2 activation in TMD8-BTK Cys481Ser xenografted mice. The findings support the development of pirtobrutinib in MYD88 driven lymphomas, including those resistant to ibrutinib on the bases of BTK Cys481 mutations. DisclosuresBranagan: Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Yang: Blueprint Medicines Corporations: Current Employment, Current holder of individual stocks in a privately-held company. Treon: BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding.

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

Are Novel Therapies Worth the Cost for Young Patients?: A Cost-Effectiveness Analysis of Frontline Therapies with or without Radiation for Early-Stage Unfavourable Hodgkin Lymphoma

Background: A variety of frontline treatment regimens exist for early-stage unfavourable Hodgkin lymphoma (HL), offering personalization of risk versus benefit in this primarily young population of patients. While radiation therapy has been a mainstay of treatment due to improved progression-free survival (PFS), recent studies have challenged this paradigm, using a PET-driven approach (HD17) or incorporating novel agents (nivolumab-AVD (N-AVD), brentuximab-AVD (A-AVD)). Long term risks of radiation and chemotherapy include secondary breast and other cancers, and heart failure; however novel regimens are more costly with uncertainty surrounding long-term efficacy.Methods: A cost-effectiveness and cost-utility analysis was conducted to compare five published frontline approaches for early-stage unfavourable HL: HD17, two H10 approaches, N-AVD, and A-AVD without radiation (Table 1). A Markov model was constructed with a lifetime horizon using TreeAge Pro 2021 (Figure 1). The base case was a 20-year-old female with a mediastinal mass who would require chest field radiation. Baseline estimates in the model were derived from the literature, including risk of relapse after each line of therapy, risk of late complications (breast cancer, secondary cancer, and/or heart failure), risk of death (from complications, lymphoma, and background mortality), and health state utilities. A Canadian public health care payer's perspective was taken, and costs are estimated in 2021 Canadian dollars. Global discounting of 3% was used.Results: Probabilistic sensitivity analyses were performed (10,000 simulations). First, we evaluated the uncertainty of long-term PFS using novel regimens (N-AVD or A-AVD); at a willingness-to-pay of $50,000/QALY, N-AVD was the most cost-effective regimen when 5-year PFS was at least 92% (Table 2). If 5-year PFS with N-AVD was <92%, HD17 became the most cost-effective approach. There was no PFS threshold at which A-AVD was the most cost-effective regimen. Holding the 5-year PFS of novel regimens at 92%, the model remained robust to multiple deterministic sensitivity analyses testing key variables including health state utilities (of relapse post-transplant, breast cancer, second malignancy, heart failure), costs (of radiation, autologous stem cell transplant, breast cancer, second malignancy, heart failure), and risks (of breast cancer after radiation, cardiovascular disease after radiation and/or chemotherapy,). However, if the risk of developing second cancer was less than 2% after 5 years with HD17 approach (current estimates 1% at 48 months in HD17 to 2% at 43 months in HD14 (which used a similar regimen)), or if the median overall survival after secondary cancer was over 9 years, HD17 became the most cost-effective regimen. The threshold cost for brentuximab to make A-AVD the most cost-effective regimen was <$5000 per dose (current price $14,520 CAD).Conclusions: If the long term PFS of nivolumab-AVD is greater than 92%, it could be the most cost-effective regimen when treating a young female patient with early-stage unfavourable Hodgkin lymphoma. This model accounts for increased costs with nivolumab added to chemotherapy, due to potential reduced incidence of late effects. However, there remain uncertainties in efficacy and risk regarding novel therapies as only non-randomized Phase II studies with short follow-up durations have been published; further trials of these approaches are being planned. HD17 remains the most cost-effective approach among published Phase III regimens. Long term follow-up of HD17 will also be meaningful to understand the risk of second cancer with this approach, which may impact its cost-effectiveness. [Display omitted] DisclosuresCrump: Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

Long Term Follow-up of the PRIMA Study: Half of Patients Receiving Rituximab Maintenance Remain Progression Free at 10 Years

