Princess Margaret Cancer Centre Research Articles

Risk Stratification for Relapsed/Refractory Classical Hodgkin Lymphoma Integrating Pretransplant Deauville Score and Residual Metabolic Tumor Volume

IntroductionPositron emission tomography (PET) positivity before autologous stem cell transplantation (ASCT) predicts poor prognosis in relapsed/refractory (rel/ref) classical Hodgkin lymphoma (cHL). However, there is limited data regarding the value of pre-ASCT residual metabolic tumor volume (rMTV) assessed by PET to predict post-ASCT outcomes. We aimed to evaluate the role of pre-ASCT Deauville score (DS) combined with rMTV in patients with rel/ref cHL who underwent salvage ASCT, and also to establish a risk model integrating pre-ASCT DS, rMTV, and other clinical risk factors.MethodsThis is a retrospective cohort study using clinical data of patients with rel/ref cHL identified from the lymphoma database and the ASCT database of the Princess Margaret Cancer Center, Toronto, Canada. Following criteria were required: (1) patients (≥18 yrs) with histologically confirmed rel/ref cHL between January 2014 to March 2019; (2) treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-equivalent regimens; (3) chemosensitive disease after salvage therapy; (4) restaging PET before ASCT clearance. Pre-ASCT PET scans were assessed using the Deauville 5-point scale, and rMTV was computed in the scans with DS 4 or 5 using the 41% maximum standardized uptake value threshold method. Receiver operating characteristics analysis was used to determine an optimal cutoff of rMTV 41% for event prediction. The primary endpoint was event-free survival (EFS), defined as time form ASCT to first documented disease progression, any new lymphoma therapy, death from any cause, or last follow-up.ResultsA total of 106 patients fulfilled the eligibility criteria and were included. Median age was 33.5 yrs (range, 18-70), and 72 (68%) were male. The cohort characteristics at time of progression were 55 (52%) patients with advanced stage, 28 (26%) with B symptoms, 39 (37%) with extranodal disease, and 39 (37%) with primary refractory disease, defined as achieving less than a complete response, disease progression during first-line therapy, or time to relapse (TTR) 3 months or less. All patients received gemcitabine, dexamethasone, cisplatin (GDP) regimen as salvage therapy. Based on the response to GDP therapy, 24 patients required second (N=20) or third (N=4) salvage regimens before ASCT (brentuximab vedotin [BV] alone or combination with bendamustine [N=16], pembrolizumab [N=9], and mini-BEAM [N=3]). 32 patients (30%) received planned pre- or post-ASCT involved field radiation for DS 4-5 lesions. 4 patients received post-ASCT BV consolidation.With a median follow-up of 26.2 months (interquartile range [IQR], 14.4-49.2), 2-year EFS and overall survival rates were 72.1% and 93.1%, respectively. Pre-ASCT DS was determined as 1-3 (N=63, 59%) and 4-5 (N=43, 41%). None of the patients with DS 5 had new lesions. Patients with pre-ASCT DS 1-3 had significantly better EFS than those with DS 4-5 (2-year; 80.8% vs 59.2%; P=0.002; Fig 1A).Median rMTV 41% of the 43 patients with DS 4-5 was 5.1 cm 3 (IQR, 2.0-24.7). The optimal cutoff of rMTV 41% was 4.4 cm 3. Patients with rMTV low (< 4.4cm 3, N=21) had better EFS than those with rMTV high (N=22; 2-year, 75.0% vs 45.4%; P=0.009), but had similar 2-year EFS when compared with patients with DS 1-3 (80.8%, P=0.280; Fig 1B)In the multivariable analysis for EFS, a combined assessment of pre-ASCT DS/rMTV 41% and rel/ref status at time of progression were independently associated with EFS (for DS 4-5/rMTV low, hazard ratio [HR] 1.58; for DS 4-5/rMTV high, HR 4.72; P<0.001: for primary refractory disease, HR 2.26; P=0.026). Based on these results, we stratified patients into 3 groups according to the post-ASCT outcomes: low-risk (relapsed disease [i.e., TTR > 3 months] and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=54), intermediate-risk (refractory disease and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=30), and high-risk (pre-ASCT DS 4-5/rMTV high irrespective of rel/ref status, N=22) groups. The risk model was significantly associated with EFS (intermediate vs low, HR 3.26, 95%CI 1.20-8.83, P=0.020; high vs low, HR 7.61, 95% CI 2.89-20.01, P<0.001; Fig 1C).ConclusionWe propose a risk stratification model integrating a combination of DS and rMTV 41% on pre-ASCT PET and rel/ref status at time of progression, which allow discrimination of post-ASCT outcomes in patients with rel/ref cHL. The model may serve as a tool to facilitate risk-stratified treatment decisions. [Display omitted] DisclosuresMetser: POINT Biopharm Inc: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Crump: Roche: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees. Kuruvilla: Seattle Genetics: Honoraria; Amgen: Honoraria; Antengene: Honoraria; AbbVie: Honoraria; Janssen: Honoraria, Research Funding; BMS: Honoraria; Medison Ventures: Honoraria; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Roche: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; Pfizer: Honoraria. Kridel: Gilead Sciences: Research Funding.

Dynamic Stromal Changes in Myelofibrosis Patients Pre/Post JAK Inhibition Is Revealed in Clinically Archived Bone Marrow Biopsies By Smooth Muscle Actin (SMA)-CD34 Dual Immunohistochemistry

