AI Therapeutics Research Articles

Central Nervous System (CNS) Involvement of Richter Transformation: A Single Center Experience

Central Nervous System (CNS) Involvement of Richter Transformation: A Single Center Experience

High Dimensional Tissue-Based Spatial Analysis of the Tumor Microenvironment of Follicular Lymphoma Reveals Unique Immune Niches inside Malignant Follicles

High Dimensional Tissue-Based Spatial Analysis of the Tumor Microenvironment of Follicular Lymphoma Reveals Unique Immune Niches inside Malignant Follicles

The Utility of Granulocyte Colony Stimulating Factor in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy with Axicabtagene Ciloleucel

Background: Infection during the period of neutropenia following chemotherapy represents a major cause of morbidity and mortality in patients with malignancy.(Freifeld, et al, 2011, Baden LR, et al, 2012) Several guidelines recommend granulocyte colony stimulating factor (GCSF) to reduce the duration and severity of chemotherapy-induced neutropenia and abate infection risk.(Lyman, et al 2018, Aapro, et al, 2011, Smith, et al, 2015). Optimal GCSF administration following chimeric antigen receptor (CAR) T-cell therapy remains undefined and requires characterization. Methods: The Mayo Institutional Review Board approved this retrospective, single-center study. Electronic medical records for patients prescribed axicabtagene ciloleucel were reviewed until disease relapse, death, or a maximum of 60 days after infusion. Baseline characteristics and laboratory values were abstracted prior to lymphodepleting chemotherapy. GCSF support was originally prescribed when the absolute neutrophil count (ANC) declined below 500 cells/mm3 and discontinued when the ANC exceeded 1000 cells/mm3 (neutropenia) for 2 consecutive days. A practice change was made where GCSF was recommended only in those with febrile neutropenia and an increased concern for infection. The primary endpoint was the difference in the total days of neutropenia for patients receiving and not receiving GCSF. Secondary outcomes compared total days of severe neutropenia, number of neutropenia episodes, infection rates by GCSF use, and outcomes by protocol change. Neutropenia and severe neutropenia were defined as an ANC below 500 cells/mm3 and 100 cells/mm3, respectively. Updated data with more patients will be presented at the conference. Results: The 60 included patients had a median age of 59 (IQR: 44, 63) years, 38 (63%) were male and 53 (88%) were Caucasian. Significantly fewer patients were prescribed GCSF according to infection-related concerns compared to ANC-based indication, 18% vs. 94%, p<0.001. Because only 3 subjects received GCSF based on infection-related concerns, results based on GCSF use versus no use is shown here. GCSF was prescribed to 35 (58%) patients for a median of 8 (IQR: 6, 12) doses with a median cumulative dosage of 3840 mcg (IQR 2100-5400) and median time to first dose of 3 days (IQR: 1, 4) post CAR T-cell infusion. Table 1 displays additional baseline characteristics and laboratory parameters according to GCSF support utilization. GCSF prescribed: Table 2 displays outcomes by GCSF use. Total days of neutropenia were similar between groups (13 vs. 16, p=0.52) with a trend towards significantly fewer days of severe neutropenia when prescribed GCSF (6 vs. 9, p=0.129). Patients prescribed GCSF were more likely to experience multiple episodes of neutropenia (83% vs. 43% p=0.002) with a significantly greater median number of episodes (3 vs. 1, p=0.002) when compared to those not prescribed GCSF. GCSF use significantly decreased the median days of the first neutropenia episode (6 vs. 12, p=0.001). There was a trend for decreased median days of severe neutropenia in the first episode with GCSF (5.0 vs. 8.0, p=0.236). Figure 1 displays a trend towards a lower overall risk of infection (HR 0.55, 95%CI: 0.16-1.87, p=0.34) and lower risk of bacterial infection (HR: 0.49, 95% CI: 0.18-1.31, p=0.15); however, these were not statistically significant. Conclusion: Patients prescribed GCSF according to ANC-based indication were significantly more likely to experience multiple neutropenia episodes; however, duration of first neutropenic episode and days of severe neutropenia during the first neutropenic episode were significantly reduced. Interestingly, the total days of neutropenia and severe neutropenia were similar between groups. It is possible that using the parameter of ANC more than 1000 cells/mm3 for 2 consecutive days is not the optimal criteria for stopping GCSF. Risk of overall and bacterial infection was lower with ANC-based initiation of GCSF, although non-significant likely due to small sample size. The potential benefit for using CSF and the optimal timing after CAR T-cell infusion requires further, rigorous, prospective investigation. Disclosures Ansell: ADC Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding. Bennani:Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding.

