Presence of Residual Disease Detected by Multidimensional Flow Cytometry Identifies Patients with AML At High Risk of Relapse – a Report From the Children's Oncology Group,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3545-3545 ◽  
Author(s):  
Michael R. Loken ◽  
Todd A. Alonzo ◽  
Laura Pardo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Advisory Committees ◽  
Free Survival ◽  
Post Induction ◽  
Risk Patients ◽  
Disease Free

Abstract Abstract 3545 We previously demonstrated that presence of post induction residual disease detected by multidimensional flow cytometry (MDF) was associated with higher relapse risk and worse survival in a cohort of 225 children treated on AAML03p1. In this study we used a similar methodology in examining the post induction marrow specimens in patients treated on the COG AML phase III trial AAML0531. This study randomized 1022 children and young adults without Down Syndrome (DS) to an MRC based chemotherapy backbone with or without Gemtuzumab Ozogamicin (GO) in the first and fourth course of therapy. Of the 1022 eligible patients, 784 patients consented to participate in the correlative biology study and submitted marrow specimens by the end of first course for evaluation of disease status by MDF. Of these 784 marrow specimens, residual disease (RD) defined as ≥0.1% blasts by MDF was identified in 240 patients (31%). Prevalence of RD in patients in morphologic CR was 20% vs. 63% in those who failed to achieve a morphologic CR (37% of those who were not in morphologic CR had no RD by MDF). Presence of RD varied by risk groups, where those with favorable risk features (CBF AML) had an RD prevalence of 14%, high risk patients (-7, -5/del5q, high risk FLT3/ITD, course 1 blasts >15%) had an RD prevalence of 68% and the intermediate risk patients had an RD prevalence of 27%. Patients with RD who were in morphologic CR or PR at the end of the first course had disease-free survival (DFS) at 3 years of 34% vs. 60% in those without RD (p<0.0001). Corresponding overall survival (OS) at 3 years was 54% and 76% in those with and without RD, respectively (p<0.0001). We further evaluated the ability of post induction RD to predict outcome in specific risk categories. Of the 180 patients considered favorable risk by cytogenetic features who were in morphologic CR or PR at end of first course, 23 had RD by MDF (13%). Presence of RD in this favorable risk cohort was not associated with worse disease-free survival (DFS, p=0.54). Similar lack of prognostic significance was observed in patients considered high risk (p=0.38). In contrast to high and low risk patients, in 435 patients with no known risk features (intermediate risk) 118 patients had RD detected by MDF (27%). DFS at 3 years from end of first course in patients with RD was 33% vs. 55% for those without RD (p<0.0001). Corresponding OS at 3 years for those with and without RD was 51% and 70%, respectively (p<0.001). This study demonstrates the significance of early response to chemotherapy as measured by MDF in predicting clinical outcome in childhood AML. It also demonstrates that the presence of RD may not be predictive of outcome in those with high or low risk features. Multi-dimensional flow cytometry has been incorporated into the current COG phase III AML trial. Disclosures: Smith: Eisai: ; Archimedes Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics:.

Multidimensional Flow Cytometry Significantly Improves Upon the Morphologic Assessment of Post-Induction Marrow Remission Status – Comparison of Morphology and Multidimensional Flow Cytometry; A Report From the Children's Oncology Group AML Protocol AAML0531

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 939-939 ◽  
Author(s):  
Michael R. Loken ◽  
Todd A. Alonzo ◽  
Laura Pardo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Disease Free Survival ◽  
Initial Response ◽  
Advisory Committees ◽  
Free Survival ◽  
Post Induction ◽  
Remission Status ◽  
Disease Free