The natural history of BCR-ABL1 negative myeloproliferative neoplasms (MPNs) is progression towards an overt myelofibrotic (MF) phase with variable risk to develop secondary acute myeloid leukemia. Current treatments include Janus kinase inhibitors (JAKi) which can temporarily alleviate MF-related symptoms but are non-curative and most patients eventually progress to a more advanced stage. Given the negative prognostic impact of bone marrow fibrosis in MPNs and generally poor outcome post JAKi failure, it would be important to identify in situ biomarkers that address the initiation, perpetuation and early reversal of the fibrotic reaction.The current clinical standard for bone marrow fibrosis assessment involves reticulin/trichrome stains that detect relatively static extracellular matrix products rather than the fibrosis driving cells directly. To address this, we have developed a smooth muscle actin stromal-vascular (SMA-CD34) dual immunohistochemical (IHC) technique amenable to morphologic scoring and complemented with a CellProfiler image analysis pipeline. SMA was prioritized over other validated stromal IHC markers given work by others in experimental models demonstrating SMA+ myofibroblasts to be the differentiated output of critical fibrosis inducing Gli1+ ‘driver’ mesenchymal stem/progenitor cells in MPN.Herein, we demonstrate the feasibility of our translational approach using a clinically annotated cohort of MF patients from the Princess Margaret Cancer Centre MPN Registry. After selecting for high quality (>1.0 cm) paired pre and post JAKi biopsies amenable to image and transcriptome-based analysis, the pilot cohort was comprised of 13 cases with 38% high-risk, 54% intermediate-2 and 8% intermediate-1 risk by DIPSS. Driver mutations were JAK2 V617F (77%), CALR (15%) and other (8%). JAKi therapies included ruxolitinib (31%) + pelabresib (23%), momelotinib (15%), itacitinib (15%) and pacritinib (8%).The SMA-CD34 stromal assessment at baseline revealed distinct interstitial myofibroblast patterns and vascular perturbations not captured by conventional clinical hematopathology assessment (e.g. SMA+ dilated sinusoids). A SMA-CD34 scoring system was developed using a 4-point scale representing normal (0 pts), increased vascularity (1 pt), focal interstitial SMA (2 pts), multifocal interstitial SMA (3 pts) and diffuse SMA (4 pts). Scoring was then performed by blinded hematopathologists. A trend towards JAK2 mutated MF cases demonstrating higher SMA grade at baseline was noted. Interestingly, variable trajectories in SMA scores emerged following treatment with JAKi. Specifically, SMA signals had increased in 15%, decreased in 46% and were stable in 38% post-JAKi when using a morphologic SMA grading scheme. When compared to reticulin fibrosis, the severity of SMA signals had diverged in 1/3 of the cases (e.g. SMA grade decreased, reticulin grade stable).To further complement the SMA-CD34 morphologic grading, a CellProfiler image analysis pipeline was developed yielding a non-vessel associated normalized SMA area metric as a supervised correlate of the clinical SMA scoring system (R 2 = 0.68). Additional supervised and unsupervised bioinformatic approaches for clustering of relevant SMA-CD34 features including an algorithm that informs SMA spatial patterns with respect to niche elements such as arterioles (CD34+SMA+), sinusoids (CD34+) and adipocytes is in development.Lastly, Nanostring Fibrosis V2 panel was employed on a subset that met RNA concentration and quality metrics. Exploratory interpretation showed significant differentially expressed genes in pre vs. post JAKi specimens related to lipid metabolism such as ADIPOR1, SCD, ELOVL6 as well as the chemokine CXCL16. This may suggest a link between fatty acid metabolism and inflammatory differentiation along the SMA-vascular axis in the bone marrow modulated by JAKi treatment.SMA-CD34 IHC stratifies MF bone marrow biopsies differentially from standard WHO reticulin/trichome grading providing a practical formalin-fixed paraffin embedded (FFPE) tissue-based biomarker for assessing fibrosis related bone marrow niche elements from archived clinical samples. While our pilot numbers precluded statistical evaluation by JAKi-type, clinical response and NGS mutational profile at this time, further studies are underway to validate the SMA-CD34 signature on a larger MF cohort. [Display omitted] DisclosuresGupta: Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Incyte: Honoraria, Research Funding; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy.

Preliminary Findings of Focus Group Analysis to Support the Needs of Adolescent and Young Adult Patients and Survivors of Cancer: Steps Toward a National Adolescent and Young Adult Supportive Care Program.

Adolescents and young adult (AYA) oncology care has evolved to address their unique supportive care needs, yet deficiencies remain. We planned a multiphase sequential mixed methods study beginning with focus groups (FGs) with AYAs receiving care at the Princess Margaret Cancer Centre, to improve supportive care delivery. Herewith, we report on the preliminary findings from first phase of project and outline future expected goals. Our findings suggest four major themes identified from FG discussion with AYAs: (1) having peer-driven support, (2) incorporating hybrid approach to information delivery, (3) integrating general practitioners in AYAs care, and (4) providing AYAs-specific supportive care programs.

The Prediction of Mandibular Osteoradionecrosis (ORN) in Head and Neck Radiotherapy Using CT-Derived Radiomic Features

The overall lifelong risk of mandibular Osteoradionecrosis (MORN) in head and neck (HN) radiotherapy (RT) is 4-8% which may result in poor health-related quality of life (QOL). Most of these patients (70-94% of cases) developed within the first 3 years after radiotherapy. The most effective way to limit MORN is to reduce mandibular volumes receiving high RT doses. However, this strategy may also result in a reduced dose to the tumor due to its proximity to the mandible, and therefore must be restricted to patients deemed most vulnerable to MORN. The objective of this study was to design a machine learning model to predict the probability of MORN prior to HN RT. Our models were based on CT-derived radiomic features extracted from mandible contours, along with the patient's clinical features. We hypothesized that these features are related to MORN and incorporating them into a prediction model will help to identify patients at risk of MORN.Patient data was retrospectively collected from the Princess Margaret Cancer Centre, University Health Network and based on our inclusion criteria. Radiomic features were then extracted from the mandible for each patient. Patients' records have also been reviewed to collect previously published clinical risk factors called demographic-clinical (DMC) such as: prescribed radiation dose, ECOG status, smoking, drinking, TNM status, stage, chemotherapy administration, Human papillomavirus (HPV) infection, the occurrence of loco-regional failure and distant metastasis. Finally, a Random Forest (RF) classifier and three regressors (Deep Survival, Random Survival Forest (RSF) and Cox), were independently trained on three sets of features (radiomic, DMC and combined) to predict the patient's risk of ORN in 3 years after radiotherapy. Applying regressors, we were able to incorporate the time to ORN for the modelling and investigate the usefulness of having such information.In total, we analyzed CT images from 223 OPC patients with known MORN status (149 negative, 74 positive). We extracted a total of 1874 radiomic features from the segmented mandible for each patient. The best result obtained with Random Forest classifier (AUC = 0.86, 95% CI, P-value < 0.001) when it was trained upon combined features (Radiomics and DMC). ECOG, T status, smoking and HPV status are the top DMC features by mRMRe method. Among radiomic features, first order statistic features were mostly informative especially when images have been filtered by wavelet transform. However, our best regression model (RSF, c-index = 0.74, P-value = 0.01) were inferior to RF model that reflect non-efficiency of incorporating the time to ORN for the prediction.Our results showed the ability of multivariable Random Forest model in the prediction of MORN when radiomic features combined with DCM parameters. These results have the potential to assist us to detect patients vulnerable to developing MORN and adjust the operational strategies before treatment.

Anti-thymocyte globulin and post-transplant cyclophosphamide predisposes to inferior outcome when using cryopreserved stem cell grafts.

During 2020, the concurrent novel COVID-19 pandemic lead to widespread cryopreservation of allogeneic hematopoietic cell transplant grafts based on National Marrow Donor Program and European Society of Blood and Marrow Transplantation recommendations, in order to secure grafts before the start of conditioning chemotherapy. We sought to examine the impact of this change in practice on patient outcomes. We analyzed the outcomes of 483 patients who received hematopoietic stem cell transplantation (HSCT) between August 2017 and August 2020, at Princess Margaret Cancer Centre, Canada, in the retrospective study, comparing the outcomes between those who received cryopreserved or fresh peripheral blood stem cell grafts. Overall compared with those who received fresh grafts (n=348), patients who received cryopreserved grafts (n=135) had reduced survival and GRFS, reduced incidence of chronic graft-versus-host disease (GvHD), delay in neutrophil engraftment, and higher graft failure (GF), with no significant difference in relapse incidence or acute GvHD. However, recipients of cryopreserved matched-related donor HSCT showed significantly worse OS, NRM, GRFS compared with fresh grafts. Multivariable analysis of the entire cohort showed significant impact of cryopreservation on OS, relapse, cGvHD, GF, and GRFS. We conclude that cryopreservation was associated with inferior outcomes post-HSCT, possibly due to the combination of ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem cell graft; further studies are warranted to elucidate mechanisms for this observation.

