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Novel targeted therapeutics alone or in rational combinations are likely to dominate the future management of various hematological neoplasms. However, the challenges currently faced are the molecular heterogeneity in driver lesions and genetic plasticity leading to multiple resistance pathways. Thus, progress has overall been gradual. For example, despite the advent of targeted agents against actionable drivers like FLT3 in acute myeloid leukemia (AML), the prognosis remains suboptimal in newly diagnosed and dismal in the relapsed/refractory (R/R) setting, due to other molecular abnormalities contributing to inherent and acquired treatment resistance. Nuclear export inhibitors are of keen interest because they can inhibit several active tumorigenic processes simultaneously and also synergize with other targeted drugs and chemotherapy. XPO1 (or CRM1, chromosome maintenance region 1) is one of the most studied exportins involved in transporting critical cargoes, including tumor suppressor proteins like p27, p53, and RB1. Apart from the TSP cargo transport and its role in drug resistance, XPO1 inhibition results in retention of master transcription factors essential for cell differentiation, cell survival, and autophagy, rendering cells more susceptible to the effects of other antineoplastic agents, including targeted therapies. This review will dissect the role of XPO1 inhibition in hematological neoplasms, focusing on mechanistic insights gleaned mainly from work with SINE compounds. Future potential combinatorial strategies will be discussed.

Background The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. Methods In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. Results Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). Conclusions Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.

Simple Summary Non-Hodgkin’s lymphomas (NHL) are cancers of the white blood cells. While some NHL subtypes, such as Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), grow and spread aggressively, others, like follicular lymphoma (FL), are indolent in nature. Irrespective of how fast they grow, all NHL subtypes can spread to other organs in the body if not treated. In this study, we have demonstrated that the targeted inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) in different NHL subtypes by a novel, orally bioavailable, dual inhibitor KPT-9274 can lead to energy depletion, inhibition of cell proliferation, and ultimately apoptosis. KPT-9274 treatment shows potent anti-tumor effects in DLBCL and MCL subcutaneous xenograft models and enhances mice survival in a systemic FL model. Therefore, this study demonstrates the potential of targeting PAK4 and NAMPT by a small molecule inhibitor KPT-9274 for NHL therapy. Abstract Diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma (FL), and mantle cell lymphoma (MCL) are aggressive non-Hodgkin’s lymphomas (NHL). Cure rates are suboptimal and novel treatment strategies are needed to improve outcomes. Here, we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) is critical for lymphoma subsistence. Dual targeting of PAK4-NAMPT by the Phase I small molecule KPT-9274 suppressed cell proliferation in DLBCL, FL, and MCL. Growth inhibition was concurrent with apoptosis induction alongside activation of pro-apoptotic proteins and reduced pro-survival markers. We observed NAD suppression, ATP reduction, and consequent cellular metabolic collapse in lymphoma cells due to KPT-9274 treatment. KPT-9274 in combination with standard-of-care chemotherapeutics led to superior inhibition of cell proliferation. In vivo, KPT-9274 could markedly suppress the growth of WSU-DLCL2 (DLBCL), Z-138, and JeKo-1 (MCL) sub-cutaneous xenografts, and a remarkable increase in host life span was shown, with a 50% cure of a systemic WSU-FSCCL (FL) model. Residual tumor analysis confirmed a reduction in total and phosphorylated PAK4 and activation of the pro-apoptotic cascade. This study, using various preclinical experimental models, demonstrates the therapeutic potential of targeting PAK4-NAMPT in DLBCL, FL, and MCL. The orally bioavailable, safe, and efficacious PAK4-NAMPT dual inhibitor KPT-9274 warrants further clinical investigation.

Although mechanistic studies clarifying the molecular underpinnings of AML have facilitated the development of several novel targeted therapeutics, most AML patients still relapse. Thus, overcoming the inherent and acquired resistance to current therapies remains an unsolved clinical problem. While current diagnostic modalities are primarily defined by gross morphology, cytogenetics, and to an extent, by deep targeted gene sequencing, there is an ongoing demand to identify newer diagnostic, therapeutic and prognostic biomarkers for AML. Recent interest in exploring the role of circular RNA (circRNA) in elucidating AML biology and therapy resistance has been promising. This review discerns the circular RNAs’ evolving role on the same scientific premise and attempts to identify its potential in managing AML.

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization dependent inactivation of critical cellular proteins. Earlier we showed that over-expression of the nuclear export protein exportin 1 (XPO1) is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that the selective inhibitor of nuclear export (SINE) compound selinexor and the second generation SINE eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with three different PARP inhibitors (PARPi) namely olaparib, veliparib and rucaparib in a mCRPC model. Growth inhibition was determined by MTT assay. Drug synergy analysis was done and the isobolograms were generated from Calcusyn 2.1 software (Biosoft, Cambridge, UK). Other techniques include: colony formation assay, apoptosis determination by flow cytometry (annexin V-propidium iodide), real time RT-qPCR (SYBR green I), western blotting, immunofluorescence etc. For the determination of band density, NIH ImageJ 1.5Oi software was utilized. KPT-8602 synergized with all three studied PARPi (CI Taken together, this study revealed the therapeutic potential of a novel combination including second generation SINE compound KPT-8602 and PARP inhibitors for the growth inhibition of mCRPC cells. Pre-clinical xenograft studies testing the efficacy of SINE-PARPi as well as a phase II clinical study combining KPT-8602-PARPi is planned. Citation Format: Md. Hafiz Uddin, Yiwei Li, Amro Aboukameel, Husain Y. Khan, Vijendra Singh, Shriya Reddy, Suresh Kumar Balasubramanian, Yosef Landesman, Trinayan Kashyap, Elisabeth I. Heath, Asfar S. Azmi. Nuclear export inhibitor KPT-8602 synergize with PARP inhibitors in castration resistant metastatic prostate cancer [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 1091.

Somatic mutations of the CUT-like homeobox 1 ( CUX1 ) gene ( CUX1 MT ) can be found in myeloid neoplasms (MNs), in particular, in myelodysplastic syndromes (MDSs). The CUX1 locus is also deleted in 3 of 4 MN cases with −7/del(7q). A cohort of 1480 MN patients was used to characterize clinical features and clonal hierarchy associated with CUX1 MT and CUX1 deletions ( CUX1 DEL ) and to analyze their functional consequences in vitro. CUX1 MT were present in 4% of chronic MNs. CUX1 DEL were preferentially found in advanced cases (6%). Most MDS and acute myeloid leukemia (AML) patients with −7/del(7q) and up to 15% of MDS patients and 5% of AML patients diploid for the CUX1 locus exhibited downmodulated CUX1 expression. In 75% of mutant cases, CUX1 MT were heterozygous, whereas microdeletions and homozygous and compound-heterozygous mutations were less common. CUX MT/DEL were associated with worse survival compared with CUX1 WT . Within the clonal hierarchy, 1 of 3 CUX1 MT served as founder events often followed by secondary BCOR and ASXL1 subclonal hits, whereas TET2 was the most common ancestral lesion, followed by subclonal CUX1 MT . Comet assay of patients’ bone marrow progenitor cells and leukemic cell lines performed in various experimental conditions revealed that frameshift mutations, hemizygous deletions, or experimental CUX1 knockdown decrease the repair of oxidized bases. These functional findings may explain why samples with either CUX1 MT or low CUX1 expression coincided with significantly higher numbers of somatic hits by whole-exome sequencing. Our findings implicate the DNA repair dysfunction resulting from CUX1 lesions in the pathogenesis of MNs, in which they lead to a mutator phenotype.

Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).

Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36–59%) and 58% (95% CI: 45–69%), respectively. The cumulative incidence of GIII–IV aGVHD at 3 months was 9.9% (95% CI: 5.0–16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7–45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5–89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8–75.4%]) prior to alloHCT (p = 0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL.

The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the “real-world” setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD−). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD− at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest “real-world” experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study.

Background Inotuzumab ozogamicin (InO) is an anti-CD22 monoclonal antibody–drug (calicheamicin) conjugate that has shown superior efficacy compared to conventional chemotherapy in relapsed/refractory (RR) B-cell acute lymphocytic leukemia (ALL) patients. We sought to find the safety and efficacy of InO in a real-world setting. Patients and Methods A multicenter cohort analysis on 84 RR ALL patients who received InO outside of clinical trials was conducted to evaluate response and toxicity. Results The median (range) age of patients at InO initiation was 50 (20-87) years. Forty patients (48%) had ≥ 3 therapies and 23 patients (27%) underwent allogeneic hematopoietic stem-cell transplantation (allo-HCT) before InO. The median (range) number of cycles of InO provided was 2 (1-6), and cumulative dose was 3.3 (1.8-9.3) mg/m2. Overall response rate (complete remission/complete remission with incomplete count recovery) was 63%; 44% had complete remission with minimal residual disease negativity. Twenty-three patients (27%) with response received allo-HCT. The median duration of response was 11.5 months and when censored at allo-HCT was not reached (51% in remission at 2 years). The median overall survival after InO was 11.6 months and when censored at time of allo-HCT was 13.6 months. The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), veno-occlusive disease (2%), and hyperglycemia (2%). In multivariate analysis, allo-HCT after InO did not retain favorable significance for duration of response (hazard ratio = 1.27; 95% confidence interval, 0.89-1.61; P = .2) or overall survival (hazard ratio = 1.10; 95% confidence interval, 0.37-3.25; P = .85). Conclusion InO was well tolerated and had significant efficacy in RR B-cell ALL patients.

Pure red cell aplasia is an orphan disease, and as such lacks rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-cell large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In each of the aforementioned, the pathogenetic mechanisms may involve autoreactive cytotoxic responses. We selected 62 uniformly diagnosed pure red cell aplasia patients and analyzed their pathophysiologic features and responsiveness to rationally applied first-line and salvage therapies in order to propose diagnostic and therapeutic algorithms that may be helpful in guiding the management of prospective patients, 52% of whom were idiopathic, while the others involved large granular lymphocytic leukemia, thymoma, and B-cell dyscrasia. T-cell-mediated responses ranged between a continuum from polyclonal to monoclonal (as seen in large granular lymphocytic leukemia). During a median observation period of 40 months, patients received a median of two different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall response rate of 76% (53/70). Oral cyclophosphamide showed activity, albeit lower than that produced by cyclosporine. Intravenous immunoglobulins were effective both in parvovirus patients and in hypogammaglobulinemia cases. In salvage settings, alemtuzumab is active, particularly in large granular lymphocytic leukemia-associated cases. Other potentially useful salvage options include rituximab, anti-thymocyte globulin and bortezomib. The workup of acquired pure red cell aplasia should include investigations of common pathological associations. Most effective therapies are directed against T-cell-mediated immunity, and therapeutic choices need to account for associated conditions that may help in choosing alternative salvage agents, such as intravenous immunoglobulin, alemtuzumab and bortezomib.

Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS.

Background: Acute myeloid leukemia (AML) is frequently characterized by mutations in FMS-like tyrosine kinase 3 (FLT3). FLT3 is mutated in one-third of de novo AML patients and recurrent in relapsed/refractory (R/R) AML. More frequent FLT3 internal tandem duplications (ITD) and less frequent tyrosine kinase domain (TKD) point mutations are prognostically important in AML and are associated with an inferior outcome. Although targeted therapy with FLT3 inhibitors improves prognosis in FLT3 mutated AML patients, there is a lack of evidence regarding the superiority of efficacy of various FLT3 inhibitors in clinical practice and the therapeutic pipeline. Broadly grouped as type 1 (targets ITD and TKD, e.g., midostaurin) and type 2 (targets only ITD, e.g., quizartinib) inhibitors, there is no consolidated summary of the difference in efficacy between these two classes of FLT3 inhibitors in R/R AML and high-risk myelodysplastic syndrome (HR-MDS). Hence, we conducted a systematic review and meta-analysis of various type 1 and 2 FLT3 inhibitors tested in clinical trials to compare their clinical effectiveness in treating R/R AML and HR-MDS. Methods: PubMed and EMBASE databases were searched for clinical trials published between 1/1/2000 and 5/26/2021 using a combination of keywords and subject headings related to FLT3 inhibitors and AML. Two independent reviewers screened titles/abstracts and full texts, with a third reviewer resolving conflicts. Studies were included if they were (1) full-length published journal articles that (2) reported the results of single-arm or double-arm phase I/II/III clinical trials in patients with R/R AML or HR-MDS. Outcomes of interest were composite response rate (CRc=complete response + complete response with incomplete count recovery) and overall response rate (ORR). Results: Record screening resulted in the initial inclusion of 30 studies for qualitative analysis (Fig. 1). Due to poor representation of R/R AML patients and post-transplant FLT3 inhibitor outcomes, two studies were excluded from quantitative analysis, leaving 28 studies for the final analysis. The studies had a total of 1927 R/R AML and HR-MDS patients with a median age of 61.5 years (range, 13-91) and a median of three (range, 0-10) prior lines of treatment. Giltertinib (n=3 studies) was the most frequently studied type 1 inhibitor, and quizartinib (n=6) and sorafenib (n=5) were the most frequently studied type 2 inhibitors. Heterogeneity testing using Cochran's Q test and I 2 values showed the presence of heterogeneity for both CRc (p Conclusion: Both type 1 and 2 inhibitors are effective as monotherapy in R/R AML and HR-MDS patients. Though not statistically significant, better ORR for type 2 than for type 1 inhibitors in the R/R setting provides a background to explore the biological heterogeneity of response and preferential sensitivity to ITD-targeted therapy alone rather than the dual inhibitor. More prospective randomized study designs comparing type 1 and 2 inhibitors in the R/R and de novo setting are needed. Figure 1 Figure 1. Disclosures Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy; Novartis: Consultancy. Balasubramanian: Servier Pharmaceuticals: Research Funding.

