Prostate Cancer: Early Detection and Assessing Clinical Risk Using Deep Machine Learning of High Dimensional Peripheral Blood Flow Cytometric Phenotyping Data

Detecting the presence of prostate cancer (PCa) and distinguishing low- or intermediate-risk disease from high-risk disease early, and without the need for potentially unnecessary invasive biopsies remains a significant clinical challenge. The aim of this study is to determine whether the T and B cell phenotypic features which we have previously identified as being able to distinguish between benign prostate disease and PCa in asymptomatic men having Prostate-Specific Antigen (PSA) levels < 20 ng/ml can also be used to detect the presence and clinical risk of PCa in a larger cohort of patients whose PSA levels ranged between 3 and 2617 ng/ml. The peripheral blood of 130 asymptomatic men having elevated Prostate-Specific Antigen (PSA) levels was immune profiled using multiparametric whole blood flow cytometry. Of these men, 42 were subsequently diagnosed as having benign prostate disease and 88 as having PCa on biopsy-based evidence. We built a bidirectional Long Short-Term Memory Deep Neural Network (biLSTM) model for detecting the presence of PCa in men which combined the previously-identified phenotypic features (CD8+CD45RA-CD27-CD28- (CD8+ Effector Memory cells), CD4+CD45RA-CD27-CD28- (CD4+ Effector Memory cells), CD4+CD45RA+CD27-CD28- (CD4+ Terminally Differentiated Effector Memory Cells re-expressing CD45RA), CD3-CD19+ (B cells), CD3+CD56+CD8+CD4+ (NKT cells) with Age. The performance of the PCa presence ‘detection’ model was: Acc: 86.79 ( ± 0.10), Sensitivity: 82.78% (± 0.15); Specificity: 95.83% (± 0.11) on the test set (test set that was not used during training and validation); AUC: 89.31% (± 0.07), ORP-FPR: 7.50% (± 0.20), ORP-TPR: 84.44% (± 0.14). A second biLSTM ‘risk’ model combined the immunophenotypic features with PSA to predict whether a patient with PCa has high-risk disease (defined by the D’Amico Risk Classification) achieved the following: Acc: 94.90% (± 6.29), Sensitivity: 92% (± 21.39); Specificity: 96.11 (± 0.00); AUC: 94.06% (± 10.69), ORP-FPR: 3.89% (± 0.00), ORP-TPR: 92% (± 21.39). The ORP-FPR for predicting the presence of PCa when combining FC+PSA was lower than that of PSA alone. This study demonstrates that AI approaches based on peripheral blood phenotyping profiles can distinguish between benign prostate disease and PCa and predict clinical risk in asymptomatic men having elevated PSA levels.

CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group

PURPOSE Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial ( NCT01371981 ). MATERIALS AND METHODS AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels. RESULTS The study population was divided into CD123 expression–based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations ( P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations ( P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis. CONCLUSION CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.

Colon Cancer with Complete Pathological Response to Only 1 Cycle of Capecitabine: Treatment Modification in the Perspective of COVID-19 Pandemic

Incidence of colorectal cancer has surged in the past few decades, currently it accounts for approximately 10% cancer related mortality. Upfront curative surgery is the main stay of treatment for localized disease followed by adjuvant chemotherapy for high-risk disease; however, neo adjuvant chemoradiation followed by surgery and chemotherapy is a standard treatment for rectal cancer. Here, we present a case of a young male aged 33 years with eight months’ history of per rectal bleeding, associated with fever and weight loss who was later diagnosed as sigmoid colon adenocarcinoma. The patient managed to have only one cycle of neoadjuvant capecitabine, as his definitive surgery was delayed due to the rife in pandemic situation of Covid-19. Notably, follow up laparoscopic LAR specimen showed no residual disease, nevertheless, there was an eosinophilic abscess with a giant cell reaction and Ova of Ascaris lumbricoides, which seemingly contributed in achieving pathological complete response with minimal therapy.

