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Ein nicht kleinzelliges Lungenkarzinom (NSCLC) wird seit jeher mit einer schlechten Prognose und einer geringen Überlebensrate von bis zu 5 Jahren in Verbindung gebracht, aber der Einsatz zielgerichteter Therapien beim NSCLC hat die Behandlungsergebnisse für die Patienten in den letzten 10 Jahren verbessert. Die Entwicklung neuer zielgerichteter Therapien beschleunigt sich und damit auch der Bedarf an molekularen Tests für neue Mutationen, die als Ziele geeignet sind. Da die Komplexität der Biomarkertests beim NSCLC zunimmt, besteht ein Bedarf an Leitlinien für den Umgang mit dem im Fluss befindlichen Behandlungsstandard beim NSCLC, für pragmatische molekulare Testbedingungen und für die Optimierung des Ergebnisberichts. Eine multidisziplinäre Expertengruppe mit Vertretern aus der medizinischen Onkologie, der Pathologie und der klinischen Genetik kam über virtuelle Treffen zusammen, um Konsensusempfehlungen für Tests auf neue geeignete Zielmutationen beim NSCLC zu erarbeiten. Die Arbeitsgruppe betonte, wie wichtig es ist, alle potenziellen Zielmutationen genau und rechtzeitig zu testen, um die Behandlung der Krankheit mit gezielten Therapien zu optimieren. Daher empfiehlt das Expertengremium, dass alle möglichen Zielmutationen routinemäßig bei der Diagnose von NSCLC als Teil eines umfassenden Panels getestet werden, wobei Methoden verwendet werden sollten, die alle relevanten mutierten Zielgene erkennen können. Darüber hinaus sollten auf Wunsch des behandelnden Arztes umfassende Biomarkertests durchgeführt werden, wenn sich eine Resistenz gegen eine zielgerichtete Therapie entwickelt. Die multidisziplinäre Expertenarbeitsgruppe gab auch Empfehlungen für die Berichterstattung ab, um die nötige Klarheit und einfache Interpretation der Ergebnisse durch die behandelnden Ärzte zu gewährleisten und der raschen Entwicklung der klinischen Anwendbarkeit dieser Mutationen Rechnung zu tragen. Molekulare Tests auf alle geeigneten Zielmutationen beim NSCLC sind der Schlüssel für die Behandlungsentscheidung und den Zugang zu neuen Therapien. Diese Konsensusempfehlungen sind als Leitfaden für die weitere Optimierung der molekularen Tests auf neue geeignete Zielmutationen gedacht.

IntroductionCancer of unknown primary remains a challenging clinical entity. Despite receiving empiric chemotherapy, median overall survival is approximately 6-12 months. Site-specific therapy based on molecular characterization has been shown to improve outcomes; however, feasibility outside of clinical trials, especially in community centers, is lacking. This study explores the application of rapid next-generation sequencing in defining cancer of unknown primary and to identify therapeutic biomarkers.MethodsA retrospective chart review was performed by identifying pathological samples designated cancer of unknown primary. Next-generation sequencing testing was based on an automated workflow utilizing the Genexus integrated sequencer, validated for clinical use. Genomic profiling was further integrated within a routine immunohistochemistry service, with results reported directly by anatomic pathologists.ResultsBetween October 2020 and October 2021, 578 solid tumor samples underwent genomic profiling. Among this cohort, 40 were selected based on an initial diagnosis of cancer of unknown primary. The median (range) age at diagnosis was 70 (42-85) and 23 (57%) were female. Genomic data were used to support a site-specific diagnosis in 6 patients (15%). Median turnaround time was 3 business days (IQR: 1-5). Most common alterations identified were KRAS (35%), CDKN2A (15%), TP53 (15%), and ERBB2 (12%). Actionable molecular targeted therapies were identified in 23 (57%) patients, including alterations in BRAF, CDKN2A, ERBB2, FGFR2, IDH1, and KRAS. Immunotherapy-sensitizing mismatch repair deficiency was identified in 1 patient.ConclusionThis study supports the adoption of rapid next-generation sequencing among patients with cancer of unknown primary. We also demonstrate the feasibility of integration of genomic profiling with diagnostic histopathology and immunohistochemistry in a community practice setting. Diagnostic algorithms incorporating genomic profiling to better define cancer of unknown primary should be considered for future study.

In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition (MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.