Response to Bridging Therapy (BT) before CAR-T Cell Infusion Predicts Outcomes for Relapsed/Refractory (R/R) Aggressive B-Cell Non-Hodgkin Lymphoma (NHL)

Background: Real world multi-institutional data of anti-CD19 CAR-T therapy from across the US shows similar response rates and toxicities as that of the registration trials. For axicabtagene ciloleucel (axi-cel), bridging therapy (BT) during CAR-T manufacturing was not allowed. Real world data shows that patients who received BT had lower complete remission (CR) rates, duraiton of response (DOR) and overall survival (OS). Whether the poorer outcome is due to the effect of the BT or the aggressive biology of the disease is unknown. Patients with lower disease burden had higher response rate in the registration study ZUMA-1 for axi-cel. We examined the impact of response to BT on CAR-T outcome. Specifically, we also describe our experience using polatuzumab vedotin, bendamustine and rituximab (Pola-BR), also a recently approved therapy for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), prior to CAR-T as salvage (ST) and BT. Methods: A retrospective review of 63 patients who received axi-cel for NHL from June 2016 - March 2020 at Mayo Clinic, Rochester was performed. ST was defined as the last therapy prior to leukapheresis and grouped into categories - autologous stem cell transplant (ASCT), and non-ASCT (chemotherapy and immunotherapy) . BT was defined as lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Response to all lymphoma-directed therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death. Results: Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing that would reduce the likelihood of eligibility to receive CAR-T. The decision and choice of BT was at the discretion of the treating physician. Sixty-eight percent (n=43) of the patients received BT (19 chemo, 24 immunotherapy). Demographics of the patients based on their response to BT are shown in table 1. More patients in the BT responder group had received chemotherapy as type of bridge (58% vs. 33%). With a median follow up of 12-months for those still alive, significant improvement in EFS was seen in patients who had partial response (PR) or stable disease (SD) to BT than patients who continued to progress (median 12 months vs. 3 months, p = 0.01) [Figure 1A]. OS however, was not significant between the two groups (median OS 18 months - responders vs. 12 months non-responders, p = 0.19) [Figure 1B]. We also describe in the case series below 11 patients who received Pola-BR in salvage setting (ST) and/or BT (Table 2). Due to the lymphopenic effects of bendamustine, it was avoided before T-cell collection if possible. Two patients, however, received bendamustine as part of Pola-BR for salvage therapy as its need was determined per the managing physician. Axi-cel was successfully manufactured for all 10 patients. One patient did not have measurable disease after Pola-BR BT and remains on observation. A second patient died before CAR-T infusion from progressive disease. Four of the nine patients treated with CAR-T remained in response. Updated outcome will be presented. Conclusion: While patients who received BT have worse EFS than those who didn't, having some control of lymphoma after BT was associated with better EFS compared to patients who continued to have progressive disease after BT. Preliminary data from Pola-BR case series shows 60% (6/10) patients achieved PR/SD before CAR-T infusion, but requires longer follow up for its impact on survival. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Ansell:AI Therapeutics: Research Funding; Takeda: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy.

Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study

Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Estimates and Timing of Therapy Initiation during the First Decade for Patients with Follicular Lymphoma Who Were Observed at Diagnosis

Background: Observation or "wait and watch" (W/W) strategy remains a viable option in the rituximab era for asymptomatic, stage II-IV, low-tumor burden patients with FL grade 1-2, 3A. Studies to date both in pre and post rituximab era have not shown an overall survival benefit from immediate treatment in such low-risk patients.To improve our understanding and to better counsel FL patients on W/W strategy, we sought to estimate the incidence of treatment initiation at landmark time points in our prospectively observed cohort from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). We further evaluate the association between the presence of GELF criteria (MER treatment criteria) at diagnosis and initiation of treatment patterns, transformation rates and cause of death in FL patients managed by W/W. Methods: FL patients on W/W strategy were identified from MER of the University of Iowa/Mayo Clinic Lymphoma SPORE. From 2002-2015, consecutive patients with newly diagnosed FL were offered enrollment. Patients were managed per treating physician and followed prospectively. Baseline clinical and pathological data were abstracted using a standard protocol. Cumulative incidence estimates of treatment initiation for follicular lymphoma were calculated using transformation to large cell lymphoma (as the first event) and death due to any cause as competing risks. Transformation was defined based on biopsy-proven disease. Patients were retrospectively considered to meet treatment criteria at diagnosis if they had the presence of any GELF criteria components per available abstracted data in the MER database. Not all GELF criteria were prospectively assessed and captured for all patients, and thus the MER treatment criteria utilized here will be conservative for formal GELF assessment. Results: A total of 401 FL patients were identified in MER on W/W strategy. Baseline characteristics for W/W patients showed a favorable profile such as normal LDH (89%), low and intermediate FLIPI score in 48% and 35% respectively, no B symptoms (97%), low tumor burden (<4 nodal groups) in 72%, and GELF positive vs. negative in 36% and 64% respectively. At a median follow up of 8 years (IQR 5.9-12), 64% initiated treatment for FL only. Cumulative incidence estimates of treatment initiation at sequential time points were calculated from the initiation of observation (Table1&2). At diagnosis, the likelihood of treatment initiation was 15%, 26%, and 42% in the next 1, 2, and 5 years. The incidence of treatment initiation decreased over time as patients remained treatment-free after diagnosis (Figure 1A [blue curve]). Patients that met MER treatment criteria had increased rates of therapy initiation (33.2% vs. 21.9%) in the next two years and untreated transformation to large cell lymphoma [red curve] (8.7% vs. 4.5%) during the next 5 years (Figure 1B). Despite this, the rate of lymphoma related death at 10 years was similar between groups (met treatment criteria = 6.2% vs. 7.1%) (Figure 1C, [green curve]). Discussion: The longer duration of W/W strategy suggests a decreasing need for treatment over time. We provide time point estimates, which would be helpful for counseling patients. Of note, long-term continuous oncologic assessment and follow-up is necessary since approximately 66% of patients in this mature cohort initiated treatment by 8 years median follow up. MER treatment criteria at diagnosis identified patients with higher rates of transformation and therapy initiation in the first two years but did not identify those with worse lymphoma specific survival. Identification of biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Witzig:MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Maurer:Morphosys: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding. Nowakowski:NanoString: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy; Kymera: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees.