Background: Mutations in FMS like tyrosine kinase gene 3 (FLT3) are the most common genetic aberrations in acute myeloid leukemia (AML). Internal tandem duplications (ITD) are the most frequent FLT3 mutations, occurring in 20-30% of patients (pts) with newly diagnosed AML, and a minority are tyrosine kinase domain mutations. FLT3 mutation confers adverse prognosis in pts treated with standard chemotherapy (chemo) alone, and relapse risk is also higher compared to FLT3-wild type AML (HR-1.75). Studies of FLT3 inhibitors as monotherapy or in combination with chemo in the treatment of pts with FLT3-ITD relapsed/refractory (R/R) AML are associated with mixed results. No evidence synthesis has yet focused on the effect of FLT3 inhibitor alone in the treatment of R/R AML and high-risk myelodysplastic syndrome (HR-MDS). Hence, we analyzed the efficacy of various FLT3 inhibitors from different clinical trials used as monotherapy to treat pts with R/R AML and HR-MDS. Methods: We conducted a systematic review and meta-analysis of clinical trials of FLT3 inhibitors for pts with R/R AML and HR-MDS. We searched EMBASE and PubMed for clinical trials published between 1/1/2000 and 5/26/2021 using a combination of keywords and subject headings related to FLT3 inhibitors and AML. Titles/abstracts and full texts were screened by two independent reviewers, with conflicts arbitrated by a third reviewer. Studies were included if they were (1) full-length published journal articles that (2) reported the results of single-arm or double-arm phase I/II/III clinical R/R AML or HR-MDS. Outcomes of interest were composite response rate (CRc=complete response + complete response with incomplete count recovery) and overall response rate (ORR). Results: Thirty studies were included after the application of inclusion criteria (Figure 1). Two were excluded due to inadequate representation of pts with R/R AML and outcomes reported for stem cell transplant following FLT3 inhibitor use, respectively. Hence, 28 studies were included in the meta-analysis, with a total of 1927 pts. Quizartinib and sorafenib were the most frequently studied inhibitors (6 and 5 studies, respectively, Table 1). Heterogeneity testing was performed using Cochran's Q test and I 2 values. The Cochran's Q test p-value was less than 0.10 (p Conclusion: Most FLT3 inhibitors are effective as monotherapy for the treatment of pts with FLT3-mutated-R/R AML. Pooled response rates are notably higher in studies involving second-generation FLT3 inhibitors, particularly quizartinib and gilteritinib. Though not conclusive, the efficacy spectrum of various FLT3 inhibitors in the R/R setting could help design future studies and guide appropriate treatment selection; however, further validation is needed. Prospective clinical trials are required to compare the effectiveness of newer generation FLT3 inhibitors in pts with FLT3-mutated-R/R AML. Figure 1 Figure 1. Disclosures Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy. Balasubramanian: Servier Pharmaceuticals: Research Funding.

Somatic and germline (GL) variants of CSF3R are found in myeloid neoplasia (MN) and severe congenital neutropenia (SCN). In particular, somatic gain-of-function mutations in the juxtamembrane region of the receptor occur in chronic neutrophilic leukemia (CNL) or secondary AML. Another hotspot for somatic nonsense variants frequently mutated in these categories of pts involves the intracellular domain which regulates inhibitory growth pathways. We hypothesized that the somatic CSF3R variants could reveal previously unrecognized GL SCN mutations. When we studied a cohort of 2,610 pts with MN, we identified a total of 68 CSF3R variants (CSF3RMT). Using a bioanalytic pipeline, we assigned pathogenicity and type of origin (somatic vs. GL) to these variants, particularly those not previously described. In total, we found 32 GL (CSF3RGL) and 36 somatic (CSF3RS) mutations. Of the GL variants, 4 were previously described in pts with SCN consistent with heterozygous loss of function of the CSF3R gene. However, 15 additional alterations were located in similar regions and were predicted to be pathogenic while 13 variants were previously never described. Most of the CSF3RGL mutations were identified in pts with AML and MDS (88%). Interestingly, 2 (6%) pts had co-existing idiopathic neutropenia that progressed to secondary MDS. Another pt had aplastic anemia that eventually progressed to secondary AML. CSF3RGL were most often located in either the intracellular domain (44%) or the extracellular domain (34%) while none of the CSF3RGL mutations were found in the juxtamembrane region (Fig1). AML was detected in 21% of the pts with a CSF3RGL intracellular domain mutation and 18% of the pts with extracellular domain mutations. Of the germline missense variants, E808K (28%), R698C (9%), and E149D (9%) were the most frequently detected. Among the pts with E808K, 22% developed AML. The previously non-reported variants were detected in either the intracellular (50%) or the extracellular domain (50%). Missense variants were detected in 9/10 of the novel mutations in the following locations: L723V (20%), R428K (10%), G731R (10%), V406fs (10%), G687S (10%), P682H (10%), T154I (10%), and S413L (10%). One truncating mutation was found (c.1865-6delC) and it was located in intron 14 and has unknown impact on CSF3R function. Complex karyotype was noted in 19 % of the cases with CSF3RGL. DNMT3A (19%), NRAS (13%), FLT3 (9%), and BCOR (9%), were the most commonly found co-mutations. CSF3R S mutations were all heterozygous and found in 18 pts with AML and 18 pts with MDS and other MN. Overall, these lesions mapped within the intracellular proximal and distal domains (53%), the extracellular domain (14%) the juxtamembrane domain (25%), and the transmembrane domain (8%). Of note, MDS/MPN pts with CSF3RS mutations (11%) had lesions distributed between the intracellular, juxtamembrane and extracellular domains while none of the AML pts had mutations in the extracellular domain. Of all mutations, 36% were truncating events previously described in the context of post SCN AML while 61% were missense mutations. T618I was the most frequent CSF3RS detected (25%), followed by Q749X (11%), Q741X (9%), Q743X (6%). Juxtamembrane hits (CNL-like lesion) were all in the same canonical region (T618I). In contrast, somatic hits otherwise typical for post SCN AML were found in 33% of CSF3RS alterations and included the following: Q749X(4), Q741X (3), Q739X (2), S742X, Q743X, and E405K (not typical for post SCN AML). Taken together the combined allelic burden of these variants did not exceed that of general population (OR: 0.9503) suggesting that they are not significant risk alleles. Of note is that none of these variants were found to be in biallelic (somatic/GL) configurations. Complex karyotype was found in 19% of the pts with CSF3RS followed by del7q in 13% of cases. Importantly, an antecedent history of neutropenia was noted only in 14% of the pts carrying CSF3RS. Regarding associated mutations, ASXL1 (43%), RUNX1 (23%), SETBP1 (23%), TET2 (23%), DNMT3A (17%), SRSF2 (16%), EZH2 (14%), IDH2 (11%), and NRAS (11%) were the most common co-mutations. We have investigated CSF3RS mutations for the presence of GL alterations, but compound heterozygous configurations were not identified. We concluded that CSF3R mutations typically associated with SCN transformation to myeloid neoplasia can occur without GL variants associated with this defect. Figure 1 Figure 1. Disclosures Balasubramanian: Servier Pharmaceuticals: Research Funding. Patel: Apellis: Consultancy, Other: educational talks, Speakers Bureau; Alexion: Consultancy, Other: educational talks, Speakers Bureau. Advani: Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; OBI: Research Funding; Immunogen: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding. Carraway: AbbVie: Other: Independent review committee; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Other: Independent review committee; Astex: Other: Independent review committee; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Maciejewski: Novartis: Consultancy; Regeneron: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy.