Abstract Abstract 939 Initial response to induction chemotherapy is a significant predictor of outcome in leukemias, where those with rapid response have an improved outcome compared to the non-responders. Morphologic evaluation of post induction marrow has been the gold standard in assessing remission status in leukemias, where those with <5% blasts are considered to be in complete remission (CR), whereas those with '5% blast are considered induction failures. MRC AML 10 study, using morphologic assessment of remission, delineated a clinically significant threshold of 15% marrow blasts after induction I, where those with 5–15% blasts were shown to have a similar outcome to those in morphologic CR, while those with >15% blasts were considered to be high risk. The Children's Oncology Group (COG) phase III AML protocol AAML0531 which treated 1022 eligible patients without Down Syndrome (DS) on an MRC based chemotherapy backbone, utilized the >15% post induction morphologic blast threshold, as assessed at the institutional level, to allocate patients to specific risk groups based on the observed post induction 1 blast prevalence. In this study, all patients regardless of initial response would receive a second course of similar induction chemotherapy. Those with 5–15% blasts after course 1 with no other risk features who achieved a CR after the second course were considered intermediate risk, but those with >15% post course 1 blasts who achieved a CR after course 2 were considered high risk and allocated to stem cell transplantation from the most suitable donor in first CR. As part of this trial, multidimensional flow cytometry (MDF) was used to assess marrow response after each course of induction chemotherapy. As morphologic evaluation would not be able to distinguish normal and malignant blasts in the marrow, we inquired whether morphologic CR status correlates with MDF findings. Of the 1022 eligible non-DS patients treated on AAML0531, 784 patients had consented to the correlative biology studies and had available MDF data for correlation with morphology. Of the 784 patients, 185 patients (24%) had failed to achieve a morphologic CR (>5% blast by morphology) after the initial course of chemotherapy, of which 94 were partial remissions (PR, 5–15% blast) and 91 were persistent disease (PD, >15%). Of these 185 patients who failed to achieve a morphologic CR, 67 patients (36%) had no evidence of disease by MDF, and the remaining 64% had MDF detectable disease. Clinical outcome evaluation of these patients who failed induction (>5% blast) at the end of course 1 based on MDF status demonstrated that disease free survival for those with MDF detectable disease was 24% compared to that of 52% in those with induction failure with no MDF detectable disease (p<0.0001). Corresponding Overall survival was 48% and 76%, respectively (p=0.005). As 15% blast threshold at the end of induction 1 was used as a threshold for risk allocation, we specifically evaluated the prevalence and clinical implications of MDF-detectable disease in this cohort of high risk patients. Of the 91 patients with >15% blast after course I, 25 (27%) had no evidence of disease by MDF. Disease-free survival at 3 years from end of induction in this high risk cohort with and without MDF-detectable disease was 20% and 55%, respectively (p<0.0001) with a corresponding OS of 47% and 83% (p=0.014). This study highlights the fact that morphologic evaluation of marrow specimens may not be adequate for post induction disease assessment. Multi-dimensional flow cytometry provides significant information for accurate assessment of response. Disclosures: Smith: Seattle Genetics:; Eisai:; Archimedes Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees.

Phase III postneoadjuvant study evaluating sacituzumab govitecan, an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS602-TPS602
Author(s):  
Frederik Marmé ◽  
Elmar Stickeler ◽  
Jenny Furlanetto ◽  
Carsten Denkert ◽  
Marcus Schmidt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Invasive Disease ◽  
Phase Iii ◽  
Nodal Involvement ◽  
Free Survival ◽  
Risk Of Recurrence ◽  
Disease Free

