Durable Disease-free Survival Research Articles

Estimating the impact of adjuvant treatment with nivolumab on long-term survivorship rates compared with surveillance: Analyses of disease-free survival (DFS) from the phase 3 CheckMate-274 trial.

528 Background: Durable DFS and cure are the ultimate goals for the treatment of muscle invasive urothelial carcinoma (MIUC) with radical cystectomy. This analysis employed mixture cure models (MCMs) to estimate the underlying cure fraction among high-risk MIUC patients following radical resection in the Phase 3 CheckMate-274 study. Methods: MCMs were applied to patient-level DFS data from the trial (minimum follow-up: 31.6 months). Intention-to-treat (ITT) population and the subpopulation with tumor PD-L1 expression ≥1% were analyzed separately for nivolumab (NIVO) and placebo (PBO) arms. In MCMs, the patient populations were assumed to consist of two exclusive subgroups as cured and uncured. Cured subgroup was assumed to be free of disease recurrence and disease-related mortality risks. The uncured subgroup was at the risk of both disease recurrence and all-cause mortality. DFS for the cured subgroup was estimated using background mortality rates published by WHO matched to the trial’s demographic characteristics. DFS for the uncured subgroup was modelled using parametric distributions, which were characterized along with the cure fraction by maximum likelihood methods. Model selection was primarily based on clinical plausibility of estimated DFS for the uncured subgroup. Visual comparison of the fits from the MCMs to the reported DFS data from the trial and goodness-of-fit statistics also assisted model selection. Results: In the trial, 353 patients were treated with NIVO (mean age: 65.3; male: 75.1%; PD-L1≥1%: 39.7%) and 356 patients were in PBO control (mean age: 65.9; male: 77.2%; PD-L1≥1%: 39.9%). Selected models estimated almost all uncured patients to experience recurrence within 5 years. The estimated cure fraction in the ITT population ranged from 43.1%-45.1% in the NIVO arm (95% CI: 36.7%-51.6%), and 36.4%-37.0% in the PBO arm, (95% CI: 30.9%-43.0%) for clinically plausible models. Projected range of 10-year mean DFS for the ITT patients was 4.38-4.47 years in the NIVO arm and 3.61-3.64 years in the PBO arm. Estimated cure fractions in the PD-L1≥1% subpopulation ranged from 59.1%-61.0% in the NIVO arm (95% CI: 48.9%-72.0%), and 35.9%-36.9% in the PBO arm, (95% CI: 27.5%-45.9%). Projected range of 10-year mean DFS for the PD-L1≥1% subpopulation was 5.54-5.65 years in the NIVO arm and 3.54-3.57 years in the PBO arm. Conclusions: In the adjuvant treatment of MIUC, relative to radical resection only, systemic therapy with NIVO is associated with a 6-9 percentage points higher cure fraction in the ITT population. Tumor PD-L1≥1% expression was associated with higher cure fractions in the NIVO arm but had only negligible impact on the underlying cure fraction in the PBO arm. Clinical trial information: NCT02632409 .

Re: Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancera

Re: Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancera

Development and Validation of a Predictive Model for Metastatic Melanoma Patients Treated with Pembrolizumab Based on Automated Analysis of Whole-Body [18F]FDG PET/CT Imaging and Clinical Features.

Antibodies that inhibit the programmed cell death protein 1 (PD-1) receptor offer a significant survival benefit, potentially cure (i.e., durable disease-free survival following treatment discontinuation), a substantial proportion of patients with advanced melanoma. Most patients however fail to respond to such treatment or acquire resistance. Previously, we reported that baseline total metabolic tumour volume (TMTV) determined by whole-body [18F]FDG PET/CT was independently correlated with survival and able to predict the futility of treatment. Manual delineation of [18F]FDG-avid lesions is however labour intensive and not suitable for routine use. A predictive survival model is proposed based on automated analysis of baseline, whole-body [18F]FDG images. Lesions were segmented on [18F]FDG PET/CT using a deep-learning approach and derived features were investigated through Kaplan-Meier survival estimates with univariate logrank test and Cox regression analyses. Selected parameters were evaluated in multivariate Cox survival regressors. In the development set of 69 patients, overall survival prediction based on TMTV, lactate dehydrogenase levels and presence of brain metastases achieved an area under the curve of 0.78 at one year, 0.70 at two years. No statistically significant difference was observed with respect to using manually segmented lesions. Internal validation on 31 patients yielded scores of 0.76 for one year and 0.74 for two years. Automatically extracted TMTV based on whole-body [18F]FDG PET/CT can aid in building predictive models that can support therapeutic decisions in patients treated with immune-checkpoint blockade.

Indications and Outcomes for Deferred Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Combination Therapy: Can Systemic Therapy be Withdrawn in Patients with No Evidence of Disease?

BackgroundUpfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. ObjectiveTo investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design, setting, and participantsThis was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysisWe measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitationsAt median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. ConclusionsCN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summaryIn our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.

562 - Reduced Intensity Allogeneic Transplantation Combined with Prophylactic/Pre-Emptive Usage of Donor Lymphocyte Infusion Enables Durable Disease-Free Survival in Older Patients with Myeloid Disease

562 - Reduced Intensity Allogeneic Transplantation Combined with Prophylactic/Pre-Emptive Usage of Donor Lymphocyte Infusion Enables Durable Disease-Free Survival in Older Patients with Myeloid Disease

Tumor immune-gene expression profiles and peripheral immune phenotypes associated with clinical outcomes of locally advanced pancreatic cancer following FOLFIRINOX

BackgroundA comprehensive analysis of peripheral immune cell phenotypes and tumor immune-gene expression profiles in locally advanced pancreatic cancer patients treated with neoadjuvant chemotherapy in a phase II clinical trial was carried out.MethodsPatients were treated with neoadjuvant modified folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin (mFOLFIRINOX) followed by surgery and adjuvant gemcitabine at the Asan Medical Center. Correlations between survival outcomes and baseline peripheral immune cells and their changes during preoperative chemotherapy were analyzed. Patients who had surgery were divided into two groups according to achievement of disease-free survival >10 months (achieved versus failed). Differential expression and pathway analysis of immune-related genes were carried out using the Nanostring platform, and immune cells within the tumor microenvironment were compared by immunohistochemistry.ResultsForty-four patients were treated in the phase II clinical trial. Higher baseline CD14+CD11c+HLA-DR+ monocytes (P = 0.044) and lower Foxp3+CD4+ T cells (P = 0.02) were associated with poor progression-free survival of neoadjuvant mFOLFIRINOX. During the preoperative chemotherapy, PD-1 T cells significantly decreased (P = 0.0110). Differential expression and pathway analysis of immune-genes from the resected tumor after neoadjuvant treatment revealed transforming growth factor-β pathway enrichment and higher expression of MARCO (adjusted P < 0.05) associated with early recurrence. Enrichment of the Th1 pathway and higher peritumoral CD8+ T cells (P = 0.0103) were associated with durable disease-free survival from surgery (>10 months) following neoadjuvant mFOLFIRINOX.ConclusionsOur results identify potential immune biomarkers for locally advanced pancreatic cancer and provide insights into pancreatic cancer immunity.

Third analysis of a randomized trial of finite abiraterone acetate (AA) plus LHRH agonist (LHRHa) versus LHRHa in biochemically recurrent, non-metastatic hormone-naïve prostate cancer (M0HNPC).

135 Background: In pre-operative studies, a short duration of AA + LHRHa produced marked cytoreduction in a subset of men with high-risk prostate cancer (PCa). However, in M0HNPC, androgen signaling inhibition (ASI) is reserved for men with short PSA doubling time. We reasoned that the subset of men who experience cytoreduction with pre-operative AA + LHRHa would also benefit from a short duration of AA + LHRHa at PSA recurrence. This report is a one-year follow-up of our second analysis (ASCO Annual Meeting 2018; PMID 34536949). Methods: FINITE is a phase II trial that randomized (1:1) to two treatment groups, 8 months of LHRHa alone or LHRHa plus AA 1000 mg and prednisone 5 mg daily (NCT01786265). Eligible patients had a rising PSA after definitive therapy and no prior systemic therapy. At disease progression, men were eligible for crossover to 8 months of the alternative therapy. The primary endpoint was PSA-free survival at 12 months (≤ 0.1 ng/dL). Time to PSA progression was calculated from date of initial treatment to date of PSA progression, defined as first occurrence of a rising PSA, if PSA remained detectable after treatment, or when the PSA ≥ 1 ng/dL, if it was undetectable after treatment and confirmed 4 weeks thereafter. The probabilities of PSA progression were defined using the Kaplan-Meier method. Results: 199 men were randomized, and 197 received initial treatment (LHRHa = 99, LHRHa + AA = 98). Median age at enrollment was 65 years, median PSA was 0.95 ng/dL (range 0.1 – 33.3), and median testosterone was 342.5 ng/dL (10-986). At data cut-off (October 1, 2021), men who received LHRHa + AA were more likely to be PSA-free 12 months after completing treatment (34% vs. 19%, p = 0.02). 168 men (85%) had experienced PSA progression, and median time to PSA progression was 24.3 months for entire cohort. Receipt of LHRHa + AA was associated with longer time to PSA progression than LHRHa alone (27.2 vs. 19.9 months, p = 0.003). Conclusions: Our findings support that finite treatment with AA + LHRHa produces more durable disease-free survival than LHRHa. The finite duration of AA + LHRHa is a toxicity-sparing approach that may allow for a transition from a treatment to curative paradigm for a subset of men with M0HNPC. Further analyses will aim to link the subset of men who benefit from finite AA + LHRHa between localized high-risk PCa and M0HNPC. Clinical trial information: NCT01786265.

Trends in Late Mortality and Life Expectancy after Autologous Blood or Marrow Transplantation (BMT) Performed over Three Decades - a BMT Survivor Study (BMTSS) Report

Background: Advances in therapeutic and supportive care strategies have led to increasing use of autologous BMT to ensure durable disease-free survival in patients with hematologic malignancies. However, autologous BMT recipients carry a high burden of morbidity. The cumulative effect of autologous BMT and the long-term morbidity on life expectancy remains unknown. Further, the impact of changes in transplant practice (older age at BMT, increasing proportion of patients undergoing autologous BMT for plasma cell dyscrasias [PCD], increasing use of peripheral blood stem cells [PBSCs] and decreasing use of total body irradiation [TBI]) on late mortality and life expectancy remains unknown. We determined trends in life expectancy and cause-specific late mortality after autologous BMT performed over a 33y period (1981-2014) using the resources offered by BMTSS - a multi-institutional collaborative designed to examine late morbidity and mortality after BMT.Methods: This retrospective cohort included 4,702 individuals who lived ≥2y after autologous BMT performed between 1981 and 2014 at three transplant centers. We examined trends in life expectancy and late mortality over four eras: 1981-1999; 2000-2005; 2006-2010; 2011-2014. Endpoints included all-cause, recurrence-related mortality (RRM) and non-recurrence-related mortality (NRM) and projected reduction in life expectancy. Information on vital status and cause of death was obtained from National Death Index (NDI) Plus program and Accurinct databases. End of follow-up was 04/19/2021.Results: Median age at BMT was 53y (range, 0-78); 58.7% were male, 67.8% non-Hispanic white. Median follow up after BMT was 9y (range, 2-36). PCD was the most common indication for autologous BMT (42.3%). PBSCs were used for 91.6% of the transplants and TBI was used for conditioning in 23.1% of the patients. Across the four eras, the median age at BMT increased (40y→58y), as did the proportion of patients receiving autologous BMT for PCD (13.7%→60.0%) and the proportion of patients receiving PBSCs as the stem cell source (66.6%→99.5%). There was a dramatic decline in the proportion of patients conditioned with TBI (56.4%→5.2%), and those transplanted for acute myeloid leukemia/ myelodysplastic syndrome (AML/MDS) (15.4%→0.2%). Conditional on surviving ≥2y after autologous BMT, patients experienced a 25.8% reduction in life expectancy, representing 7.0y of life lost. In an analysis adjusted for all relevant demographic and clinical predictors and restricted to 5y of follow-up, the years of life lost declined across the four eras from 5y to 1.6y (Fig 1) The adjusted hazard of all-cause mortality also declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005=0.77; 95%CI=0.7-0.9; HR 2006-2010=0.62; 95%CI=0.5-0.7; HR 2011-2014=0.5; 95%CI=0.4-0.6; P trend <0.0001) (Fig 2). Mediation analysis revealed that the reduction in late mortality was evident among those transplanted for Hodgkin lymphoma (HL) or PCD, and among those who did not receive TBI . The 30y cumulative incidence of NRM (29.2%) was higher than that RRM (23.8%) (Fig 3). The adjusted hazard of RRM declined over the four eras (reference: 1981-1999; HR 2011-2014=0.55; 95%CI=0.4-0.7, P trend: <0.0001). Cause-specific late mortality declined for mortality related to infection (P trend <0.0001), subsequent malignant neoplasms (P trend=0.01), cardiovascular disease (P trend=0.001), and renal disease (P trend=0.0002), but not for pulmonary disease (P trend=0.3).Conclusions and Relevance: Late mortality among autologous BMT recipients has declined over a 30y period, likely due to changes in transplant practice (reduction in use of TBI) and improvement in disease-specific therapeutic strategies (newer therapeutic options for PCD and reduction in dose/volume of radiation for HL). Continued efforts need to focus on mitigation strategies for disease recurrence, subsequent neoplasms, infections, and cardiovascular, renal and pulmonary disease in this population. [Display omitted] DisclosuresArora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

Abstract P4-01-17: Viable circulating ensembles of tumor associated cells persist in patients with no radiologically detectable disease after treatment in breast cancer

Abstract Oncological orthodoxy holds that (metastatic) breast cancer is an incurable disease. Response evaluation in metastatic breast cancer is determined by clinical, biochemical and radiological parameters, FDG PET CT being the imaging modality of choice for most types of breast cancer. However, even in cases where FDG PET CT and/or normalisation of serum tumour markers imply complete response to systemic therapy, durable disease-free survival is uncommon. To explore the mechanistic basis underlying persistent disease in spite of apparently effective systemic therapy, we hypothesized that Circulating Metastatic Disease (CMD) in the form of viable tumor cells or clusters might be a feature of persisting breast cancer. To address this, we obtained 15ml of peripheral blood from 927 known and previously treated cases of breast cancers immediately prior to FDG PET CT restaging. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation. Circulating Ensembles of Tumor Associated Cells (C-ETACs), which are clusters of heterotypic apoptosis resistant cells of tumorigenic origin were enriched by a novel process using a combination of commercially available stabilizing agents. C-ETACs were characterized by immunostaining for EpCAM, pan-CK and CD45 as well as GCDFP-15 or GATA3. 927 patients underwent FDG PET CT of whom 731 (78.9%) had evidence of FDG avid residual disease. 196 patients (21.1%) had no metabolically active disease, among whom C-ETACs were detected in 171/196 cases (87.2%). The presence of CMD in a high proportion of cases in patients with no evidence of metabolically active disease implies that the majority of patients in whom conventional parameters of disease are negative have residual disease and are not biologically cured. Citation Format: Ajay Srinivasan, Dadasaheb Akolkar, Darshana Patil, Timothy Crook, Cynthe Sims, Revati Patil, Vineet Datta, Anantbhushan Ranade, Pradip Fulmali, Pradip Devhare, Pooja Fulmali, Shoeb Patel, Akshay Ainwale, Sneha Puranik, Rajan Datar. Viable circulating ensembles of tumor associated cells persist in patients with no radiologically detectable disease after treatment in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-17.

Impact of age and induction therapy on outcome of 180 adult patients with acute myeloid leukemia; retrospective analysis and literature review

The prognosis of acute myeloid leukemia (AML) remains poor. Among 180 patients, the median age was 53 (14-88) years. The overall 2-year disease free survival (DFS) was 28.6% (+/- 3.4), 47.7% (+/- 6.6%) for ≤ 40, 23.6% (+/- 5.8%) for 41–60 and 11.7% (+/- 4.2%) for ≥61 (p< 0.0001). The overall 2-year survival (OS) was 45.3% (+/- 3.8%), 78.6% (+/- 5.5%) for ≤40, 43.5% (+/- 6.9%) for 41–60 and 15.8% (+/- 4.8%) for ≥61 (p< 0.0001). Induction outcome of ≥61 was best in high dose chemotherapy (HDC) group (p < 0.0001). Only those ≤40 had durable DFS and OS. HDC appears to improve the outcome of older AML patients.

Salvage Curative-Intent Reirradiation Stereotactic Body Radiation Therapy for Isolated Pelvic and/or Paraortic Recurrences of Gynecologic Malignancies

PurposeTo determine the feasibility of stereotactic body radiation therapy (SBRT) for isolated nodal recurrences of gynecologic malignancies within a previously irradiated area. Methods and MaterialsA retrospective review was performed on 20 patients who underwent 21 curative-intent reirradiation SBRT treatments for locoregional recurrences of gynecologic malignancies. Disease control and survival outcomes were analyzed with the Kaplan-Meier method and log-rank test. Treatment toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.03. ResultsAll patients had an isolated pelvic, paraortic, or intra-abdominal nodal recurrence, with the exception of 1 patient who had a concurrent paraortic and right acetabulum metastasis, both of which were irradiated with SBRT. Primary sites included cervix (30.0%), uterus (55.0%), vulva (5.0%), vagina (5.0%), and ovary (5.0%). Median prior external beam radiation therapy dose was 45 Gy. Recurrences were in field in 14 (66.7%) and marginal in 7 (33.3%). SBRT was directed to the pelvis in 13 cases (61.9%) and to paraortic or celiac nodes in 8 (38.1%). The most common SBRT regimen was 40 to 45 Gy in 5 fractions (n = 12). At a median follow-up of 31.2 months, 3-year actuarial in-field local control, distant progression-free survival, and overall survival were 61.4%, 44.0%, and 51.9%, respectively. At the time of last follow-up, 9 (45.0%) patients remained alive without evidence of disease. Actuarial 3-year risk of grade ≥2 and grade ≥3 late toxicities was 38.1% and 14.3%, respectively. ConclusionsSBRT for isolated pelvic or intra-abdominal recurrences of gynecologic malignancies within a previously irradiated field is feasible with an acceptable toxicity rate. With this approach, about half of patients achieved durable disease-free survival.

Abstract A81: Early TLR-mediated killing of leukemia in bone marrow is correlated with durable protection against B cell precursor acute lymphoblastic leukemia

Abstract The ability of Toll-like receptor (TLR)-induced innate immune responses to activate adaptive immune responses offers considerable therapeutic potential for cancer treatment, most likely as part of combination therapies. The potent immunostimulatory capacity of TLR agonists provides means to generate antigen-specific antitumor T cell responses from antigen-nonspecific innate immune stimulation. B cell precursor (BCP) acute lymphoblastic leukemia (ALL) exhibits the very low mutational burden common to other pediatric cancers. Despite this limited neo-antigenicity, we previously reported the ability of CpG oligodioxynucleotides (ODN), a ligand for TLR9, to mediate anti-leukemia activities that establish long-term protection against ALL outgrowth in a transplantable syngeneic model using cell lines. CpG ODN also reduced the burden of primary human ALL in mouse xenografts, primarily via induction of NK cell-mediated cytotoxicity. However, our recent demonstration that endosomal TLR agonists generated distinct effects on pre-leukemic BCP cells, coupled with the divergent effects of TLR ligands on the immunogenicity of primary human ALL cells suggest that there are significant variables that contribute to the overall outcome of TLR stimulation in the context of BCP cell malignancy. In this study, we compared the ligands for TLR3 (polyI:C), TLR7/8(R848) and TLR9 (CpG ODN) for their ability to elicit control of primary ALL cells and correlated protection with early innate immune activation to identify the necessary component of a long-term protective anti-leukemic response. We adoptively transferred syngeneic primary ALL cells to wild-type mice then administered TLR ligands starting at day 7 for 3 doses every 4 days. 21 days after leukemia challenge, we evaluated the disease burden in the peripheral blood, spleen, and bone marrow of recipients. While a significantly lower disease burden was observed in all three anatomical compartments of mice treated with polyI:C, CpG ODN- and R848-treated mice failed to control the early outgrowth of transferred cells in the spleen and bone marrow, respectively. While R848-treated mice had a slightly delayed disease progression with median survival (MS) of 40 days compared to that of 28 days of PBS-treated control group, CpG ODN treatment conferred a significant survival advantage where over 57% of treated mice achieved a prolonged disease-free status. Despite successfully inducing systemic anti-ALL responses, poly I:C treatment failed to confer durable protection, achieving only a modest increase in disease-free survival in treated mice (MS=42 days). Moreover, CpG ODN-induced long-term survival in the absence of effective early immune-mediated control of ALL in spleen implies that bone marrow is not only an important homing niche supporting the survival and proliferation of leukemia blasts prior to migration into the circulation, but a critical target site for controlling disease progression. Furthermore, to investigate the early innate immune responses associated with the differential overall effects induced by TLR agonists, we evaluated the activation status of innate immune system using RAG-knockout mice. A single administration of CpG ODN, but not polyI:C nor R848, was sufficient to rapidly induce anti-ALL immune responses involving activated natural killer and antigen-presenting cells in the bone marrow of the mice bearing ALL in 4 days. This suggests that CpG ODN has superior capacity to initiate innate immune-mediated anti-ALL immune responses and activate subsequent antigen-specific T cell responses. TLR-mediate innate immune responses induced early in life are distinct from that induced in adult life. Given the peak incidence of pediatric ALL between 3-5 years of age, we are currently examining the influence of age on the TLR-induced anti-ALL immune responses to further evaluate the therapeutic benefits of TLR ligands. Our results demonstrate the differential magnitude of tissue-specific innate immune-mediated control of leukemia outgrowth induced by TLR stimulations correlating with durable disease-free survival. These findings provide mechanistic explanation for TLR-mediated protective immune responses and highlight the potential target site necessary for effective elimination of leukemia cells. Citation Format: Sumin Jo, Peter van den Elzen, Gregor S.D Reid. Early TLR-mediated killing of leukemia in bone marrow is correlated with durable protection against B cell precursor acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A81.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Minimal residual disease-based effect and long-term outcome of first-line dasatinib combined with chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia

The use of imatinib combined with chemotherapy has demonstrated improved outcome in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, a substantial proportion of patients continue to die as a result of disease progression. We assessed the minimal residual disease (MRD)-based effect and long-term outcome of first-line incorporation of dasatinib (100 mg once daily) into chemotherapy alternatively for adults with Ph-positive ALL. The primary end point was the major molecular response (MMR) rate by the end of the second dasatinib cycle. Patients with a donor proceeded to allogeneic stem cell transplantation (SCT) as early as possible. MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction (4.5-log sensitivity) using bone marrow samples. Fifty-one patients (median age, 46 years) were enrolled and treated with this strategy. After the first dasatinib cycle, 50 patients (98.0%) achieved complete remission (CR). By the end of the second dasatinib cycle, 46 (93.9%) of 49 assessable patients had persistent CR, and 38 (77.6%) had MMR (32.7%) or undetectable MRD (44.9%). On the basis of the MRD kinetics by this time point, the numbers of early-stable, late, and poor molecular responders were 23 (46.9%), 15 (30.7%), and 11 (22.4%), respectively. Thirty-nine patients (76.5%) underwent allogeneic SCT in CR1. After a median follow-up of 54 months, the 4-year cumulative incidence of relapse and disease-free survival (DFS) rate for all patients were 30.0% and 52.0%, respectively, and the corresponding outcomes among those receiving allogeneic SCT in CR1 were 20.5% and 64.1%, respectively. Poor molecular responders had a higher risk of relapse and DFS than those of early-stable molecular responders. This dasatinib-based protocol was effective for achieving a good quality molecular response and durable DFS in adults with Ph-positive ALL. clinicaltrials.gov, NCT01004497.

Abstract A038: The feasibility of inducing effective systemic immune responses to human metastatic melanoma with intralesional secreted cytokines

Abstract The induction of new additional immune responses to potential neoantigens on metastatic melanoma resulting in dense lymphocytic infiltrates might cause regression of metastases and could enhance the effects of anti-check point therapies. The blocking of CTLA-4 or PD-1/PD-L1, which normally constrain immune responses, results in significant prolongation of life and up to 7% complete responses (CRs) of metastatic melanoma when used individually. Insufficient nascent anti-melanoma immunity may account for the relatively low frequency of CRs. Also the lack of specificity in the dis-inhibition of immune responses can cause adverse reactions. We investigated a different strategy: inducing new specific immune responses to metastatic melanoma with mixed secreted cytokines. The development of immune responses is regulated by multiple cytokines/chemokines (CKs) acting in concert. To mimic this secretory environment, in a non-randomized prospective study, 88 patients with multiple palpable cutaneous/subcutaneous metastases (stages IIIC and IV-M1a) received weekly injections of autologous secreted CKs into some metastatic nodules while other metastases were never injected. CKs were prepared ex-vivo by stimulating PBMCs with recall microbial antigens to which the patients were sensitive as assessed by PBMC proliferative responses. The secreted mixtures contained individual cytokines at picogram to nanogram concentrations. New immune responses were identified by the development of dense lymphocytic infiltrates in never-injected metastases, consisting of CD8 and smaller numbers of CD4 T cells. This study was conducted before the availability of current therapies. After multiple injections into some metastatic nodules, never-injected metastases developed dense tumor-infiltrating lymphocytes (TILs) and often regressed completely. CD8 TILs from metastases directly killed fresh autologous melanoma cells ex-vivo in an MHC-restricted manner without in- vitro boosting. Although both never-injected and injected metastases often regressed completely, in some patients new metastases appeared even while never- injected nodules were regressing. The new metastases often regressed with or without injections. In 40% of subjects all never-injected and injected metastases regressed completely for &amp;gt; 2 months. 20% remained free of disease for 5 to 28 years (median 60 months, range 2 to 334 months). Median overall survival of patients, progressing and regressing, was 28.5 months (4-348 months), with 55% of patients surviving 2 years, and 30% 5 years. Durable disease-free survival also occurred in recipients of intracutaneous CKs mixed with irradiated autologous melanoma cells. No adverse events occurred. We conclude that intralesional secreted, mixed CKs can induce new systemic and effective cellular immune responses to metastatic melanoma. Mixtures of secreted cytokine/chemokines (CKs) may be more effective in inducing the development of immune responses than individual CKs. These immune responses were associated with a surprisingly high frequency (40%) of complete regressions and prolonged disease-free periods of 1 to 28 years. These new anti-melanoma cellular immune responses also might enhance the frequency of clinical responses to subsequent anti-check point therapies. Citation Format: Fred T. Valentine, Frederick M. Golomb, Matthew Haris, Daniel F. Roses. The feasibility of inducing effective systemic immune responses to human metastatic melanoma with intralesional secreted cytokines. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A038.

Adrenalectomy for metastasis: long-term results and predictors of survival.

The purpose of this study was to analyze our experience with surgically treated isolated adrenal metastases in order to find those factors which can significantly affect survival. This method includes a retrospective single-center chart review. We evaluated how overall survival and disease-free survival (DFS) were influenced by demographic, tumor, and procedure-related variables. Thirty-seven adrenalectomies were performed in 34 patients. Procedures included 25 laparoscopic and 12 open adrenalectomies. Median follow-up was 49 months. Median overall survival was 63 months. Patients submitted to laparoscopic approach had a median survival of 57 months while it was 65 months for those who underwent open procedure (p = 0.67). DFS was 30 months, and these were 35 and 25 months after laparoscopic approach and open approach, respectively (p = 0.59). The concurrent resection of the adrenal metastasis with the primary tumor was the only factor influencing DFS (HR 6.8 95 % CI 1.2-37.3, p = 0.02). Patients with non-small cell lung cancer (n = 15) had a median survival of 63 months and DFS of 35 months. Our experience confirms that adrenalectomy, regardless of the surgical approach, can offer durable disease-free and overall survival outcomes for surgical candidates with isolated adrenal metastases.

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma.

Autologous hematopoietic cell transplantation (auto-HCT) is the standard consolidation therapy for plasma cell myeloma patients following induction therapy. Auto-HCT improves disease-free survival (DFS), but is generally not curative. The allogeneic HCT experience demonstrated that T-cell immunotherapy can confer long-term DFS. Preclinical and clinical data indicate that myeloma-associated Ags elicit humoral and cellular immune responses (IRs) in myeloma patients. These findings strongly suggest that the immunotherapeutic strategies, including immune checkpoint inhibitors, therapeutic cancer vaccines and adoptive cellular therapies, are promising avenues of clinical research that may be most applicable in the minimal residual disease state following auto-HCT. These strategies are designed to prime or augment antimyeloma IRs and promote a 'host-vs-myeloma' effect that may result in durable DFS. Innovative clinical trials investigating immune checkpoint inhibitors and cancer vaccines have demonstrated that robust immunity against myeloma-associated Ags can be elicited in the setting of auto-HCT. A diverse array of immunotherapeutic strategies have entered clinical trials in myeloma, including PD-1/PD-L1 inhibitors, DC/myeloma cell fusion vaccines and adoptive chimeric Ag receptor T-cell therapy, and further investigation of combinations of immunologic and pharmaceutical agents are expected in the near future. In this review, we will discuss the preclinical data supporting immunotherapy in auto-HCT for myeloma, clinical investigation of these strategies and the future prospects of immunotherapy in pursuit of the goal of curative therapy.

Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM)–Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin Lymphoma: An Analysis of Outcomes from the British Society of Blood and Marrow Transplantation

The role of allogeneic stem cell transplantation (SCT) in the management of aggressive non-Hodgkin lymphoma (NHL) remains to be defined, but the number of procedures performed continues to increase. We report here the outcomes of allogeneic SCT using carmustine, etoposide, cytarabine, and melphalan (BEAM)-Campath (Genzyme Corporation, Cambridge, MA) conditioning for aggressive NHL as reported to the British Society of Blood and Marrow Transplantation (BSBMT). This retrospective study identified 46 patients who reported to the BSBMT registry as having undergone BEAM-Campath conditioned allogeneic SCT for aggressive NHL between 1999 and 2010. Disease histology was diffuse large B cell lymphoma (DLBCL, n = 25), DLBCL/Burkitt lymphoma (n = 5), and T cell lymphoma (n = 16). At diagnosis, the median age was 42.5 (range, 17 to 59), 37 had advanced stage disease (Ann Arbor III/IV), 28 had 2 or more extra-nodal sites of disease, and 23 had elevated lactate dehydrogenase. International prognostic index was high or high/intermediate in 58%. The median number of prior therapies was 3 (range, 1 to 5) and 5 patients had previously undergone transplantation (4 autologous, 1 allogeneic). The median age at transplantation was 44.8 (range, 18 to 59), with 34 patients demonstrating chemo-sensitive disease and 22 undergoing transplantation in first response. Performance score was good in 40 patients and all engrafted with a median of 14 days (range, 11 to 27) to neutrophil recovery. At latest follow-up, 20 patients were alive with 17 in complete remission. Acute graft-versus-host disease (GVHD) developed in 7 patients and chronic GVHD developed in 13 (7 limited, 6 extensive). Five patients died from nonrelapse causes, with a cumulative incidence of nonrelapse mortality of 7% at 100 days and 11% at 3 and 5 years. Twenty-one patients died after lymphoma relapse, with a cumulative incidence of relapse/progression of 51% at 1 year and 53% at 5 years. Disease status at transplantation had no impact on relapse rate. Progression-free survival was 41% at 1 year and 36% at 5 years. Overall survival was 54% at 1 year and 42% at 5 years. Overall, BEAM-Campath–conditioned allogeneic SCT is well tolerated and able to deliver durable disease-free survival to a subset of patients with aggressive NHL. However, the high relapse rates indicate further investigation is needed to identify those patients most likely to benefit.

MP64-04 RETROPERITONEAL PARTIAL NEPHRECTOMY FOR POSTERIOR TUMORS: IS IT BETTER THAN THE TRANSPERITONEAL APPROACH?