Aggressive non-Hodgkin's lymphomas (NHLs) [diffuse large b-cell lymphoma (DLBCL), grade 3b follicular lymphoma, and mantle cell lymphoma (MCL)] have dismal cure rates, especially in the relapsed/refractory setting, substantiating the need for novel treatment strategies to improve outcomes. Here we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT) are essential for lymphoma subsistence and dual-targeting PAK4-NAMPT by the small molecule inhibitor KPT-9274 (orally bioavailable phase 1 compound), previously shown to be cancer cell-selective, acts by energy depletion, inhibiting cell proliferation and eventual apoptosis as a reasonable treatment strategy for aggressive NHLs. To demonstrate PAK4-NAMPT is essential for lymphoma survival, we showed increased PAK4 expression in primary NHL tissue (n=94) than in normal lymph nodes (n=8) (Fig1A). Lymphoma cell lines were sensitive to the PAK4/NAMPT dual inhibitor KPT-9274 (induced apoptosis with an EC 50 of 95.17 nM in WSU-DLCL2 and 13.9 nM in WSU-FSCCL cells). Similar results were obtained with positive controls PAK4 [PF-3578309] and NAMPT specific inhibitors [FK-866]. RT-PCR confirmed PAK4 and NAMPT down-expression in KPT-9274 treated WSU-FSCCL cells. Western blot of WSU-DLCL2 and WSU-FSCCL cells treated with KPT-9274 showed significant reductions in BCL-2 and enhanced cleaved-Caspase-3 and cleaved-PARP expression. We then assessed the impact of KPT-9274 on the cellular ATP and NAD pool since NAMPT inhibition can suppress both and induce cell death. NAD/NADH and ATP levels decreased in both cell lines [WSU-DLCL2 & WSU-FSCCL], with increasing KPT-9274 concentrations (Fig.1B&1C). We then showed KPT-9274 to synergize with the standard of care chemotherapy cyclophosphamide, vincristine, and adriamycin used for NHL management (decreased IC25 and IC50 in several combination treatments). In lymphoma xenografts, mice with transplanted WSU-DLCL2 fragments showed ~50% reduction in tumor volume (p 150-day increase in host life span compared to control and 3/6 mice were cured) (Fig.1F). After day 150, the remaining mice were dissected to confirm cures. Blood smears drawn from mice post three weeks of KPT-9274 treatment showed a significant reduction of circulating WSU-FSCCL cells validating its efficacy systemically (Fig.1G). Since exogenous niacin can regenerate NAD regulated by NAMPT in a rate-limiting step, the impact of niacin co-dosing with KPT-9274 was evaluated on tumor growth using the Z-138 MCL tumor xenograft model in nude mice. Tumor-bearing mice were treated with vehicle, KPT-9274 (200 mg/kg BID), niacin (30 mg/kg), or a combination of KPT-9274/niacin. All groups that received KPT-9274 treatment showed reductions in tumor size, while the vehicle control and niacin alone groups showed a rapid increase in tumor volume. Both KPT-9274 and combo groups showed a significant decrease in tumor growth compared to control (p=0.0002); however, there were no statistically significant differences between the KPT-9274 and the KPT-9274/niacin combo (Fig.1H). Similarly, in another MCL xenograft model, KPT-9274 resulted in a statistically significant reduction in JeKo-1 tumors compared to control (p = 0.0059). Niacin did not affect the tumor growth suppression induced by KPT-9274 treatment. No animals died in this study. Thus, supplementing niacin with KPT-9274 may alleviate the adverse effect without compromising the efficacy of the treatment. Also, KPT-9274 treated Z-138 residual tumors showed a reduction in PAK4, GEF-H1, paxillin, vinculin, cyclin D1, Dvl2, and Ki67 and enhancement in apoptosis by IHC staining (Fig.1I). The anti-tumor potential of KPT-9274 ± niacin in several aggressive lymphoma models strongly supports its efficacy in this setting. It strengthens our phase I study design to evaluate safety and tolerability and anti-tumor activity in patients with advanced solid malignancies or NHL (NCT02702492). Figure 1 Figure 1. Disclosures Balasubramanian: Servier Pharmaceuticals: Research Funding. Zonder: Caelum Biosciences: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Amgen: Consultancy; Alnylam: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Intellia: Consultancy. Senapedis: Karyopharm Therapeutics: Ended employment in the past 24 months, Patents & Royalties; Omega Therapeutics: Current Employment; Restorbio: Other: Personal fees. Baloglu: Karyopharm Therapeutics: Current Employment, Other: Personal fees. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Landesman: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Azmi: Karyopharm Therapeutics: Research Funding.

The gold standard for the diagnosis of MDS relies on morphologic alterations hampered by a great deal of subjectivity. Cytogenetic and clinical features allow for clinical classifications predictive of survival. However, with a few exceptions (SF3B1MT, del5q, and certain balanced translocations), neither classic histo-morphology nor prognostic scoring systems (e.g., IPSS-R) are reflective of pathogenic underpinnings. To date supervised analyses of mutational data did not succeed to produce profiles specific or predictive of traditional disease sub-entities. Large cohorts with clinical annotation and a sufficient follow-up allow for innovative biostatistical approaches to subgroup patients according to molecular profiles. Objective operator-independent subcategorization may be congruent with common pathogenic links, rational applications of targeted therapeutics and better prognostications. We hypothesized that machine-learning (ML) strategies used for analysis of mutational/cytogenetic profiles will enable recognition of invariant disease subcategories according to their molecular configurations. Herein, we compiled a meta-analytic database (our cohorts and publicly available sources) of 3,011 MDS (median age 71yrs) and 6,788 pAML/sAML. Results of deep targeted sequencing of a panel of 55 myeloid mutations were collected together with cytogenetics. We then performed unsupervised analysis of MDS and AML patients using Bayesian Latent Class Analysis (BLCA). A consensus matrix was then clustered using Ward's criteria to generate final cluster assignment based on the highest silhouette value. To identify genomic signatures, we used Random Forest classification and extracted mutations with highest global importance indicated by mean decrease in accuracy. Using BLCA we identified 5 unique genomic clusters (GCs) with 3 distinct prognostic outcomes [low risk (LR), intermediate risk (Int), and high risk (HR)] that were validated by survival analysis (Fig.1A,B). The LR group included GC-1 and was characterized by the highest prevalence of normal cytogenetics (100%) and SF3B1 MT (25%) with co-occurring DNMT3A MT (14%), and absence of ASXL1 MT, ETV6 MT, STAG2 MT, TP53 MT, and complex/abnormal cytogenetics. Int group included GC-2 and GC-4. GC-2 was characterized by a higher percentage of abnormal cytogenetics cases than LR group and absence of STAG2 MT, SRSF2 MT, ASXL1 MT, TP53 MT, and normal/complex cytogenetics. GC-4 had the highest frequency of SRSF2 MT (52%) with co-occurring ASXL1 MT (59%), TET2 MT (40%), normal karyotype, and absence of complex/abnormal cytogenetics. Finally, HR included GC-3 and GC-5. GC-3 included ASXL1 MT (67%) with co-occurring SRSF2 MT (47%), TET2 MT (37%), STAG2 MT (22%), and absence of normal cytogenetics. GC- 5 had the highest frequency of -5/del(5q) (50%), -7/del(7q) (43%), -17/del(17p) (16%) and the highest odds of complex karyotype (92%) as well as TP53 MT (48%). Paralleling the genomic ML-based clustering, the clinical relevance of these subgroups was reflected in significantly different survivals [median (95% CI)]: i) GC-1 [69 (59-80)], ii) GC-2 [35 (29-41)], iii) GC-3 [12 (10-16)], GC-4 [27 (22-34)], and GC-5 [9 (7-11)] months (Fig.1C). We then classified the MDS cohort according to the recently published and validated AML GCs (Awada et al Blood 2021) to investigate overlapping genomic features. Overall, 90% of MDS GC-1 and 67% of MDS GC-2 had the same molecular architecture of AML GC-2 and 70% of MDS GC-5 had the same molecular features of AML GC-4. In addition, 98% of MDS GC-3 and 92% of MDS GC-4 had the same features of AML GC-3 (Fig.1D). In sum, we propose a novel objective molecular classification of MDS and related diseases that allows subgrouping of patients according to shared pathogenesis for a better prognostic resolution without errors derived from subjectivity. The model was then internally and externally validated using a cohort of 200 cases. Results of a validation cohort and online URL site of molecular clustering will be presented at the meeting. Figure 1 Figure 1. Disclosures Balasubramanian: Servier Pharmaceuticals: Research Funding. Patel: Alexion: Consultancy, Other: educational talks, Speakers Bureau; Apellis: Consultancy, Other: educational talks, Speakers Bureau. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astex: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

