Abstract: Background: The addition of Rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the overall survival of patients with diffuse large B cell lymphoma (DLBCL) by 10–15%. To evaluate the biological basis of survival for DLBCL, we profiled gene expression in biopsy samples from patients treated with R-CHOP. Methods: Whole genome Affymetrix U133 2.0 plus arrays were used to profile gene expression in pre-treatment biopsies from patients with de novo DLBCL who received CHOP (n=181) or R-CHOP (n=233). Samples were classified as germinal center B cell-like (GCB), activated B cell-like (ABC) or unclassified DLBCL. A multivariate gene expression-based survival predictor was created using CHOP cases as training and R-CHOP cases as validation set. Results: R-CHOP treated patients with GCB DLBCL had a more favorable survival than those with ABC DLBCL, with 3-year overall survival rates of 84% and 56%, respectively (p & lt;0.001). A multivariate model created from 3 gene expression signatures – termed “germinal center B cell”, “stromal-1”, and “stromal-2” – predicted survival in both CHOP and R-CHOP cases, defining quartile groups among R-CHOP-treated patients with 3-year overall survival rates of 89%, 82%, 74%, and 48% (p & lt;0.001), and 3-year progression-free survival rates of 84%, 69%, 61% and 33% (p & lt;0.001). The germinal center B cell signature genes were more highly expressed in the malignant cells, whereas the stromal-1 and stromal-2 signature genes were more highly expressed in the non-malignant cells. The stromal-1 signature was associated with favorable outcome when expressed, and reflected extracellular matrix deposition and infiltration by histiocytic innate immune cells. In contrast, the prognostically unfavorable stromal-2 signature reflected angiogenesis and tumor blood vessel density. Conclusion: Survival in DLBCL is critically influenced by the composition of the tumor microenvironment, suggesting that therapeutic interference with microenvironmental interactions might further improve outcome in DLBCL. Specifically, inhibition of angiogenesis may be beneficial for a subset of patients with high relative expression of the stromal-2 signature and increased tumor blood vessel density.

Abstract: Gene expression profiling has been used to distinguish two major subtypes of diffuse large B cell lymphoma (DLBCL), termed germinal center B cell-like (GCB) DLBCL and activated B cell-like (ABC) DLBCL. Following CHOP-like chemotherapy, GCB and ABC DLBCLs had distinct 5-year survival rates of ∼60% and ∼30%, respectively. Prognostic gene expression signatures in CHOP-treated DLBCL include the lymph node signature, which reflects a non-malignant host response, the MHC class II signature, both favorable when expressed and the proliferation signature which is adverse when expressed. The addition of rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the outcome for DLBCL patients. We therefore investigated, if gene expression signatures that predicted survival among DLBCL patients treated with CHOP remained predictive for DLBCL patients treated with R-CHOP. Gene expression profiling was performed on 156 samples from previously untreated patients with DLBCL using Affymetrix U133 plus arrays. All patients received rituximab and CHOP-like chemotherapy. Samples were classified as GCB DLBCL, ABC DLBCL, or unclassified, and were assessed for expression of the lymph node and proliferation signatures. A Cox-proportional hazards model was used to determine the association of these gene expression features with overall survival (OS). 71 DLBCL samples were classified as GCB DLBCL, 63 as ABC DLBCL, and 22 were unclassified. The addition of rituximab improved OS for both GCB and ABC DLBCL compared to historical controls treated with CHOP-like chemotherapy alone. After a median follow-up of 2.3 years, GCB DLBCL had a more favorable OS than ABC DLBCL, with 3-year OS rates of 86% vs. 68% (p = 0.014). The 3-year OS rate of unclassified DLBCLs was 69%. The lymph node signature was associated with favorable OS (p = 0.023) and the proliferation signature with inferior OS (p = 0.009), whereas the MHC class II signature was not associated with OS (p = 0.44). In summary, addition of rituximab to CHOP-like chemotherapy improved OS for both GCB and ABC DLBCL but ABC DLBCL remained inferior to GCB DLBCL. The prognostic value of the lymph node and proliferation signatures were maintained in the context of R-CHOP therapy. An understanding of the biological attributes of DLBCL tumors that are reflected in these gene expression signatures remains critical to our ability to improve survival of these patients.

