Clinical Outcomes in Relapsed/Refractory Multiple Myeloma Patients Receiving Sequential Elotuzumab and Daratumumab: A Single Center Experience

Daratumumab and elotuzumab are monoclonal antibodies approved by the FDA in November 2015 for the treatment of relapsed/refractory multiple myeloma (RRMM). Daratumumab was approved as a single therapy targeting plasma cell surface CD38, while elotuzumab was approved as part of combination therapy (with lenalidomide), targeting SLAMF7 to impact natural killer cell activation. While both therapies are involved in the recruitment of cellular cytotoxic mechanisms against multiple myeloma, the efficacy of each after a patient has relapsed on the other therapy is unclear. We conducted a retrospective analysis of 26 patients with RRMM at the University of Miami Sylvester Comprehensive Cancer Center that received both elotuzumab and daratumumab between January 2016 and December 2018 to determine if progression-free survival (PFS) with each monoclonal antibody is affected by previous treatment with the other. Median age at time of treatment was 59.7 years, and 58% of patients were female. Median number of treatments prior to first monoclonal antibody was 4, and median time to first monoclonal antibody was 58 months. Seventeen patients received daratumumab prior to elotuzumab, while nine patients received elotuzumab prior to daratumumab. Patients that received daratumumab first received on average 2 treatments before receiving elotuzumab, while patients receiving elotuzumab first received 1 treatment on average before receiving daratumumab, and time between treatments was significantly shorter for patients receiving daratumumab first (3.7 months vs. 12.4 months, p = 0.0009). Overall survival (OS) and cumulative PFS trended higher in patients receiving elotuzumab first but did not reach significance (OS 37 months vs. 21.7 months, p = 0.07, and PFS 15.5 months vs. 7.6 months, p = 0.09). PFS with initial elotuzumab was higher than with initial daratumumab (11.9 months vs. 3.5 months, p = 0.0124). PFS on daratumumab trended favorably when elotuzumab was administered first (9.4 months vs. 3.0 months), although not significant (p = 0.19). In patients receiving daratumumab, 47% initially demonstrated response, all with eventual progression, with 40% responding to later elotuzumab therapy. Conversely, 56% of patients receiving elotuzumab first demonstrated a response, with 44% eventually progressing over time, and 56% responding to subsequent daratumumab therapy. These results generate a plausible hypothesis related to a possible potentiating effect of elotuzumab that extends after therapy regimen has changed and warrants further investigation into the sequencing of these two therapies in RRMM and the interplay of their different immunologic impact. Disclosures Hoffman: Seattle Genetics: Research Funding; Loxo: Current equity holder in publicly-traded company; Celgene: Honoraria, Speakers Bureau

Unusual Presentation of Renal Medullary Carcinoma With Undiagnosed Sickle Cell Trait

Renal medullary carcinoma (RMC) is an extremely rare malignancy that has been described in younger male patients of African descent with a history of sickle cell disease or trait. We describe a rather unique case of RMC in an older male patient who initially presented with acute on chronic urinary retention and concern for infection. Further investigation revealed a history of hematuria and long-standing microcytic anemia, and the patient was found to have sickle cell trait (SCT) as part of a workup for malignancy of unknown primary. Imaging findings initially interpreted as hydronephrosis later characterized a mass in the renal pelvis concerning for a genitourinary malignancy, later biopsy-proven RMC. RMC typically presents in its advanced stages, with associated poor prognosis, and treatment options are limited and have been extrapolated from standard regimens for other genitourinary malignancies. Therefore, early clinical suspicion in patients with microcytic anemia, flank pain, hematuria, and urinary symptoms, can aid in the diagnosis of RMC and allow for prompt intervention

Abstract PO-55: Single-center experience of chimeric antigen receptor T-cell (CAR-T) immunotherapy in relapsed/refractory large B-cell lymphoma identifies association of acute toxicities with inferior disease outcomes