While the clinical impact and the mechanistic contribution of TP53 mutations have been a subject of intense research, many questions about its role in myeloid neoplasia (MN) remain unanswered. Previous molecular studies have confirmed the assertion that biallelic inactivation confers less favorable prognosis as opposed to monoallelic hits. These evidences agree with the observation that carriers of Li-Fraumeni syndrome do not always exhibit a complete penetrance of the recessive TP53 lesion. Thus, the presence of a residual function of TP53 appears to be somehow protective until it is offset by additional damage of contralateral allele or compound heterozygous hits in synergistic pro-leukemogenic pathways. TP53 can be affected by lesions of diverse configurations (e.g. biallelic, homo/hemizygous) targeting different locations [missense mutation (ms) in various hotspots vs truncations], and their assessment in terms of clinical consequences is complex. Only large cohorts of patients allow to discern the often discrete nuances of TP53 effects in individual inactivation patterns. We have compiled molecular and clinical data of a meta-analytic cohort (CCF and public datasets) of 1,011 patients with TP53 alterations, along with 3,419 cases found to be TP53 wild type (WT). A total of 1,258 TP53 mutations/deletions were found, 66% classified as biallelic and 37% as monoallelic hits (including single deletions). We investigated the closest hotspot ms mutations, hypothesizing that lesions mapping sequences in proximity will have the same phenotypic impact. Next, we arranged ms mutations into 6 main sites with each one containing lesions mapping within 5 amino acidic positions from the canonical hotspot location. These sites were mutated in 58% of patients with presence of truncating hits in 27% of cases. When ms mutation sites were compared to each other, a less dismal survival was observed for only the R175H hotspot (p .03). Most hotspots are known to exhibit dominant-negative effects (likely due to tetramer protein configurations) and thus, inhibit >50% of the TP53 activity as opposed to truncations which should inactivate ~50%. Consequently, one would expect that hotspot mutations produce a more aggressive phenotype. However, patients with ms hits had similar survival as those with truncating mutations (p=.6), likely because truncations were more often biallelic than ms mutation (81% vs 65%, p=.006). Indeed, we can stipulate that the strength (functional impairment) conveyed by a mutation will inversely correlate with the propensity to acquire biallelic hits. Therefore, we hypothesized that truncations (inactivating less TP53) would require an additional hit if compared to the stronger dominant-negative ms lesions. Notably, double hits were identified in 81% of cases carrying truncating mutations vs. 66% in those with ms canonical sites mutations (p Carriers of biallelic mutations had worse prognosis than those with monoallelic hits in adjusted multivariate analysis (HR 2.2 95% CI 1.8-2.7 p When focusing on the accompanying genomic landscape of our cohort, we found that 45% of cases had TP53 mutations as the sole molecular lesion vs 55% of patients who also harbored co-occurring somatic events. In particular, complex karyotype was more frequent among patients without co-occurring mutations (79% vs 57%, p In summary, our study demonstrates the complexity of assigning a correct clinical impact to TP53 mutations, which are characterized by a high degree of genomic heterogeneity. In addition to the genetic context, TP53 role may also vary in different subtypes of MN (e.g., AML vs MDS) shaping in a different fashion individual patients' trajectories. Disclosures Balasubramanian: Servier Pharmaceuticals: Research Funding. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Carraway: Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Takeda: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee. Maciejewski: Novartis: Consultancy; Regeneron: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy.

Extramedullary deposits of leukemic blasts, also often called myeloid sarcoma (MS), constitute an unusual presentation of AML, which can occur in isolation (IMS, often in the de novo setting) or in the context of a fully-blown leukemic process (LMS) either at diagnosis or relapse. This peculiar variant of an acute leukemia may be due to distinct phenotypic features promoting homing of blasts to non-hematopoietic locations or/and be a result of specific molecular lesions (perhaps related to a specific genotype). So far, systematic studies of these phenomenon have been scarce with the largest cohorts reporting on 70 pts and less over the last decade. By applying machine learning (ML) to perform latent class analysis of molecular features in AML patients (n=6,788), we have identified and validated 4 molecular clusters characterized by distinct clinical phenotypes (Awada et al Blood 2021). Genomic cluster-1 (GC-1) was characterized by predominantly normal karyotype and NPM1 MT that co-occurred with DNMT3A MT and FLT3 ITD, and IDH2 R140. In GC-2 mostly abnormal karyotype was present with CEBPA Bi, and IDH2 R172K, FLT3 ITD/TKD and lack of NPM1 MT. GC-3 had highest frequency of ASXL1 MT, BCORL1 MT, and DNMT3A MTalong with splicing factor mutations. Finally, GC-4 had the highest percentage of complex karyotype and TP53 MT. We observed a significant difference in survival [medians, months] across the molecularly-defined subgroups: GC-1 [34.1]; GC-2 [26.5]; GC-3 [15.8]; and GC-4 [9.2]. However, the genomic clustering (GCs 1-4) did not favor pAML over sAML (progressed from previous myeloid disorders). These unbiased molecular features were then compared to those found in 91 MS pts (median age 64 years) to discern their possible origins from specific genomic AML clusters vs. an as yet described unique MS genomic signature. Among the 91 pts, 19% of them were IMS while 81% were LMS (of which 43% were de novo vs. 57% refractory/relapsed). Soft tissue (32%), skin (22%), lymph nodes (13%), and gastrointestinal tract (13%) were the most common extramedullary sites involved. An involvement of more than two sites was observed in 15 (16.5%) cases. MS-specific phenotypic features were explored based on immunohistochemical (IHC) stains and flow cytometry studies. MS neoplastic cells showed reactivity with CD43 (54% of cases), muramidase/lysozyme (53%), CD117 (39%), myeloperoxidase (35%), CD33 (32%), CD45 (30%), and CD34 (30%). Flow cytometry of the LMS cases demonstrated that 90% of patients expressed surface CD13, CD33, CD45, and HLA-DR while positivity for CD38 was present in 83% of cases, and CD117 and CD34 in 60%. By comparison to our AML cohort, MS patients had a significant higher median age at the time of diagnosis (64 vs. 62 years p=0.041) and leukocyte counts (WBC 7k vs. 4k/uL, p=0.002), higher percentage of sAML (67% vs. 40% p Disclosures Balasubramanian: Servier Pharmaceuticals: Research Funding. Patel: Apellis: Consultancy, Other: educational talks, Speakers Bureau; Alexion: Consultancy, Other: educational talks, Speakers Bureau. Mukherjee: McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Acceleron: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Genentech: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria; BioPharm: Consultancy; Jazz Pharmaceuticals: Research Funding. Advani: Macrogenics: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Research Funding; OBI: Research Funding; Abbvie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.