High-Dimensional and Single-Cell Transcriptome Analysis of AITL Tumor Microenvironment Reveals Gross Expansion of Novel Dysfunctional CD8+ T Cell Populations, Global Shift in B Cell Phenotypes

BACKGROUND: Angioimmunoblastic T cell lymphoma (AITL) has a unique histological profile comprised of a relatively small number of malignant CD4+ T-cells of TFH phenotype inter-mixed with an extensive infiltrate of multi-lineage immune cells. In our study, we have utilized mass cytometry, high-dimensional analysis, and single-cell transcriptome analysis to provide novel insights into the unique phenotypes that comprise this intra-tumoral microenvironment. We then extended this work to explore clinical associations including peripheral serum analysis of AITL patients and normal controls. To our knowledge, this represents the first such analysis of its kind in AITL. METHODS: We designed two novel CyTOF antibody (Ab) panels to identify and characterize cells of T, B, NK, monocyte and fDC lineages. Samples analyzed included a cohort of 25 biopsy specimens from 8 histologically confirmed AITL patients (5 lymph node (LN), 3 spleen (SP)) and 17 normal controls across key comparator immune tissue types (7 LN, 6 SP, 4 tonsil (TL)). Extensive high-dimensional analysis of CyTOF data was then performed to provide novel insights into key phenotypes and trends of malignant and non-malignant populations in AITL. We then performed CITE-Seq on control and AITL samples to gain further insight into the RNA transcriptome of key T cell populations at the cellular level. Finally, peripheral serum analysis of cytokines, soluble immune receptors, and ligands were then measured by multiplex ELISA from a separate cohort of 22 samples (5 AITL, 17 control) distinct from the individuals analyzed in the original high-dimensional study cohort. RESULTS: While the presence of "reactive" CD8+ populations is a known histologic hallmark of AITL, we describe the gross expansion of novel CD8+ populations with distinctive immunophenotypic features which have not previously been detailed in this malignancy. Using single-cell protein expression data from CyTOF, these expanded CD8+ populations can be broadly categorized as "effector memory" (CCR7-, CD45RO+, CD45RA-) and further characterized phenotypically by markers of progressive exhaustion, checkpoint inhibition, and terminal differentiation (PD1++, TIGIT++, ICOS+, TIM3+). Further analysis of the single-cell transcriptome from these expanded CD8+ populations via CITE-Seq revealed an expression signature consistent with dysfunction and limited cytotoxic activity (including significant down-regulation of granzyme, perforin, and IFN-g) when compared to benign and malignant controls. Interestingly, when compared to CD8+ populations of identical phenotype found in control tissues, these cells also featured marked upregulation of XCL2 and XCL1 in AITL. Additionally, global shifts in infiltrating CD19+ B cell phenotypes were seen in AITL, marked specifically by diminished expression of both CXCR5 and CD73. Finally, soluble PD-1 and other key immune molecules implicated in the expanded tumor microenvironment were found to be significantly increased in the peripheral serum of AITL patients compared to controls (1567.9 pg/mL (1109.3 S.E.) in AITL vs 29.79 (8.84 S.E.) in controls; P<0.0001). CONCLUSIONS: High-dimensional and single-cell transcriptome analysis of the AITL microenvironment yielded several novel insights which have not been previously described in this malignancy. Highlights include the gross expansion of distinct CD8+ populations - the majority of which are of an exhausted, dysfunctional phenotype featuring marked upregulation of XCL2 and XCL1 - and the global loss of CXCR5 and CD73 expression among AITL CD19+ B cell populations. Taken together, this suggests the presence of aberrant non-malignant immune subsets within the AITL microenvironment which may contribute to novel mechanisms of immune escape. Disclosures Cerhan: NanoString: Research Funding; BMS/Celgene: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding; Trillium: Research Funding; Takeda: Research Funding.