Abstract In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III study was designed to evaluate the potential benefit of 2 years of rituximab (R) maintenance after response to first line R-chemotherapy induction regimens (patients registered from 12/2004 until 4/2007). At a median follow up of 3 years (Lancet 2011) and 6 years (Blood 2013 122:509), a significant sustained improvement in progression free survival (PFS) was demonstrated in patients receiving R-maintenance; hazard ratios (HR) of 0.55 and 0.58, respectively. We report here the long term results of this study with 4 additional years of follow-up. Patients initially randomized between observation (n=513) and R-maintenance (n=505) were all followed for 7 years after randomization and thereafter until the 31/12/16 after having given an informed consent for this extended follow-up period consisting of a yearly physician visit (imaging procedures were according to local center practices after year 7). At data-base lock, the median follow-up of the entire patient cohort was 9 years (9.7 years for the 607 patients agreeing to extended follow-up). Median PFS for patients in the observation arm was reached at 4.06 years as compared to 10.49 years in the R-maintenance arm (Log-Rank, P = 60 years, male sex and high FLIPI category, but not randomization arm, were all associated with a higher risk of death in a Cox regression model. In summary, PRIMA study long term follow-up demonstrates that R-maintenance after induction immunochemotherapy provides a significant long term PFS benefit over observation. Despite the lack of OS benefit, it is noteworthy that more than half of the patients in the R arm remain free of disease progression and have not required new anti-lymphoma treatment beyond 10 years. With the prolonged life-expectancy of patients with follicular lymphoma, it is important to consider long term treatment-related toxicities and the risk of secondary malignancies related to repeated therapeutic interventions. Obtaining truly durable response with 1st line induction followed by R-maintenance remains an appealing treatment strategy for these patients. Disclosures Salles: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Consultancy; morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Feugier: Roche: Consultancy, Honoraria, Research Funding. Lopez-Guillermo: Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Roche: Consultancy, Other: Research grant. Belada: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Haioun: Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria; JANSSEN: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria; PFIZER: Consultancy, Honoraria. Martin: Gilead: Consultancy; Janssen: Honoraria; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Delmer: Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria. Simpson: Onyx: Research Funding; Celgene: Honoraria, Other: travel expenses; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Roche: Honoraria. Leppa: Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Janssen Cilag: Consultancy, Research Funding; Merck: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Soubeyran: CELGENE: Honoraria; TEVA: Honoraria; Roche: Research Funding; Pierre Fabre: Honoraria; SPECTRUM: Honoraria. Ribrag: Roche: Honoraria, Other: travel, accommodation, expenses; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Pharmamar: Consultancy; Esai: Honoraria, Research Funding; ArgenX: Research Funding; Servier: Consultancy, Honoraria. Estell: Janssen: Membership on an entity's Board of Directors or advisory committees. Assemat: LYSARC: Employment. Zeuner: Roche: Employment. Coiffier: Celltrion, Inc: Consultancy, Honoraria. Tilly: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Gilead: Honoraria; Immunogen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Single cell RNA-sequence analysis to identify transcriptomic differences associated with treatment outcome and ethnicity in circulating tumor cells (CTCs) from patients (pts) with metastatic colorectal cancer (mCRC).