TPS602 Background: Women with triple-negative breast cancer (TNBC) having residual disease after neoadjuvant chemotherapy (NACT) as well as HR-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥ 3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. Sacituzumab govitecan is approved for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC. Therefore, sacituzumab govitecan may represent a new option against the resistant residual disease after standard NACT. Methods: SASCIA is a phase III, prospective, international, multi-center, randomized, open label, parallel group study in patients with HER2-negative BC with residual disease after NACT (NCT04595565). Eligible patients must have received taxane-based NACT for 16 weeks, including at least 6 weeks of a taxane. Patients should be at high risk of recurrence after treatment, defined as having centrally confirmed HER2-negative BC (IHC score 0-1 or FISH negative according to ASCO/CAP guideline) assessed preferably on tissue from postneoadjuvant residual invasive disease of the breast and either HR-negative (<1% positive stained cells), with any residual invasive disease > ypT1mi after NACT or HR-positive (≥1% positive stained cells), with a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before NACT. Radiotherapy should be delivered before the start of study treatment. Patients are randomized 1:1 to receive either sacituzumab govitecan 10 mg/kg body weight (days 1, 8 q3w for eight cycles) or treatment of physician´s choice (capecitabine 2000 mg/m² day 1-14 q21 or platinum-based chemotherapy i.e. carboplatin AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles or observation). Randomization is stratified by HR status (HR-positive vs negative) and nodal involvement after NACT (ypN+ vs ypN0). In patients with HR-positive BC, endocrine-based therapy will be administered according to local guidelines. The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints include comparison of overall survival (OS, key secondary endpoint), distant disease-free survival, locoregional recurrences-free interval, safety, compliance, iDFS and OS according to stratified and - predefined subgroups, patient reported outcome, and quality of life between treatment arms. As of February 2 2021, 7/1200 patients have been randomized in Germany. International study groups will join soon. Clinical trial information: NCT04595565.

scholarly journals Adjuvant Gemcitabine-Oxaliplatin (GeMOX) after Curative Surgery in High-risk Patients with Cholangiocarcinoma

2009 ◽  
Vol 3 ◽  
pp. CMO.S3360
Author(s):  
Bernard Paule ◽  
Paola Andreani ◽  
Marie-Pierre Bralet ◽  
Catherine Guettier ◽  
René Adam ◽  
...  
Keyword(s):  
Survival Rate ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Disease Free Survival ◽  
Curative Surgery ◽  
Free Survival ◽  
High Risk Factors ◽  
Risk Patients ◽  
Disease Free Survival Rate ◽  
Disease Free

Background There is no standard adjuvant chemotherapy to prevent recurrent cholangiocarcinoma (CCA), a rare cancer with poor prognosis. We assessed the efficacy and safety of GEMOX on intrahepatic and hilar CCA with high-risk factors after curative surgery. Patients and Methods Twenty two patients (mean age: 57 years old) with CCA received 6 cycles of GEMOX: gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2, q3w after a curative surgery. Results All patients completed 6 cycles of GEMOX. EGFR membranous expression was present in 20 CCA. The 5-year survival rate was 56% (CI 95%: 25.7–85.4); 2-year disease free survival rate was 28% (CI 95%: 3.4–52.6). Median time to progression was 15 months. The rate of recurrence after surgery and chemotherapy was 63% (14/22). Two patients died of disease progression. Twelve patients received cetuximab/GEMOX at the time of relapse. Six died after 12 months (9–48 months), three are still alive suggesting a clinical applicability of EGFR inhibitors in CCA. Conclusion Adjuvant chemotherapy with GEMOX alone seems ineffective in intrahepatic and hilar CCA with a high risk of relapse. Additional studies including targeted therapies to circumvent such poor chemosensitivity are needed.

First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 391-391
Author(s):  
Dean F. Bajorin ◽  
Johannes Alfred Witjes ◽  
Jürgen Gschwend ◽  
Michael Schenker ◽  
Begoña P. Valderrama ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Radical Surgery ◽  
Unmet Need ◽  
Disease Free Survival ◽  
Phase 3 ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Disease Free

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 524-524 ◽  
Author(s):  
Carmen D Schweighofer ◽  
Florence Cymbalista ◽  
Carolin Müller ◽  
Raymonde Busch ◽  
Raphael Porcher ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Early Stage ◽  
Phase Iii ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Risk Patients ◽  
Binet Stage