Structural and functional variability of human leukocyte antigen (HLA) is the foundation for competent anti-tumor and infectious adaptive immune responses. HLA genomic heterogeneity enables the presentation of a broad immune-peptidome, sustaining an efficient diversification of T cell receptor repertoires (TCR). 1,2,3 Any perturbation impacting this diversity may be at the basis of pathological processes, hampering antigen presentation capabilities and T-cell reactivity. In allogeneic hematopoietic cell transplantation (allo-HCT) setting, the graft versus leukemia (GvL) effect should ensure disease control allowing the recognition of recipient neoantigen burden by donor T-cell effectors. However, the molecular dissection of graft versus host responses (GvH) remains elusive. Herein, by means of a broad immunogenetic study of a cohort of patients with myeloid malignancies who received a donor matched allo-HCT, we investigated how dysfunction of HLA variability could have an impact on alloreactive responses, ultimately hindering disease control. To that end, we combined NGS-based HLA genotyping and TCR-beta sequencing to molecularly characterize the HLA region in terms of locus-specific divergence and somatic mutational profile, and dissect features and clonotypic spectra of TCR repertoires. We first hypothesized that more diverse HLA genotypes could better present leukemic neoantigen burden than less diverse complexes, enhancing the GvL effect. Hence, we performed a matched-pair analysis between allo-HCT recipients relapsing after 3mo (median 6.2 mo. [IQR=4.6-12]), N=75) compared to patients without recurrence (N=193, matched for ethnicity, age, disease, graft source and conditioning regimens) and characterized the patterns of HLA evolutionary divergence (HED), 1 a metric recently conceived to quantitate the pair-wise distance (based on physiochemical composition) between the amino acids located within the peptide-binding groove of two homologous HLA alleles. Overall, the relapsed group was characterized by a lower global (class I/II) mean HED (p=.0029) compared to non-relapsed patients, with major differences seen for C (p=.0041), DQB1 (p=.0291), and DPB1 (p=.0396) loci. When studying the landscape of post-transplant TCR reconstitution (+3 months) in a subset of 25 patients, we observed an inverse correlation between TCR clonal expansion and global HED (AdjR 2=0.04, p= Altogether these findings pinpoint the role of the dysfunction of the structural variability of HLA complexes within both germline (HED) and somatic (HLA loss/mutations) scenarios as mechanisms hampering a successful neoantigen presentation and TCR recovery processes, possibly conveying a higher risk of disease relapse or treatment-resistance. Disclosures Balasubramanian: Servier Pharmaceuticals: Research Funding. Carraway: Takeda: Other: Independent review committee; AbbVie: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy; Novartis: Consultancy.

Distinct clinical and biological implications of various DNMT3A mutations in myeloid neoplasms

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

Introduction Loss of KDM6A expression has been reported as a potential drug resistance mechanism in AML. Here, we describe the clinical characteristics and treatment outcomes in our cohort of AML patients with KDM6A mutations. Methods We annotated a cohort of 293 AML patients who were treated at our center between Jan 2016 and Dec 2019. These cases were subjected to multiamplicon targeted deep NGS, including all ORFs of KDM6A and other recurrently mutated myeloid genes among a panel of 54 genes. Results Total of eleven patients (3.75%) were found to have KDM6A mutation. Median age at the time of mutation detection was 68 years. At the time of KDM6A mutation detection, three patients were newly diagnosed (2.6% of new diagnosis), three were in complete remission (CR), and the remaining five were in relapse stage (5.31% of relapsed patients). Missense mutation was the most common mutation type (five patients), followed by frameshift (three patients), splicing variant (two patients), and intronic mutation (one patient). Among eight patients who had active AML at the time of KDM6A mutation detection, five had adverse risk cytogenetics features, and seven had a co-existent mutation in other genes (most common in epigenetic regulator genes in five). Among three newly diagnosed patients, two patients died during induction; one patient required two cycles of daunorubicin and cytarabine before achieving CR, and at the time of relapse was noted to have the same mutation. Among five patients who were in relapse at the time of mutation detection, two of them were refractory to three different induction regimens at the time of initial diagnosis; both achieved CR after allogeneic stem cell transplant (ASCT), but relapsed after 13 and 98 months. None of the patients with relapse achieved CR with chemotherapy, but one with ASCT, and continues to be in remission at 22-month follow-up. Among three patients who were in CR at the time of KDM6A mutation detection, two of them have monoclonal plasma cells in bone marrow, and one patient had an allele frequency of 100%, likely germ cell origin. Conclusion KDM6A gene mutations are rare in AML and associated with poor response to chemotherapy.

Introduction Blinatumomab (Blina) and inotuzumab ozogamicin (Ino) have shown remarkable responses in relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL), however, a significant number of patients (pts) relapse. Prior reports suggest that allogeneic hematopoietic stem cell transplantation (SCT) consolidation after Blina/Ino may be associated with increased transplant related complications. To address this issue, we assembled a large retrospective multi-center cohort of RR ALL pts who received SCT after Blina/Ino. Methods Medical records of RR ALL pts who received SCT after Blina or Ino at 11 academic transplant centers across USA were reviewed. These pts were evaluated for response and toxicity after SCT. Results From December 2014 to May 2019, 223 and 86 pts who received Blina and Ino, respectively, for RR ALL outside clinical trials were identified. Among them 85 (38%) pts in the Blina group (gp) and 21 (25%) pts in the Ino gp who achieved remission and underwent SCT were included in this analysis. Median age of pts in the Blina and Ino gp was 59 (range [R], 18-72) and 43 (R, 20-75) years, respectively. Median number (no.) of therapies (Rx) prior to SCT in Blina and Ino gp was 2, ranging from 2-5 and 2-6, respectively. Five (6%) and 2 (5%) pts in the Blina and Ino gp, respectively, received second SCT. Median time from remission to SCT in Blina gp was 1.7 months (mo) (R, 0.20 to 13.2) and in Ino gp was 4.3 mo (R, 1-13.3). In the Blina and Ino gp: 36.5% vs. 38%, 42% vs. 42%, 15% vs. 9.5% and 6% vs. 9.5% had matched related donor (MRD), matched unrelated donor (MUD), haploidentical and cord blood SCT, respectively. Acute graft versus host disease (aGVHD), chronic (c) GVHD, veno-occlusive disease (VOD) and infectious complications post SCT were observed in 28 (33%), 14 (16.5%), 2 (2%) and 12 (14%) pts, respectively, in the Blina gp. While in the Ino gp, 8 (38%), 1 (5%), 3 (14%) and 4 (19%) pts had these complications, respectively. Six (7%) and 2 (9%) pts had TRM within 100 days of SCT in Blina and Ino gp, respectively. The median PFS and OS in Blina gp was not reached (NR); 66% were progression free and 62% were alive at 2 yrs (Fig 1 A & B). Similarly, median PFS and OS in the Ino gp was NR; 53% were progression free at 6 mo and 53% were alive at 1 yr mark (Fig 1 C & D). In the Blina gp, history of CRS (p= 0.41), no. of prior Rx (p= 0.5), time from response to SCT (p=0.48), and type of donor (p= 0.7) were not significantly associated with GVHD. Similarly, in the Ino gp, no. of prior Rx (p= 0.6), time from response to SCT (p=0.84), type of donor (p= 0.9) were not significantly associated with GVHD. Occurrence of VOD in the Ino gp was not significantly associated with type of donor (p= 0.3), second SCT (p= 0.1), no. of prior Rx (p= 0.6), myeloablative conditioning (p> 0.9) or time from response to SCT (p= 0.5). Conclusion Our real-world analysis suggests that SCT is feasible and effective after Blina or Ino in pts with RR ALL.