Good Outcome after R-Hyper-CVAD/R-MA in High-Risk Aggressive B-Cell Lymphoma: A Single-Center Experience

INTRODUCTION Patients with high-risk aggressive B-cell lymphoma exhibit poor survival after R-CHOP-like immunochemotherapy. More intensive regimens yield higher rates of remission but also of complication, which have hindered their use, particularly in older patients. At Karolinska, the standard intensive regimen has been R-Hyper-CVAD/R-MA for patients with high-risk characteristics, such as high age-adjusted international prognostic index (aaIPI) and extranodal disease. METHODS In this analysis, high-risk disease was defined as aaIPI ≥ 2 or any extranodal involvement. We examined Karolinska's 136 patients who received at least one cycle of R-Hyper-CVAD/R-MA in first-line therapy for high-risk disease, excluding Burkitt, transformed, and primary CNS lymphoma. Patients were diagnosed between 2006 and 2020; 89 were diffuse large B-cell lymphoma, 23 high-grade B-cell lymphoma, 17 primary mediastinal B-cell lymphoma, 4 T cell/histiocyte-rich B-cell lymphoma, 2 aggressive B-cell lymphoma unspecified, 1 lymphomatoid granulomatosis grade 3. For outcome, we investigated progression-free survival (PFS). RESULTS In this cohort of 136 patients with high-risk disease treated with at least one cycle of R-Hyper-CVAD/R-MA, the median age was 52 years (range, 19-69); 36 patients (26%) were 61-69 years old. Lactate dehydrogenase was elevated in 92%, stage III-IV disease was seen in 93%, WHO performance status ≥2 in 49%, aaIPI = 3 in 38%, extranodal disease in 30%, CNS involvement in 17%, and Charlson comorbidity index ≥2 in 11%. At 5 years, the PFS in all patients was 72% and in the 50 patients with aaIPI = 3, 66% (Figure 1). In patients ≤60 years old, 5-year PFS was 76% (aaIPI = 3, 69%). In patients 61-69 years, the 5-year PFS was 58% (aaIPI = 3, 59%). Six out of 136 patients (4%) died from toxicity during induction therapy (3/6 were 61-69 years old). CONCLUSIONS This is to our knowledge the largest published single-center series of patients treated with R-Hyper-CVAD/R-MA for high-risk aggressive B-cell lymphoma. Outcome in these patients aged 19-69 years was excellent, with 5-year PFS 72%. Particularly patients with aaIPI = 3 showed rather good outcome with 5-year PFS 66%. For comparison, in Sweden the 5-year overall survival of R-CHOP-treated patients ≤60 years with aaIPI = 3 is 40% (Melén CM et al. Brit J Haematol. 614-622. 2016). We will continue to explore R-Hyper-CVAD/R-MA as primary therapy for high-risk aggressive B-cell lymphoma. Figure 1 Figure 1. Disclosures Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding.

Unifying the Definition of High-Risk in Multiple Myeloma

Introduction: There is considerable heterogeneity in the clinical outcome of newly diagnosed multiple-myeloma (NDMM) with some patients having a good prognosis while others fail to respond or relapse quickly after therapy progressing rapidly to death. Using risk scores based on clinical, biochemical and genetic features it is possible to predict some of this variation giving an ability to segment the disease into risk strata. Clinical studies have suggested that patients with standard-risk disease have benefited more from the recent advances in therapy compared to those with high-risk disease. The development of clinical trials specifically recruiting patients with high-risk disease features offers the potential to improve the outcome of a subgroup of patients with a very poor clinical outcome. To perform such studies is it important to have a unifying definition of high-risk including standard parameters, group size and outcome of individual risk strata so that clinical trial rigor can be achieved (e.g., common entry criteria, statistical power). In order to understand the size and feasibility of such studies we analyzed the Myeloma Genome Project (MGP) dataset to assess multiple risk factors and scores to determine and compare how they perform as risk stratifiers with each other. Methods: The MGP dataset is a large set of molecular and clinical data from 1273 patient with NDMM. Data were available on clinical variables (Albumin (Alb), B2-microglobulin (B2M), LDH, age), cytogenetic variables [t(4;14), t(14;16), t(14;20), 17p-, TP53 mutations, 1q+ and 1p-] and gene expression analysis (GEP70). A literature search was used to identify risk models used in clinical studies. Survival analysis was performed in R. The median follow-up at the time of analysis was 54.5 (53.2-56.5) months. Results: The median patient age was 66 years, with 641 (50.4%) patients over age 65. The sex ratio (M:F) was 1:0.66. African American, White, and Asian constituted 17%, 76%, and 2%, of cases respectively. 26.7% received a stem cell transplant. We determined the size of the strata and actual risk (measure by the hazard ratios, HR) compared to standard risk cases for both PFS and OS of the various clinical models available, data are summarized in Figure 1. When looking at individual risk scores, the HR for progression for t(4;14), TP53 inactivation (deletion and mutations), gain(1q), and del(1p) were 1.4, 1.1, 1.3, and 1.1 respectively. When considering overall survival these HR were 1.4, 1.7, 1.5, and 1.4 respectively. We went on to analyze the impact of these events in combination and show that combined, there is increased specificity, especially for OS (HR 2.3-5.1) but they identify small subsets making up &lt;10% of patients. We then analyzed the purely clinical scores (ISS) and combined clinical/genetic scores. We show again, that the more specific risk scores (double hit, Boyd IV, GEP70) identify between 7-13% of cases with HR (2-3.1) for OS. When we looked specifically at the younger patients (=&lt; 65), similar trends were seen with GEP70 by RNA-seq offering one of the most interesting means of identifying HR cases. Conclusion: In this large NDMM dataset, we demonstrate the clear variation in risk groups that occur dependent upon the approach used resulting in heterogeneous levels of risk, strata size, and performance. With the exception of GEP70, none of the single features are sensitive or specific enough to identify all cases. Risk models based on a combination of markers improve the ability to detect true high-risk disease but there remains variability. At a molecular level the inclusion of TP53 inactivation, and 1q+ improve the performance of the ISS. This analysis provides insights into standardizing the definition of high-risk and the generation of consensus definitions for clinical trial entry. Figure 1 Figure 1 Figure 1. Disclosures Braunstein: Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cairns: Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Davies: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