Abstract Chimeric antigen receptor T (CAR-T) cells are an emerging approach for the treatment of hematologic and solid tumor malignancies. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel were the first FDA-approved CAR-T therapies targeting CD19 for patients with relapsed/refractory (r/r) large B-cell lymphoma. Pivotal studies showed complete response (CR) rates of 58% and 40%, respectively, and we sought to investigate if the data are similar to our single-center results. We carried out a retrospective analysis of patients diagnosed with r/r diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, or mantle cell lymphoma who were treated with axi-cel or tisagenlecleucel at Sylvester Comprehensive Cancer Center in Miami, FL between January 2016 and October 2019. Primary objectives were to identify clinical characteristics associated with improved overall and progression-free survival (OS and PFS). Secondary analyses included incidence of post-CAR-T toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our analysis included 44 patients: 32 received FDA-approved commercial product and 12 received axi-cel through clinical trials. Median age at time of CAR-T therapy was 62 years, and 70% of patients were male. Median number of prior treatments was 4, and 14 patients had undergone prior hematopoietic stem cell transplantation (12 autologous, 2 allogeneic). By day-30 post-treatment PET scan, 25 patients (57%) achieved CR or partial response (PR), while 16 (36%) had progressive (PD) or stable disease (SD). The remaining 3 patients decompensated rapidly post-infusion. Overall, patients with a CR or PR at 30 days had significantly improved OS and PFS compared to patients with PD or SD (OS p = 0.009, PFS p < 0.001). Univariate analyses showed patients requiring aggressive supportive measures in the post-infusion period had decreased OS compared to those who did not: requirement for ICU care (p = 0.018), vasopressor use (p = 0.01), and steroid treatment (p = 0.018) were all associated with inferior survival. There was no survival difference in DLBCL patients classified as double expressor or double hit; however, patients with germinal center B-cell (GCB) DLBCL trended strongly towards improved OS (p = 0.073) compared to non-GCB patients. CRS affected 35 patients (80%), while 24 patients (55%) experienced ICANS. Incidence of toxicities did not vary significantly in patients who received CAR-T commercially or in clinical trials. Patients who did not experience CRS had improved OS (p=0.061), and of patients who had CRS or ICANS, SD/PD patients had significantly worse PFS (p= <0.001, p= 0.024). This single-center retrospective analysis of patients receiving CAR-T therapy for r/r large B-cell lymphoma showed that incidence and management of toxicities and factors such as tumor subtype associate with treatment response. Further investigations into these factors may provide more insight into optimal management of patients undergoing CAR-T therapy. Citation Format: Fahmin Basher, Caroline A. Coughlin, Deukwoo Kwon, Lazaros Lekakis, Jonathan Schatz. Single-center experience of chimeric antigen receptor T-cell (CAR-T) immunotherapy in relapsed/refractory large B-cell lymphoma identifies association of acute toxicities with inferior disease outcomes [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-55

Is There an Unequal Benefit of Autologous Stem Cell Transplant in Different Cytogenetic Groups of High Risk Patients with Multiple Myeloma: The University of Miami Experience