Background The impact of activating alterations in non–small cell lung cancer (NSCLC) (epidermal growth factor receptor [EGFR] mutation/anaplastic lymphoma kinase [ALK] translocation) in prognosticating patients with brain metastasis (BM) is not well defined. This study was sought to identify this impact in NSCLC patients with BM accounting for the known validated variables. Methods Among 1078 NSCLC-BM patients diagnosed/treated between January 1, 2000 and December 31, 2015, three hundred and forty-eight with known EGFR/ALK status were analyzed. Overall survival (OS) and intracranial progression-free survival (PFS) were measured from the time of BM. Results Ninety-one patients had either ALK (n = 23) alterations or EGFR (n = 68) mutation and 257 were wild type (WT; negative actionable mutations/alterations). Median age of EGFR/ALK+ NSCLC BM patients was 60 years (range 29.8–82.6 y) and ~50% (n = 44) had Karnofsky performance status (KPS) score >80. Median number of BM was 2 (1 to ≥99). The median OS for the ALK/EGFR+ NSCLC BM was 19.9 versus 10.1 months for the WT (P = 0.028). The number of BM in the EGFR/ALK+ group did not impact OS (BM = 1 with 21.1 months vs 2–3 with 19.1 months and >3 with 23.7 months, P = 0.74), whereas fewer BM in the WT cohort had significantly better OS (BM = 1 with 13.8 mo, 2–3 with 11.0 mo and >3 with 8.1 mo; P = 0.006) with the adjustment of age, KPS, symptoms from BM and synchronicity. Conclusions Number of BM does not impact outcomes in the EGFR/ALK+ NSCLC patients, implying that targeted therapy along with surgery and/or radiation may improve OS irrespective of the number of BM. Number of BM, extracranial metastasis (ECM), and KPS independently affected OS/PFS in WT NSCLC BM, which was consistent with the known literature.

To retrospectively analyze and assess the outcomes and prognostic factors in patients with anaplastic meningioma (AM) (WHO Grade III). Clinical data and outcome [overall (OS) and progression-free (PFS) survival] from 18 patients with Grade III meningioma (AM, based on World Health Organization 2016 definition) initially treated between March 2000 and June 2015 were analyzed. Eleven patients (61%) were male, median age at diagnosis was 63 (range 48-86), and 55% (10/18 patients) had good performance status (KPS ≥ 80). Eight patients (45%) had lower grade disease (Grade I-n = 2; Grade II-n = 6) prior to being upgraded to AM. Ten patients had fractionated radiation after primary surgery, eight patients had salvage fractionated RT, stereotactic radiosurgery (SRS) boost along with primary RT in 1 patient, and salvage SRS to 18 separate areas in 14 patients. Salvage chemotherapy was mainly considered in third or fourth recurrences. 13 (72%) patients recurred and 10 (56%) have died. Median PFS was 14.5 months (95% CI 6.9-22.2). The 5-year survival rate was 40 ± 15% and median OS was 55.8 months (95% CI 27.7-80.3). Of all factors examined, only Karnofsky performance status (KPS) affected outcome (PFS p = 0.0003; OS p = 0.0003). With median OS of 55 months (4.6 years) our results are consistent with existing reports of the poor outcomes for AM patients. From the available data, surgical resection followed by RT and salvage radiosurgery and/or chemotherapy can lead to extended survival; however the benefit may decrease with successive treatments.

Recent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution.

Background: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate composed of anti-CD22 antibody conjugated to the cytotoxic agent calicheamicin, which is approved for relapsed/ refractory (RR) B-cell acute lymphocytic leukemia (ALL), based on efficacy demonstrated in a randomized control trial. We sought to investigate the safety and efficacy of InO in the "real world" setting. Methods: We conducted a retrospective multicenter study in collaboration with 11 U.S. academic institutions, and evaluated the outcome of patients (pts) with RR B-cell ALL, who received InO outside of clinical trials. These pts were evaluated for response to InO, duration of response, overall survival (OS) and toxicity. Demographic and disease characteristics were summarized using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared via log-rank test. Duration of response was estimated among pts who achieve complete remission (CR)/CR with incomplete count recovery (CRi). Results: From June 2016 to May 2019, 84 pts with RR-B cell ALL were identified. Baseline characteristics are summarized in Table 1. The median age of pts at InO initiation was 50 years (yrs) (range, 20-87). Twenty-two (27.5%) pts had t(9;22) (Ph+ve) and 6 (7.5%) pts had t(4;11) (MLL gene) chromosomal abnormalities. Nine (11%) and 20 (25%) pts had CNS disease at diagnosis and at relapse, respectively. Median number of therapies prior to InO was 2 (range, 0-7), 40 (48%) pts had ≥ 3 therapies and 23 (27%) pts had allogeneic stem cell transplantation (allo-HCT) prior to InO. Forty (48%) pts received blinatumomab prior to InO. Fourteen (17%) pts received InO in combination with chemotherapy and/ or tyrosine kinase inhibitor (TKI). Overall response rate (CR/CRi) was 63%; 44% had CR with minimal residual disease (MRD) negativity by flow cytometry. Response rate in Ph+ve B-cell ALL was 73%. Twenty-three (27%) pts were successfully bridged to allo-HCT. Median response duration with InO was 11.5 months (mo); 32.5% had sustained response at 2 yrs (Fig. 1a). Median response duration post InO, censored at allo-HCT was not reached (NR) (51% in remission at 2 yrs) (Fig. 1b). Median OS after InO was 11.6 mo and 32% were alive at 2 yrs (Fig. 1c). Median OS post InO, censored at of allo-HCT was 13.6 mo (Fig. 1d). Median OS after InO in Ph+ve pts was NR (71% alive at 1 yr). Forty-nine percent, 27%, 6% and 5% of pts discontinued InO due to progression, allo-HCT, adverse events and maintenance therapy, respectively. Nineteen (30%) pts had dose interruptions. In terms of toxicities, 14 (17%) and 7 (8%) pts had grade (G)1-2 and G3 transaminases secondary to InO, respectively. One pt each had G2 and G3 pancreatitis, respectively. One (1%) and 2 (2%) pts had G2 and G4 veno-occlusive disease secondary to InO, respectively. Two of these pts were treated with defibrotide. Two (2%) pts died due to InO toxicity. A complete description of adverse events are summarized in Table 1. Conclusion: Our real-world data obtained by multicenter collaboration suggest that InO was well tolerated and had significant efficacy in this heavily treated patient population of RR B-cell ALL. Disclosures Liedtke: Celator: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Curran:Incyte: Research Funding; Merck: Research Funding; Gilead: Research Funding. Podoltsev:Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Abbvie: Research Funding. Atallah:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy.