Global Transcriptional States of Follicular Lymphoma B Cells Highlight Distinct Groups of Tumor Identity Associated with Somatic Alterations and Tumor Microenvironment

Background: Follicular Lymphoma (FL) is the second most common non-Hodgkin lymphoma and presents with significant clinical, cellular, molecular, and genetic heterogeneity. Despite the name and defining microanatomic location, the genetic and molecular identity and pathogenesis of the FL tumor cell is largely uncharacterized. Prior clinical and molecular classifications of FL have been primarily driven by pathologic classification (Grade 1-3b), genetic classification (M7-FLIPI), or gene expression profiling (IR-1/2). Using a unique cohort of 93 FL tumors, we have explored the transcriptomic signature of purified FL B cells, along with their matched whole tumor, and identified unique molecular subsets which are defined by distinct pathway activation, immune content, and genomic signatures identified through whole exome sequencing (WES). Methods: Frozen tumor biopsies from 93 untreated FL (Grade 1-3b) patients enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE were used for the study. DNA was isolated from whole tumor cell suspensions and RNA was isolated from both whole tumor and B cell enriched cell suspensions. RNA sequencing (RNAseq) and WES was performed in the Mayo Clinic Genome Analysis Core. RNAseq and WES data were processed using the Mayo Clinic standard pipeline and novel driver genes were identified using 20/20+ driver analysis. Copy number variants were identified using GISTIC 2.0. NMF clustering and single sample gene set testing, for B cell lineage and tumor microenvironment (TME) signatures, was performed in R using the NMF and SingScore packages. Results: NMF consensus clustering of FL B cell RNAseq data identified two distinct subsets, C1 (n=32) and C2 (n=57). Clinically, C1 was associated with being FL grade 3 (p<0.001) and more aggressive therapy (e.g. immunochemotherapy) at diagnosis while other clinical factors were similar between the groups. To determine the biologic underpinnings that drove the NMF analysis, the top NMF metagenes were incorporated (n=389 for C1 and n=293 for C2) for GO analysis. Among those genes were AICDA, IRF4, and EZH2 in C1, and BCL2 in C2. Additionally, we identified significant gene set enrichment with NMF metagenes and calculated differential gene set expression comparing C1, C2, and normal B cells (n=5). Together, these analyses suggest C1 displays significantly (p<0.05) enhanced DNA replication and metabolic activity, whereas C2 displays significantly enhanced cytoskeleton rearrangement, repressed inflammatory cytokine signaling, and NF-kB activity. Based on recent scRNAseq data suggesting that FL derives from distinct germinal center B cells, the B lineage difference between C1 and C2 was explored. Both subgroups were heterogeneous for dark (DZ), intermediate (INT), light (LZ) zones, and plasmablast (PBL) gene signatures. When compared to benign B cell samples, C1 was enriched for a pre-PBL (p<0.01), and C2 for an INT phenotype related to a LZ signature (p<0.01). To define if a genomic signature was associated with C1 and C2, mutations and copy number variants (>5% frequency) were examined. TNFAIP3, TP53, and BCL6 alterations were enriched in C1 samples, whereas C2 associated with alterations in BCL2, KMT2D, CREBBP, REL, and MYC. Finally, B cell clusters were analyzed for TME signatures. C1 samples displayed significant enrichment of macrophage, cytotoxic cell, gamma-delta-Tcell, and endothelial cell TME elements (p<0.05) consistent with an inflamed/hot tumor. In contrast, C2 samples exhibited significantly lower signatures (p<0.05) in all entities except for the fibroblast signature, compared to C1 and normal, consistent with an immune desert phenotype. Conclusion: Our results suggest that B cells from FL patients display two distinct transcriptomic signatures. C1 identifies an immunologically active tumor, driven by TNFAIP3 alterations, with pre-PBL characteristics, DNA replication and repair, inflammatory cytokine secretion/signaling, and hyper-metabolic characteristics. C2 identifies an immunologically quiet tumor, driven by alterations in BCL2 and chromatin modifiers, with an intermediate GC phenotype, repressed cytokine signaling, and active cell cycle progression and cytoskeleton rearrangement. This study improves our understanding of the mechanisms driving FL tumors and motivates further investigation into the relationship between tumor intrinsic factors that may influence the TME. Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Celgene / BMS: Research Funding. Ansell:ADC Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Novak:Celgene/BMS: Research Funding.