BACKGROUND: Stratification using cytogenetics (CG), either metaphase karyotyping or fluorescence in situ hybridization (FISH) is used to identify patients (pts) with multiple myeloma (MM) who are at higher risk of relapse and tend to have poorer survival. It is largely unknown if autologous stem cell transplantation (auto-HCT) after high dose melphalan (200 mg/m2) is able to modify the survival of some of these high-risk MM pts and to make it comparable to standard risk. METHODS: Pts were classified as high risk (HR) if either conventional cytogenetics or FISH demonstrated at least one of the following 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16), realizing that the inclusion of 13q- by FISH alone and 1p- in the HR MM definition is controversial. Pts with normal chromosomes or those with trisomies and hyperdiploidy were considered standard-risk (SR). We compared progression-free survival (PFS) and overall survival (OS) via a retrospective analysis of pts at the University of Miami Sylvester Comprehensive Cancer Center who underwent auto-HCT between January 2014 and December 2017 for MM. Survival analyses were performed using the log-rank test, with significance at p-value < 0.05. RESULTS: Male pts comprised 56% of the population, and 40% of pts were of Hispanic ethnicity. Of 205 pts undergoing auto-HCT, 108 (53%) had at least one HR cytogenetic abnormality. Interestingly, the depth of response to pre-transplant induction was higher in pts classified as HR, with 71% (77 of 108) achieving at least a very good partial response (VGPR), while 24% (23 of 96) SR pts achieved VGPR. While OS remained largely unaffected in HR pts (34.0 m vs. 35.1 m, p = 0.27); HR pts had an inferior PFS compared to SR pts (21.9 m vs. 25.7 m, p = 0.041). The presence of trisomies did not negate the poorer PFS of HR pts. When we evaluated specific HR CG abnormalities, OS and PFS in patients with 1q+ or t(4;14) were surprisingly comparable to SR pts, indicating a significant benefit from auto-HCT. On the other hand, OS was significantly decreased in pts with 1p- when compared to standard risk (16.5 m vs. 35.1 m, p = 0.004) or other high-risk patients (16.5 m vs. 35.4 m, p = 0.01), implying that 1p- group derive no benefit from auto-HCT. Similarly, OS was shorter in pts with t(14;16) (16.5 m vs. 34.4 m, p = 0.025) and with 17p- (26.6 m vs. 35.1 m, p=0.01), however the PFS was not affected in these populations. In pts with 13q-, PFS was significantly shorter (20.3 m vs. 25.7 m, p=0.023) compared to SR pts without affecting OS. CONCLUSION: At our center in a retrospective analysis of 205 pts: a) patients with HR MM responded better and faster than SR pts to induction, b) those with 1p- did not derive any benefit from transplant and c) pts with 17p- and t(14;16) had some short term benefit (similar PFS to SR group) but at the end their OS remained inferior. Nevertheless, we consider a very important finding the fact that, by having auto-HCT, pts with 1q+ and t(4;14), equalized their PFS and OS to those of SR pts. Based on these findings, patients with 1q+ and t(4;14) should still have a transplant in CR1 even after optimal induction. Whether 17p- and t(14;16) pts can extend PFS benefit after transplant into OS benefit with maintenance regimens stronger than lenalidomide alone remains to be determined. Disclosures Hoffman: Celgene: Honoraria, Speakers Bureau; Loxo: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding

Aseptic Meningitis after Recovery from SARS-CoV-2 in an Allogeneic Stem Cell Transplant Recipient

SARS-CoV-2 emerged as a worldwide pandemic in late 2019 and initially was described as a primary respiratory illness. The clinical manifestations of COVID-19 are now known to encompass nearly all organ systems, including the central nervous system. We present a case of an allogeneic hematopoietic stem cell transplant recipient who recovered from documented SARS-CoV-2 infection and later presented with symptoms of meningitis. While cerebrospinal fluid analysis did not reveal any bacterial or viral etiologies, evidence of an inflammatory state, including ophthalmologic findings of episcleritis, indicate what is likely the first reported case of aseptic meningitis associated with SARS-CoV-2 infection after initial clinical recovery

Hypogammaglobulinemia and Its Implications in Patients Treated with Daratumumab: A Single Institution Experience