P45.07 Real-World Clinically-Relevant Toxicities of ALK TKIs in a Cohort of Patients With Advanced/Metastatic ALK+ NSCLC

Treatment with ALK-TKIs significantly prolongs overall survival (OS) in patients with ALK+ non-small cell lung cancer (NSCLC). Approximately 20-40% of patients experience adverse events (AEs) leading to dose reductions/temporary discontinuation in the published phase III trials and permanent treatment discontinuation due to toxicity in approximately 5-15%. Toxicity profiles of the different inhibitors overlap but some are also distinct. We describe rates of clinically-significant AEs and specific toxicity profiles in a real-world cohort of patients with ALK+ NSCLC. Patients with ALK+ advanced NSCLC at Princess Margaret Cancer Centre were included in this analysis; date of data cut-off was March 18, 2021. All AEs leading to treatment modifications were abstracted retrospectively along with clinico-demographic, treatment and survival data. Treatment modifications included dose reduction and temporary/ permanent discontinuation due to toxicity. Of 147 patients with advanced ALK+ NSCLC, 138/94% received at least one ALK-TKI: alectinib (103/75%), crizotinib (75/54%), ceritinib (31/22%), lorlatinib (27/20%) and brigatinib (22/16%). In total, 258 individual ALK TKI lines (138 first-line, 72 second-line, 30 third-line, 20 fourth-to-seventh lines) of TKI-treatment were given. Median follow-up time was 26.4 months; 79 patients in active follow-up had ongoing ALK-TKI treatment at data cut-off. Summing all treatment durations, median (IQR) duration of receiving any ALK-TKI therapy/patient was 19.1 (29.0) months. While on ALK-TKI, 170 adverse events (AE) leading to treatment modifications occurred. In 112/66% cases these were related to a single AE: 59/53% were attributed to symptomatic toxicities; 53/47% were attributed to asymptomatic laboratory abnormalities. In contrast, 58/34% treatment modifications were attributed to a combination of AEs. Combined AEs were mostly symptom-related (23/40%) and symptom and lab-related (30/52%) and only rarely driven by multiple asymptomatic laboratory abnormalities alone (5/8%). Overall, 74/54% patients had at least one ALK-TKI treatment modification due to toxicity. Older aged patients (median age 62 vs 53 years, p=0.007) and never-smokers (84% vs 68%, p=0.04) were significantly associated with increased risk of AEs leading to treatment modification. Counting only one treatment modification per patient per ALK-TKI, treatment modifications occurred in 102/40% treatment lines: 28/37% patients on crizotinib, 19/61% with ceritinib, 33/32% with alectinib, 9/41% with brigatinib, and 8/30% with lorlatinib. Permanent discontinuation was observed in 63/24% treatment lines overall and in a much higher rate with crizotinib and ceritinib (45/43%) compared to the new generation-TKIs (alectinib, brigatinib and lorlatinib; 18/12%). As expected, AEs leading to treatment modifications were mainly gastrointestinal (26%) and liver toxicity (16%) with crizotinib and ceritinib, whereas the spectrum of AEs with the new-generation TKIs (alectinib, brigatinib, lorlatinib) leading to treatment modifications was broader, with less gastrointestinal (7%) and liver toxicity (10%) but more myalgia/CK elevation (6%) and slightly more neurotoxicity (5%). Median overall survival (OS) in patients with at least one treatment modification trended, but was not significantly different from patients without any treatment modification (47.0 vs 57.8 months, p=0.09). In a real-world cohort, treatment modifications on ALK-TKI were needed frequently, even with the newer generation of ALK-TKIs, highlighting the importance of availability of different ALK-TKIs for patients experiencing AEs to ensure tolerable targeted treatment.

P45.09 Real-World Sequencing of ALK-TKIs in Advanced Stage ALK-positive NSCLC patients in Canada

Overall survival (OS) of patients with ALK+ Non-Small Cell Lung Cancer (NSCLC) has been prolonged with the introduction of ALK-tyrosine kinase inhibitors (TKI) over the last decade. The aim of this analysis was to study treatment patterns, sequencing of ALK-TKIs and outcomes in a real-world cohort of ALK+ NSCLC patients. Data were analyzed for all patients with advanced/metastatic ALK+ NSCLC seen at Princess Margaret Cancer Centre (data cut-off date March 18, 2021), regardless of whether they were initially diagnosed with early stage (relapsed) or de novo advanced/metastatic NSCLC. Clinico-demographic, treatment and survival data were collected retrospectively. Of 147 patients with advanced/metastatic ALK+ NSCLC, 32 were initially early-stage, while 115 were de novo advanced/metastatic. The median age was 59 years (range: 31 – 93); 84 (57%) were female; 111 (76%) were never-smokers; 32 (22%) had an ECOG performance status (PS) of 0, while 78 (55%) were PS1, and 33 (23%) were PS2+; 54 (47%) were Asian; 40 (35%) were Caucasian. Median follow-up time was 26.9 months from diagnosis of advanced/metastatic disease. Among the 147 patients, 138 (94%) received ALK-TKIs: 66 (48%) received only one ALK-TKI, while 42 (30%) had received two; 30 (22%) had received at least three. Overall, 75 (54%) had received crizotinib; 103 (75%) alectinib; 31 (22%) ceritinib; 22 (16%) brigatinib and 27 (20%) lorlatinib. Crizotinib (74; 54%) and alectinib (59; 43%) were given as first ALK-TKI in the majority of cases, whereas ceritinib, brigatinib and lorlatinib mainly were administered after failure of previous ALK-TKI and/or other systemic therapy in 26 (31%) in second-line, 25 (30%) in third-line, 12 (15%) in fourth-line, and 17 (21%) in fifth-line or beyond. Median progression-free survival irrespective of treatment line given was 9 months for crizotinib, 41.6 months for alectinib, 3.1 months for ceritinib, 3.7 months for brigatinib and 2.8 months for lorlatinib. Unlike clinical trials, brigatinib and lorlatinib were given often in PS 2+ patients near end-of-life or as fourth or fifth-line treatment. After removing such patients, median PFS was 7.1 (95%CI 1.8-NA) for brigatinib and 7.2 (95%CI 1.4-NA) for lorlatinib. Median overall survival (OS) from advanced/metastatic disease was 56.7 months, but is likely to increase as the first-line alectinib cohort matures. Median OS for patients treated first-line with crizotinib was 46.1 months, and not yet reached in patients treated with first-line alectinib. A total of 31 (21%) patients died within two years of diagnosis of advanced/metastatic disease. These patients did not significantly differ in age, sex or PS from patients with prolonged survival. Of these patients, 6 (19%) never received an ALK-TKI, but the majority received two lines (21; 68%) of ALK-TKI treatment. Sequencing of multiple ALK-TKIs has improved outcomes, but there is no single sequencing standard. Use of next generation ALK-TKIs in earlier lines of treatment may lead to more effective outcomes. Despite substantial progress, approximately 20% of patients still do poorly; identification of novel drug resistance mechanisms may further improve outcomes.

P48.05 Is Relapse-Free Survival at 2-Years an Appropriate Surrogate for Overall Survival at 5-Years in EGFR-mutated Resected NSCLC?

The phase 3 ADAURA trial identified a highly significant hazard ratio (HR) of 0.17 for disease-free (i.e., relapse-free) survival (RFS) favoring adjuvant osimertinib, but a non-significant immature overall survival (OS) HR of 0.40. However, is RFS an appropriate surrogate for OS in this setting? OS is still the gold standard in health technology assessments, but it will take years for ADAURA’s OS data to mature. In the ADAURA-eligible setting, we compared HRs for clinico-demographic-treatment variables between RFS censored at 2 years (RFS-2YRS) with OS censored at 5 years (OS-5YRS), and explored reasons why such a relationship may exist. A retrospective analysis from Princess Margaret Cancer Centre of all patients with EGFR-mutated resected NSCLC (diagnosed 2012-2018) utilized Kaplan-Meier curves and Cox regression to compare RFS-2YRS and OS-5YRS for common clinico-demographic-treatment variables. We explored how these patients were managed after relapse, and compared their OS outcomes to patients with de novo advanced/metastatic EGFR-mutated disease. Among 104 patients with EGFR-mutated resected NSCLC, female=66%; median age=67 years; never-smokers=73%; Stage IB=41%; Stage II=34%; Stage IIIA=25%. Univariable Cox regression results comparing RFS-2YRS and OS-5YRS are presented in the table. Overall, HRs were either similar or slightly attenuated at OS-5YRs when compared to RFS-2YRS. Among the n=63 (61%) patients who relapsed, 81% were due to distant metastases. Only 8% were treated with curative surgery or chemoradiation at the time of relapse (an additional 3% were offered but declined curative treatment). The remaining patients (92%) were managed as advanced/incurable cancer. Of those treated at Princess Margaret, 75% received first-line EGFR-TKI therapy, while 4% received other systemic therapies; 8% had developed multifocal disease that was monitored rather than treated systemically; and 8% died before systemic therapy could be started or had concurrent comorbid conditions. Starting with diagnosis of advanced/metastatic disease, there were no differences in the OS of this relapsed cohort (n=63) versus 252 de novo advanced/metastatic NSCLC (log-rank p=0.29). The adjusted HR for OS was 0.82 (95% CI: 0.55-1.24 ). Among early-stage patients with EGFR-mutated resected NSCLC, 92% were treated as advanced/metastatic disease at the time of relapse. Their survival (from the time of relapse) was similar to those diagnosed initially with EGFR-mutated advanced/metastatic cancer. This information helps explain why relapse-free survival censored at 2-years represents an acceptable surrogate endpoint for overall survival at 5-years.

MP61-08 TOWARDS PERSONALIZED CARE OF CT1A PAPILLARY RCC DIAGNOSED ON BIOPSY

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging/Surveillance III (MP61)1 Sep 2021MP61-08 TOWARDS PERSONALIZED CARE OF CT1A PAPILLARY RCC DIAGNOSED ON BIOPSY Johan Björklund, Douglas C Cheung, Robert J Hamilton, John Kachura, Michael Jewett, Alexandre R Zlotta, and Antonio Finelli Johan BjörklundJohan Björklund More articles by this author , Douglas C CheungDouglas C Cheung More articles by this author , Robert J HamiltonRobert J Hamilton More articles by this author , John KachuraJohn Kachura More articles by this author , Michael JewettMichael Jewett More articles by this author , Alexandre R ZlottaAlexandre R Zlotta More articles by this author , and Antonio FinelliAntonio Finelli More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002101.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Papillary Renal Cell Carcinomas (pRCC) are divided histologically into type 1 (pRCC1) and type 2 (pRCC2), but there are histological subtypes of pRCC that are unclassifiable (pRCCX). The subtypes cannot be discerned on imaging, but are clinically relevant: pRCC2 is associated with more aggressive disease, where pRCC1 carries a relatively low risk of metastases. Our objective was to evaluate the clinical and pathologic outcomes for biopsy-proven pRCC small renal masses (SRM) within our institutional database. METHODS: All SRM with a first pRCC histology at renal biopsy were included between 1994 to 2020 at Princess Margaret Cancer Centre, Toronto, Canada. Patients were evaluated for treatment strategy, follow-up, intervention, and pathologic concordance on subsequent nephrectomy. The pRCC was divided into pRCC1, pRCC2 and pRCCX if no subtype was specified. Active surveillance (AS) was defined as not undergoing intervention within 1 year of biopsy diagnosis. RESULTS: 178 SRM with biopsy-proven pRCC were identified. On their first diagnostic biopsy, 116 (65%) were pRCC1, 19 (11%) were pRCC2, and 43 (24%) were pRCCX. 52 (29%) had at least one follow-up biopsy and the median follow-up time was 42 months (IQR 21-76). The primary management strategy was surgery in 66 (37%), RFA in 52 (29%), and AS in 60 (34%) patients. Median age at biopsy was 64 and median size of the SRM was 2.4 cm (IQR 1.8 – 3). 71 patients underwent surgery either primarily or after AS or RFA. 4 patients managed with AS went on to have Nephrectomy and 6 AS patients had a subsequent RFA. Of the 40 patients with pRCC1 on biopsy, 32 (80%) had a pRCC1 on surgical pathology, of the 10 with pRCC2 on biopsy 30% had pRCC2 on surgical pathology, and of the 21 patients with pRCCX on biopsy 6 29% had pRCCX on surgical pathology. A total of 7 (10%) patients has other RCC on SP, Table 1. CONCLUSIONS: A biopsy of pRCC1 was highly predictive for pRCC1 on surgical pathology with no patients reclassifying to the more aggressive pRCC2, while 2 (5%) reclassified to other RCC. A biopsy with pRCC1 was much more correlated to a similar outcome on surgical pathology than pRCC2 and pRCCX. Only 10 (16%) patients shifted strategy from AS to treatment indicating it a reasonable strategy for the patients managed with AS in this cohort. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1085-e1086 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Johan Björklund More articles by this author Douglas C Cheung More articles by this author Robert J Hamilton More articles by this author John Kachura More articles by this author Michael Jewett More articles by this author Alexandre R Zlotta More articles by this author Antonio Finelli More articles by this author Expand All Advertisement Loading ...

Out‐of‐pocket costs associated with head and neck cancer treatment

BackgroundOut‐of‐pocket costs (OOPC) associated with treatment have significant implications on quality of life and survival in cancer patients. Head and neck cancer patients face unique treatment‐related challenges, but to date OOPC have been understudied in this population.AimsThis study aims to identify and measure OOPC for patients with head and neck cancer (HNC) in Ontario.MethodsHNC patients between 2015 and 2018 at Princess Margaret Cancer Centre in Toronto were recruited. Participants completed OOPC questionnaires and lost income questions during radiation, post‐surgery, and 3, 6, 12, and 24 months after completion of treatment. Associations between OOPC and treatment modality and disease site were tested with multivariable hurdle regression.ResultsA total of 1545 questionnaires were completed by 657 patients. Median estimated OOPC for the total duration of treatment for participants undergoing chemoradiation was $1452 [$0–14 616], for surgery with adjuvant radiation or chemoradiation (C/RT) was $1626, for radiation therapy alone was $635, and for surgery alone was $360. The major expenses for participants at the mid‐treatment time‐point was travel (mean $424, standard error of the mean [SEM] $34) and meals, parking, and accommodations (mean $617, SEM $67). In multivariable analysis, chemoradiation, surgery with C/RT, and radiation were associated with significantly higher OOPC than surgery alone during treatment (791% higher, p < .001; 539% higher, p < .001; 370% higher, p < .001 respectively) among patients with non‐zero OOPC. Participants with non‐zero OOPC in the laryngeal cancer group paid 49% lower OOPC than those with oropharyngeal cancers in adjusted analysis (p = .025).ConclusionsPatients undergoing treatment for HNC pay significant OOPC. These costs are highest during treatment and gradually decrease over time. OOPC vary by patient demographics, clinical factors, and, in particular, treatment modality.

