Schiff, David

Abstract Abstract 879 Background: Several solid organ transplant (SOT) PTLD series have reported that PCNS disease is a poor prognostic factor (e.g., Leblond et al, JCO 2001; Maeker et al, JCO 2007; Knight et al JCO 2009; Evens et al, JCO 2010). However, these reports contained small PCNS PTLD numbers and most series studied patients (pts) in the pre-rituximab era. Methods: We performed an International retrospective analysis of PCNS SOT-related PTLD diagnosed from 1998 through 2010. Cases with secondary CNS localization were excluded. Detailed pt and disease characteristics, including frontline therapy, were evaluated. Fisher's exact test was used to compare PCNS PTLD vs non-PCNS PTLD cases. Further, univariate associations with survival were determined, while a multivariate Cox regression proportional hazards model was performed. Results: 71 PCNS PTLD cases were identified, of which 65 had complete data. There were 35 men and 30 women; the median age was 53 years (range, 20–77 years). The most common type of SOT was kidney in 72%, followed by lung 18% and 5% each pancreas and heart. The median time from SOT to PCNS PTLD was 46 months (range, 2 to 504 months). Further, only 18% occurred within 12 months of SOT, and 32% of PTLD diagnoses occurred > 10 years after SOT. 85% of pts had received prior mycophenolate, while 30% received tacrolimus prior to PCNS PTLD. According to WHO histology, 83% of PCNS PTLD cases were monomorphic subtype (all B-cell), while tumor was EBV+ in 93% despite EBV being detectable in the peripheral blood (by PCR) in only 38% of these cases. In addition, 49% of pts had poor performance status (i.e., 2–4), 48% had elevated LDH, and 48% were hypoalbuminemic at diagnosis. Interestingly, several of these characteristics were notably different when compared with a non-PCNS PTLD cohort (Table 1A). All pts here presented with CNS-related symptoms and 98% had abnormal findings on MRI showing a parenchymal brain lesion(s); 50% of pts had >1 CNS lesion and 40% had involvement of deep regions of the brain. Further, 12% had concomitant CSF involvement, while no pts had ocular involvement. In terms of therapy, 89% of pts had reduction in immunosuppression (RI). Additional frontline therapy consisted of high dose methotrexate (HD-MTX)-based therapy in 43% (46% of whom also received concurrent rituximab), whole-brain radiation in 20% (61% with rituxmab), high-dose cytarabine (HDAC)-based in 15% (30% with rituximab), while 11% received rituximab alone and 11% had no other therapy (i.e., RI alone). Altogether, 48% of pts received rituximab as part of initial therapy. The overall response rate (ORR) was 55% with 30% complete remission (CR) rate. With a median follow-up of 39 months (1–135), the 3-year progression-free survival (PFS) and overall survival (OS) for all pts were 31% and 32%, respectively (Figure 1). Pts who received rituximab vs not as a component of first line therapy had superior PFS (40% vs 22%, respectively, p=0.02) and borderline improved OS (43% vs 22%, respectively, p=0.06), while pts who did not receive rituximab nor HD-MTX-based therapy as frontline therapy did particularly poor (PFS and OS both 10%). Several pre-treatment and treatment-related factors predicted survival on univariate analysis (Table 1B). When analyzing only pre-treatment related factors in the Cox multivariate regression model, only increasing age remained significant (PFS: HR 1.04 [95%CI 1.00–1.07], p=0.031; and OS: HR 1.04 [95%CI 1.01–1.08], p=0.020). With treatment-related factors included in the model, response to frontline therapy (CR or partial remission) was the dominant predictive factor of survival on multivariate analysis (PFS: HR 0.136 [95%CI 0.047–0.390], p=0.0002; and OS: HR 0.130 [95%CI 0.045–0.381], p=0.0002). Conclusion: These data represent the largest report of PCNS PTLD to date. PCNS PTLD appears to represent a distinct biologic and clinical entity within the PTLD spectrum that retains EBV positivity, occurs late, and presents with additional high-risk features. Furthermore, outcome of PCNS PTLD remains overall modest. However, these data suggest that rituximab and HD-MTX appear to favorably impact survival. Continued study of this subset of pts is critically needed. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 995 PCNSL is an aggressive primary brain tumor characterized by a perivascular accumulation of malignant lymphoid cells. Most PCNSLs (90%) are diffuse large B-cell lymphoma (DLBCL); the remaining 10% are poorly characterized low-grade, Burkitt, and T-cell lymphomas. Since most patients are biopsed, genomic analyses are challenging. To determine the pattern of genetic alterations in PCNSL, frozen samples and formalin fixed embedded paraffin sections from 17 EBV and HIV negative and immunocompetent patients were studied by array-based comparative genomic hybridization (aCGH) using Sureprint G3 (1 million probes) array (Agilent). B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and BCL-6. All cases were characterized by complex genomic aberrations with a median of 21 copy-number abnormalities (CNA) per patient (range 10–49). Overall, 22 minimal deleted regions (MDR) and 14 minimal amplified regions (MAR) were found in more than 20% of patients. Focal deletion affecting CDKN2A (9p21) was the most common CNA, found in 14 of 17 cases (82%); biallelic in six cases. Losses of 6q were observed in 71% of cases. Deletions of 6q23.3 (TNFAIP3) and 6q21 (PRDM1) were found in 59% (10/17) and 47% (8/17) of cases, respectively. Other common CNA were deletions of 6p21 (9/17; 53%), 3p21.1 (5/17; 29%), 3q26.32 (5/17; 29%), 8q12.1 (5/17; 29%), 10p14-p15.3 (5/17; 29%), 12q24.31 (5/17; 29%) and gains of 12q21-q24 (9/17; 53%), 7q21-q31 (6/17; 35%), 19q13 (6/17; 35%), 3q27.3 (5/17; 29%) and 11q24.1-q25 (5/17; 29%). Interestingly, several CNA were unique to PCNSL and were not identified in related entities as the typical DLBCL. Besides in CDKN2A, homozygous deletions were recurrently found in TMEM30A and TOX, the latter a regulator of T-cell development. Another 64 genes, including B2M, CD58, ETV6, LAPTM, MHC class II genes, PRDM1, TNFRSF10A and TNFRSF10B were also homozygously deleted. CD58, which encodes for a member of the immunoglobulin family and regulates the adhesion and activation of T lymphocytes, was also recurrently affected by focal monoallelic losses from 15 nucleotides to 1–2 exons, affecting the Ig-like C2-type domain as was confirmed by DNA resequencing. Focal heterozygous deletions affect TBL1XR1, a negative regulator of the NF-kB and Wnt pathways, and the putative tumor suppressor BCL7A in 29% of cases each. Pathway analysis done including the most commonly affected genes (Ingenuity Pathway Analysis) highlights the importance of networks associated with apoptosis and lymphocyte differentiation and proliferation, especially of T lymphocytes. In summary, this study showed evidence for a highly complex genome and identified target genes of potential relevance in the pathogenesis of PCNSL. The genomic profile described here is unique to PCNSL, thus helping to genetically differentiate this entity from the typical DLBCL and other related lymphomas. Disclosures: Fonseca: Genzyme: Consultancy; Medtronic: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Research Funding; Intellikine: Consultancy; Cylene: Research Funding; Onyx: Research Funding; FISH probes prognostication in myeloma: Patents & Royalties.