Identification of a Novel Role for PD-1 Signaling in Promotion Tumor Proliferation in B-Cell Lymphoma

Identification of a Novel Role for PD-1 Signaling in Promotion Tumor Proliferation in B-Cell Lymphoma

Waldenström Macroglobulinemia in the Very Elderly (≥75 years):Clinical Characteristics and Outcomes

Waldenström Macroglobulinemia in the Very Elderly (≥75 years):Clinical Characteristics and Outcomes

Lenalidomide/RCHOP (R2CHOP) Produces High Response Rates and Overall Survival in New, Untreated Diffuse Large B Cell Lymphoma Transformed from Follicular Lymphoma- Results from MC078E

Introduction: Transformation of low grade follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBCL) carries a poor prognosis. In retrospective studies, 5-year survival of transformed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) without autologous stem cell transplant is 40-60%, underscoring need to improve frontline treatment of transformed DLBCL beyond R-CHOP. The overall response rate (ORR) to lenalidomide used as a single agent for relapsed transformed non Hodgkin lymphoma was 45% with 21% complete response (CR) rate and a median duration of response of 12 months (Witzig et al, Ann Onc 2011). These data provided the rationale to include patients with transformed DLBCL (with historical and concurrent FL) in MC078E, a phase II clinical trial testing lenalidomide plus R-CHOP (R2CHOP) for patients with new and untreated de novo and transformed DLBCL (NCT00670358). Here we present analysis of the subset of transformed DLBCL patients. Methods: Adult patients with transformed DLBCL and either historical or concurrent FL, stage >=2, measurable disease by Positron Emission Tomography/computed tomography (PET/CT) and adequate organ function were included. Patients with Central Nervous System (CNS) involvement, significant comorbidities, active non-lymphomatous malignancy, life-threatening thromboembolism (TE) and contraindication to aspirin prophylaxis were excluded. Study participants received up to 6 cycles of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg /m2) on day 1, prednisone (100 mg) on day 1-5, pegfilgrastim on day 2, and Lenalidomide 25 mg day 1-10 of 21 day cycle. Tumor lysis prophylaxis was per local practice; patients also received TE prophylaxis with aspirin. Primary outcome was event free survival (EFS) at 12 months, where an event was defined as death, progression or subsequent anti-lymphoma therapy. Secondary outcomes included ORR, CR, progression free survival (PFS), and overall survival (OS). Response was evaluated by PET/CT after cycle 2 and cycle 6 with revised response criteria (Cheson et al, 2007). Adverse events were recorded according to CTCAE version 3.0. The Kaplan-Meier method was used to estimate time to event endpoints. Results: Thirty-nine patients were accrued from August 5, 2013 to July 28, 2020 and 33 were eligible by central pathology review. Median age was 64 (range 24-80) years and 18 (54%) were >60 years old. Eighteen (54%) were male, and 32 (97%) had ECOG performance status <2. Twenty-three (70%) had historical FL and 10 (30%) had concurrent FL. Twenty-six (79%) had advanced stage (III-IV). Median number of extra nodal sites were 1 (0-4). Thirteen (39%) had high international prognostic index (IPI) (4-5). Thirty-two (97%) completed at least 2 cycles (30 completed all 6 cycles) and were evaluable for response. ORR was 97% (32/33), 29 (88%) had CR and 3 had PR. EFS at 12 months was 87.9% (95% CI: 71.8, 96.6). Two-year PFS and OS were 84.5% (95% CI: 72.8%-98%) and 96.9% (95% CI: 91-100%) (Figure 1). Twenty nine completed study protocol, 4 discontinued protocol early for disease progression (1), adverse event (AE) (1), refusal (1) and noncompliance (1). Thirty (91%) had hematologic AE of grade 3 or above, 27 (82%) had neutropenia, 16 (48%) had thrombocytopenia, and 7 (21%) had anemia. Sixteen (48%) had grade 3 or above non-hematologic AE. Eight (24%) had febrile neutropenia. There were 3 deaths on this study, 1 due to progressive DLBCL, 1 due to AML and 1 due to malignant melanoma. Conclusion: R2CHOP appears effective in transformed DLBCL with high response rates, event free, progression free and overall survival seen in current study. This study supports the inclusion of anthracycline naive patients with transformed DLBCL in future randomized studies of lenalidomide or other novel immunomodulatory (IMiD) analogues. Disclosures Wang: Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Kymera: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; NanoString: Research Funding.

Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy

Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy

Impact of Cell of Origin (COO) on Long Term Outcomes Post Autologous Hematopoietic Cell Transplant in Patients with Relapsed/ Refractory Chemotherapy Sensitive De-Novo Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction The molecular basis for the clinical heterogeneity observed in DLBCL was initially elucidated with gene expression profiling, identifying three distinct subgroups with prognostic relevance based on COO namely activated B-cell like (ABC), germinal center B-cell like (GCB) and a type 3 subtype. Shortly afterwards the Han's algorithm was developed allowing for widespread applicability and correlation of gene expression with protein expression. GCB profile at diagnosis is generally associated with superior long term outcomes compared to non-GCB in patients treated with conventional chemo-immunotherapy. Patients with relapsed/refractory disease (R/R) after front-line therapy undergo salvage treatment and, upon demonstration of objective response, proceed with high dose therapy and autologous transplantation (auto-HCT). Whether COO by Han's algorithm retains its prognostic significance post auto-HCT in patients with R/R DLBCL is not well established. Methods A retrospective analysis was carried out using the Mayo database across all three sites. It included all patients between 18-75 years of age who were diagnosed with de-novo DLBCL and underwent first auto-HCT for R/R disease. Patients must have received salvage treatment and shown chemotherapy sensitive disease. Patients with transformed DLBCL or other variants and those who underwent auto-HCT in first complete remission for high risk disease were excluded. Patients who had less than a partial response at time of transplantation and still underwent auto-HCT were also excluded. Primary endpoints included overall survival (OS); relapse and relapse-free survival (RFS). Continuous variables were summarized as mean (standard deviation) and median (range). Categorical variables were reported as frequency (percentage). Continuous baseline variables were compared between GCB and non-GCB using Wilcoxon rank sum test and categorical baseline variables were compared with Chi-squared test. Kaplan-Meier method was used to estimate 5 and 10-year rates of freedom from long-term events and draw corresponding survival curves. Multivariate Cox regression models were used to evaluate the impact of cell of origin on long-term survival after adjusting for baseline factors. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results A total of 357 patients underwent auto-HCT between 2005 and 2018. Cell of origin was determined for 284 patients and these were included in the analysis. Median age was 61 (range: 19-78) years, and 64% patients were male. GCB and non-GCB patients did not differ significantly with regards to baseline factors (Table 1). During a median follow up of 1.7 years, 139 patients died, 151 had relapse and 175 either died or had relapse. Five year OS for GCB patients versus (vs) non-GCB was at 44% vs 64% (p=0.004) (Figure 1); relapse was at 67% vs 49% (p=0.012) and RFS was at 28% vs 50% (p=0.003). The difference between GCB and non-GCB groups remained statistically significant in multivariate analysis, with GCB patients 60% more likely to die and 50% more likely to experience relapse compared to non-GCB patients. The only other factor that retained significance in multivariate analysis for both endpoints was response at the time of transplant (Table 2A-C). Conclusions In this analysis, GCB DLBCL results in worse OS and higher relapse vs. non-GCB DLBCL following an auto-HCT. It is unclear if relapse/progression of GCB subtype after front-line therapy alters its natural history into a more aggressive disease. Disclosures Ansell: Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; Bristol Myers Squibb: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding. Foran:Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding. Tun:Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding; Bristol-Myers Squibb: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Infused Autograft-Absolute Lymphocyte Count Predicts Superior Survival in Diffuse Large B-Cell Lymphoma Patients Post-Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation: A Matched-Control Study