Assessing cultural and linguistic diversity and distress screening completion in gynecologic oncology patients (iCALD)

<h3>Objectives:</h3> Optimally caring for oncology patients of culturally and linguistically diverse (CALD) backgrounds poses a unique set of challenges. We aimed to describe CALD gynecologic oncology patient characteristics and distress screening completion in a large, multicultural academic cancer center. <h3>Methods:</h3> This was a retrospective study of patients with a primary gynecologic malignancy treated in the medical, surgical, or radiation oncology and palliative care clinics at Princess Margaret Cancer Centre (PM), Toronto, Canada, from January 1 to December 31, 2019. Data was generated from electronic health records and other databases. Non-English patients were defined as those who listed a primary language on Electronic Patient Records other than English on initial registration. Edmonton Symptom Assessment System-revised (ESAS-r) was available in various languages, and completion rates were assessed and descriptive statistics performed. <h3>Results:</h3> In 2019, there were 19,343 patient visits recorded in gynecologic oncology clinics, and 4684 unique patients (mean visits per patient=4.13). 1656 (8.6%) patient visits were registered as non-English speakers (376 [8.6%] out of 4684 unique patients) comprising more than 40 languages (Figure 1). Most common spoken languages were Mandarin (15.5%), Portuguese (11.6%), Cantonese (10.9%), Spanish (7.8%) and Italian (7.3%). ESAS-r completion rates in the gynecologic oncology clinics were lower in non-English (18.4%) than English (36%; p<0.001) patient visits. Of the most common spoken non-English language populations, ESAS-r completion rates were highest in Spanish patient visits (24%), followed by Mandarin (21.7%), Cantonese (20.6%), Portuguese (17.6%) and Italian (10.8%). <h3>Conclusions:</h3> The PM gynecology clinic sees a significant proportion of patients of CALD backgrounds. Completion rates of ESAS-r are significantly lower amongst patients of CALD backgrounds. These results suggest that linguistic sensitivity in assessing and treating gynecologic cancer patients is paramount. Further research focusing on optimizing care in CALD populations should be considered.

Construct Validity of the EuroQoL-5 Dimension and the Health Utilities Index in Head and Neck Cancer.

ObjectiveThe objective of this study was to evaluate the construct validity of 2 health utility instruments—the EuroQoL–5 Dimension (EQ-5D) and the Health Utilities Index–Mark 3 (HUI-3)—and to compare them with disease-specific measures in patients with head and neck cancer.Study DesignProspective cross-sectional analysis.SettingPrincess Margaret Cancer Centre.MethodsPatients were administered the EQ-5D, HUI-3, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its head and neck cancer module (EORTC QLQ-H&N35), and the University of Washington Quality of Life Questionnaire (UWQoL). Several a priori expected relations were examined. The correlative and discriminative properties of the various instruments were examined.ResultsA total of 209 patients completed the 4 questionnaires. A significant ceiling effect was observed among EQ-5D responses (23% reported a maximum score of 1). The EQ-5D (rho = 0.79) and HUI-3 (rho = 0.60) had a strong correlation with the social-emotional domain of the UWQoL. The EQ-5D had a moderate correlation with the physical domain of the UWQoL (rho = 0.42), whereas the HUI-3 had a weak correlation (rho = 0.29). The EQ-5D and HUI-3 were able to distinguish among levels of health severity measured on the EORTC QLQ-C30 though not the QLQ-H&N35. Comparatively, the UWQoL was able to distinguish levels of disease severity on the EORTC QLQ-C30 and QLQ-H&N35.ConclusionThe results of this study demonstrate that disease-specific domains from head and neck quality-of-life instruments are not strongly correlated with the EQ-5D and HUI-3. Consideration should be put toward development of a disease-specific preference-based measure for health economic evaluation.Level of evidence4.

Light Chain Amyloidosis (AL) Associated With B Cell Lymphoma a Single Center Experience

IntroductionLight chain (AL) amyloidosis and B‐cell lymphoma represent 5% to 7% of all AL, Systemic amyloidosis, deposits in sites remote from the underlying lymphoma, and peritumoral amyloidosis deposition is within the immediate vicinity. Materials and MethodsWe conducted a retrospectively study to identify and describe AL with B cell lymphoma at Princess Margaret Cancer Center from 01 January 1997 to 31 July 2019. ResultsThirty-five patients with AL and lymphoma, an incidence of 6, 2%, median age of diagnosis of 66 (range 47 to 86), majority male, most had underlying Waldestrom's Macroglobulinemia. 21 patients with peritumoral AL (PAL), and 15 with systemic AL. 42.8% of the patients had major organ involvement. 35% got treatment with Rituximab with alkylator, 20% received proteasome inhibitors, 17% patients were on a watch and wait approach, amyloid response showed very good partial response > 45.8%, and lymphoma ORR was 42.8%, with a median follow up of 31.5 months. A 36 month overall survival (OS) and progression-free survival (PFS) showed worse outcomes for heart involvement OS (P = .002), PFS (0.057) and IgM subtype OS (P = .02), PFS (0.01). ConclusionWe have shown adverse outcome with IgM AL and to document a differences in OS and PFS not previously reported for PAL.

Limited-stage small cell lung cancer: Outcomes associated with prophylactic cranial irradiation over a 20-year period at the Princess Margaret Cancer Centre

Background & purposeProphylactic cranial irradiation (PCI) is recommended for limited-stage small-cell lung cancer (LS-SCLC) patients with good response to concurrent chemoradiation. We report our institution’s 20-year experience with this patient population and associated clinical outcomes. Materials & methodsA retrospective cohort of consecutive LS-SCLC patients treated with curative intent chemoradiation at our institution (1997–2018) was reviewed. Overall survival (OS) was calculated using the Kaplan-Meier method, and significant covariates determined by the Cox proportional hazards model. Covariates predictive of PCI were determined using Fisher's exact test and the Mann-Whitney test. Brain failure risk (BFR) was calculated using the cumulative incidence method treating death as a competing event. Treatment cohorts (historic vs. contemporary) were stratified by the median year of diagnosis (2005). ResultsA total of 369 patients with LS-SCLC were identified, of which 278 patients were notionally PCI eligible. PCI was given to 196 patients (71%). Younger age was associated with PCI utilization (p < 0.001). PCI utilization rates did not change between the historic and contemporary treatment era (p = 0.11), whereas magnetic resonance imaging (MRI) use at baseline and follow-up became more prevalent in the contemporary era (p = <0.001). On multivariable analysis, PCI utilization was associated with improved OS (HR 1.88, 95% CI 1.32–2.69) and decreased BFR (HR 4.66, 95% CI 2.58–8.40). Patients who had MRI follow-up had a higher incidence of BFR (HR 0.35, 95% CI 0.18–0.66) in multivariable analyses. ConclusionsFor LS-SCLC patients at our institution, PCI is more frequently utilized in younger patients, and the utilization rate did not change significantly over the past 20 years. PCI was independently associated with improved OS and lower BFR. Omission of PCI in LS-SCLC patients should not be routinely practiced in the absence of further prospective data.