Background: NRG1 fusions represent a rare and potentially actionable oncogenic alteration found in ~0.2% of solid tumors. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks aberrant NRG1 fusion protein binding to HER3 thereby preventing ligand-dependent activation and dimerization resulting in complete inhibition of the PI3K/AKT and MAPK downstream signaling pathways. Seribantumab has shown significant anti-tumor activity in PDX models and in patients (pts) with solid tumors harboring NRG1 fusions. Methods: CRESTONE (NCT04383210) is a phase 2 study of seribantumab in adult pts with solid tumors harboring NRG1 fusions who received at least one prior therapy and were naïve to ERBB-targeted therapy (Cohort 1); pts previously treated with ERBB-targeted therapies (exploratory Cohort 2) and pts with tumors harboring additional molecular alterations (exploratory Cohort 3). Here, we present updated efficacy results for pts in Cohort 1 dosed at 3 g IV QW. Safety data are evaluated for pts enrolled in Cohort 1 and exploratory Cohorts 2 and 3. Results: As of Dec 2, 2022, 51 pts were enrolled across all cohorts with 30 pts in Cohort 1 dosed at 3 g IV QW. Median age was 62 years (range 19-84); median prior lines of therapy was 2 (range 1-7); tumor types included non-small cell lung cancer (NSCLC, n=30), pancreatic adenocarcinoma (PDAC, n=6), biliary tract/cholangiocarcinoma (CCA, n=6), breast (n=4), and others (n=5); 15 different NRG1 fusion partners were identified with CD74 (22%) and SLC3A2 (16%) as the most frequently reported. In the overall safety population, 41 pts (80%) reported at least one treatment-related adverse event (TRAE). The most common TRAEs (occurring in ≥20% of pts) were diarrhea (41%), fatigue (29%), rash (24%), and nausea (22%). Four pts (8%) experienced Gr 3/4 TRAEs; no Gr 5 TRAEs. The safety profile for Cohort 1 was similar to the overall safety population. Among the 30 pts in Cohort 1, 22 were evaluable for investigator assessed (INV) response per RECIST v1.1; 2 pts (9%) had confirmed complete response (CR), 6 pts (27%) had confirmed partial response (PR), and 13 pts (59%) had stable disease (SD) as their best overall response (BOR). The INV objective response rate (ORR, confirmed PR + CR) was 36% and disease control rate (DCR, confirmed PR+CR+SD) was 95%. The overall duration of response ranged from 1.4 to 17.2 months. In pts with NSCLC, the INV-ORR was 39% and DCR was 94%. Conclusions: Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option. Citation Format: Tejas Patil, Daniel R. Carrizosa, Mark E. Burkard, Karen L. Reckamp, Jayesh Desai, Young Kwang Chae, Stephen V. Liu, Kartik Konduri, Shirish M. Gadgeel, Jessica J. Lin, Parneet K. Cheema, David R. Spigel, Alison M. Schram, Valerie M. Jansen, Yasir Y. Elamin. CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT229.

PURPOSE Plasma detection of EGFR T790M mutations is an emerging alternative to tumor rebiopsy in acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. Validation of analytical sensitivity and clinical utility is required before routine diagnostic use in clinical laboratories. PATIENTS AND METHODS Sixty-three patients with advanced EGFR-mutant lung cancer at 7 Canadian centers, who were being screened for the ASTRIS trial (ClinicalTrials.gov identifier: NCT02474355 ), participated in this companion study. Plasma T790M mutation was detected using droplet digital polymerase chain reaction, Cobas (Roche Diagnostics, Indianapolis, IN), or next-generation sequencing in 4 laboratories. T790M concordance was assessed between plasma and tumor samples. RESULTS Assessment of T790M in tumor biopsy tissue was successful in 81% of patients; 49% had confirmed T790M results (tumor or plasma) for ASTRIS. Plasma testing in this companion study yielded T790M results in 97% of patients; 62% had T790M-positive results, 36% had negative results, and 2% had indeterminate results. Of 38 patients with negative or indeterminate biopsy results, 55% had positive plasma T790M results, increasing the proportion with T790M-positive results to 73%. Sensitivity of plasma T790M testing was 75%. Overall concordance between tissue and plasma was 64%, and concordance among laboratories was 90.3%. Response to osimertinib and duration of therapy were similar irrespective of testing method (overall response rate, 62.5% for tissue, 66.7% for plasma, and 70.6% for both). CONCLUSION This multicenter validation study demonstrates that plasma EGFR T790M testing can identify significantly more patients than biopsy alone who may benefit from targeted therapy.