An Interim Analysis of the Turkish Myeloma Registry Among the Patients Who Have Received up to Two Lines of Therapy

Introduction: To investigate the demographics and treatment details of the myeloma patients who were diagnosed and followed up in Turkey and received up to two lines of therapy. Methods: Patients who were recorded on the database of Turkish Myeloma Registry project were included in this study if they had only received one or two lines of therapy. Demographics, patient, and disease related parameters both at the time of diagnosis and at the follow up and treatment outcomes were presented. Results: A total of 532 patients were included in the study, and 44% of the patients were female. Median age at the time of diagnosis was 63 (30-106). 47.7% of the patients were diagnosed with IgG myeloma. According to the ISS risk stratification, 20.4% of patients had ISS 1, 34.7% of patients had ISS 2 and remaining 44.9% had ISS 3 disease. Defining high risk disease as harboring one or more of these following cytogenetic abnormalities; del 17p, t(4;14), t(14;16) or t(14;20); 7.1% of the patients were classified as having a high risk disease. Most commonly used frontline therapy approach was bortezomib cyclophosphamide dexamethasone combination (VCD) (76.5%) and followed by bortezomib dexamethasone (VD) (8.8%), and bortezomib lenalidomide and dexamethasone combination (VRd) (7.1%). Overall response rates (a better response than stable disease according to IMWG response assessment criteria) were 87.6% in VCD induced patients; 63.3% in VD induced patients and 92% in VRd induced patients. The PFS obtained by these frontline approaches was 17.8 months in patients who were able to proceed with high dose chemotherapy with ASCT support and 8.4 in patients who were not able to (p&lt;0.01), with an overall PFS of 15.3 months. With regard to the induction approach, PFS was 21.1 months for VRD, 15.3 months for VCD and 7.6 months for VD (p=0.08). Regarding maintenance, 23.6% of patients were maintained by lenalidomide alone, 62.7% of patients were maintained by a combination of lenalidomide and dexamethasone or bortezomib alone (2.7%). PFS after the first line of the treatment was 22.2 months in maintained patients and 12.2 in un-maintained patients (HR: 0.532, p=0.001, CI95% 0.359-0.790). Regarding the second line therapy Rd was the leading option (34.8%) and VRd (17.8%), Carfilzomib based (16.3%), VCD (8.1%) were the followings. Conclusion: As the main concern of this study was to document the demographic features and clinical parameters of a Turkish Myeloma population and to give an idea about the treatment patterns and outcomes in frontline setting and first relapse an overall survival was not calculated. Progression free survival obtained after frontline therapy was relatively shorter than the ones which were presented by other real- world registries. Outcomes of second line therapy will be presented as follow up after 2nd line therapy exceeds a certain threshold. We hope, the results obtained from this study can have a role in the approval and re-imbursement of the current standard of care options. Disclosures No relevant conflicts of interest to declare.

Prostate Cancer Disparities in Risk Group at Presentation and Access to Treatment for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study With Disaggregated Ethnic Groups

PURPOSE We identified (1) differences in localized prostate cancer (PCa) risk group at presentation and (2) disparities in access to initial treatment for Asian American, Native Hawaiian, and Pacific Islander (AANHPI) men with PCa after controlling for sociodemographic factors. METHODS We assessed all patients in the National Cancer Database with localized PCa with low-, intermediate-, and high-risk disease who identified as Thai, White, Asian Indian, Chinese, Vietnamese, Korean, Japanese, Filipino, Hawaiian, Pacific Islander, Laotian, Pakistani, Kampuchean, and Hmong. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of (1) presenting at progressively higher risk group and (2) receiving treatment or active surveillance with intermediate- or high-risk disease, adjusting for sociodemographic and clinical factors. RESULTS Among 980,889 men (median age 66 years), all AANHPI subgroups with the exception of Thai (AOR = 0.84 [95% CI, 0.58 to 1.21], P > .05), Asian Indian (AOR = 1.12 [95% CI, 1.00 to 1.25], P > .05), and Pakistani (AOR = 1.34 [95% CI, 0.98 to 1.83], P > .05) men had greater odds of presenting at a progressively higher PCa risk group compared with White patients (Chinese AOR = 1.18 [95% CI, 1.11 to 1.25], P < .001; Japanese AOR = 1.36 [95% CI, 1.26 to 1.47], P < .001; Filipino AOR = 1.37 [95% CI, 1.29 to 1.46], P < .001; Korean AOR = 1.32 [95% CI, 1.18 to 1.48], P < .001; Vietnamese AOR = 1.20 [95% CI, 1.07 to 1.35], P = .002; Laotian AOR = 1.60 [95% CI, 1.08 to 2.36], P = .018; Hmong AOR = 4.07 [95% CI, 1.54 to 10.81], P = .005; Kampuchean AOR = 1.55 [95% CI, 1.03 to 2.34], P = .036; Asian Indian or Pakistani AOR = 1.15 [95% CI, 1.07 to 1.24], P < .001; Native Hawaiians AOR = 1.58 [95% CI, 1.38 to 1.80], P < .001; and Pacific Islanders AOR = 1.58 [95% CI, 1.37 to 1.82], P < .001). Additionally, Japanese Americans (AOR = 1.46 [95% CI, 1.09 to 1.97], P = .013) were more likely to receive treatment compared with White patients. CONCLUSION Our findings suggest that there are differences in PCa risk group at presentation by race or ethnicity among Asian American, Native Hawaiian, and Pacific Islander subgroups and that there exist disparities in treatment patterns. Although AANHPI are often studied as a homogenous group, heterogeneity upon subgroup disaggregation underscores the importance of further study to assess and address barriers to PCa care.

Frontline Treatment of the Young, Fit Patient with CLL: A Canadian Perspective

From a Canadian perspective, there has been a limited discussion on the frontline management of young, fit patients with chronic lymphocytic leukemia (CLL). The prevalence of this population ranges between 2 and 22 per 100,000 persons in Canada and varies by region. Until recently, fixed-duration fludarabine-based chemoimmunotherapy (CIT) was the primary treatment option in Canada for this patient population. The ECOG1912 trial has since demonstrated that ibrutinib and rituximab therapy are as effective as fludarabine-cyclophosphamide-rituximab (FCR) in this population. The ALLIANCE trial showed that rituximab added no incremental benefit to ibrutinib. Canadian payors and physicians adopted ibrutinib monotherapy as the CLL standard of care, even in the young, fit population, although frontline ibrutinib therapy is often reimbursed by provincial public drug plans only in patients with high-risk disease or those who are unfit to receive fludarabine. Young, fit patients with CLL and their physicians may now choose between continuous ibrutinib monotherapy and fixed-duration CIT with FCR. Factors affecting this choice include patient preference and the short- and long-term toxicity profiles of both regimens, and a risk-based algorithm is provided. As new continuous-therapy options enter the market, all treatment choices present benefits and risks that must be communicated to the patient.