The Risk Of BK Virus Haemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation Is Increased With Myeloablative Conditioning, CMV Viremia and Acute Gvhd

IntroductionBK virus associated hemorrhagic cystitis (HC) is a common complication post allogeneic hematopoietic cell transplantation (HSCT). A number of retrospective studies have suggested a variety of risk factors for HC following HSCT including busulfan-containing myeloablative conditioning regimens, unrelated donors, and the occurrence of graft versus host disease (GVHD). However, these risk factors were not observed consistently and have led us to review the incidence and risk factors for BK-HC confirmed by microbiologic test at our institution. Methods and patientsWe retrospectively reviewed 339 patients who received HSCT between 2009 and 2012 at the Princess Margaret Cancer Centre, Toronto Canada. The diagnosis of BK-HC was based on clinical features, urinalysis and detection of BK virus by urine PCR. The cumulative incidence of BK-HC was calculated considering competing risks and Gray's method was used for univariable analysis. To confirm the results of the univariable analysis, we conducted a multivariable analysis using the Fine-Gray method and EZR software. ResultsOut of 339 patients, 79 patients (23.3%) developed BK-HC. The median onset was 47 days (range 16-749) after HSCT. The median time to resolution of symptoms was 21 days (range 4-260). The clinical grades were as follows: grade 1 (n=14, 17.9%), 2 (n=34, 43.0%), 3 (n=22, 27.8%) and 4 (n=8, 10.1%). Sixty-two patients (83.7%) out of 74 had urine BK virus PCR testing which showed a high titer of BK virus PCR (mean 2.56x1010 (SD 7.41x1010) and median 6.19x109). The cumulative incidence of BK-HC at 2 years was 24.0% (95% CI, 19.4-28.9). There was no difference in transplant characteristics between the HC and non-HC groups, in terms of age, gender, gender match, diagnosis, HLA match and donor type, stem cell source, T-cell depletion, GVHD prophylaxis and CMV serostatus. However there was a higher incidence of BK-HC in the group of patients receiving myeloablative conditioning (62/208, 29.8%) vs (17/132, 12.9%, p<0.001) in the reduced intensity conditioning group. In the univariable model three risk factors for BK-HC were identified: myeloablative conditioning (31.2% in myeloablative vs 12.4% in reduced intensity; p<0.001), HLA mismatch (34.9% in mismatched vs 22.0% in matched, p=0.027), CMV viremia (28.6% in CMV+ vs 19.1% in CMV-; p=0.023) and acute GVHD (30.2% in aGVHD vs 12.0% in without aGVHD; p<0.001). Unrelated donor or T-cell depletion did not increase the risk of HC in univariable analysis. Multivariable analysis confirmed that these 3 factors were independent risk factors for BK-HC: myeloablative conditioning (p<0.001; HR 2.38, 95% CI, 1.35-4.17), CMV viremia (p=0.012; HR 1.77, 95% CI, 1.10-2.83) and aGVHD (p<0.001; HR 2.26, 95% CI, 1.23-4.13). HLA mismatch was not an independent risk factor. The 2-year overall survival (OS) of the study cohort was 51.6%. The development of BK-HC did not affect transplant outcomes with respect to OS (p=0.446). We observed a higher incidence of 1-year non-relapse mortality (NRM) in the BK-HC group 39.7% vs 24.2% in the non HC group, but this was not confirmed in the multivariable analysis. ConclusionSymptomatic BK-HC is a frequent complications following HSCT with a 2-year cumulative incidence of 24.0%. Three risk factors for BK-HC were identified including myeloablative conditioning, CMV viremia and aGVHD. While this infection did not adversely impact survival, it is associated with significant morbidity and constitutes an unmet need given the lack of effective therapy. Disclosures:No relevant conflicts of interest to declare.

Induction Therapy With Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) For Primary Plasma Cell Leukemia (pPCL)

IntroductionPrimary plasma cell leukemia (pPCL) is an uncommon, highly aggressive plasma cell dyscrasia with a poor prognosis. A limited number of small retrospective studies have reported promising results in treating PCL using the novel agent bortezomib (btz). We therefore undertook a retrospective study of our cohort of patients (pts) with newly diagnosed pPCL treated with cyclophosphamide, btz, and dexamethasone (CyBorD) as front-line therapy. MethodsBetween August 2008 and June 2013, 10 newly diagnosed pts with pPCL (≥20% PCs in peripheral blood and/or absolute PCs ≥ 2.0x109/L) were referred to Princess Margaret Cancer Centre. Pts received a median of 4 (range 4-8) 28-day cycles of CyBorD induction consisting of weekly cyclophosphamide 300 mg/m2po, weekly btz 1.5 mg/m2IV or SQ, and dexamethasone in pulse fashion for cycles 1 and 2 and then weekly as well. Hematologic responses were assessed using IMWG consensus criteria for serological, and, if available, bone marrow, criteria. Survival times were measured from the time of first treatment. ResultsThe median age was 54 yrs (range 45-68); 6 were male. Median (range) hemoglobin was 85 g/L (27-135), creatinine 212 umol/L (57-404), albumin 37g/L (25-47), LDH 215 U/L (163-537) and β2-microglobulin 441 nmol/L (295-1136); median WBC was 10.6 (4.8-32.2), ANC 2.0 (1.4-3.3), and platelet count 94 (36-159) x 109/L. Abnormal cytogenetics were common; of 9 pts with FISH results available, 4 pts had deletion 13q (44.4%), 3 had deletion 17p (33.3%), 3 had t(14;16) (33.3%), 4 had t(11;14) (44.4%) and 2 had other changes (22.2%). The overall response rate (ORR defined as ≥ PR) after CyBorD induction was 100% and included PR in 3 pts (33.3%), VGPR in 5 pts (50%), and CR in 2 pt (20%). Nine pts underwent successful stem cell (SC) mobilization with cyclophosphamide + G-CSF (median CD 34+ cells 3.42 x 106/kg [range 2.16-7.31]); 1 pt, who has been given 8 cycles to date, is awaiting a second attempt at SC collection. Two other patients relapsed after completion of planned induction while awaiting transplant; these required additional therapy to control the disease before ASCT. In total, 9 pts have undergone subsequent ASCT, including tandem ASCT in 4 pts. After ASCT, 1 pt received maintenance therapy with thalidomide, while 6 more recently treated pts were given lenalidomide maintenance. Best responses post-ASCT were as follows: ≥ PR in all 9 pts (100%, specifically PR in 1 (11.1%), VGPR in 4 (44.4%), and CR in 4 (44.4%, including 1 pt with nonsecretory disease in documented CR pre-ASCT who was not formally reassessed but clinically remained in CR after ASCT). Five patients have relapsed post-ASCT with time to relapse from ASCT of 13.5 mos (range 3-38), including both pts who had progressed and required additional therapy before ASCT (time to relapse 3 and 4 months). The median PFS for all pts from the start of therapy was 18 mos (range 4-44 mos).Currently, 7 pts (70%) are alive after a median follow-up of 25 mos (range 8-58); 5 of these pts are alive without relapse after a median of 25 mos (range 8-28) while 2 pts (20%) are alive after ≥ 1 relapse at a median of 49 mos (range 39-58). Three pts (30%) have died from disease a median of 20 mos (range 7-24) after commencing therapy.During CyBorD induction, 5 pts required hospitalization for a median of 10 days (range 6-53); heme toxicity was generally mild, with only 1 grade 4 neutropenia and no grade 3 or 4 thrombocytopenia. Other toxicities included: mild peripheral neuropathy in 5 pts (50%) (grade 1 in 4; grade 2 in 1) in addition to grade 1 shingles (10%), grade 2 drug fever attributed to btz (10%), and anemia requiring transfusion (10%). ConclusionsAlthough compromised by the small sample size, our study suggests that induction with CyBorD for pts with pPCL produces a high initial ORR with a favorable toxicity profile. However, disease progression is common in this entity and can occur early, while waiting for ASCT; these pts have a particularly poor outcome even after reinduction and subsequent ASCT. Although CyBorD is an effective initial regimen for patients with pPCL, innovative therapies will be needed to maintain long-term disease control. Disclosures:Reece:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BMS: Research Funding; Otsuka: Honoraria, Research Funding; Onyx: Consultancy. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Trudel:Sanofi: Honoraria; GSK: Research Funding; Celgene: Honoraria.