Introduction: Daratumumab is an IgG Kappa monoclonal antibody (mAB) to CD38, a surface glycoprotein expressed on plasma cells. It was approved in 2015 as monotherapy for Multiple Myeloma (MM) patients who failed three prior lines of therapy. Its approval was then expanded to second line and most recently first line. As such, patients are now getting earlier and longer exposure to this mAB. Disease response to daratumumab is monitored by demonstrating a fall in paraprotein levels. It is becoming widely appreciated that hypogammaglobulinemia (HGGE) ie. (IgG<600mg/dl) with risk of infection, is a potential complication for patients on daratumumab. The immune mediated attack by daratumumab on CD38 expressing plasma cells also results in destruction of normal lymphocytes, resulting in impaired production of polyclonal immunoglobulins and diminished immunity. We aim to explore the incidence, severity and clinical significance of HGGE in patients on daratumumab. Methods: We conducted a retrospective chart review of all patients treated with daratumumab as single agent or in combination (November 2015-June 2019), who had documented baseline and post therapy quantitative IgG levels. Demographics, subtype of plasma cell disease, bone marrow cytogenetics/FISH, serial IgG levels, incidence of significant infections and need for IVIG therapy were collected as part of this exploratory data analysis. Results: Among 145 eligible patients, 53% were male, 37% Hispanic, 19% Black/African American and 72% were age<70 at diagnosis. The majority of patients had an IgG paraprotein (56.6%), followed by IgA (18.6%), Free Kappa only (13.1%) and Free Lambda only (9.7%). Hispanics were more likely to have high risk cytogenetics (OR=2.29, p=0.0804). 34.5% of patients had previous autologous stem cell transplant. At baseline 30.3% of all patients had HGGE; 58.1% non-IgG patients and only 9.6% IgG patients. The mean baseline IgG level in IgG patients was 1986.1 mg/dl and for non-IgG patients was 698.1 mg/dl. After being treated with daratumumab, 61.4 % of all patients developed HGGE; 42.2% of IgG patients and 87.1% of non-IgG patients. The mean Nadir IgG level for the IgG subtype cohort was 643.7 mg/dl and for the non-IgG cohort was 355.9 mg/dl. The incidence of significant infection in total group was 23.4% (21.7% in IgG vs 25.8% in non-IgG). Bacterial pneumonia and sepsis were the two most common infections. Despite the relatively high incidence of HGGE in this cohort, only 11 were treated with IVIG. (5 IgG vs 6 non-IgG). Using a univariate logistic regression model, Black/ African Americans and patients with higher baseline IgG were less likely, but non-IgG patients were more likely to develop HGGE (all p<0.05) . Conclusion: Our study identifies a high incidence of meaningful HGGE in patients on daratumumab. In the non-IgG subtype, the relationship is straightforward, as any drop in IgG reflects a drop in polyclonal immunoglobulins and impaired humoral immunity. In contrast, in the IgG subtype, a fall in IgG levels has two components; a fall in the monoclonal protein (indicative of favorable disease response) as well as a fall in polyclonal IgG. There was a lower incidence of pre and post treatment HGGE in the IgG cohort compared to the non-IgG cohort( ie.IgA, IgD, Free Kappa and Free Lambda). In contrast the incidence of infection in both cohorts were very similar. This suggests that polyclonal HGGE in IgG subtype plasma cell disorders may be largely undetected and undertreated, due to apparently normal IgG levels caused by pathologic production of monoclonal IgG. When we attempt to subtract the monoclonal element (m-spike in the serum protein electrophoresis) from the total IgG, the magnitude of hypogammaglobulinemia in the IgG cohort approximates that of the non-IgG group. Given that daratumumab adds a small amount to the measured m-spike, further techniques to quantify true polyclonal IgG levels in the IgG cohort are needed. The incidence and depth of HGGE associated with daratumumab has not been previously well quantified. Our study demonstrates that the incidence of HGGE doubled after therapy with daratumumab (30.3% vs 61.4%). This data will sensitize physicians and possibly lead to generation of guidelines for closer monitoring of IgG, use of IVIG and other precautions in patients on daratumumab. In our own institution, we anticipate the detection of HGGE and use of IVIG in these patients to increase substantially. Disclosures Hoffman: Celgene: Speakers Bureau

Prevalence of EGFR mutation testing in early-stage lung cancer: Implications of the ADAURA trial for clinical practice

e20507 Background: It is reported that about 20% of patients with resected NSCLC adenocarcinoma harbor an EGFR driver mutation in the United States. Up to the recent approval of osimertinib in the adjuvant setting for resected EGFR + NSCLC based on the ADAURA trial, routine molecular profiling of early-stage lung cancer had not been standard of care. We hypothesize that there is a significant proportion of patients with resected adenocarcinoma with unknown EGFR status who could benefit from treatment that are missed with our current testing practices. Methods: We performed a retrospective analysis of Stage IB-IIIA lung adenocarcinomas resected at the University of Miami from 2014 to 2019. Eligible patients were identified from the Cancer Registry and information on EGFR mutation testing and treatment was obtained from chart review. We evaluated the prevalence of EGFR mutation testing in this population and outcomes based on EGFR mutation status. Disease free survival (DFS) and clinico-pathologic characteristics were evaluated. We estimated the number of patients that would have been eligible for EGFR testing and adjuvant osimertinib therapy in the pre-ADAURA era in our patient cohort. Results: A total of 120 patients had resected stage IB-IIIA adenocarcinoma during this five-year period (Stage IB 42.5%; Stage IIA 13.3%; Stage IIB 25%; Stage IIIA 19.2%) with a median age of 66 years. Most were females (59%), NHWs (51.5%), Hispanics (46.9%), and former smokers (66.7%). Out of patients with Stage IB-IIIA NSCLC with adenocarcinoma, 42.5% completed recommended adjuvant platinum-based chemotherapy. Only 40% of patients were referred for EGFR testing during this study period. The prevalence of EGFR mutations in this population was 10.8% (13 /120), but 59% of cases had no available EGFR testing. The most prevalent mutation was L858R (53.8%) followed by exon-19 deletions (30.8%). A total of 6 patients received an EGFR TKI therapy during the follow up period (2 in the adjuvant setting). With a median follow up of 12 mos, the rate of recurrence by stage was: Stage IB (3.9%); Stage IIB (10%); Stage IIIA (13%). Median time to disease progression or death was 13 months in this subgroup. There was no difference in disease free survival for patients with EGFR testing and those without results available in this short follow up period. Conclusions: Based on this retrospective review, up to 60% of patients with early-stage NSCLC with non-squamous histology have no available EGFR testing in the pre-ADAURA era. Of the anticipated 20% of patients with expected EGFR mutations based on historical controls, we have only identified half of patients that would have been eligible for adjuvant osimertinib. This study establishes the importance of upfront EGFR mutation testing in all NSCLC patients, not only to prognosticate, but also to identify the subset of patients who could benefit from adjuvant EGFR therapy