Background Blinatumomab is a bispecific T cell antibody construct, that binds and allows CD-3 positive cytotoxic T cells to recognize and eradicate CD19-positive acute lymphocytic leukemia (ALL) blasts. The drug is approved for patient (pts) with relapsed/ refractory (RR) B-cell ALL and those with minimal residual disease (MRD) based on efficacy in clinical trials. We sought to evaluate the safety and efficacy of blinatumomab in the "real world" setting. Methods We conducted a retrospective multicenter study in collaboration with 11 U.S. academic institutions, and evaluated the outcome of RR B-cell ALL pts, who received blinatumomab outside of clinical trials. These pts were evaluated for response, duration of response (DOR), overall survival (OS) from the time of blinatumomab initiation and toxicity. DOR was estimated among pts who had achieved complete remission (CR)/CR with incomplete count recovery (CRi). Survival curves were estimated using the Kaplan-Meier method and compared via log-rank test. Results From December 2014 to May 2019, 239 pts with B-cell ALL were identified. Baseline characteristics are summarized in Table 1. The median age of pts at blinatumomab initiation was 48 years (yrs) (range, 18-85). Sixty-one (26%) pts had Philadelphia chromosome [t(9;22)] positive (Ph+ve) disease. Sixty-one (26%) pts had ≥ 3 prior therapies and 46 (19%) pts had allogeneic stem cell transplantation (allo-HCT) prior to blinatumomab. Twenty-two (9%) pts received inotuzumab ozagamicin prior to blinatumomab. Twenty-nine (12%) pts received blinatumomab in combination with tyrosine kinase inhibitor (TKI). Twelve (5%) pts received blinatumomab for MRD. Response rate (CR/CRi) in pts with RR disease was 61%; 44% had CR with MRD negativity by flow cytometry. Rate of CR/CRi in Ph+ve B-cell ALL was 74.5%. Among 12 pts who received Blinatumomab for MRD, 9 (75%) pts achieved MRD negativity. Overall 113 (48%) pts were successfully bridged to allo-HCT. Median DOR in pts with RR disease was 32.1 months (95% CI; 9.5-not reached [NR]) (Fig. 1a) and when censored at allo-HCT was 14.8 months (95% CI; 5.2-NR) (Fig. 1b). Median OS in pts with RR disease after blinatumomab was 12.7 months (95% CI; 9.2 -17.9) (Fig. 1c) and when censored at allo-HCT was 8.6 months (95% CI; 6.4-11.6) (Fig.1d). Median OS after blinatumomab in RR B-cell ALL Ph+ve pts was NR (59% alive at 2 yr). Among pts who received blinatumomab for MRD, median DOR was NR and 54% sustained MRD negativity at 2 yrs. Median OS was 34.7 months (95% CI; 8.8-34.7) in group of pts who received blinatumomab for MRD. Seven (3%) pts discontinued blinatumomab due to adverse events and 40 (21%) pts had dose interruptions. Cytokine release syndrome (CRS) of any grade (G) was reported in higher number of pts (93 [39%]) compared to clinical trials, though G3-4 CRS appears to be similar (G1-2 [36%], G3-4 [3%]). Forty-four (44%) pts were treated with steroids and 8 (8%) pts required tocilizumab with steroids for CRS. Ninety-three percent of pts had complete resolution of CRS. CNS toxicities were observed in 31 (13%) pts, among them 60% (n= 19) had G3-4 toxicities. Hepatic toxicities were observed in 84 (35%) pts as outlined in Table 1. Six (2.5%) pts died due to blinatumomab induced toxicities. Conclusion: Our real-world data with multicenter collaboration suggest that overall blinatumomab was well tolerated and had led to significant response in pts with RR B-cell ALL. Disclosures Advani: Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Aldoss:AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; Agios: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau. Podoltsev:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding. Curran:Incyte: Research Funding; Merck: Research Funding; Gilead: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah:Helsinn: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Jazz: Consultancy.

With advances in stereotactic and neuroimaging techniques, various minimally invasive image-guided techniques have gained widespread acceptance in the field of neuro-oncology. Laser interstitial thermal therapy (LITT) is an image-guided technique that involves generation of high temperatures using a laser fiber, to ablate pathological tissue. Radiation necrosis (RN) and radiosurgery resistant brain metastasis often pose significant challenges to the treating physicians. In the last two decades, various studies have documented the efficacy of LITT in managing radiosurgery resistant metastases, radiation necrosis, surgically inaccessible malignant gliomas and ablation of epileptogenic foci. The aim of this paper is to summarize the current literature on the efficacy of LITT in patients with radiation necrosis and brain metastasis. We have also touched upon the physical properties of currently available LITT systems and the mechanism of action of laser therapy including histopathological changes.

e13516 Background: Primary central nervous system lymphoma (PCNSL), a form of extranodal non-Hodgkin lymphoma represents 3% of primary CNS tumors. It is aggressive but typically confined to the CNS. Despite improvements in the management of PCNSL, more than 50% of patients eventually relapse. There are limited data on PCNSL from larger cohort studies. Methods: With IRB approval, the Cleveland Clinic Neuro-Oncology Center database was used to identify patients treated between 2006-2015 for PCNSL. Overall survival (OS) from the diagnosis of PCNSL and progression free survival (PFS) were the primary and secondary end points respectively. Cox proportional hazards models were used for data analysis. Results: 86 PCNSL patients were included in the analysis. Only 5% (4/76) were HIV positive. The median age of diagnosis was 63 (range 15 - 86) and 50% were males. 88% of patients presented only with brain lesion, 8% only in eye and 4% had both brain and eye involvement. 15% of patients (12/81) had positive CSF findings. Treatment included: chemotherapy (CT) alone (39% of patients); chemoimmunotherapy (CIT) (32%); CIT with radiotherapy (RT) (13%); RT alone (11%); CT with RT (4%); and immunotherapy (IT) alone (1%). Among 23 patients (31%) who received RT upfront, 74% had WBRT (n = 17). The most common upfront therapy was high dose methotrexate (HD MTX) (44%), followed by HD MTX with rituximab (23%), RTOG 0227 (12%), RTOG 1114 (11%) and rest 14% included rituximab or temozolomide or other cytotoxic chemotherapy alone or in combinations. The most common relapse site was brain (72%), followed by eyes (12%) and spine (8%). The median follow-up was 26 months. At last follow up, 41% had died and 93% of which were PCNSL-related. The median PFS and OS were 17.7 months and 84 months, respectively. There was a trend towards superior PFS in upfront IT vs. no IT (20 vs. 14 months, p 0.08). Better performance status (KPS > 80 vs. < 80, HR 0.42 (p = 0.033)) and PFS ≥ 24 months compared to ≤ 24 months (p = 0.0012) were associated with improved OS. Conclusions: We report a large single institution cohort of PCNSL patients treated in the era of immunotherapy. In our cohort, better KPS (≥80) and PFS ≥ 24 months had improved OS. Upfront IT showed a trend towards improved PFS.