The ADAURA trial demonstrated the benefit of adjuvant osimertinib among patients with resected, early-stage, epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). To understand the potential population impact, it is critical to deduce the prevalence, management, and outcomes of this patient population in the real-world setting before use of adjuvant osimertinib.Using PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2012-2019), a retrospective, multi-center, observational cohort study was conducted among patients with early-stage (IB-IIIA) resected NSCLC who had not received neoadjuvant therapy. Study outcomes included EGFRm prevalence, treatment patterns, recurrence outcomes, and overall and disease-free survival (OS/DFS).Among patients undergoing reflexive EGFRm testing by a pathologist at time of diagnosis irrespective of disease stage (N = 535), 23 % were EGFRm-positive; 15.9 % had common mutations and 5.6 % had uncommon mutations. Within the EGFRm-positive cohort (N = 156), mean age at diagnosis was 68 years, 65 % of patients were female, and 35 % were of Asian descent. At diagnosis, 48 %, 31 %, and 21 % had stage IB, II, or IIIA disease, respectively; 46 % received adjuvant therapy after resection. Half of patients experienced disease recurrence, typically involving distant sites; central nervous system metastasis varied from 12 % to 15.0 % across disease stages. EGFR tyrosine kinase inhibitors were the most commonly received therapy after first metastatic recurrence. Median OS (DFS) was not reached, 71.2 (22.8) months, and 50.1 (18.0) months among stage IB, II, and IIIA patients. Patients with uncommon EGFRm had a lower probability of survival than those with common EGFRm (2 years: 87 % vs 91 %-94 %; 4 years: 56 % vs 73 %-82 %).Approximately-one-quarter of patients with resected, early-stage NSCLC were EGFRm-positive in this study. These patients had high recurrence rates and suboptimal long-term survival after treatment with current therapies. New adjuvant treatments are warranted.

The increased use of immune checkpoint inhibitors across cancer programs has created the need for standardized patient assessment, education, monitoring, and management of immune-related adverse events (irAEs). At William Osler Health System in Brampton, Ontario, a practical step-wise approach detailing the implementation of cancer immunotherapy in routine practice was developed. The approach focuses on four key steps: (1) identification of patient educators; (2) development of patient education materials; (3) development of patient monitoring tools; (4) involvement and education of multidisciplinary teams. Here, we provide an in-depth description of what was included in each step and how we integrated the different elements of the program. For each step, resources, tools, and materials that may be useful for patients, healthcare providers, and multidisciplinary teams were developed or modified based on existing materials. At our centre, the program led to improved patient comprehension of irAEs, the ability to act on symptoms (patient self-efficacy), and low rates of emergency room visits at first presentation for irAEs. We recognize that centres may need to tailor the approaches to their institutional policies and encourage centres to adapt and modify the forms and tools according to their needs and requirements.

3006 Background: NRG1 fusions are rare oncogenic drivers found in ̃0.2% of all solid tumors. These fusions elicit ERBB3/HER3 overactivation to drive tumor growth and cancer cell survival. Currently there are no approved targeted therapies for NRG1 fusion-positive tumors. Furthermore, patients (pts) with tumors harboring NRG1 fusions have poor outcomes with standard therapies. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that suppressed tumor growth in NRG1 fusion-driven preclinical models. Here, we present initial clinical data from the CRESTONE study (NCT04383210). Methods: CRESTONE is a Phase 2, global, multicenter, open-label study of seribantumab in adult pts with locally advanced or metastatic solid tumors harboring NRG1 fusions. A dose ranging phase established the RP2D as a 3g once weekly (QW) intravenous dose administered until treatment discontinuation criteria are met. In the expansion phase, cohort 1 will enroll at least 55 pts who had received at least one prior therapy and are naïve to ERBB-targeted therapy. Exploratory cohorts 2 or 3 will enroll pts previously treated with ERBB-targeted therapies and/or tumors harboring additional molecular alterations. The primary endpoint is objective response rate (ORR) by independent central review per RECIST v1.1. Initial data from cohort 1 pts who received seribantumab 3g QW with investigator (INV)-assessed response per RECIST v1.1 are reported. Results: By JAN-13-2022, 12 pts have received seribantumab 3g QW in cohort 1. Median age was 65 years (range 44–76), 67% were female, and median number of prior therapies was 1 (range 1–5). 92% (11/12) of pts had non-small cell lung cancer (NSCLC); 5 different NRG1 fusion partners ( ATP1B1, CD74, ITG B1, SDC4, SLC3 A2) were reported by local next-generation sequencing tests. Among 10 pts evaluable for INV-assessed response, the confirmed ORR was 30%, and the disease control rate was 90% (1 complete response, 2 partial responses, 6 stable disease, 1 progressive disease). 58% (7/12) of pts remain on study treatment, including 2 pts with NSCLC who achieved objective responses with an ongoing duration of response of 6 and 8.5 months. Seribantumab 3g QW was well tolerated with no drug discontinuations or dose reductions. Across all cohorts (n = 29), the most frequently (≥20%) reported treatment-related adverse events (TRAEs) were diarrhea (38%), fatigue (34%), and rash (24%), all were grade 1 or 2. One grade 3 TRAE of vomiting occurred; there were no Grade 4 or 5 TRAEs. Efficacy analysis is ongoing and updated efficacy data from evaluable pts in cohort 1 will be presented. Conclusions: Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions and has a favorable safety profile. These data support the continued evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study. Clinical trial information: NCT04383210.

TPS9158 Background: In cancer, the accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via the high affinity A2A receptor (A2AR), causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. This results in increased tumor cell survival and immune escape (Blay 1997; Merighi 2003; Muller-Haegele 2014). Therefore, inhibiting A2AR could reverse immunosuppression and re-establish immune surveillance in the tumor microenvironment. Inupadenant is an antagonist of the A2AR with potent inhibition of A2AR even at the high concentrations of adenosine present in the tumor microenvironment. Ongoing clinical studies have established inupadenant as a molecule with a favorable safety profile with preliminary evidence of clinical activity in multiple tumor types, including durable PRs in patients who have exhausted standard treatment options (Buisseret 2021). The standard treatment for patients without a driving mutation who progress on first-line IO is a platinum-based doublet chemotherapy regimen. Carboplatin plus Pemetrexed (C+P) is the preferred chemotherapy in nonsquamous mNSCLC. Study A2A-005 will evaluate the efficacy of inupadenant in combination with C+P as a second-line therapy in adult patients with nonsquamous mNSCLC (post-IO). A successful outcome from study A2A-005 will help address a high unmet need for this patient population and could lead to new therapeutic options. Methods: This is a 2-part study. The first part is an open label dose-finding part to determine the safety and recommended Phase 2 dose (RP2D) of inupadenant in combination with C+P (N = 40). In Part 2, 150 patients will be randomized 1:1 to inupadenant or placebo, both in combination with C+P. Tumor response will be determined according to RECIST 1.1 criteria and safety findings will be reviewed by the Safety Review Committee (for Part 1) and the Data Monitoring Committee (for Part 2). Key eligibility criteria include 1) mNSCLC of nonsquamous pathology, 2) have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy, and have progressed (IO/IO combination therapy is allowed), 3) have measurable disease as defined by RECIST v1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. Primary endpoints are RP2D (for Part 1) and PFS (for Part 2). Secondary endpoints include change in tumor size, ORR, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. The study will be conducted in approximately 11 countries in North America and Europe. Clinical trial information: EudraCT 2021-005487-22.

9043Background: The primary ALEX (NCT02075840) analysis showed superior investigator (INV)-assessed PFS with ALC vs CZ (HR 0.47, 95% CI 0.34–0.65, p

e18329 Background: Detection of EGFRmutations in circulating tumor DNA (ctDNA) in peripheral blood has been shown to have high concordance with definitive tumor biopsy samples. Patients’ perceived value and willingness to pay for novel technology can help inform policy and funding decisions in the public healthcare system. Methods: Canadian patients undergoing screening for the ASTRIS clinical trial (NCT02474355) were invited to participate in a national Canadian validation study of blood-based ctDNA T790M testing. All participants had metastatic EGFRmutant lung cancer with acquired resistance to EGFR kinase inhibitors. In addition to collection of blood samples and demographic data, patients completed a structured interview measuring their perceived value of blood-based ctDNA testing as an alternative to tumor biopsy and willingness to pay for testing using both open-ended and iterative bidding approaches. The study was supported by a grant from AstraZeneca. Results: 55 patients have been accrued of a planned 60. As of 01/31/2017, demographic data for 55 and willingness to pay data for 52 patients were available, the rest are pending. The median age of the cohort is 64 years (range 31-87), 68% are Asian (36/53), 56% female (31/55). Patients received a median of 1 prior line of treatment (range 1-7); all received prior EGFR kinase inhibitor therapy (66% gefitinib), and 34% also received prior cytotoxic chemotherapy (18/53). All but one patient preferred to have the blood test over repeat tumor biopsy. Patients were personally willing to pay a median of $400 CAD for the test (IQR $600, range 0-$10000). Patients estimated that a reasonable price for the test was a median of $150 (IQR $300, range 0-$2500). Conclusions: Lung cancer patients value ctDNA testing highly and prefer it to tumor biopsy. Despite the expectation that services like molecular testing should be covered through the Canadian public healthcare system, patients expressed willingness to pay out of pocket for ctDNA blood testing, reflecting perceived major value of this technology.