Clinical attributes and outcomes in metastatic non-small cell lung cancer bearing BRAF mutations treated with targeted therapy versus immunotherapy

e21219 Background: Mutations in BRAF oncogene have been identified in about 2-4% of non-small cell lung cancer (NSCLC) patients. Combination of tyrosine kinase inhibitors (TKI), dabrafenib and trametinib has shown improved and enduring results in both first line and second line setting. Given the rarity of BRAF mutations, and the approval of TKI, the role of Immune Checkpoint Inhibitors (ICI) still needs to be ascertained. Methods: We conducted a retrospective review of 19 BRAF-mutant lung cancer patients from 2013-2020 at the University of Miami. Clinicopathologic features, and patient’s response to chemotherapy/ICI vs anti-BRAF targeted therapy (ABTT) was investigated. Duration of response (DOR) was calculated from the initiation of therapy, and Overall survival (OS) was calculated from the diagnosis of metastatic disease. OS was estimated by Kaplan-Meier method and log-rank test was used to compare groups. Hazard ratio (HR) and corresponding 95% confidence interval were estimated using Cox proportional hazards regression model. All tests were two sided and statistical significance was considered when p<0.05. Results: Total 19 patients with a median age of 63 (range 54-87) were identified from a cohort of 575 sequenced lung cancer patients (prevalence of 3.3%). 6 patients were never-smokers, 13 former/current smokers; 10 were women; 10 were Non-Hispanic White, 8 Hispanic, and 1 African American. Majority had adenocarcinoma (n=17) and non-V600E BRAF mutation (n=13)). PD-L1 expression testing (n=11) was negative in 55% (n=6 of 11), low in 9% (n=1 of 11), and high in 36% (n=4 of 11). All patients presented with metastatic disease; lung (16), bone (7), brain (5), and liver (4). 47.4% (n=9) of patients received platinum-based doublet chemotherapy as first-line (FL) treatment; 21.1% (n=4) received combined chemotherapy+ICI as FL; 5% (n=1) received ABTT as FL. Overall, 47% (n=9) received ABTT; 11.1% (n=1) as FL, 33.3% (n=3) as second line, 44.4% (n=4) as third line, and 11.1% (n=1) as fourth line. Median OS in the entire cohort was 1.86 years (95 % CI :1.26-2.32). Median DOR to ICI as first line or second line agent was 3 months (mos) (range 0.5-25mos). Median DOR to TKI in BRAFV600E cases was 13 mos (range 7-53mos), as second line agent or beyond. Among patients with BRAFV600E mutation, median OS was 4.89 years (95% CI 4.31-NA) in recipients of ABTT, and 1.68 years (95% CI not estimable) in patients who did not receive ABTT. Conclusions: In our BRAF-mutant NSCLC cohort, median DOR was greater in patients treated with ABTT, than those with ICI. ABTT treated BRAFV600E-mutant patients had longer OS, in comparison to those treated without ABTT. Our analysis highlights a potentially significant benefit of ABTT, and an unsatisfactory response with ICI, in patients harboring BRAFV600E mutation; therefore, the role of ICI in this subgroup needs further investigation

Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism.

Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1(+/+) or Fli1(+/-) T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1(+/-) lupus T cells compared to animals receiving Fli1(+/+) lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1(+/-) T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1(+/+) T cells. Moreover, the Fli1(+/-) T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1(+/+) T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus