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Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.

Supplemental Table 1. Summary of the clinical and histopathologic characteristics of Merkel cell carcinoma patients. Supplemental Table 2. Summary of antibodies used in this study. Supplemental Table 3. Correlation between tumor associated immune infiltrate and co-localized expression of CD31 and B7-H3 in Primary MCCs.

Progression-free survival curves for groups A, B, C, and D.

Supplemental Figure 1. Dynamic range of co-localized expression of CD31 and B7-H3 in primary Merkel cell carcinoma. Each CD31+ and B7-H3+ cell centroid was tabulated as a series of (X, Y) coordinates (cell centroids). The frequency of their respective overlap for each of the 52 primary MCCs was calculated within a given distance as indicated: blue boxes show G-function colocalization index applying a 1 pixel (1.57 �m) minimum distance of overlapped expression as our cutoff, and green boxes show G-function colocalization index applying a 2 pixel (3.14 �m) minimum distance of overlapped expression as our cutoff.

Purpose:Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease.Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid.Results:Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC.Conclusions:Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT).Experimental design: Patients were enrolled on three consecutive phase II clinical trials. Patients received two doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P = 0.82). The 5-year overall survival rates were 73% and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (1 year) after initial induction chemotherapy (P = 0.97).Conclusions: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit. Clin Cancer Res; 24(10); 2304–11. ©2018 AACR.

Supplemental Figure 2. Correlation between B7-H3/CD31 G-function co-localization index in MCPyV-positive MCCs. Plots showing the correlation B7-H3/CD31 G-function co-localization index for each primary MCPyV-positive MCC plotted against tumor size (A), depth of invasion (B), invasion beyond skin (C) and metastasis beyond SLN (D). G-function calculated according to a 1 pixel (1.57 �m) radius.

Supplemental Figure 3. Correlation between B7-H3/CD31 G-function co-localization index in MCPyV-negative MCCs. Plots showing the correlation B7-H3/CD31 G-function co-localization index for each primary MCPyV-negative MCC plotted against the frequency of associated malignancies (A) and lymphovascular invasion (B). G-function calculated according to a 1 pixel (1.57 �m) radius.

Patient demographic characteristics and baseline disease characteristics for groups A, B, C, and D

Supplemental Figure 4. Correlation between B7-H3/CD31 G-function co-localization index and vascular density. Plots showing the correlation B7-H3/CD31 G-function co-localization index plotted against vascular density for the whole cohort of primary MCC (vascular density tabulated as the average of the regions of interest in each of the 52 tumors).

Purpose Chemotherapy side effects diminish quality of life and can lead to treatment delay. Nausea and vomiting can occur prior to chemotherapy because of classical conditioning. We studied the effects of 20‐minute behavioral interventions, administered by oncology nurses, of higher intensity (mindfulness relaxation—MR) or lower intensity (relaxing music—RM), on anticipatory nausea and vomiting (ANV). Patients and methods Patients undergoing chemotherapy for solid tumors were randomized to MR (N = 160), RM (N = 159), or standard care SC (N = 155). Subjects were mostly female (91.8%) and white (86.1%) with breast cancer (85%). Most patients had early stage disease (Stage I: 26%; II: 52.9%; III: 19%; IV: 0.1%). Anticipatory nausea and vomiting were assessed at the midpoint and end of the chemotherapy course using the Morrow Assessment of Nausea and Emesis (MANE). Results Compared to SC, there was reduced anticipatory nausea at the midpoint of chemotherapy in those receiving MR (OR 0.44, 95% CI 0.20‐0.93) and RM (OR 0.40, 95% CI 0.20‐0.93), controlling for age, sex, cancer stage, and emetogenic level of chemotherapy. There was no difference between treatment groups in anticipatory nausea at the end of chemotherapy or in anticipatory vomiting and postchemotherapy nausea and vomiting at either time point. Conclusion A brief nurse‐delivered behavioral intervention can reduce midpoint ANV associated with chemotherapy., Chemotherapy administration can result in conditioned nausea and vomiting. This multi‐centred randomized controlled trial demonstrates the superiority of 2 preemptive behavioural interventions in reducing conditioned nausea.

Factors correlated with biopsy tissue adequacy and the prevalence of within-biopsy variability were evaluated. Totally, 1149 research biopsies were performed on 686 patients from which 5090 cores were assessed. Biopsy cores were reviewed for malignant percentage (estimated percentage of cells in the core that were malignant) and malignant area (estimated area occupied by malignant cells). Linear mixed models and generalized linear mixed models were used for the analysis. A total of 641 (55.8%) biopsies contained a core with p

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (pEGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, pConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid. Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.

The differential immunophenotypic characteristics of early T precursor (ETP) acute lymphoblastic leukaemia/lymphoma (ALL) remain incompletely characterized. The study group (n = 142) included 106 (74·7%) men and 36 (25·3%) women with a median age of 34·9 years (range, 2-79) at diagnosis. Patients were subtyped by flow cytometry immunophenotyping as follows: 33 (23·2%) ETP; 32 (22·5%) early non-ETP; 60 (42·2%) thymic; and 17 (12·1%) mature. Excepting definitional markers, there was a significant differential expression of the markers CD2, CD10, CD33 and TdT between ETP-ALL and non-ETP-ALL. Positive CD33 expression (≥20% of leukaemic blasts) was detected in 21/33 (63%) ETP-ALL compared with 17/95 (17·9%) non-ETP-ALL (P < 0·001). Notably, targeted anti-CD33 therapy with IMGN779 resulted in significant growth inhibition and increased apoptosis in ETP-ALL cells in vitro. An 11-marker T-ALL immunophenotype score discriminated reliably between ETP and non-ETP ALL. Longitudinal analysis of ETP-ALL cases in this study demonstrated that the immunophenotype may be occasionally dynamic but is largely stable over the disease course. In summary, identification of ETP-ALL might be enhanced by using an 11-marker T-ALL immunophenotype score. CD33 expression is frequent in ETP-ALL, and in vitro data suggest that exploring anti-CD33 therapy in ETP-ALL is warranted.

Persistence of IDH1 or IDH2 mutations in remission bone marrow specimens of patients with acute myeloid leukemia has been observed, but the clinical impact of these mutations is not well known. In this study, we evaluated 80 acute myeloid leukemia patients with known IDH1 R132 or IDH2 R140/R172 mutations and assessed their bone marrow at the time of remission to determine the potential impact of persistent IDH1/2 mutations. Approximately 40% of acute myeloid leukemia patients given standard treatment in this cohort had persistent mutations in IDH1/2. Patients with an IDH1/2 mutation had an increased risk of relapse after 1 year of follow-up compared to patients without a detectable IDH1/2 mutation (59% versus 24%; P

9049 Background: Primary resistance to immune checkpoint inhibitor (ICI) therapy remains a major challenge in clinical oncology. Here, we describe the clinical outcome of patients who experienced radiologic progression within 12 weeks of therapy with nivolumab and ipilimumab (I+N) for metastatic non-small cell lung cancer (mNSCLC). Methods: The LONESTAR study is an ongoing phase III study (NCT03391869). Study enrolls patients with immunotherapy naïve mNSCLC (prior chemotherapy is allowed). All patients receive I+N for 12 weeks and are randomized to experimental therapy vs. control arm if they did not have disease progression. Patients who experience radiologic progression per RECIST v1.1 are not randomized and removed from the study. Treatment beyond progression is allowed if they clinically benefit from the systemic therapy. We prospectively collected clinicopathologic and radiologic outcome data from patients who experienced radiologic progression within 12 weeks of I+N therapy and have not randomized to investigational therapy. We described the primary progression pattern. We collected subsequent treatment, radiologic, and toxicity data and calculated clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Results: Of the 194 patients who received at least one dose of I+N therapy, 72 patients had clinical and/or radiologic progression at ≤ 12 weeks. Thirty-five (35; 48%) patients did not receive subsequent treatment, 21 (29%) patients received subsequent 2nd line systemic therapy, and 16 (22%) patients were continued on I+N beyond radiologic progression due to ongoing clinical benefit. Among patients treated with 2nd line therapy, 13 patients were treated with platinum doublet +/- anti-PD-(L)1, seven (7) patients were treated with single-agent chemotherapy +/- VEGF inhibitor, and one (1) patient was treated with targeted therapy. The PFS for the 2nd line therapy was 6.5 months (95%CI: 4.8, 8.9), and OS was 10.4 months (95%Cl: 6.6, 16.1). Among the 16 patients treated with I+N beyond progression, 13 had a mixed response to induction therapy, where primary progression was most frequently observed in mediastinal lymph nodes. LCT with radiotherapy was utilized with I+N in 10 patients. The median duration of post-progression treatment with I+N plus LCT was 8.7 months (95%Cl: 5.9, 22.3) and 5.6 months (95%Cl 4.4, 11.5) with I+N alone. The OS was 19.5 months (95% CI: 6.2,18.7). Conclusions: In this study cohort, primary resistance to I+N was observed in 37% of the patients, and in a subset of these patients treated with post-progression I+N, either alone or in combination with LCT, durable clinical benefit was observed. Further studies are warranted to identify which patients are most likely to benefit from post-progression I+N. Clinical trial information: NCT03391869.

The Dako 28-8, Dako 22C3, and Ventana SP142 assays are among the approved programmed death ligand 1 (PD-L1) immunohistochemical companion/complementary diagnostics associated with cancer treatment. To address the concordance of these assays in triple-negative breast cancer (TNBC), we examined PD-L1 expression in 98 TNBC tumors and compared the positive rates using the three assays and three scoring methods: immune cell (IC), tumor cell (TC), and combined tumor cell and immune cell (TCIC) (an equivalent to combined positive score, or CPS). The positive rate for PD-L1 expression with a 1% cutoff was highest with 28-8, followed by the 22C3. These two assays demonstrated almost perfect or substantial agreement in all three scores. There was less agreement between SP142 and the other assays. Using the IC score or the TCIC score at a 1% cutoff (CPS 1), 4% of tumors were positive for PD-L1 with SP142 but negative with the other assays. Using SP142 with a 1% cutoff as a reference, the optimal cutoff for best agreement was at 1% for IC, 30% for TC, and 2% for TCIC (CPS 2) with the other two assays. A 2% cutoff for the 22C3 TCIC (CPS 2) yielded the best agreement with SP142 1% IC cutoff (kappa 0.65). Our study showed the lowest positive rate with SP142 among the three assays. However, the other two assays were not able to identify all tumors that would test positive with SP142 using IC or TCIC/CPS. It is unlikely to achieve high agreement between SP142 and the other two assays by changing the analytical cutoffs.

Background In the evaluation of PD-L1 expression to select patients for anti-PD-1/PD-L1 treatment, uniform guidelines that account for different immunohistochemistry assays, different cell types and different cutoff values across tumor types are lacking. Data on how different scoring methods compare in breast cancer are scant. Methods Using FDA-approved 22C3 diagnostic immunohistochemistry assay, we retrospectively evaluated PD-L1 expression in 496 primary invasive breast tumors that were not exposed to anti-PD-1/PD-L1 treatment and compared three scoring methods (TC: invasive tumor cells; IC: tumor-infiltrating immune cells; TCIC: a combination of tumor cells and immune cells) in expression frequency and association with clinicopathologic factors. Results In the entire cohort, positive PD-L1 expression was observed in 20% of patients by TCIC, 16% by IC, and 10% by TC, with a concordance of 87% between the three methods. In the triple-negative breast cancer patients, positive PD-L1 expression was observed in 35% by TCIC, 31% by IC, and 16% by TC, with a concordance of 76%. Associations between PD-L1 and clinicopathologic factors were investigated according to receptor groups and whether the patients had received neoadjuvant chemotherapy. The three scoring methods showed differences in their associations with clinicopathologic factors in all subgroups studied. Positive PD-L1 expression by IC was significantly associated with worse overall survival in patients with neoadjuvant chemotherapy and showed a trend for worse overall survival and distant metastasis-free survival in triple-negative patients with neoadjuvant chemotherapy. Positive PD-L1 expression by TCIC and TC also showed trends for worse survival in different subgroups. Conclusions Our findings indicate that the three scoring methods with a 1% cutoff are different in their sensitivity for PD-L1 expression and their associations with clinicopathologic factors. Scoring by TCIC is the most sensitive way to identify PD-L1-positive breast cancer by immunohistochemistry. As a prognostic marker, our study suggests that PD-L1 is associated with worse clinical outcome, most often shown by the IC score; however, the other scores may also have clinical implications in some subgroups. Large clinical trials are needed to test the similarities and differences of these scoring methods for their predictive values in anti-PD-1/PD-L1 therapy.

Background MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. However, its mechanism of action and suitability as a therapeutic target are unknown. Methods A monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target. Results Analysis of molecular interactions between MUC18 and JM1-24-3 revealed that the downstream signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18. JM1-24-3 inhibited melanoma cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo. Conclusion These results confirm that MUC18 is mechanistically important in melanoma growth and metastasis, suggest that the MUC18 epitope identified is a promising therapeutic target, and that the JM1-24-3 mAb may serve as the basis for a potential therapeutic agent.

Additional file 1.

The 2017 revision of the World Health Organization (WHO) classification includes substantial changes to the subclassification of chronic myelomonocytic leukemia (CMML): (1) a 3-tiered blast-based scheme including a novel "CMML-0" category replacing a 2-tiered system in place since 2001 and (2) 2 CMML subtypes, myelodysplastic (MDS-CMML) and myeloproliferative (MP-CMML), based on a white blood cell count cutoff of 13 × 109/L. The clinical utility of this subclassification scheme, particularly the expansion of blast-based subgroups, has not been validated. In this study, a large single-institution CMML patient cohort (n = 629) was used to assess the prognostic impact of the newly proposed categories. Patients were risk stratified according to the CMML-specific Prognostic Scoring System (CPSS) and the MD Anderson Prognostic Scoring System. MP-CMML patients had significantly shorter overall survival (OS; P < .0001; hazard ratio: 0.53, 95% confidence interval: 0.42-0.65) and median duration to acute myeloid leukemia (AML) transformation (P < .0001; 15.2 vs 22.0 months) compared with MDS-CMML patients. The CMML-0 group included 36.4% patients with higher risk CPSS categories and 11.2% of patients with high-risk cytogenetics. Among treatment-naive patients (n = 499), there was a marginal difference in OS between the CMML-0 and CMML-12017 subgroups (P = .0552). The WHO 2017 blast-based categories were not associated with AML-free survival. Incorporation of the WHO 2017 blast-based subgroups in a modified CPSS scheme had a neutral effect and did not improve its prognostic strength. Our data support the inclusion of MP-CMML and MDS-CMML subtypes in the WHO 2017 revision. Although of some utility in MP-CMML, the 3-tiered blast-based system is not well supported in this study.

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT). Experimental design: Patients were enrolled on three consecutive phase II clinical trials. Patients received two doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning. Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P = 0.82). The 5-year overall survival rates were 73% and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (1 year) after initial induction chemotherapy (P = 0.97). Conclusions: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit. Clin Cancer Res; 24(10); 2304–11. ©2018 AACR.