3041 Background: CTCs are a promising diagnostic and prognostic biomarker in colorectal cancer. The analysis of CTCs at the single-cell level may allow to capture tumor heterogeneity and identify novel prognostic and predictive markers in mCRC. Our aim was to evaluate whether the transcriptome profile of CTCs was associated with progression-free survival (PFS) in pts receiving treatment for mCRC and whether we could identify significant differences based on pts’ ethnicity. Methods: Single CTCs were prospectively collected from 25 pts undergoing treatment for mCRC at the USC/Norris Comprehensive Cancer Center between April and October 2019. Pre-treatment peripheral blood was processed using CTC-FIND comprised filter separation and immunomagnetic depletion of CD45/50-expressing cells to collect ultra-pure CTCs samples. After isolation to single cell, CTCs were processed by single cell RNA-sequence (scRNAseq). Principal component analysis was used for clustering expression data. DESeq2 was used to identify differentially expressed genes between pts with short ( &lt; 150 days) and long term ( &gt; 150 days) PFS, as well as between Hispanic and non-Hispanic ethnicity with control for FDR ( Q &lt; 0.1). Ingenuity pathway analyses (IPA) of enriched pathway networks were performed. Results: Main pts characteristics were as follow: median age = 52 years; M/F = 18/7; Hispanics/non-Hispanics = 7/18; treatment line (n pts) = 1st (5), 2nd (11), ≥ 3rd (9). We identified 59 single CTC and CTC cluster from 22/25 pts (range 1-9, median = 2/pt). scRNAseq analysis identified two separate clusters of pts based on PFS (short term vs long term). Hispanic pts were mainly distributed within the short term PFS cluster. The IPA of the network of top 40 enriched pathways showed several pathways related with metabolism, such as Sirtuin signaling, mitochondrial dysfunction and oxidative phosphorylation, and IL6/JAK/STAT signaling pathways in pts with short term PFS ( Q &lt; 0.05). When comparing Hispanic vs non-Hispanic pts, we detected enrichment of neuroinflammation signaling pathway in Hispanics, including CXCL8 (fold change, FC: 11.04), GAD2 (FC: 4.77), IRAK3 (FC: 17.06), PLCG2 (FC: 4.65) and TYROBP (FC: 8.43) (all Q &lt; 0.05). Conclusions: In our study CTCs transcriptome profiles showed an association with PFS in pts receiving treatment for mCRC, with an enrichment in mitochondria-related pathways and IL6/JAK/STAT signaling in the CTCs of pts with shorter PFS. Additionally, CTCs scRNAseq identified differentially expressed genes in Hispanic pts, displaying enrichment in neuroinflammation signaling. These results highlight the potential of CTCs molecular profiling as a tool to identify novel prognostic and predictive biomarkers in mCRC and actionable molecular pathways which may impact tumor spread and treatment response

Effect of Cadherin-11 Expression on the Prognosis of a Newly Diagnosed Primary Glioblastoma

BackgroundCadherin-11, a cell-to-cell adhesion molecule, is associated with higher tumor grade and decreased patient survival. The purpose of this study was to investigate the clinical significance of cadherin-11 expression in the progression and prognosis of a newly diagnosed primary glioblastoma (GBL).MethodsBetween 2007 and 2016, 52 out of 178 patients diagnosed with a GBL and satisfied the following criteria: 1) a new primary GBL, 2) gross-total resection, 3) immunohistochemically-available tissue, and 4) standardized adjuvant treatment.ResultsIn terms of staining intensity, the low-intensity cadherin-11 group showed longer progression-free survival (PFS) than the high-intensity cadherin-11 group (median PFS, 12.0 months [95% CI, 11.1–12.9] vs. median PFS, 6.0 months [95% CI, 3.7–8.3]; p<0.001). The low-intensity cadherin-11 group revealed longer overall survival (OS) than the high-intensity cadherin-11 group (median OS, 20.0 months [95% CI, 11.8–16.6] vs. median OS, 15.0 months [95% CI, 11.8–18.2]; p=0.003). The staining intensity of cadherin-11 was a statistically significant factor in PFS and OS in terms of univariate and multivariate analyses (univariate analysis: p<0.001 and p=0.005; multivariate analysis: p<0.001 and p=0.005).ConclusionOur clinical study demonstrates high cadherin-11 expression may be associated with poor PFS and OS for a newly diagnosed primary GBL.