Abstract 207: The cBioPortal for Cancer Genomics

Abstract The cBioPortal for Cancer Genomics is an open-source software platform that enables interactive, exploratory analysis of large-scale cancer genomics data sets with a user-friendly interface. It integrates genomic and clinical data, and provides a suite of visualization and analysis options, including OncoPrint, mutation diagram, variant interpretation, survival analysis, expression correlation analysis, alteration enrichment analysis, cohort and patient-level visualization, among others. The public site (https://www.cbioportal.org) hosts data from almost 300 studies spanning individual labs and large consortia. Data is also available in the cBioPortal Datahub (https://github.com/cBioPortal/datahub/). In 2020 we added data from 21 studies, totaling almost 30,000 samples. In addition, we added data to existing TCGA PanCancer Atlas studies, including MSI status, mRNA-seq z-scores relative to normal tissue, microbiome data, and RPPA-based protein expression. The cBioPortal also supports AACR Project GENIE with a dedicated instance hosting the GENIE cohort of 112,000 clinically sequenced samples from 19 institutions worldwide (https://genie.cbioportal.org). The site is accessed by over 30,000 unique visitors per month. To support these users, we hosted a five-part instructional webinar series. Recordings of these webinars are available on our website and have already been viewed thousands of times. In addition, more than 50 instances are installed at academic institutions and pharmaceutical/biotechnology companies. In support of these local instances, we continue to simplify the installation process: we now provide a docker compose solution which includes all microservices to run the web app as well as data validation, import and migration. We continue to enhance and expand the functionality of cBioPortal. This year we significantly enhanced the group comparison feature; it is now integrated into gene-specific queries and supports comparison of more data types including DNA methylation, microbiome, and any outcome measure. We also expanded support of longitudinal data: the existing patient timeline has been refactored and now supports a wider range of data and visualizations; a new “Genomic Evolution” tab highlights changes in mutation allele frequencies across multiple samples from a patient; and samples can now be selected based on pre- or post-treatment status. Other features released this year include: allowing users to add gene-level plots for continuous molecular profiles in study view, enabling users to select the desired transcript on the Mutations tab, and integration of PathwayMapper. The cBioPortal is fully open source (https://github.com/cBioPortal/) under a GNU Affero GPL license. Development is a collaborative effort among groups at Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Children's Hospital of Philadelphia, Princess Margaret Cancer Centre, Bilkent University and The Hyve. Citation Format: Jianjiong Gao, Tali Mazor, Ino de Bruijn, Adam Abeshouse, Diana Baiceanu, Ziya Erkoc, Benjamin Gross, David Higgins, Prasanna K. Jagannathan, Karthik Kalletla, Priti Kumari, Ritika Kundra, Xiang Li, James Lindsay, Aaron Lisman, Pieter Lukasse, Divya Madala, Ramyasree Madupuri, Angelica Ochoa, Oleguer Plantalech, Joyce Quach, Sander Rodenburg, Anusha Satravada, Fedde Schaeffer, Robert Sheridan, Lucas Sikina, S. Onur Sumer, Yichao Sun, Paul van Dijk, Pim van Nierop, Avery Wang, Manda Wilson, Hongxin Zhang, Gaofei Zhao, Sjoerd van Hagen, Kees van Bochove, Ugur Dogrusoz, Allison Heath, Adam Resnick, Trevor J. Pugh, Chris Sander, Ethan Cerami, Nikolaus Schultz. The cBioPortal for Cancer Genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 207.

Abstract 3098: Leukemia stem cells demonstrate enhanced DNA damage repair and chemoresistance in AML

Abstract Leukemia stem cells demonstrate enhanced DNA damage repair and chemoresistance in AML Relapse of acute myeloid leukemia (AML) is common and the main cause of mortality in this disease. Leukemia stem cells (LSCs) contribute to relapse however the mechanisms underpinning chemoresistance are not well understood. Here, we explored the DNA damage response in AML LSCs to investigate if enhanced DNA repair contributes to relapse and chemoresistance. We discovered that expression of DNA repair pathway genes were up-regulated in functionally defined LSC vs bulk AML cells (n= 227, accession number GSE76008), NES = 1.74, FDR = 0.057, and undifferentiated (n= 7) vs committed AML samples (n = 4, Princess Margaret Cancer Centre cohort), NES = 2.041, FDR = 0.000. Next, we investigated the expression of DNA damage repair genes and response to DNA damage in FACs sorted stem and bulk fractions of 8227 cells. 8227 cells are low passage primary AML cells that maintain a hierarchical organization with functionally defined stem cells in the CD34+CD38- fraction. Compared to bulk cells, the stem cell fraction of 8227 cells had increased expression of genes associated with DNA repair through homologous recombination (RAD51, XRCC2, XRCC3) and non-homologous end joining (XRCC4, XRCC5, PRKDC). Sorted 8227 cells were treated with daunorubicin, an intercalating anthracycline that causes double stranded breaks. DNA damage and repair were evaluated by measuring foci of 53BP1, RAD51 and γH2AX by fluorescent microscopy and quantified using image J. Compared to bulk cells, 8227 stem cells demonstrated increased DNA damage repair with increased foci of 53BP1 and RAD51 and decreased γH2AX foci. We recently discovered that the metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus to maintain stem cell number and function. Therefore, to understand how stemness impacts DNA damage repair, we selectively over-expressed HK2 in the nucleus of 8227 and NB4 cells by tagging HK2 with a nuclear localizing sequence. Over-expressing nuclear HK2 increased stem cell function as shown by clonogenic growth assays and engraftment into mouse marrow. We then treated these cells with daunorubicin and measured DNA damage repair. Increasing stem cell number and function by over-expressing nuclear HK2, increased 53BP1 and RAD51 foci and decreased γH2AX foci, similar to the phenotype observed in LSCs. As measured by the COMET assay, these cells had decreased levels of double strand DNA breaks under basal conditions and increased repair of DNA breaks after treatment with daunorubicin treatment. Over-expression of nuclear HK2 also conferred resistance to daunorubicin as measured by clonogenic growth assays. In summary, LSCs have increased levels of DNA repair genes and increased rates of DNA damage repair after exposure to chemotherapy. The accelerated DNA damage repair seen in LSCs may contribute to chemoresistance and subsequent disease relapse. Citation Format: Grace Egan, G.E. Thomas, Parasvi Patel, Veronique Voisin, Rose Hurren, Neil MacLean, Razq Hakem, Aaron D. Schimmer. Leukemia stem cells demonstrate enhanced DNA damage repair and chemoresistance in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3098.

Treatment Outcomes in the Management of Lymphoblastic Lymphoma (LBL) in Adults: An Institutional Review

▪IntroductionLymphoblastic lymphoma (LBL) is a rare and aggressive form of Non-Hodgkin's Lymphoma (NHL) representing only 1-2% of overall cases. LBL consists of B-cell (B-LBL) and T-cell (T-LBL) variants with T-LBL accounting for 90% of adult cases. LBL is felt to represent the nodal disease equivalent to acute lymphoblastic leukemia (ALL). In fact, the WHO Classification of Tumors of Hematopoietic and Lymphoma Tissues classifies LBL and ALL as a single entity with variants based on genetic and molecular phenotype. As with many other centers, the Princess Margaret Cancer Centre has employed a similar treatment strategy for LBL as with ALL given their biological similarities.MethodsWe conducted a retrospective analysis of 43 patients at Princess Margaret Cancer Centre with LBL who initiated treatment between 1995 and 2015. Patients had a histologically confirmed diagnosis of Pre-T Lymphoblastic Lymphoma, Pre-B Lymphoblastic Lymphoma or Lymphoblastic Lymphoma NOS confirmed by a hematopathologist at the University Health Network. Patients were treated with a variety of regimens including dose intensive or paediatric ALL protocols and less dose-intensive (NHL) protocols. The primary endpoint was the rate of overall survival (OS) at 5 years. Survival times were calculated from chemotherapy start date to last follow-up date. Plots were created using Kaplan-Meier and Log Rank test was used to compare patient groups' survival experience. Secondary endpoints included the rates of complete remission (CR), progression-free survival (PFS) at 5 years and the frequency of treatment-related toxicities and their impact on OS and PFS. We hypothesized that age was likely an important factor in determining toxicity as well as treatment efficacy.ResultsA total of 43 patients with LBL were identified in our database. The median age was 33 with a range of 5-83 years and the male-to-female ratio was approximately 3:1. The majority of patients (88%) had T-LBL subtype and 24 patients (56%) were stage IV at presentation. With respect to chemotherapy regimen, 23 patients (53%) received Dana Farber, 11 patients (26%) received another ALL-type regimen, a pediatric protocol was given in 4 patients (9%) and 5 patients (12%) received a less-dose intensive (NHL) regimen.A complete response (CR) was seen in 29/39 (74%) of patients and a partial response (PR) seen in 7/39 (18%) of patients. Rates of overall survival (OS) and progression-free survival (PFS) at 5 years were non-significantly higher in patients treated with ALL protocols including the Dana Farber (DF) protocol (90% and 88% respectively) compared to less dose-intensive regimens (53% and 60% respectively). A statistically significant difference in OS and PFS in patients less than or equal to age 50 was seen compared to those greater than age 50. On the other hand, clinical stage, LDH level at diagnosis and ECOG performance status did not have prognostic significance.With respect to toxicity, 14 patients experienced a total of 24 toxicity events of interest including venous thromboembolism, hypersensitivity reactions, febrile neutropenia, ileus and other gastrointestinal complications. In those who received DF, 10/23 (43%) of patients experienced a toxicity compared to 4/20 (20%) of patients who received a regimen other than DF (p-value=0.12). Of note, toxicity had no impact on 5-year OS as 85% patients with a toxicity outcome survived at 5 years compared to 80% without a toxicity outcome (p-value=0.49).ConclusionALL treatment protocols have higher rates of OS and PFS in patients with LBL compared to less dose-intensive protocols with no significant difference in toxicity. Given the balance of benefit (favorable OS, PFS and CR rate) with aggressive ALL protocols versus the risks of toxicity (higher rates which do not appear to negatively influence OS), we believe our data favors treatment with ALL regimens in younger adults with LBL. Future research on LBL should assess the treatment experience at other centers given the relative rarity of this disease as well as assess long-term efficacy and toxicity outcomes. [Display omitted] DisclosuresKukreti:Celgene: Honoraria; Amgen: Honoraria. Crump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Roche: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy, Honoraria; Hoffman LaRoche: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding; Lundbeck: Honoraria; Merck: Honoraria.

Migration in the Management of Philadelphia Positive ALL: Towards a Lower Risk of VTE

Background:Patients (pts) with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) have been reported Vu k et al Cancer Medicine. 2015;4(1):27-35. doi:10.1002/cam4.332.to have a higher incidence of venous thromboembolism (VTE). It has been suggested that the incidence of VTE in ALL pts is affected by the use of L-Asparaginase (ASNase) which is an integral part of many chemotherapy regimens. Consistent with this we previously reported a high VTE rate (22%) in pts with Philadelphia chromosome negative (Ph - ALL) that were treated with a modified Dana Farber Cancer Institute (DFCI) chemotherapy regimen containing high dose ASNase as part of the intensification phase. In 2001 imatinib was added to our modified DFCI chemotherapy regimen for Ph+ ALL which included 30 weeks of high dose of ASNase during intensification. However, due to a relative intolerance to the combination of ASNase and imatinib, the ASNase was omitted from the protocol in 2008. In this abstract we compare the incidence of VTE in Ph+ALL pts pre and post 2008 and Ph-ALL patients.Methods:We conducted a retrospective chart review of 130 adult pts with Ph + ALL treated at Princess Margaret Cancer Center between 2001-2015. All Ph+ pts were treated first line with imatinib mesylate in addition to our modified version of the DFCI chemotherapy protocol. As noted, before Feb 1, 2008 the intensification phase included ASNase, while after that date ASNase was omitted. In addition to the Ph+ patients we assessed the incidence of VTE in Ph- ALL patients. From July-2001 to May-2009 no VTE prophylaxis (prx) was given. For the Ph- cases, enoxaparin 0.62 mg/kg was given during intensification from June2009 to Dec2014; following that the dose was increased to 0.90 mg/kg of enoxaparin. VTE was diagnosed by ultrasound or CT pulmonary embolism study. VTEs were further classified as line related or unrelated.ResultsTwenty eight thrombotic events were detected in 25/130 (19.2%) pts with Ph + ALL. VTE with pts received minim one dose ASNase Pre Feb 1, 2008: 8/47 17% post Feb 1, 2008 without ASNase: 17/83 :20.4% One third (7/25)of the VTE were associated with a venous access device. Documented pulmonary embolism occurred in five patients. Almost all events occurred while on therapy with the largest proportion (9/25:36%) occurring while on the intensification phase; 3/19 events and 5/44 during the intensification phase. Three pts developed VTE after receiving and allogeneic SCT (allo SCT). There was no association with age, gender, weight, and allo SCT and the development of VTE.For the Ph- ALL group receiving prophylaxis the incidence of VTE during intensification was 18.9% (low dose) vs 13.3% (high dose).Discussion:We have previously identified an incidence of 21.7% VTE in Ph - ALL patients treated with a modified DFCI chemotherapy that occurred during intensification. The current series describes a similar rate (19.2%) of VTE in Ph + ALL patients despite over 2/3rd of these patients never receiving ASNase. This rate is similar to that reported in other series regardless of whether or not ASNase was given. When we compare the Ph+ ALL group that never received VTE prophylaxis to the Ph- ALL patients who received prophylaxis after 2009 there was no significant difference in the incidence of VTE.Conclusions:This information indicates that the pathogenesis of VTE in Ph + ALL patients may be more complex than previously thought and it is not related to the use of ASNase as the incidence of VTE was the same before and after the use of ASNase in the imatinib treated group. Further evaluation of Ph + ALL and its treatment as an inherently prothrombotic state, using proteomic and advanced genomic analysis, may identify risk factors that can be addressed so as to ameliorate the morbidity caused by VTE events. [Display omitted] DisclosuresGupta:Incyte: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Consultancy, Honoraria. Yee:Astex: Research Funding; Novartis Canada: Honoraria; Karyopharm: Research Funding; Oncoethix: Research Funding; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.