An article in a recent edition of Current Oncology explored the validation of progression-free survival (pfs) as an endpoint in clinical trials of antineoplastic agents for metastatic colorectal cancer, metastatic renal cell carcinoma, and ovarian cancer. The support for pfs as a surrogate endpoint for overall survival (os) was elucidated. As with the aforementioned tumour types, advanced non-small-cell lung cancer (nsclc) has seen a rise in active agents since the year 2000. Those agents range from improved cytotoxics such as pemetrexed, to targeted therapies such as tyrosine kinase inhibitors of the epidermal growth factor receptor and agents that target the EML4&ndash, ALK gene mutation. More recently, it has also become apparent that histology plays an important role in the response to and outcomes of treatment. With the therapeutic options for patients with advanced nsclc increasing, concerns are being raised that the efficacy of drugs measured by os may be diluted in clinical trials, thereby underestimating their true clinical benefit. That possibility, together with the need to have efficacious drugs available to patients earlier, has resulted in the search for a surrogate to the os endpoint in advanced nsclc. The present article follows up the recent article on pfs as a surrogate. Although advances in identifying pfs as a valid surrogate endpoint for os have been made in other tumour types, in advanced nsclc, such surrogacy has not been formally validated. Until it has, os should remain the primary endpoint of clinical trials in advanced nsclc.

Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations ; influence of pharmacogenomics on response and toxicity of drug therapies ; value of biomarker tests ; limitations and costs of tests ; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients

Background: Post-transplant lymphoproliferative disorder (PTLD) is an uncommon, heterogeneous disease that occurs in the setting of immune suppression following solid organ transplantation. As the transplant population ages over time, the spectrum of PTLD histologies and their treatment has evolved; we report here our recent experience with PTLD from a large multi-organ transplant program. Methods: We identified patients from the Multi-Organ Transplant Program at University Health Network (UHN) who were diagnosed with PTLD between January 1, 2000 and December 31, 2015. We describe the characteristics and outcomes of this cohort, with a focus on the outcome of patients with the diffuse large B cell (DLBCL) subtype of PTLD treated in the rituximab era. Results: A total of 140 patients were diagnosed with PTLD at UHN during this time period (Table 1): 38% were female and median age at time of diagnosis was 50 (interquartile range, IQR Q1/Q3, 37 to 62 years). The most commonly implicated transplants were liver and kidney (33% and 32%), as well as lung (20%) and heart (7%). The median time from organ transplantation to PTLD diagnosis was 61 months (IQR 9 to 136), with 70% of cases occurring more than 12 months following solid organ transplant. Pathologically, the majority of the patients had monomorphic PTLD, with DLBCL (n = 86) being most common. Where classifiable by the Hans algorithm (n = 68), the majority of the DLBCL types were of the non-germinal center B cell type (non-GCB, 76.5%). Of 24 DLBCL patients with available FISH, 7 had a MYC translocation (29%). Treatment and outcome varied by PTLD subtype (Table 2). For the overall cohort (n = 140), the median OS was 5.1 years. Highlighting competing risks, less than half of patients died of PTLD, with the remainder of mortality due to complications of solid organ transplantation, or less commonly, due to treatment-related mortality. Polymorphic PTLD (n = 17) was treated in a variety of ways ranging from reduction in immunosuppression (RIS) alone to R-CHOP; median OS was 10.3 years. Less common histologic subtypes (Hodgkin, Burkitt, T cell) were treated with therapies specific to those lymphomas. For DLBCL (n = 86), treatment consisted of RIS alone (10.5%; OS 4.4 years) or RIS followed by local treatment (involved field radiation or surgical resection) (7.0%; OS not reached); single agent rituximab (R) (22.1%; OS not reached); sequential R followed by CHOP (11.6%; OS 1.5 years), or upfront R-CHOP (43.0%; OS 3.4 years). Median OS for patients classified as non-GCB was not worse than those classified as GCB (OS 6.2 vs. 4.7 years, p = 0.93). In the DLBCL cohort, 20 patients had progression during or after first line therapy, with 14 patients receiving additional treatment. Patients with early relapse during initial therapy or within the first 3 months (n = 13) did poorly compared to patients with later relapse occurring after 3 months (n = 7; median OS 0.7 vs 5.6 years, p < 0.01). This was similar to the entire cohort, where 40 patients relapsed and early relapsed/refractory patients also had poor outcomes compared to late relapsing patients (median OS 0.8 vs. 5.1 years, p Conclusion: In this recent retrospective cohort, PTLD was generally late onset and the median OS of all patients was 5 years. The most common histology was DLBCL (non-GCB subtype), but cell of origin did not influence outcome. Patients with early relapse or refractory disease had poor overall survival. Due to competing risks and comorbidities, many PTLD patients continue to have poor outcomes despite modern treatment strategies. Disclosures Jain: Roche Canada: Research Funding. Prica:Janssen: Honoraria. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria. Kuruvilla:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria.