Single-Cell Cytokine Analysis of LV20.19 Bispecific CAR T-Cell Products from a Phase I Clinical Trial

Introduction Anti CD19 CAR T-cell therapy is a breakthrough immunotherapeutic approach for relapsed, refractory B-cell malignancies. Despite initial excitement, long term progression free survival with single antigen targeted CD19 CAR T-cells range from 30-40% in aggressive B-cell NHL. Loss of target due to selective pressure against CD19 can lead to antigen downregulation and development of a CD19-negative clonal population. To overcome this resistance mechanism, we recently completed a Phase 1 anti-CD19, anti-CD20 (LV20.19) CAR T-cell trial demonstrating the safety of 2.5x10e6 cells/kg dose in patients with relapsed, refractory B-cell lymphomas (in press in Nature Medicine). We report below single cell cytokine studies from final LV20.19 CAR T-cell products using the Isoplexis single-cell proteomics device. Methods LV20.19 CAR T-cells were manufactured onsite using the CliniMACS Prodigy device on a fixed 14-day manufacturing platform with IL-2 for cell expansion (NCT03019055). Isoplexis cytokine analysis was limited to the cohort of patients treated at goal dose of 2.5x10e6 cells/kg (n=16). Leftover LV20.19 CAR T-cells from the original product were thawed, CD4 and CD8 T cells were enriched by immunomagnetic sorting, and the T-cell subsets separately stimulated with CD19-engineered K562 stimulators overnight. The stimulated cells were loaded onto single-cell, Adaptive Immune Isocode chips, and the chips read for 18 hours in an Isolight instrument to assess single-cell production of 32 individual cytokines. Isospeak software was used to analyze the single-cell data. Results 15 patients had adequate samples for analysis. Results were stratified by response (complete responders (CR) versus partial responders (PR) or progressive disease (PD)). The Isoplexis device was utilized to generate a polyfunctional (i.e., ability to produce more that 1 cytokine) index score (PSI) that has been previously reported (Rossi et al. Blood 2018) to correlate with CAR T-cell treatment outcomes. At Day 28 after LV20.19 CAR T-cell therapy, there were 11 CR patients and 4 PR/PD patients. CD4+ LV20.19 CAR T-cells from complete responders had a non-statistically significant decreased PSI score versus CD4+ cells from PR/PD patients (Figure 1A, p=0.38). The PSI score among CD8+ T-cells was similar (p=0.71) (Figure 1A). The increased PSI score among CR patients' CD4+ LV20.19 CAR T-cells was driven primarily by cells producing effector (IFNg and TNFb) cytokines. On a singular cytokine level, compared to PR/PD patient cells, CR patient CAR T-cells produced significantly higher levels of CCL-11, GM-CSF and IL-17A (Figure 1B; p&amp;lt;0.05). Notably, CR patients had dramatically higher percentages of individual CD4+ cells that secreted these 3 cytokines as compared to PR/PD patients (Figure 1B). Conclusion CD4+ LV20.19 CAR T-cells in responding patients trended towards a higher PSI than non-responding patients. At the single cell level, differences in the PSI among CD4+ LV20.19 CAR T-cells from responding patients were driven primarily by a few cytokines including IL-17A, CCL11, GM-CSF, IFNg, and TNFb, which may be key to clinical response. While our results are limited by sample size and only 4 PR/PD patients in this cohort, identification of cytokines correlating with response will allow selective modulation to improve clinical outcomes while limiting CRS. Ongoing studies with LV20.19 CAR T-cells will further delineate the role of IL-17A, GM-CSF and CCL-11 production as potential biomarkers of clinical response with bispecific CAR T-cell products. Disclosures Johnson: Cell Vault: Research Funding; Miltenyi Biotec: Research Funding. Fenske:Medical College of Wisconsin: Current Employment. Hamadani:Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&amp;D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. Dropulic:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents &amp; Royalties: CAR-T immunotherapy. Schneider:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents &amp; Royalties. Hari:GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy; BMS: Consultancy; Amgen: Consultancy. Shah:Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Lily: Consultancy, Honoraria; Cell Vault: Research Funding; Kite Pharma: Consultancy, Honoraria.