Abstract: Background: Philadelphia chromosome-positive (Ph+) CML is a myeloproliferative disease characterized by the presence of the abnormal Ph+ in hematopoietic cells. Imatinib, dasatinib and nilotinib are BCR-ABL TKIs commonly used in the treatment of CML-CP. Many patients on BCR-ABL TKI therapy will experience adverse events (AEs). Some of the more common AEs associated with first- and second-generation BCR-ABL TKIs include fluid retention, diarrhea, rash, musculoskeletal pain, nausea, vomiting, muscle cramps, and headache. Some patients will be unable to tolerate these AEs and will discontinue therapy. The current study aimed to assess the efficacy and safety of nilotinib in patients with CML-CP who are responsive to but intolerant of treatment with imatinib or dasatinib. Although the study was stopped early due to low recruitment, here we present results on cross-intolerance and molecular response in the patients who were switched from imatinib or dasatinib to nilotinib. Methods: Eligible adult patients had: Ph+ CML-CP associated with BCR-ABL quantifiable by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR); received ≥3 months imatinib or dasatinib or both; were 〈 1% (IS) BCR-ABL level in the blood during imatinib or dasatinib treatment; and were experiencing any non-hematological AEs (any grade) that persisted for ≥1 month or recurred at least once despite supportive care. After a washout period of ≥3 days, patients were switched to nilotinib 300 mg BD and treated for up to 24 months. The dose could be reduced to 450 mg QD for safety reasons. Treatment interruptions, dose reductions and dose re-escalation to 300 mg BD were allowed for management of AEs. The primary outcome was achievement of MR4.5 (BCR-ABL ≤0.0032%) by 24 months. Major molecular response (MMR; BCR-ABL ≤0.1%) and MR4.0 (BCR-ABL ≤0.01%) were also assessed in an exploratory capacity at each visit (month 1, 2, 3, then every 3 months to month 24). Secondary endpoints included the kinetics of molecular response. Preliminary results are summarized descriptively. Planned enrolment was 130 patients. Results: The study was stopped early due to low recruitment; 20 patients were enrolled (mean age 53.9 years [range 31-77]; 14 female). 16 patients had received prior imatinib therapy, 4 patients prior dasatinib. Median nilotinib treatment duration was 494 days (mean 480, SD 167.6 days). At screening, 30% of patients were not in MMR, 45% had MMR and 25% had MR4.0. By month 3 and 24 of nilotinib treatment, 55% (11/20) and 65% (13/20) of patients, respectively, achieved at least a 1 log reduction in BCR-ABL levels. 35% (7/20) of patients achieved MR4.5 between baseline and month 3 of nilotinib treatment, and 50% (10/20) achieved MR4.5 at any time up to month 24. The proportion of patients with a molecular response at each visit up to month 15 is shown in the Figure. AEs during prior treatment with imatinib and dasatinib included gastrointestinal events (nausea, vomiting, diarrhea), superficial edema, myalgia, fatigue, rash, and headache, among others. 68% of AEs had resolved by month 3 of nilotinib treatment. Among the 13 evaluable patients on prior imatinib, 7 (54%) had resolution of all AEs during treatment with nilotinib; of 3 evaluable patients on prior dasatinib, 3 (100%) had AE resolution on nilotinib. Grade 3/4 AEs during nilotinib therapy occurred in 3 patients: diabetes mellitus, fatigue, neutropenia, pneumonia, osteoarthritis, and hyperuricemia. Conclusions: Although early termination of the study has not allowed for a robust analysis, these results suggest that nilotinib is effective and well tolerated in most patients intolerant of imatinib or dasatinib. During the first 3 months of switching to nilotinib, 55% of patients had achieved at least a 1 log reduction in BCR-ABL levels, and 35% of patients had achieved MR4.5. The cumulative rate of MR4.5 by 24 months was 50%. Achievement of this endpoint has been linked to favorable long-term outcomes, such as treatment-free remission. Furthermore, the majority of the AEs had resolved by month 3 of nilotinib therapy. This improved tolerance to nilotinib may result in improved treatment adherence. As such, although further study in a larger population is needed for confirmation, these results provide further evidence that nilotinib is a favorable option to establish a molecular response in patients intolerant of imatinib or dasatinib. Disclosures D'Rozario: BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy. Yeung:Ariad: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Novartis Pharmaceuticals: Employment. Gervasio:Novartis Pharmaceuticals: Employment. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with & lt;30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Abstract: Background: Outcome of AML pts is known to be impacted by genetic factors such as cytogenetic abnormalities and gene mutations and sociodemographic factors such as age and race. Neighborhood factors are increasingly recognized as important drivers of disparities in cancer outcomes. Neighborhood socioeconomic deprivation has been associated with worse survival of numerous cancers, but studies in AML are lacking. Understanding the role of social deprivation in AML outcomes, and its impact in the context of known prognostic factors could identify areas that may benefit from additional health care resources. Methods: We analyzed the clinical and molecular features of 1,242 younger AML (age range, 17-59 y) pts similarly treated with intensive cytarabine/daunorubicin-based chemotherapy on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols between 2001 and 2013. A neighborhood social deprivation index (SDI) was assigned to all pts based on pt reported zip code of residence. SDI was population weighted with resulting scores (1-100) corresponding to US zip code percentiles of SDI (e.g., 100 = top 1% of US population in zip codes of highest deprivation). We defined 2 SDI levels, low (1-50 n=664) and high (51-100, n=578), that were analyzed for associations with clinical and molecular features and outcomes. Results: Demographic and baseline clinical features did not differ between high and low SDI pts, except for a higher percentage of self-reported non-Hispanic Black pts residing in high compared to low SDI areas (15% v 2%, p & lt;.001). In contrast, a higher percentage of self-reported non-Hispanic White AML pts resided in low compared to high SDI areas (94% v 79%). A lower percentage of pts residing in high SDI areas underwent allogeneic transplant in 1 st complete remission (CR) compared to those in low SDI areas (10% v 17%, p & lt;.001). Concerning clinical outcomes, there were no significant differences in early death (7% v 6%) or CR (67% for both) rates between low and high SDI pts. However, pts residing in high SDI areas had shorter disease-free survival (DFS; median: 1.3 v 2.4 y, p=.001; Fig. 1A) and overall survival (OS; median: 1.9 v 2.9 y, p & lt;.001; Fig. 1B). Notably, White AML pts residing in high SDI areas had worse DFS (3-y rates: 37% v 46%, p=.003) and OS (3-y rates: 42% v 48%, p=.006) than those low SDI areas. In contrast, there were no associations between SDI and survival among Black AML pts, indicating that systemic racism may outweigh poverty-associated survival impact. We next assessed whether differences in molecular features between high and low SDI groups may help explain the observed survival disparities (n=656 pts). While we found no statistically significant differences in the frequencies of known prognosis-associated gene mutations by SDI levels, there was a trend towards lower frequencies in genes belonging to the cohesion complex and methylation-associated genes (both p=.06), indicating possible differences in underlying disease biology. Percentages of high and low SDI pts did not differ significantly within any of the 3 genetic-risk groups in the 2017 European Leukemia Net (ELN) classification. However, when we analyzed outcomes of pts within the ELN groups, we found that among pts belonging to the ELN Favorable-risk group, high SDI score was associated with shorter OS (p=.03) than low SDI score, but this was not true for ELN Intermediate- or Adverse-risk pts. Lastly, in multivariable analysis for OS in younger AML pts, a high SDI score associated with shorter OS (HR: 1.28, CI: 1.10-1.48, p=.01; Table 1), after correction for ELN groups (p & lt;.001), thereby highlighting that a pts socioeconomic status predicts outcome independently from our routinely used molecular-based, clinical risk stratification. Conclusion: In younger AML pts, residence in areas with high socioeconomic deprivation was associated with poor survival, especially for pts classified in the ELN favorable-risk group. With the exception of patient racial-ethnic identity and receipt of allogeneic transplant in first CR, SDI did not associate with clinical or molecular characteristics. Thus, area social deprivation among younger AML pts should be further investigated to overcome potentially avoidable survival disparities. Support: U10CA180821, U10CA180882 U24CA196171; Clinicaltrials.gov Identifiers: NCT00048958, NCT00899223, NCT00900224; https://acknowledgments.alliancefound.org Figure 1 Figure 1. Disclosures Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Blum: Nkarta: Research Funding; Celyad Oncology: Research Funding; Abbvie: Honoraria; AmerisourceBergen: Honoraria; Xencor: Research Funding; Forma Therapeutics: Research Funding; Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria. Uy: Agios: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; GlaxoSmithKline: Consultancy; Genentech: Consultancy; Macrogenics: Research Funding; Astellas: Honoraria, Speakers Bureau; Jazz: Consultancy. Stone: Abbvie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Glaxo Smith Kline: Consultancy; Innate: Consultancy; Jannsen: Consultancy; Jazz: Consultancy; Macrogenics: Consultancy; Novartis: Consultancy, Research Funding; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Paskett: Pfizer: Research Funding; Merck: Research Funding. Eisfeld: Karyopharm (spouse): Current Employment.