Abstract Introduction Patients with asymptomatic early Rai or Binet stage chronic lymphocytic leukemia (CLL) do not benefit from mono-chemotherapy. Therefore, clinical observation without treatment (watch&wait; W&W) has been the gold standard for the management of these patients. Chemoimmunotherapy with FCR improves the outcome of patients with advanced CLL, but its efficacy in early stage disease has not been investigated. Several clinical and biological variables identify those patients who have a high risk of an aggressive disease course and who might benefit from early interventions. Consequently, this trial was conducted to test the value of FCR treatment in patients with early stage, high-risk CLL. Methods This report represents the endpoint and safety analysis of a randomized German-French cooperative phase III trial comparing the efficacy of early versus deferred FCR therapy in treatment-naïve Binet stage A CLL patients with a high risk of disease progression. Risk assessment was performed using 4 prognostic markers: Lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, an unmutated immunoglobulin heavy chain variable region gene (IGHV) status, and presence of unfavorable cytogenetics (del11q, del17p, trisomy 12) by fluorescence-in-situ hybridization. Presence of at least 2 versus less than 2 of these factors defined “high-risk” versus “low-risk” CLL. High-risk CLL patients were further randomized to receive either 6 cycles FCR (HR-FCR) or to be followed by a W&W strategy (HR-W&W). Patients with low-risk CLL were observed only (LR-W&W). Results Between 2005 and 2010, a total of 824 patients was enrolled, 423 patients in 69 centers of the German CLL Study Group and 401 patients in 25 centers of the French Cooperative Group on CLL. The diagnosis of CLL needed to be established no longer than 12 months prior to enrollment and patients were required to present with previously untreated stage Binet A CLL at the time of inclusion. Overall, 800 patients (97.1%) were stratified, 201 of them categorized as high-risk CLL (25.1%). There was no significant difference between high-risk patients from the two study groups regarding common baseline characteristics (e.g., age, sex, comorbidity, immunophenotype) and the distribution of risk factors used for stratification. 100 out of 201 high-risk patients were randomized to receive FCR therapy (HR-FCR), while 101 patients were allocated to the HR-W&W arm. 18 out of 100 patients (18%) withdrew consent for FCR therapy before treatment was started. 71 (86.6%) of 82 treated patients completed ≥4 cycles. The most common of 228 CTC grade III/IV adverse events reported within 12 months after treatment initiation were hematotoxicity (73.2% of patients) and infections (19.5% of patients). Three patients (3.7%) developed fatal CTC grade V infections (2 septic bacteremias, 1 of them with pulmonary aspergillosis; 1 encephalitis). Out of 79 patients available for response assessment until month 12 after treatment start, 76 showed a complete or partial remission (ORR 96.2%), 2 patients had stable disease (2.5%) and 1 patient had progressed (1.3%). After a median follow up of 46 months (range 0-88 months), HR-FCR patients demonstrated a significantly improved event-free survival (EFS) compared to HR-W&W patients (median EFS not reached versus 24.5 months, respectively, P<0.0001, Fig. 1). Overall survival was not significantly different between HR-FCR and HR-W&W with 181 high-risk patients (90%) being alive at last follow up. Both, HR-FCR and HR-W&W patients exhibited a significant shorter event-free and overall survival than LR-W&W patients, demonstrating an efficient prognostic segregation of patients by the risk assessment used for this trial (analysis based on the German LR-W&W cohort only, complete German-French LR-W&W data will be presented at the meeting). Conclusion This is the first randomized phase III trial investigating the efficacy of FCR chemoimmunotherapy in early stage CLL. So far, the study has revealed two major results: 1. A combination of clinical and biological factors can be used to identify early stage CLL patients who experience a rapid disease progression with unfavorable outcome, 2. FCR chemoimmunotherapy substantially improves event-free survival in early stage high-risk CLL. Disclosures: Langerbeins: Roche: travel grants Other. Cazin:roche: meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees; GSK: meeting invitation, meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees. Fischer:Mundipharma: Travel grants, Travel grants Other; Roche: Travel grants Other. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

scholarly journals Triple Intrathecal Therapy (Methotrexate/Hydrocortisone/Cytarabine) Does Not Improve Disease-Free Survival Versus Intrathecal Methotrexate Alone in Children with High Risk B-Lymphoblastic Leukemia: Results of Children's Oncology Group Study AALL1131