Autologous Stem Cell Transplantation (ASCT) for T-Cell Non Hodgkin Lymphoma (T-NHL) Patients Who Achieve Complete Remission with First-Line Treatment: A Systematic Review and Meta-Analysis

Introduction: There is currently no consensus on the optimal frontline therapy for patients with T cell Non-Hodgkin lymphomas (T-NHL). Consolidative autologous stem cell transplant (ASCT) is frequently offered to the patients with chemosensitive disease based on retrospective and prospective studies showing improved progression-free survival (PFS) when compared with historical controls getting chemotherapy alone. However, it remains unclear whether there is a good risk subset of patients who achieve first complete remission (CR1) following induction chemotherapy and who might not benefit from upfront ASCT. To date, no randomized control trials (RCTs) exist and available data is conflicting. We perform a systematic review/meta-analysis of the published literature to address this question. Methods A comprehensive, systematic search (from database inception - 9/2019) of MEDLINE/PubMed, EMBASE and Cochrane databases was performed. PRISMA and Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Studies were selected from a total of 2656, screened based on predefined inclusion/exclusion criteria, and were critically appraised for outcomes of interest [progression free survival (PFS) and overall survival (OS)]. Quality of studies was assessed using Newcastle-Ottawa Scale. Hazard ratios (HRs) and corresponding 95% Cis were calculated, and the meta-analysis was performed using the random-effects model. Test for heterogeneity was performed using I2 statistic. Results Of 2656 unique records, 13 studies (prospective = 3; retrospective = 10) were selected. In 8 studies, upfront ASCT was compared to NO ASCT in patients in first complete remission (CR1), while in 5, comparison was with patients achieving either PR1 (first partial remission) or CR1. 11 (of 13) studies reported PFS. Median follow-up in these studies ranged from 22 months to 7.8 years. Results from the meta-analysis showed that T-NHL patients who underwent ASCT had an improved 5-year PFS compared to those with NO ASCT (HR 1.62, 95% confidence interval (CI) 1.22 to 2.15, I² = 38%) (Figure 1). However, no benefit was observed in 5-year OS when ASCT was compared to NO ASCT (HR 1.32, 95% CI 0.82 to 2.12, I2 = 83%) (Figure 2). A sensitivity analysis including only studies with patients transplanted in CR1 showed similar findings, with a 5-year PFS (HR 1.54, 95% confidence interval (CI) 1.01 to 2.34, I² = 38%) and 5-yr OS (HR 1.11, 95% CI 0.41 to 3.02, I2 = 90%) when compared to No ASCT. Conclusions In the absence of RCTs, the results of this systematic review/meta-analysis represents the best evidence supporting long term PFS benefits of upfront ASCT consolidation in patients with T-NHL in CR1 or CR1/PR1 after frontline chemotherapy. Disclosures No relevant conflicts of interest to declare.

Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

1359P - The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta-analysis

BackgroundTargeted therapies (TT), combo-immunotherapy (CMI) and mono-immunotherapy (MI) in combination (CRI) or not with radiotherapy are commonly used in patients with melanoma brain metastases (MBMs), but studies that directly compare these strategies are lacking. This meta-analysis aimed to better elucidate their activity and efficacy. MethodsA systematic search of Medline, Embase and conferences proceedings up to January 2019 was carried out to identify trials investigating combo TT, mono TT, MI, CMI, CRI in MBMs. The outcomes considered were progression free survival (PFS), overall survival (OS) and objective response rate (ORR) evaluated at both intra and extra-cranial sites. Random effects models were used to compare the different therapeutic strategies. ResultsWe included 15 trials, which provided 1132 patients for analyses. CMI showed a statistically significant better OS than MI (p=0.03, p=0.05, p=0.03 at 6, 18 and 24 months respectively) and combo TT (p=0.04, p=0.03, at 18 and 24 months respectively). CMI showed a statistically significant better PFS compared to combo TT (p<0.001 at 12 and 18 months), MI (p=0.02, p<0.02 and p=0.05 at 6, 12 and 18 months respectively) and mono TT (p<0.001 at 6, 12 and 18 months respectively). The intracranial ORR was higher with CMI compared to mono TT (p<0.001) and MI (p<0.001), while there was no difference between CMI and combo TT. ConclusionsThis meta-analysis suggests that CMI increases long term PFS and OS compared to MI and combo TT. Combo TT and CMI are associated with a similar intracranial response rate. The role systemic therapy in combination with radiotherapy remains to be better elucidated. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.