Introduction Day 15 absolute lymphocyte count (ALC-15) recovery after autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) is recognized as a prognostic factor for survival. ALC-15 recovery is directly dependent on the amount of collected and infused autograft-absolute lymphocyte count (A-ALC). Our group published a double-blind phase III study which showed that patients infused with an A-ALC ≥ 0.5 x 109 cells/kg experienced superior survival post-APBHSCT. Based on the results from our phase III study, on April 1, 2017, our Bone Marrow Transplant Program changed our standard clinical practice to collect an A-ALC ≥ 0.5 x 109 cells/kg in addition to stem cells for lymphoma patients undergoing APBHSCT. To continue to assess the prognostic ability of A-ALC, we evaluated the overall survival (OS) and progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) patients that underwent APBHSCT after April 1, 2017 compared with a matched-control group in a 1:1:1 ratio with DLBCL patients infused with an A-ALC < 0.5 x 109 cells/kg or an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1, 2017. Methods Eight-five consecutive DLBCL patients after our practice changed on April 1, 2017 received an A-ALC ≥ 0.5 x 109 cells/kg. For each DLBCL patient infused with an A-ALC ≥ 0.5 x 109 cells/kg after April 1, 2017, the set of potential controls was restricted to those DLBCL patients infused with an A-ALC < 0.5 x 109 cells/kg and an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1 2017 . Within this group of potential controls, the subjects were chosen who best matched for the cases in terms of clinical risk variables, including gender, age, stage, lactate dehydrogenase (LDH), performance status, extra-nodal disease, International prognostic index (IPI), and disease status prior to APBHSCT (complete or partial response), using the GREEDY algorithm. Cases were defined as DLBCL patients infused with an A-ALC ≥ 0.5 x 109 cells/kg starting from April 1 2017. Control 1 was defined as DLBCL patients infused with an A-ALC < 0.5 x 109 cells/kg prior to April 1 2017. Control 2 was defined as DLBCL patients infused with an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1 2017. We truncated the survival follow-up to 3 years starting from the date of transplant to match follow-up time between cases and controls. Both matched cases and control groups patients received BEAM conditioning. This retrospective study was approved by the Mayo Clinic Institutional Review Board according to the regulation of the Declaration of Helsinki. Results Cases, control 1 and control 2 were balanced to the clinical risk variables; age (p = 0.8); gender (p = 0.9); LDH (p = 0.6); stage (p = 0.3); performance status (p = 0.5); extra-nodal disease (p = 0.2); IPI (p = 0.6); and clinical status prior to transplant (p = 0.2). Figure 1A showed the OS and figure 1B the PFS. Both the cases and control 2 showed superior OS and PFS in comparison to control 1. Cases and control 2 showed overall similar OS and PFS. Multivariate analysis including all patients continue to depict the A-ALC ≥ 0.5 x 109 cells/kg as an independent predictor for OS (HR = 0.382, 95%CI=0.241-0.605, p < 0.0001) and PFS (HR = 0.437, 95%CI = 0.279-0.629, p <0.0001). Subgroup analysis, including all patients, shows superior OS and PFS for patients infused with an A-ALC ≥ 0.5 x 109 cells/kg for each of the following clinical variables: age [> 60 years: OS (p <0.0001); PFS (p <0.0001) or ≤ 60 years: OS (p <0.01); PFS (p , 0.02)]; extra-nodal disease [> 1: OS (p <0.008); PFS (p <0.01) or ≤1: OS (p < 0.001): PFS (p <0.0005)]; IPI [> 2: OS (p <0.01); PFS (p <0.02) or ≤ 2: OS (p <0.0008); PFS (p <0.0006)]; LDH [abnormal: OS (p <0.006); PFS (p <0.005) or normal: OS (p <0.002); PFS (p <0.002)]; performance status [> 1: OS (p <0.04); PFS (p <0.03) or ≤ 1: OS (p <0.0001); PFS (p <0.0001)]; stage [I/II: OS (p <0.006); PFS (p <0.006) or III/IV: OS (p <0.002); PFS (p <0.001)]; response prior to transplant [complete response: OS (p <0.0007); PFS (p <0.0001) or partial response: OS (p <0.01); PFS (p <0.02)]. Conclusion Our match-control study continues to support the results of our Phase III study showing that the infusion of A-ALC is a prognostic factor for survival of DLBCL patients undergoing APBHSCT. Our studies support the practice of not only collecting enough stem cells (i.e., CD34) for hematologic engraftment, but also enough immune effector cells (i.e., A-ALC) to improve clinical outcomes in DLBCL patients post-APBHSCT. Figure 1 Disclosures Ansell: Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding.

LAM-003, a Novel Oral Heat Shock Protein 90 Inhibitor for Treatment of Acute Myeloid Leukemia, Including Wild-Type and FMS-like Tyrosine Kinase 3 (FLT3)-Mutant Disease