ING1 proteins are nuclear, growth inhibitory, and regulate apoptosis in different experimental systems. Here we show that similar to their yeast homologs, human ING1 proteins interact with proteins associated with histone acetyltransferase (HAT) activity, such as TRRAP, PCAF, CBP, and p300. Human ING1 immunocomplexes contain HAT activity, and overexpression of p33ING1b, but not of p47ING1a, induces hyperacetylation of histones H3 and H4, in vitro and in vivo at the single cell level. p47ING1a inhibits histone acetylation in vitro and in vivo and binds the histone deacetylase HDAC1. Finally, we present evidence indicating that p33ING1b affects the degree of physical association between proliferating cell nuclear antigen (PCNA) and p300, an association that has been proposed to link DNA repair to chromatin remodeling. Together with the finding that human ING1 proteins bind PCNA in a DNA damage-dependent manner, these data suggest that ING1 proteins provide a direct linkage between DNA repair, apoptosis, and chromatin remodeling via multiple HAT·ING1·PCNA protein complexes.

BACKGROUND: Post transplant lymphoproliferative disorder (PTLD) is the commonest malignancy associated with pharmacologic immunosuppression after organ transplantation. Reduction in immunosuppression (RI) is a common initial strategy, but many pts require systemic therapy (ST) because of rapid disease progression. We evaluated the treatment and outcome of PTLD at a large multi-organ transplant programme to examine prognostic factors and predictors of outcome with RI and ST. METHODS: Patients (pts) were identified from the UHN Multi Organ Transplant Database and the Cancer Registry at Princess Margaret Hospital. Pts were included if they had a pathologic diagnosis of PTLD and adequate information to assess response to treatment. Variables evaluated for their influence on response to treatment and survival included age, organ transplanted, pathology, CD20+, time to PTLD from transplant, organ dysfunction, EBV+ lymphoma, stage, extranodal disease, B symptoms, CMV infection prior to PTLD, and LDH. RI was defined as a trial of „□10 days of reduction or discontinuation of calcineurin inhibitor (CNI), reduction or discontuation of mycophenolate mofitel or azathioprine and maintenance prednisone, with or without surgical resection of all known disease with repeat imaging to assess response. (Paya, Transplantation68(10):1517, 1999). Chemotherapy consisted of CHOP or equivalent regimens. Rituximab was given as a single agent 375 mg/m2 weekly ×4 doses. RESULTS: 80 pts were identified; 3 pts were excluded from the current analysis for a diagnosis of marginal zone lymphoma (2) or primary body cavity lymphoma (1). Of the 77 pts included 53 (69%) were males. 66% (51) of pts had monomorphic PTLD (44 diffuse large B cell lymphoma, DLBCL), 31% (24) had polymorphic PTLD, 3 (2%) pts had Hodgkin lymphoma-like PTLD; 79% were EBV positive by in-situ hybridization. Organ transplanted: liver 34 (44%), kidney 22 (29%), lung 16 (21%), heart 5 (7%). Fifty percent of pts presented with stage III/IV disease, 81% with extranodal disease, 52% with B symptoms and 69% with an elevated LDH. Initial therapy: RI 43 pts, chemotherapy 31 pts, RI + rituximab 1 pt, surgical resection and re-transplantation 1 pt. For those treated with RI, extent of reduction of CNI did not influence response rate, overall survival (OS) or rate of organ rejection. Overall response rate to RI was 74%; only CD20 expression on the lymphoma was associated with a higher rate of response (p=0.026). Inclusion of antiviral therapy (generally gancyclovir) reduced the risk of relapse in those responding to RI (p=0.026). Response to RI did not vary by time to PTLD diagnosis from transplantation (p=.355), however, the rate of relapse following RI was significantly higher in pts developing PTLD >1 year from transplantation (p=.017). OS in pts undergoing RI as initial treatment was 73% at 3 yrs and 66% at 5 yrs. Nine pts received single agent rituximab, either with RI or because of progression after RI; 4 of the 9 pts responded, and 3 are progression-free. Of the 31 pts treated with primary chemotherapy, 24 had a CR or PR (78%); 4 pts died of toxicity (13%). OS of pts undergoing chemotherapy as initial treatment was 62% at 3 yrs and 58% at 5 yrs. Pts who received RI +/− rituximab followed by chemotherapy for lack of response or relapse had no significant difference in OS compared to those who received frontline chemotherapy (p=0.36). Evidence of graft rejection during treatment was seen in 13 pts (30%) treated with first line RI, compared to 6 (19%) in pts treated initially with chemotherapy. The rate of graft loss was low in both groups at 7% (3) in the RI group and 3% (1) in the chemotherapy group. Median follow up of survivors is 92 months. Overall survival (OS) for the entire cohort was 110 months (95% CI: 67.6, 152.7). Investigation of independent variables affecting OS revealed that organ dysfunction at diagnosis was significantly associated with shorter survival (p=.028). CONCLUSIONs: The outcome of pts with PTLD managed with initial RI is similar to those receiving ST; however the latter is toxic and there are no reproducible variables predicting response to RI as primary treatment. OS is similar in pts receiving RI followed by ST, versus those that received first line chemotherapy, suggesting that a delay in ST for a trial of RI may be justified. Prospective controlled trials of antiviral therapy and the timing and addition of rituximab and chemotherapy are still needed to improve patient outcome and guide future therapy.

BACKGROUND: Multiple myeloma (MM) only occurs in 2% of patients under the age of 40. It has been reported that this young cohort of patients have a superior overall survival when compared to those over the age of 40. OBJECTIVE: To evaluate the clinical and laboratory features of patients ≤40 years of age at diagnosis of MM and to compare survival outcomes to patients >40 years of age. METHODS: Retrospective institutional review of all patients ≤40 years of age at time of diagnosis of MM that had underwent upfront ASCT at PMH from January 1, 1990 to July 31, 2007. Outcomes were compared to patients >40 years of age who had also undergone ASCT as upfront therapy. RESULTS: 37 patients ≤40 years of age were identified. Twenty patients were male. Immunoglobulin subtype was as follows: 49% had IgG, 19% light chain,16% IgA, 8% IgD, and 5% IgG plasma cell leukemia. The main presenting clinical feature was bone pain (63%). 73% had radiological evidence of bony disease at diagnosis and 53% of these patients required radiation prior to ASCT. Clinical features included anemia in 81%, renal insufficiency in 39% and hypercalcemia in 28%. Conditioning regimens for ASCT were high dose melphalan (200mg/m2) alone in 25 pts, VP-16 & melphalan +/− TBI in 8 pts, bleomycin & cyclophosphamide in 3 pts, and in 1 pt it was unknown. Median time to engraftment of neutrophils (>0.5 x 109/L) and platelets (>20 x 109/L) was 11 days (range 8–18) and 12 days (range 0–54), respectively. Median duration of hospitalization was 17 days (range 10–54). No treatment related mortality was experienced. Response to ASCT was as follows in 29 evaluable pts: CR in 10 (34.5%), PR in 13 (44.8%), MR in 1 (3.4%), SD in 3 (10.3%), and PD in 2 (6.9%). Five patients underwent a tandem ASCT. Maintenance therapy was instituted in 11 pts. Median progression free survival (PFS) post ASCT was 23.0 months, which is similar to the PFS of 28.5 months in patients over 40 (p=0.559). There was also no difference in median overall survival (OS) from date of ASCT between the two groups (6.6 years in pts ≤40, 6.7 years in pts >40; p=0.797). CONCLUSION: Young patients with MM present with advanced disease as evidenced by anemia, bone involvement and hypercalcemia. ASCT yields high response rates, but PFS post ASCT is less than 2 years. Although young age has been historically been considered to be a positive prognostic marker, OS post ASCT is only 6.6 years, which is equivalent to those >40 years of age. Strategies to better the outcomes of young patients with MM are required.

INTRODUCTION: The use of peripheral blood as a source of stem cells for pediatric allogeneic stem cell transplantation remains controversial. We present a retrospective analysis evaluating the safety and efficacy of allogeneic peripheral blood stem cell transplantation (PBSCT) compared to allogeneic bone marrow transplantation (BMT) for the treatment of acute leukemia at our centre. The impact of ATG added to the treatment regimen was also evaluated in this analysis. METHODS: A chart review was conducted on all pediatric patients who underwent an allogeneic stem cell transplant for acute leukemia between April 1991 and August 2003 at the Alberta Children’s Hospital. All patients who received stem cells from HLA matched or one-antigen mismatched donors were included in this analysis. Data were analyzed using SPSS. RESULTS: 85 children (ages 9 months to 17 years) met study criteria. 24 patients underwent a PBSCT while 61 patients, a BMT for the treatment of either ALL (n=54) or AML/MDS (n=31). Median follow up time was 5.9 years. Six of 24 patients in the PBSCT group, and 30 of the 61 patients in the BMT group received ATG (p=.042). There was a trend towards increased overall survival (OS) at 5 years following PBSCT (p=.078). Disease free survival (DFS) at 5 years following PBSCT and BMT was similar (p=.297). Subgroup analysis found no difference in OS or DFS between PBSCT and BMT in patients receiving (p=.221, p=.820) or not receiving ATG as part of the conditioning regimen (p=.448, p=.820). Chronic GVHD was increased following PBSCT (45.8%) compared to BMT (19.7%) (p=.015). The rate of severe cGVHD, however, was not significantly different (25% vs. 11.5% for PBSCT and BMT, p=.119) between the two groups. No patients receiving ATG prior to PBSCT developed cGVHD (p=.009). Addition of ATG to the transplant regimen had no impact on the rate of cGVHD following BMT (p=.221). There was no increase in mortality due to cGVHD following PBSCT (p=.243) or BMT (p=.865). Although, there was a trend to improved DFS in patients who developed cGVHD following PBSCT, this was not statistically significant (p=.057). Despite a statistically significant increase in TRM found in all patients with cGVHD at one year post-transplantation (p=.048), there was no difference in TRM between the PBSCT (4.2%) and BMT (14.8%) groups (p=.173). CONCLUSION: Allogeneic PBSCT is a safe and effective alternative to allogeneic BMT for the treatment of acute leukemia in the pediatric population. Although there is an increased rate of cGVHD following PBSCT this does not appear to influence OS, DFS or TRM in our analysis. Addition of ATG into the transplant regimen decreases the occurrence of cGVHD after PBSCT. Studies to further assess the role of ATG in PBSCT are warranted.

Multiple myeloma (MM) rarely occurs in patients 40 years of age and younger. This young age has been reported to correlate with improved survival in patients with MM. The objective of this study is to describe presenting features and outcomes of patientsor =40 years of age with MM who undergo autologous stem cell transplantation (ASCT) as first-line treatment, and compare overall survival (OS) and progression free survival (PFS) to patients aged 41-65 years. We performed a retrospective institutional review of all patientsor =40 years of age and 41-65 years of age at the time of diagnosis of MM who had undergone upfront ASCT from January 1, 1990, to July 31, 2007. Thirty-eight patientsor =40 years of age and 608 patients aged 41-65 were identified. There was a high rate of plasma cell leukemia (PCL) in young patients at 11% compared to the reported rate of 2%-4%. At diagnosis, there was an increased rate of renal failure in the young cohort compared to patients aged 41-65 years at 25% versus 16% and Bence Jones proteinuria at 81% versus 51%. The rate of complete or partial response was similar between the groups at 79% and 83% in the young and older cohorts, respectively. Median PFS post-ASCT was 22.0 months (95% confidence interval [CI]: 16.1, 28.0), versus 26.9 months (95% CI: 24.0, 29.8) for patients aged 41-65 years (P = .66). Median OS from date of ASCT was also similar to those over 40 years: 68.1 months (95% CI: 39.0, 97.2) versus 80.7 months (95% CI: 68.1, 93.4); P = .90. Treatment-related mortality (TRM) was low at 2.6% and 2.3% in the young and older cohorts, respectively. Despite previous reports that young age is a positive prognostic marker, our study found OS post-ASCT is equivalent to those aged 41-65 years. This study emphasizes the importance of developing strategies to better the outcomes of young patients with MM.