INTRODUCTION AND OBJECTIVES: Approximately 2.7-10% of patients with renal cell carcinoma (RCC) have lymph node (LN) metastases in the absence of distant metastatic disease. We have previously reported that patients with only nodal metastases who undergo a LND at the time of nephrectomy have durable disease-free survival. We sought to identify clinical predictors of positive lymph nodes in patients with locally advanced RCC. METHODS: IRB approval was obtained to search an institutional nephrectomy database for patients with RCC without distant metastasis who underwent radical or partial nephrectomy with a lymph node dissection (TanyNanyM0). Preoperative variables were collected such as demographic information, local/systemic symptoms, ECOG performance status (PS), laboratory values, clinical T/N stage, as well as radiographic information such as tumors size, presence of necrosis, presence of tumor thrombus, and tumor location. Univariate analysis (UVA) was performed to determine significant covariates between pN1 and pN0 patients. Continuous and categorical variables were compared using the Wilcoxon-rank sum test, and Fischer exact test, respectively. Significant covariates were then used in a multivariate logistic regression model to determine predictors of pathologically positive LNs. A subset analysis was performed between cN0pN1 and cN0pN0 patients to determine predictors of occult LN metastasis. Cancer specific survival stratified by clinical and pathologic nodal status was estimated using the Kaplan Meier Method. RESULTS: Of the 564 patients who met the inclusion criteria, 131 (23%) and 433 (77%) patients were pN1 and pN0, respectively. 60 patients were cN1pN0 and 29 patients were cN0pN1. On UVA, tumor size, clinical T/N stage, ECOG PS, local/systemic symptoms, ASA score, and abnormal Hgb and LDH were statistically significant. On MVA, the statistically significant variables were ECOG PS, cN stage, local symptoms (flank pain, hematuria), and elevated LDH. During the subset analysis, only local symptoms remained statistically significant. CSS between cN0pN0, cN0pN1, and cN1pN1 patients was also statistically significant (p<0.001). CONCLUSIONS: The presence of local symptoms, ECOG PS, cN stage, and elevated LDH were independent predictors of lymph node metastasis. Patients with clinically negative but pathologically positive LNs represent a small subset of RCC patients (7% in this cohort) and remain an elusive group to identify pre-operatively. The incidence of clinically positive but pathologically negative LNs (37%) is not insignificant.

MP64-03 PREDICTORS OF OCCULT LYMPH NODE METASTASES IN PATIENTS WITH RENAL CELL CARCINOMA: WHO SHOULD UNDERGO A LYMPH NODE DISSECTION?

INTRODUCTION AND OBJECTIVES: Approximately 2.7-10% of patients with renal cell carcinoma (RCC) have lymph node (LN) metastases in the absence of distant metastatic disease. We have previously reported that patients with only nodal metastases who undergo a LND at the time of nephrectomy have durable disease-free survival. We sought to identify clinical predictors of positive lymph nodes in patients with locally advanced RCC. METHODS: IRB approval was obtained to search an institutional nephrectomy database for patients with RCC without distant metastasis who underwent radical or partial nephrectomy with a lymph node dissection (TanyNanyM0). Preoperative variables were collected such as demographic information, local/systemic symptoms, ECOG performance status (PS), laboratory values, clinical T/N stage, as well as radiographic information such as tumors size, presence of necrosis, presence of tumor thrombus, and tumor location. Univariate analysis (UVA) was performed to determine significant covariates between pN1 and pN0 patients. Continuous and categorical variables were compared using the Wilcoxon-rank sum test, and Fischer exact test, respectively. Significant covariates were then used in a multivariate logistic regression model to determine predictors of pathologically positive LNs. A subset analysis was performed between cN0pN1 and cN0pN0 patients to determine predictors of occult LN metastasis. Cancer specific survival stratified by clinical and pathologic nodal status was estimated using the Kaplan Meier Method. RESULTS: Of the 564 patients who met the inclusion criteria, 131 (23%) and 433 (77%) patients were pN1 and pN0, respectively. 60 patients were cN1pN0 and 29 patients were cN0pN1. On UVA, tumor size, clinical T/N stage, ECOG PS, local/systemic symptoms, ASA score, and abnormal Hgb and LDH were statistically significant. On MVA, the statistically significant variables were ECOG PS, cN stage, local symptoms (flank pain, hematuria), and elevated LDH. During the subset analysis, only local symptoms remained statistically significant. CSS between cN0pN0, cN0pN1, and cN1pN1 patients was also statistically significant (p<0.001). CONCLUSIONS: The presence of local symptoms, ECOG PS, cN stage, and elevated LDH were independent predictors of lymph node metastasis. Patients with clinically negative but pathologically positive LNs represent a small subset of RCC patients (7% in this cohort) and remain an elusive group to identify pre-operatively. The incidence of clinically positive but pathologically negative LNs (37%) is not insignificant.