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 35-35 ◽  
Author(s):  
Wanda L. Salzer ◽  
Michael J. Burke ◽  
Meenakshi Devidas ◽  
Lia Gore ◽  
Joanne M. Hilden ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Clinical Signs ◽  
Disease Free Survival ◽  
Intrathecal Methotrexate ◽  
Intrathecal Therapy ◽  
Free Survival ◽  
Prognostic Features ◽  
Post Induction ◽  
Disease Free

Abstract Background: With current multi-agent chemotherapy, 88-90% of children diagnosed with High Risk B-Acute Lymphoblastic Leukemia (HR B-ALL) will be cured. However, for those patients who relapse, ~ 1/3 will have central nervous system (CNS) involvement. Thus, adequate CNS disease control for children with HR B-ALL remains a challenge. AALL1131 was designed to determine if the administration of post-Induction age-adjusted triple intrathecal therapy (ITT) with methotrexate, hydrocortisone, and cytarabine, on a modified augmented Berlin-Frankfurt-Münster (MBFM) backbone, would improve 5-year disease free survival (DFS) of children with HR B-ALL compared to age-adjusted intrathecal methotrexate (IT MTX) alone. Methods: Patients with HR B-ALL included: National Cancer Institute (NCI) HR patients <13 years of age at diagnosis without adverse prognostic features [CNS leukemia at diagnosis (≥ 5 white blood cells in the cerebral spinal fluid with blasts on cytospin and/or clinical signs of CNS leukemia), iAMP21, KMT2A (MLL) rearrangement, or hypodiploidy (<44 chromosomes and/or DNA index <0.81)] who had bone marrow minimal residual disease (BM MRD) <0.01% on Induction day 29; and NCI standard risk (SR) patients lacking favorable cytogenetics (ETV6-RUNX1 fusion or trisomy of chromosomes 4 and 10) who had peripheral blood MRD ≥1% on day 8 and BM MRD <0.01% on Induction day 29, and NCI SR B-ALL patients with favorable cytogenetics who had BM MRD ≥0.01% on Induction day 29. Newly diagnosed children with HR B-ALL were randomized post-Induction in a 1:1 fashion to receive ITT versus IT MTX. A total of 21-26 doses of post-Induction intrathecal therapy was administered during Consolidation (n=4), Interim Maintenance (n=2), Delayed Intensification (n=3), and Maintenance (n=12 for girls, n=16 for boys). Results: The post-Induction HR B-ALL randomization was closed to accrual on March 19, 2018 following planned interim monitoring that revealed a futility boundary was crossed, concluding the inability to show the superiority of ITT compared to IT MTX. Five-year DFS rates for IT MTX versus ITT were 93±3.8% and 90±4.3%, p value=0.86. The corresponding estimated hazard ratio (HR) of IT MTX vs ITT is 1.285; 95% CI of (0.822, 2.01). There were no differences in toxicities observed in patients receiving ITT compared to IT MTX. As such, the study was amended to prescribe IT MTX to all patients. Conclusion: The administration of post-induction age adjusted ITT did not improve 5-year DFS of children with HR B-ALL without CNS leukemia. IT MTX remains the standard of care for CNS prophylaxis. Disclosures Burke: Shire: Speakers Bureau; JAZZ: Speakers Bureau; AMGEN: Speakers Bureau.

Computational features of tumor-infiltrating lymphocyte architecture of residual disease after chemotherapy on H&E images as prognostic of overall and disease-free survival for triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 584-584
Author(s):  
Germán Corredor ◽  
Paula Toro ◽  
Cheng Lu ◽  
Pingfu Fu ◽  
Shaveta Vinayak ◽  
...  
Keyword(s):  
High Risk ◽  
Triple Negative ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Spatial Arrangement ◽  
Training Set ◽  
Free Survival ◽  
Model Based ◽  
Spatial Architecture ◽  
Disease Free

584 Background: Approximately 30% of all breast cancers are characterized as triple-negative (TNBC). TNBC typically occurs in younger women and is associated with a poorer prognosis relative to other breast cancer subtypes. High levels of tumor-infiltrating lymphocytes (TILs) in residual disease after Neoadjuvant chemotherapy (NACT) have previously been shown to be associated with better prognosis in TNBC. In this work, we sought to evaluate the prognostic value of computationally derived measures of TIL spatial architecture in residual TNBC after NACT. Methods: H&E-stained samples from 92 patients (pts) with TNBC (41 died, 45 had disease recurrence) and residual disease after NACT were retrospectively collected from 2 sites: Instituto Nacional de Enfermedades Neoplásicas (S1) and University Hospitals (S2). 45 pts (16 deaths, 23 recurrences) from S1 formed the training set and 47 pts (25 deaths, 22 recurrences) from S2 formed the independent validation cohort. Samples were digitized at 20x. Computerized algorithms automatically identified 2 types of nuclei (TILs and non-TILs) and built clusters for each nuclei type based on cell proximity. The spatial arrangement of these clusters was then quantified using network graph metrics. The top 5 features, determined by least absolute shrinkage and selection operator, were used to train a Cox regression model that assigned a risk of death and recurrence to each patient on the training set. The percentile 33 risk score was used as a threshold for stratifying pts on the validation set as either low or high risk. For comparison, we also employed a model based on TIL density alone. Survival analysis was used to evaluate the performance of both approaches on disease-free survival (DFS) and overall survival (OS). Results: Pts in S2 (n=47) identified as “high risk” by the model based on spatial architecture of residual TILs had a significantly shorter survival time. The median OS for pts at high risk was 25 months vs. 55 months for low-risk pts. The median DFS for pts at high risk was 32 months vs 51 months for low-risk pts. Univariable analysis showed this model was prognostic for both OS (Hazard Ratio (HR) = 2.57, 95% Confidence Interval (CI): 1.07-6.16, p=0.03) and DFS (HR=2.38, CI: 1.01-5.62, p=0.04). In contrast, the model based on TIL density was not prognostic for OS (HR=1.24, CI: 0.33-4.63, p=0.73) nor DFS (HR=1.19, CI: 0.32-4.34, p=0.78). Conclusions: A computerized image analysis model based on measurements of spatial arrangement of residual TILs and surrounding cells was found to be prognostic in TNBC pts who received NACT. This method appears to be more prognostic than TIL density alone. Additional multisite validation and multivariable analysis is needed to further establish the independent prognostic utility of TIL based image biomarkers in the post-NACT TNBC.

scholarly journals Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study

2018 ◽  
Vol 24 (7) ◽  
pp. 1554-1561 ◽  
Author(s):  
Daniel J. George ◽  
Jean-François Martini ◽  
Michael Staehler ◽  
Robert J. Motzer ◽  
Ahmed Magheli ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Immune Biomarkers ◽  
Disease Free

Low-Dose Decitabine Combined with Modified Bucy Is More Effective Conditioning Regimen for High-Risk Patients with Acute Myeloid Leukaemia/Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5750-5750
Author(s):  
Xiaowen Tang ◽  
Jing Cao ◽  
Xiaojing Shi ◽  
Ling Ge ◽  
Aining Sun ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Advanced Stage ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Related Mortality

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment options to hematologic malignancies. However, majority of patients with refractory or resistant AML/MDS can not achieve remission before transplantation. It is necessary to design a safe and effective conditioning regimen to reduce tumour burden, improve remission rates, decrease transplantation-related mortality, and improve disease-free survival (DFS) in patients with advanced acute myloid leukemia(AML) and myelodysplastic syndrom(MDS). One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies including MDS and advanced AML. Furthermore, decitabine can not only up-modulate the tumor-associated antigen express on surface of leukemia cells to increase graft-versus-leukemia (GVL) effect but also can reduce the incidence of graft-versus-host disease (GVHD) by increase the number of regulatory T Cells (Tregs). Objective: To investigate the security and efficacy of conditioning regimen containing low-dose decitabine combined with modified BUCY regimen for advanced AML/MDS patients, explore the role of immunomodulatory activity post transplantation and compared this regimen with conventional modified BUCY regimen. Methods: Between January 2012 and March 2015, a total of 156 patients were enrolled in this retrospective study. In which, there were 46 patients who received a conditioning regimen of low-dose DAC and a modified BUCY regimen(DAC group) followed by allo-HSCT, and the second cohort consisted of 110 who only received a conventional modified BUCY regimen(Con group). Comparing the baseline of two groups, there were no significant difference except there were more advanced stage patients in DAC group(63% vs 32.7%,p=0.007). A modified BUCY conditioning regimen include semustine (250 mg/m2/d) for 1 d(-10d), cytarabine (2 g/m2 q12 h) for 2 d (-9 d to -8 d), busulfan (0.8 mg/kg/6 h) for 3 d (-7 d to -5 d), and cyclophosphamide (1.8 g/m2/d) for 2 d (-4 d to -3 d). Meanwhile, patients in the DAC group received the DAC treatment for 3 to 4 d with a total of 100 mg/m2 before modified BUCY regimen. Results: In DAC group, all patients engrafted successfully, including 29/46(63%) non-remission (NR) patients. However, there were seven patients presented graft failure in Con group. The transplantation-related mortality (TRM) rate was significantly lower in DAC group(0% vs 13.6%, p=0.019). The median time of neutrophil recovery was 12(10-21)d vs 12(10-23)d, and platelet recovery was 13(10-35)d vs 14(9-40)d, respectively in DAC and Con group, and there were no significant differences. With the median follow-up of 277.5(39-985)d and 221(3-1237)d in two groups, the cumulative relapse rate(RR) was 38.2% vs 36.8% (p=0.951). The incidence rate of aGVHD was lower in DAC group(26.7% vs 46.8%, p=0.034), while there were no diference in the incidence rate of cGVHD(68.4% vs 70.7%, p=0.598). Compared with Con group, the estimated 2-year overall survival (2yr-OS) rate and 2 year disease-free survival (2yr-DFS) rate were both higher in DAC group(2yr-OS:45.6% vs 75.3%, p=0.007, Fig 1; 2yr-DFS:39.1% vs 51.5%, p=0.076). Furtheremore, for patients in advanced stage before transplant, the estimated 2yr-OS was 37.2% vs 72.7%(p=0.009) and 2yr-DFS rate was 38.5% vs 49.8%(p=0.051), respectively. For AMLs, the estimated 2yr-OS rate in DAC and Con group was 75.0% vs 43.0%(p=0.034), and for advanced stage AMLs, the estimated 2yr-OS rate was 66.1% vs 29.7%( p=0.031). Regarding the early relapse rate(RR) of 6 months post transplant, DAC group were less than that of Con group(11.5% vs 35.3%, p=0.124). Conclusion: 1. Low-dose decitabine combined with modified BUCY is a safe and effective conditioning regimen for high-risk patients with AML/MDS with low toxicity and well tolerance. 2. 100% NR patients of DAC group achieved complete remission with full donor chimerism at d30. 3.Comparing with Con group, patients in DAC group had ralative lower incidence of aGVHD, TRM and RR but relative higher estimated 2-yr OS and DFS, especially for advanced stage patients. Disclosures No relevant conflicts of interest to declare.

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