Introduction: The most commonly used conditioning regimen for autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma (MM) is high-dose melphalan. However, conventional melphalan formulations can put patients at risk of potential propylene glycol (PG)-associated toxicities. In addition, the traditional melphalan formulations are unstable at room temperature, which prevents studying longer infusion schedules. The higher stability and potentially lower toxicity of PG-free (PGF) melphalan (Evomela) supports the evaluation of different doses and prolonged infusion schedules, in addition to the traditional 30-60 minute bolus doses. Here, we report interim results of a trial designed to assess whether the characteristics of PGF melphalan allow for a higher dose or prolongation of infusion time, in order to increase the efficacy of melphalan in myeloma patients undergoing auto-HCT. Methods: The primary objective of this two-stage phase I-II trial is to evaluate the optimal dose and schedule of PGF melphalan given as a single agent preparative regimen on day -2 before auto-HCT. The study enrolls adults with non-relapsed MM, a Karnofsky performance score ≥70%, who have received ≥2 cycles of initial systemic therapy and were within 2 to 12 months of their first induction. Participants are randomized (1:1) to two different infusion schedules (30-60 minute or 8-9 hour) using Evomela (2mg/ml) at one of two doses (200 or 225 mg/m 2). The first 3 patients in each schedule were treated at the dose of 200 mg/m 2. Since no DLT was observed, the dose was escalated to 225 mg/m 2. All patients will continue to receive 225 mg/m 2 in the absence of DLT. Disease response was assessed according to the International Myeloma Working Group uniform response criteria. Minimal residual disease (MRD) was measured by using multiparametric flow cytometry (10 -5) in the bone marrow at day-90 after transplant. Secondary outcomes include incidence of treatment related mortality, rate of MRD, complete response at 90 days post auto-HCT, and progression-free and overall survival. Results: To date (July 20,2021), 24 eligible patients have been randomized. Seventeen patients (47% female, mean age 59) are eligible for assessing response 90 days post-treatment, 11 (64.7%) in schedule 1 (30-60 mins) and 6 (35.3%) in schedule 2 (8-9 hrs). The overall response rate (partial response [PR] or better) is 100%, with 5(29.4%) stringent complete remissions (sCR), 5 (29.4%) complete remissions (CR), 4(23.5%) very good partial responses (VGPR), and 3(17.6%) partial remission (PR). The CR+sCR rate is 58.8%. Of the 15 patients eligible for MRD assessment, 11 (73.3%) in schedule 1 and 4 (26.7%) in schedule 2, 11/15 (73.3%) were MRD-negative and 8/15 (53.3%) were sCR/CR+MRD-negative 90 days post-treatment. The median follow-up is 11 months (95%CI:6.1-15.4) No patient has experienced disease progression or death. Dose-limiting toxicity (DLT) is defined as grade 4 mucositis, or any grade 4 or 5 non-hematologic or non-infectious toxicity occurring within 30 days from the start of infusion. Twenty-one patients were evaluable for toxicity monitoring and no patient experienced >grade 3 adverse events with either schedule. Notably, no patient experienced ≥grade 3 esophagitis or oral mucositis. Diarrhea was the most frequent adverse event, and the incidence of grade 3 diarrhea was 18% in the short infusion arm and 43% with the longer infusion. No DLTs have been observed. On pharmacokinetics analysis, the C max was highest in the short infusion arm (p Conclusions: Preliminary trial results have demonstrated that PGF melphalan, as a high-dose conditioning regimen for auto-HCT in patients with MM, has an acceptable safety profile (no >grade 3 events). The response rates, including the CR+MRD-negative rates are encouraging. The impact of bolus versus longer infusion schedule on outcomes will be assessed after the completion of the trial. Figure 1 Figure 1. Disclosures Mehta: Kadmon: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Lee: Genentech: Consultancy; Legend Biotech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Consultancy; Oncopetides: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Thomas: Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; X4 Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Shpall: Takeda: Patents & Royalties; Affimed: Patents & Royalties; Adaptimmune: Consultancy; Magenta: Consultancy; Novartis: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Axio: Consultancy; Navan: Consultancy; Novartis: Honoraria; Magenta: Honoraria. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; Angiocrine: Research Funding; NexImmune: Research Funding; Janssen: Research Funding; Biolline: Research Funding.

BACKGROUND Immunosuppressed, RhD-negative oncology patients tend to have lower rates of sensitization to the D antigen when they receive transfusion with RhD-positive blood components. Clinical factors associated with alloimmunization to the D antigen in RhD-negative oncology patients when they receive transfusion with RhD-positive red blood cells (RBCs) have not been well defined. STUDY DESIGN AND METHODS This was a 4-year, retrospective analysis identifying RhD-negative oncology patients who received RhD-positive RBCs and were not previously alloimmunized to the D antigen. Age, sex, race, ABO group, primary oncology diagnosis, and numbers of RhD-incompatible RBC transfusions were recorded. The association between antibody formation and clinical factors was studied. The incidence of alloanti-D was calculated from a subsequent antibody-detection test performed at least 28 days after receipt of the first transfusion of RhD-positive RBCs. RESULTS In total, 545 RhD-negative oncology patients received 4295 RhD-positive RBC transfusions. Of these, 76 (14%) became alloimmunized to the D antigen. Diagnosis type was the only factor significantly associated with responder status. The logistic regression model indicated that patients who had myelodysplastic syndrome or solid malignancies were more likely to be responders than those who had acute leukemia. CONCLUSION We measured a 14% sensitization rate to the D antigen in our RhD-negative oncology population. The rate of alloimmunization was higher in patients who had solid cancers (22.6%) or myelodysplastic syndrome (23%) compared with those who had other hematologic malignancies (7%). Knowledge of diagnoses that predispose to RhD alloimmunization enables better utilization of RhD-negative RBCs during times of shortage.

Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is considered to be the standard of care treatment for transplant-eligible patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan by intravenous administration. Conventional melphalan formulations, when administered at high doses, can put patients at risk of potential propylene glycol-associated toxicities. Melphalan for injection (Evomela) is propylene glycol free (PGF), can be dissolved directly using saline, and as a PGF reformulation of Alkeran, incorporating Captisol brand of beta-cyclodextrin sulfobutyl ethers sodium salts, overcomes previous formulation limitations. In 2016 Evomela was the first product approved by the US FDA for high-dose conditioning treatment prior to HCT in MM patients and it is also indicated for the palliative treatment of patients with MM for whom oral therapy is not appropriate. Reconstituted Evomela solution can be stored in the vial for up to 1 hour at room temperature or up to 24 hours at 2-8 °C with no significant degradation. After storage in the vial, it remains stable for an additional 3 to 29 hours after, preparation of admixture solution in infusion bags at concentrations of 0.25 to 5.0 mg/mL, respectively. As well, Evomela solution in saline, at concentration of 5.0 mg/mL melphalan, was bacteriostatic through 72 hours when stored at 2-8 °C. This stability allows for less frequent handling by pharmacy and nursing staff, resulting in a concomitant decrease in exposure risks, increased convenience and administration flexibility, suggestive of an improved ease of handling and administration, when compared to Alkeran. Further, Evomela may actually be less toxic due to the absence of propylene glycol. Although increased melphalan doses have previously demonstrated signals of improved response, the most commonly used dose of melphalan is 200 mg/m2, primarily due to concerns of toxicity. Emerging data regarding higher stability and potentially less toxicity of PGF melphalan (Evomela) supports dose escalation evaluation in order to improve the outcomes. Previous trial data have shown that continuous infusion or frequent fractionated-dose delivery increases the antitumour activity of several drugs. Due to the instability of currently available Alkeran at the room temperature, infusional studies have not been feasible. This limitation is overcome by Evomela, being that the compound is stable for several hours at the room temperature, thus allowing evaluation of infusional schedules in addition to the traditional 30-60 minute bolus doses. Here, we describe a trial designed to assess whether the above noted characteristics of Evomela allow for the escalation of dose and prolongation of infusion time, in order to increase the efficacy of melphalan in patients undergoing auto-HCT. Study Design/Methods: This is a two-stage phase I-II trial to optimize the dose and schedule of Evomela given as a single agent preparative regimen for auto-HCT. Up to 60 participants may be included if they are 18-70 years of age, with non-relapsed MM, have a Karnofsky performance score ≥70%, who have received at least two cycles of initial systemic therapy, and are within 2 to 12 months of the first dose. Patients will be randomized 1:1 to two different infusion schedules (30-60 minute infusion or 8-9 hour infusion) using Evomela (2mg/ml) at two dose cohorts (200mg/ml2 or 225mg/m2). Because 2 mg/mL Evomela is stable for 10 hours, patients receiving the 8-9 hour infusion will receive the total dose in one single infusion bag. The primary objectives are to determine the optimal dose and schedule of Evomela before auto-HCT for MM and collect pharmacokinetic data and compare the exposure-response evaluations between the two infusion schedules. Secondary outcomes will include incidence of treatment-related mortality, rate of minimal residual disease negative complete response at 90 days post auto-HCT, progression-free survival and overall survival after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. The active study follow-up period will be up to one-year post auto-HCT. Figure Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Takeda: Other: Advisory Board, Research Funding; Celgene: Research Funding; KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board. Qazilbash:Amgen: Research Funding; Bioclinica: Consultancy; Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding.

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and non-coding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used functional mapping and annotation (FUMA) to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5 × 10−8) identified by GWAS. The original GWAS melanoma study included 15 990 cases and 26 409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2 and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5 × 10−6. The genes associated with melanoma risk were DEF8 (P = 1.09 × 10−57), DBNDD1 (P = 2.19 × 10−42), SPATA33 (P = 3.54 × 10−38) and MC1R (P = 1.04 × 10−36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). Amplification of CKS1B is frequently associated with the deletion of the CDKN2C gene at chromosome region 1p32 (1p–), which is also associated with inferior outcomes. In this retrospective study, we evaluated the outcomes of patients with 1q+ and/or 1p– after high-dose therapy and autologous hematopoietic cell transplantation (auto-HCT). From January 2006 to December 2015, 1491 newly diagnosed patients with MM underwent upfront high-dose therapy and auto-HCT at our institution. Of those, 899 had the fluorescent in situ hybridization (FISH) data available. FISH was performed at diagnosis and before the start of induction in 686 (76%) patients and after the initiation of induction therapy in 213 (24%) patients. We identified 100 patients with 1q+ and/or 1p– by FISH from the cohort of 899 patients. A control group (n = 287) with diploid cytogenetics and normal FISH panel was selected from the same cohort. From the above 2 cohorts, using a propensity score matched analysis, we identified matched controls for 85 of the 100 patients with 1q+/1p–. Patients were matched for age at auto-HCT, sex, International Staging System stage, induction regimen, creatinine level, disease status at auto-HCT, conditioning regimen, and maintenance therapy. Sixty-seven (79%), 4 (5%), and 14 (16%) patients had 1q+, 1p–, or both 1q+ and 1p–, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the 1q+/1p– and the control group. The median follow-up time for all patients was 29.2 months (range, 0.29 to 84.96). The cumulative incidence of 100-day nonrelapse mortality was 1.2% and 0% for the 1q+/1p– and the control group, respectively. Forty-two patients (50%) in the 1q+/1p– group achieved complete response compared with 40 patients (47%) in the control group. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 41% and 79% for the 1q+/1p– group and 56% and 86% for the control group. Patients in the 1q+/1p– group were at significantly increased risk of progression or death compared to the control group (hazard ratio [HR], 2.21; confidence interval [CI], 1.18 to 4.16; P = .014). No significant association between OS in the 2 groups was observed. The outcome of the 1q+/1p– alone (with no additional high-risk cytogenetics) and the propensity score matched control groups was also compared. Median PFS for the 1q+/1p– alone subgroup was 26.6 months, compared with 38.8 months for the control group (HR, 1.9; CI, 0.9 to 4.08; P = .09). The median OS had not been reached for the 1q+/1p– alone subgroup and was 81.1 months for the control group (HR, 1.25; CI, 0.3 to 4.6; P= .73). 1q+/1p– abnormalities with amplification of CKS1B and deletion ofCDKN2Cgenes were associated with shorter PFS compared with a propensity score matched group of patients with diploid cytogenetics and normal a FISH panel. The outcomes of 1q+/1p– patients with MM have improved with the use of more effective induction, conditioning, and maintenance therapy compared with historical controls, but we still need more effective therapeutic approaches to fully overcome the negative impact of 1q+/1p–.

Purpose: The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)–resistant BRAF-mutant melanomas. Experimental Design: The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated in vitro and in vivo. Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines. 13C-labeling and targeted metabolomics were used to evaluate the effect of OPi on cellular energy utilization. OxPhos inhibition in vivo was evaluated noninvasively by [18F]-fluoroazomycin arabinoside (FAZA) PET imaging. Results: OPi potently inhibited OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo tumor regression with single-agent OPi treatment correlated with inhibition of both MAPK and mTOR complex I activity. Unexpectedly, antitumor activity was not improved by combined treatment with MAPKi in vitro or in vivo. Signaling and growth-inhibitory effects were mediated by LKB1–AMPK axis, and proportional to AMPK activation. OPi increased glucose incorporation into glycolysis, inhibited glucose and glutamine incorporation into the mitochondrial tricarboxylic acid cycle, and decreased cellular nucleotide and amino acid pools. Early changes in [18F]-FAZA PET uptake in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy. Conclusions: Targeting OxPhos with OPi has significant antitumor activity in MAPKi-resistant, BRAF-mutant melanomas, and merits further clinical investigation as a potential new strategy to overcome intrinsic and acquired resistance to MAPKi in patients.

PurposeTo evaluate for an association between 25-hydroxyvitamin D levels (vitamin D) and outcome measures in patients with melanoma after evaluation is controlled for systemic inflammatory response (SIR) on the basis of simultaneous C-reactive protein (CRP) measurement.Materials and MethodsPlasma samples from 1,042 prospectively observed patients with melanoma were assayed for vitamin D and CRP. The associations of demographics and CRP with vitamin D were determined, followed by a determination of the association between vitamin D and stage and outcome measures from the date of blood draw. The vitamin D level was considered sufficient if it was 30 to 100 ng/mL. Kaplan-Meier and Cox regression analyses were performed.ResultsThe median vitamin D level was 25.0 ng/mL. The median follow-up time was 7.1 years. A lower vitamin D was associated with the blood draw during fall/winter months (P < .001), older age (P = .001), increased CRP (P < .001), increased tumor thickness (P < .001), ulcerated tumor (P = .0105), and advanced melanoma stage (P = .0024). On univariate analysis, lower vitamin D was associated with poorer overall (OS; P < .001), melanoma-specific survival (MSS; P = .0025), and disease-free survival (DFS; P = .0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates. Multivariable hazards ratios per unit decrease of vitamin D were 1.02 for OS (95% CI, 1.01 to 1.04; P = .0051), 1.02 for MSS (95% CI, 1.00 to 1.04; P = .048), and 1.02 for DFS (95% CI, 1.00 to 1.04; P = .0427).ConclusionLower vitamin D levels in patients with melanoma were associated with poorer outcomes. Although lower vitamin D was strongly associated with higher CRP, the associations of lower vitamin D with poorer OS, MSS, and DFS were independent of this association. Investigation of mechanisms responsible for these associations may be of value to patients with melanoma.

Introduction Large cell transformation (LCT) of mycosis fungoides (MF) is associated with an aggressive clinical course, poor overall survival (OS), and variable CD30 expression. Patients and Methods We retrospectively analyzed 1900 MF/Sezary syndrome patients' clinical, histologic and immunophenotype and identified 187 patients seen between 1982 and 2012. Results Most advanced stage patients with LCT were male 86 of 155 (55.4%) and 69 were female (44.5%). Incidence of LCT (n = 187) was 9.8% (187/1900) in skin and/or nodes of the entire MF/SS database population (n = 1900). Advanced stage patients represented 83% of patients whose median OS was 4.1 years (95% confidence interval [CI], 3.5-5.4). Early stage patients represented 17% with OS of 8.0 years. Among 187 LCT patients, 136 patients (73%) were diagnosed with LCT at the time of initial diagnosis of MF. Their median OS was 3.6 years (95% CI, 3.3-5.3). Of the 51 patients who had LCT diagnosed after their initial diagnosis of MF, their median OS was 8.8 years (P = .0001; 95% CI, 1.6-4.1). The OS for all LCT patients was 4.8 years, for patients older than 60 years of age OS was 3.7 years (95% CI, 2.7-5.4) and was 6.2 years (95% CI, 4.5-9.8) for patients younger than 60 years of age (P = .0001). An increased lactate dehydrogenase level was associated with a decreased OS (P = .03; hazard ratio, 1.5; 95% CI, 1.0-2.2). Patients with CD30 expression in ≥ 10% of the lymphocytes in skin biopsies were 40% more likely to survive than patients with low expression. Conclusion In summary, risk factors associated with disease progression were advanced age, LCT at the time of initial diagnosis of MF, high levels of lactate dehydrogenase, and CD30 expression

Background: While important for the initial diagnosis and treatment of malignancies, biopsies have an increasing role in clinical trials for correlative science to improve the molecular understanding of cancer. However, research biopsy specimens can be insufficient for analysis and their scientific impact on drug development and treatment has been questioned. The purpose of our study was to identify which inter- and intrapatient factors predict research biopsy tissue quantity and adequacy. Methods: Biopsies were obtained from patients enrolled in clinical trials across multiple cancer histologies as part of the Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO) program at MD Anderson Cancer Center. For each trial, enrolled patients typically underwent a pre-treatment biopsy, with 60% undergoing on/post treatment biopsies. Biopsy cores were either paraffin embedded or flash frozen and sent for pathology review to determine tumor area (core length times core width multiplied by proportion of core area occupied by tumor cells) as well as percentage of tumor contained in the core (fraction of core containing cellular components of tumor, including malignant and peri-tumor non-malignant cells, reported as a percentage). Results: A total of 1151 research biopsies were performed on 661 patients from which 5126 cores were evaluated (median 5 cores per biopsy). 5 or more cores were sent for pathology review in 753 biopsies (65.4%) with 4 sent in 232 cases (20.2%). Tumor area decreased across increasing core position (p Conclusions: Core position, tumor histology, and biopsy location, in addition to expected factors such as needle gauge and lesion size, appear to influence tumor tissue yield. Moreover, there is notable within-biopsy variability with respect to core adequacy which argues for real-time quality assessment of individual cores during biopsies. A substantial number of cores contain tumor amounts inadequate for molecular analysis. Despite a high rate of low tumor cellularity in at least one core of many patients, when multiple cores were taken by an experienced team, relatively few patients had inadequate samples across all cores. Citation Format: Deepak Bhamidipati, Anuj Verma, Dipen M. Maru, Dawen Sui, Grace Mathew, Wenhua Lang, Juan F. Posadas, Joshua P. Hein, Scott Kopetz, Andrew Futreal, Ignacio I. Wistuba, J. Jack Lee, Michael J. Overman, Alda L. Tam. Analysis of 1151 prospective research biopsies: Factors influencing tumor yield across patients and biopsy cores [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 808.

Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.

Purpose To investigate the association between blood levels of C-reactive protein (CRP) in patients with melanoma and overall survival (OS), melanoma-specific survival (MSS), and disease-free survival. Patients and Methods Two independent sets of plasma samples from a total of 1,144 patients with melanoma (587 initial and 557 confirmatory) were available for CRP determination. Kaplan-Meier method and Cox regression were used to evaluate the relationship between CRP and clinical outcome. Among 115 patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in CRP using nonparametric tests. Results Elevated CRP level was associated with poorer OS and MSS in the initial, confirmatory, and combined data sets (combined data set: OS hazard ratio, 1.44 per unit increase of logarithmic CRP; 95% CI, 1.30 to 1.59; P < .001; MSS hazard ratio, 1.51 per unit increase of logarithmic CRP; 95% CI, 1.36 to 1.68; P < .001). These findings persisted after multivariable adjustment. As compared with CRP < 10 mg/L, CRP ≥ 10 mg/L conferred poorer OS in patients with any-stage, stage I/II, or stage III/IV disease and poorer disease-free survival in those with stage I/II disease. In patients who underwent sequential evaluation of CRP, an association was identified between an increase in CRP and melanoma disease progression. Conclusion CRP is an independent prognostic marker in patients with melanoma. CRP measurement should be considered for incorporation into prospective studies of outcome in patients with melanoma and clinical trials of systemic therapies for those with melanoma.

PURPOSE: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan ((90)YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT). EXPERIMENTAL DESIGN: Patients were enrolled on three consecutive phase 2 clinical trials. Patients received two doses of rituximab (375 mg/m(2) and 1000 mg/m(2)) during mobilization of stem cells, followed by 1000 mg/m(2) on days +1 and +8 after ASCT with R-BEAM or (90)YIT-R-BEAM ((90)YIT dose of 0.4 mCi/kg) conditioning. RESULTS: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving (90)YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for (90)YIT-R-BEAM (P =0.82). The 5-year overall survival rates were 73%, and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (< vs. > 1 year) after initial induction chemotherapy (P = 0.97). CONCLUSIONS: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of (90)YIT does not confer a further survival benefit.

Sentinel lymph node (SLN) sampling may provide staging information without exposing patients to risks of lymph node dissection. There is no consensus protocol for optimal pathologic handling of these specimens. This study compares 2 ultrastaging protocols of SLN in endometrial carcinoma (EC). All SLN were serially sectioned perpendicular to the long axis in 2 mm intervals and entirely submitted for routine hematoxylin and eosin (HE) processing. SLN negative by routine processing had ultrastaging (US) by one of the following: method 1 (M1), 5 HE levels at 250 μm intervals with 2 unstained slides at each level; pankeratin immunohistochemistry (IHC) performed on level 1 in cases with negative HE levels or method 2 (M2), 1 HE level + 2 unstained slides cut 250 μm into the tissue block; pankeratin IHC performed in cases with negative HE. Histologic subtype, numbers of SLN, positive SLN, non-SLN, positive non-SLN, and metastasis size were recorded. A total of 178 patients had 527 SLNs (1-16 per case; median, 2 SLN) sampled during hysterectomy for the following EC histotypes: endometrioid International Federation of Gynecology and Obstetrics grade 1/2, 117 (66%); endometrioid International Federation of Gynecology and Obstetrics grade 3, 18 (10%); serous, 20 (11%); carcinosarcoma, 11 (6%); clear cell, 9 (5%); and undifferentiated, 3 (2%). In all, 172 patients had ultrastaging: M1=65; M2=58. In total, 33 patients were SLN positive. Twenty-seven had SLN submitted for US: M1=11; M2=16. Eleven patients had additional SLN detected by US: M1=5; M2=6. Of these, 8 were patients whose SLN were only detected by US representing an increase of 32% in number of patients with positive SLN. Six patients (M1=2; M2=4) with negative SLN had a positive non-SLN. Mean size of ultrastage-detected metastasis was 0.24 mm for M1 and 0.38 mm for M2. Statistical analysis comparing M1 and M2 detected no statistically significant associations with respect to number of positive SLN detected, size of metastasis or false-negative rate and method. The methods performed similarly for both low-grade and high-grade EC. A more comprehensive US protocol had no significant advantages over a single wide interval and IHC in this study population. A pankeratin IHC stain enhances metastasis detection. Additional studies are required to further test this limited protocol as well as to evaluate the clinical significance of the low volume disease detected by ultrastaging.

Cytokines such as Interleukin (IL)-12p70 ("IL-12") and IL-23 can influence tumor progression. We tested the hypothesis that blood levels of IL-12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL-12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10-unit change of IL-12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL-12p40 was associated with melanoma recurrence [hazard ratio (HR) = 1.04 per 10-unit increase in IL-12p40, 95% CI 1.02-1.06, p = 8.48 × 10(-5) ]; Elevated IL-12p40 was also associated with a poorer melanoma specific survival (HR = 1.06, 95% CI 1.03-1.09, p = 3.35 × 10(-5) ) and overall survival (HR = 1.05, 95% CI 1.03-1.08, p = 8.78×10(-7) ) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL-12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL-12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL-12p40 in advanced stage melanoma patients.

The benefit of adrenalectomy (ADX) for adrenal metastasis is not established. We evaluated outcomes after ADX for patients with adrenal metastasis. We retrospectively analyzed the records of 90 patients who underwent ADX for metastatic disease. Overall survival (OS) after ADX was calculated using the Kaplan–Meier method. Clinical factors were evaluated for associations with OS using a Cox regression model, and with operative factors using the Wilcoxon two-sample or Fisher’s exact test. The most common primary tumor types were melanoma (35, 39 %) and lung cancer (32, 35 %). A total of 49 (54 %) patients had isolated adrenal metastasis; 55 (61 %) underwent laparoscopic resection (LADX). Median OS was 2.46 years (range