Acute myeloid leukemia (AML) remains a disease with high unmet medical need. While most patients respond to initial therapy, few are cured, relapse rates are high, and most patients eventually develop life-threatening complications. FLT3-mutant disease is a particularly aggressive subtype. Recent approval of drugs targeting FLT3-mutant disease have improved short-term outcomes but not all patients respond, and duration of response is limited by secondary mutations that impede FLT3 inhibitor (FLT3i) binding (intrinsic factors) and by secreted stromal factors that activate alternative pro-survival pathways (extrinsic factors). Heat-shock protein 90 (HSP90) is a chaperone protein involved in many cellular processes and inhibition of HSP90 can have pleiotropic effects in targeting cancer cells such as degradation of oncoproteins that drive survival and proteins that mediate protective signaling. Here, we describe the nonclinical activity of LAM-003, an orally bioavailable HSP90 inhibitor (HSP90i) under clinical development for AML. To assess the anti-leukemic activity of LAM-003, we tested a panel of AML cell lines and primary AML samples. LAM-003 inhibited proliferation of both FLT3-mutant and wild-type cell lines, with preferential activity against cells harboring FLT3-ITD (geometric mean FLT3-ITD EC50 = 670 nM [n=8] vs FLT3 WT EC50 = 1400 nM [n=16]). Additionally, we observed that LAM-003 was potent in a subset of the FLT3 WT cells. To explore whether LAM-003 was effective against tumors driven by oncoproteins that are client proteins of HSP90, we focused on AML cells harboring FLT3-ITD. We confirmed that LAM-003 reduced cell surface FLT3-ITD expression and downstream signaling in MV-4-11 and MOLM-13 cells, consistent with HSP90i-mediated degradation of FLT3-ITD. In BA/F3 cells expressing FLT3-ITD with various secondary resistance mutations, we observed that LAM-003 elicited a dose-dependent reduction of FLT3 mutant cell surface expression. Moreover, BA/F3 cells expressing FLT3-ITD and the F691L mutation exhibited the expected resistance to crenolanib, yet LAM-003 retained anti-proliferative activity. Additionally, MOLM-13 cells harboring a FLT3 D835Y mutation demonstrated expected resistance to the FLT3i sorafenib and tandutinib yet remained sensitive to LAM-003. Finally, primary AML blasts harboring a D835 mutation displayed sensitivity to LAM-003 when tested ex vivo. To evaluate the potential of LAM-003 to overcome bone-marrow-stroma-derived resistance, FLT3-ITD AML cell lines (MV-4-11, MOLM-13, MOLM-14) were assayed in unconditioned or stromal-cell-conditioned medium. Conditioned medium dramatically reduced the potency of FLT3i but LAM-003 demonstrated equal potency under both conditions. We also showed that stromal cell co-culture induced FLT3i resistance in MOLM-13 cells whereas LAM-003 retained potent activity. Recognizing that the inherent genetic heterogeneity of AML blasts limits the curative potential of a single drug, we performed in vitro studies to identify drugs that synergize with LAM-003 in 3 FLT3-ITD AML cell lines. Synergy was demonstrated with FLT3i, daunorubicin, azacitidine or cytarabine, with the most robust synergy being observed with venetoclax. Extending the evaluation to AML cells wild type for FLT3 and cell lines from other hematologic indications (multiple myeloma, diffuse large B-cell lymphoma and mantle cell lymphoma), we found that the synergy was not limited to cells harboring FLT3-ITD, but rather correlated with BCL-2 abundance, suggesting a fundamental mechanism of action that depends on BCL-2 family-mediated survival. Mechanistic studies demonstrated that the combination of LAM-003 and venetoclax inhibited AKT-mediated regulation of GSK3B, resulting in MCL-1 degradation. In vivo studies using a MOLM-13 systemic model of FLT3-ITD AML demonstrated that LAM-003 monotherapy significantly improved animal survival and that the combination of LAM-003 and venetoclax significantly prolonged animal survival compared with each single agent. These nonclinical studies demonstrate that LAM-003 exhibits antileukemic activity, overcomes mechanisms of FLT3i resistance and potently synergizes with existing AML drugs. As such, our data provide strong rationale for evaluation of LAM-003 in an ongoing clinical trial in patients with AML (NCT03426605). Disclosures Beeharry: AI Therapeutics: Employment, Equity Ownership. Landrette:AI Therapeutics: Employment. Grotzke:AI Therapeutics: Employment. Gayle:AI Therapeutics: Equity Ownership. Young:AI Therapeutics: Employment, Equity Ownership. Miller:Incuron, Inc.: Consultancy; Cleveland Biolabs, Inc: Employment, Equity Ownership; Calistoga Pharmaceuticals, Inc.: Equity Ownership; AI Therapeutics: Consultancy, Equity Ownership; VelosBio Inc.: Employment, Equity Ownership; Acerta Pharma, Inc.: Equity Ownership. Xu:AI Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Rothberg:AI Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lichenstein:AI Therapeutics: Employment, Equity Ownership.

CPX-351 As First Intensive Therapy for Elderly Patients with AML

CPX-351 As First Intensive Therapy for Elderly Patients with AML

Antecedent Clonal Hematopoesis and Risk of and Mortality after Solid and Hematological Malignancies: Analyses from the Women's Health Initiative Study

Antecedent Clonal Hematopoesis and Risk of and Mortality after Solid and Hematological Malignancies: Analyses from the Women's Health Initiative Study

Newly Diagnosed AML Patient Samples Demonstrate High Degree of Concordance in Identification of Pathogenic Mutations By Next Generation Sequencing (NGS) Performed at Enrolling Institutions Compared to Central Laboratory Results in the Beat AML Master Trial

Newly Diagnosed AML Patient Samples Demonstrate High Degree of Concordance in Identification of Pathogenic Mutations By Next Generation Sequencing (NGS) Performed at Enrolling Institutions Compared to Central Laboratory Results in the Beat AML Master Trial