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive and incurable variant of non-Hodgkin lymphoma (NHL) that is confined to the central nervous system. Most PCNSL (90%) are part of the immune-privileged site-associated diffuse large B-cell lymphomas (DLBCL). Unlike nodal DLBCL, only a limited number of genetic studies have been performed in PCNSL, partly due to lack of available tissue specimens. Because of the fragmented knowledge of the genomic basis, it is still a matter of debate whether they differ from systemic DLBCL with respect to their molecular features and pathogenesis and also if there is a CNS specific signature. We performed a comprehensive genomic study in a cohort of 22 immunocompetent (HIV- and EBV-) PCNSL. DNA was extracted from FFPE tissues (N=15) and frozen tissue (N=7). Samples were analyzed using a combination of aCGH (N=18), exome sequencing (N=10), mate-pair genome sequencing (N=2) and targeted sequencing (N=8). We found a complex karyotype with a median of 21 copy-number abnormalities (range 10–47), 6 structural abnormalities, 6 frameshift indels and 67 nonsynonymous mutations. By integrating mutation and copy number data we found a group of genes recurrently mutated and/or deleted in PNCSL. Remarkable findings were the high prevalence of MYD88 activating mutations (L265P/M232T/V217F), found in 69% of cases and the biallelic loss of CDKN2A (60%). A subset of recurrent abnormalities was exclusively found in PCNSL, and not being previously identified in systemic DLBCL. Thus, 11% of PCNSL have biallelic inactivation of TOX (a regulator of T-cell development) and PRKCD (protein kinase C delta), while another 17% of cases show focal monoallelic deletions/mutations in these genes. Finally, recurrent mutations have been identified in ATM, which have not been found in nodal DLBCL. Several other genes affected have been previously identified in nodal DLBCL, such as biallelic loss of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM30A, B2M and CD58 (11% each), activating mutations of CD79B (28%) and CARD11 (19%) and translocations of BCL6 (22%). Components of the NF-kB pathways were altered in >90% of PNCSL. Pathway analysis also showed an enrichment of networks associated with immune response, proliferation, regulation of apoptosis and lymphocyte differentiation and activation. Finally, we searched for associations between genetic alterations and clinical outcome. We showed that deletions of 6q21 (PRDM1) and 6q23 (TNFAIP3) were both associated with shorter overall survival (p=0.007 and p=0.03, respectively). In summary, we report a genomic background in PCNSL similar to post-GC DLBCL but reinforcing the existence of a subset of abnormalities specific to PCNSL, suggesting their potential relevance in the disease pathogenesis. Additionally, the results obtained from FFPE samples are encouraging and larger archival tissue collections can now be analyzed in order to complement the still fragmented knowledge we have of the genetic basis of the disease. Disclosures: Stewart: Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Patents & Royalties.

Abstract Background: Isolated brain parenchyma relapse as initial site of relapse is a rare complication of NHL and carries a poor prognosis. Few large series focus on treatment characteristics and outcomes of isolated brain parenchyma relapse of NHL. Methods: The IPCG conducted a retrospective review of patient and treatment characteristics and outcomes of this complication. Following initial diagnosis and treatment of NHL (1980–2004), cases with brain parenchyma relapse as initial relapse site, with no evidence of lymphoma elsewhere in the body at the time of brain relapse, were eligible. Cases with brain, spine or leptomeningeal involvement at NHL diagnosis were not eligible. Results: 113 cases were assembled from 13 investigators in 8 countries. Preliminary data summaries are: 94 (83%) cases had diffuse large B-cell NHL, 5 (4%) follicular lymphoma, 3 (3%) Burkitt’s lymphoma, other NHL subtypes (11) . Median age at NHL diagnosis was 61yrs (16–85 yrs). 55% were male. Median ECOG at NHL diagnosis was 1. Median time from NHL diagnosis to isolated brain relapse was 1.8 yrs (3 months–15.9 yrs). 76 (67%) relapsed in brain less than 3 yrs after NHL diagnosis. Symptoms at brain relapse included mental status changes in 37%, gait/balance disturbance (27%), motor/sensory symptoms (23%). Median ECOG at brain relapse was 2. Parenchyma relapse was documented by brain imaging plus biopsy in 54 (48%), or imaging without biopsy in 58 (52%); not reported (1). 53 (48%) cases had one brain lesion; 56 (50%) had two or more lesions; not reported (4). Site of relapse was cerebral hemispheres in 53 (48%) cases, deep brain structures (brain stem/cerebellum) in 30 (27%), cerebral hemispheres and deep brain structures in 23 (21%); not reported (7). At brain relapse, CSF was positive in 11 (10%) cases, negative in 56 (50%); not reported (46[40%]). Treatment for brain relapse was chemotherapy alone in 52 (46%) cases, WBRT alone in 34 (30%), chemotherapy followed by RT in 26 (23%), and brain surgery alone (1). 78 (69%) cases are deceased. Median survival from brain parenchyma relapse to death was 1.6 yrs (95% CI: 11 months–2.6 yrs). Effect of treatment type at brain relapse on survival, will be reported. Brain lymphoma was the cause of death in 49 (63%) cases; CNS toxicity was the cause in 6 (8%) cases. Conclusion: Though a rare relapse site, prospective studies are needed to improve understanding and outcomes of isolated brain parenchyma relapse of NHL.

Abstract Abstract 420 Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that is confined to the CNS because of a poorly understood neurotropism. Most of PCNSL (90%) are part of the immune-privileged site-associated DLBCL (IPDLBCL). IPDLBCL consist in late–germinal center or post–germinal center lymphoid cells but that show very distinct characteristics that separate them from systemic DLBCL. It is still a matter of debate whether the PCNSL differ from nodal DLBCL with respect to molecular features and pathogenesis and also if there is a genomic signature specific of PCNSL. Only few genetic studies have been performed in PCNSL, partly due to the rarity of the tumors and the limited amount of available tissue. To gain insight into the genomic basis of PCNSL, we performed an integrated, high-throughput, genomic analysis in 17 immunocompetent, EBV- and HIV- cases. B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and BCL-6. Either frozen samples or formalin fixed embedded paraffin sections from 17 PCNSL were studied by array-based comparative genomic hybridization (aCGH) using Sureprint G3 (1 million probes) array. Massively parallel whole-exome sequencing was performed in 4 of these cases. Additionally, 2 cases were analyzed by mate-pair whole genome sequencing searching for chromosomal breakpoints. Sanger DNA sequencing was used for validation. All cases were characterized by complex genomic aberrations with a median of 21 copy-number abnormalities (CNA, range 10–49), 4 structural abnormalities, 6 frameshift indels and 99 nonsynonymous exonic mutations. Focal deletion affecting CDKN2A (9p21) was the most common CNA, found in 14 of 17 cases (82%); with 6 of these cases (35%) having homozygous deletion. The second most frequent CNA involved the HLA genes (6p21), found in 11 of 17 (65%) cases; 4 of them (23%) with homozygous deletions. We identified recurrent CNA and mutations in several genes previously found in systemic DLBCL. Thus, PRDM1 (BLIMP1) was deleted or mutated in 47% of cases and the translocation IgH-BCL6 was found in 30% of PCNSL. Furthermore, recurrent mutations were found in NF-kB genes CD79B (75%, 3 of 4 cases analyzed), MYD88 (70%, 7 of 10), TNFAIP3 (50%, 2 of 4) and CARD11 (50%, 2 of 4). Additionally, recurrent abnormalities were found in B2M, BCL7A, CD58, CIITA, ETV6, GNA13, PAX5, TMEM30A and TP53. Nevertheless, we identified several recurrent genetic alterations not described in systemic DLBCL. TOX (a regulator of T-cell development) and TBL1XR1 (a negative regulator of the NF-kB and Wnt pathways) were either deleted or mutated in 30% of PNCSL, something not previously described in systemic DLBCL. Additionally, chromosomal breakpoints either in DLGAP1 or DLGAP2 (play a role in neuronal cell signaling) were found in 18% of PCNSL but not in systemic DLBCL. Moreover, mutations in ATM (master controller of cell cycle checkpoint), BAI3 (inhibitor of brain angiogenesis), BTG2 (cell cycle arrest), KDM6B (histone demethylase), PKC family members PRKCD/PRKCDE, genes from the histone cluster, the protocadherin family and the WD repeat domain were found in 10% to 50% of PCNSL. Pathway analysis including the most commonly affected genes in PCNSL showed an enrichment of networks associated with immune response, NF-kB pathway, proliferation, regulation of the apoptosis and lymphocyte differentiation and activation. In summary, we show evidence of a highly complex genome and identified a subset of genes with potential relevance in PCNSL pathogenesis. The genomic profile described here reinforces the existence of a specific molecular signature in PCNSL, thus helping to genetically differentiate this entity from the nodal DLBCL and related lymphomas. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

BackgroundSrc signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab‐induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM.MethodsAfter the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14‐day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14‐day cycle. The primary endpoint was 6‐month progression‐free survival (PFS6).ResultsIn the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%‐40.0%] vs 18.4% [95% CI, 7.7%‐34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome.ConclusionsDespite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.

PURPOSE Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.

PURPOSE The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. RECOMMENDATIONS Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .