Broski, Stephen M.

Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed refractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus (VSV) has been engineered to encode interferon beta (IFNβ) and sodium iodine symporter (NIS) to produce VSV-IFNβ-NIS. The virally encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. The NIS is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. Here we present results of Arm A (patients with low tumor burden) of the Phase I clinical trial (NCT03017820) of intravenous administration of VSV-IFNβ-NIS for patients (pts) with relapsed refractory hematological malignancies: MM, AML, and TCL. Methods: This was a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (50% tissue culture infectious dose) level 1 through 1.7x10^11 TCID50 dose level 4 given as a single IV dose. The primary objective was determining the maximum tolerated dose of VSV-IFNβ-NIS alone; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding and changes in the immune profile of peripheral blood leukocytes. Adverse events (AEs) are reported based on CTCAE v4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014; 124(2):188-195) criteria. Results: From April 2017, 12 pts have received IV VSV-IFNβ-NIS in Arm A: MM (7), TCL(4) and AML(1); 3 pts were treated at each dose level (DL) 1 to 4. At DL1, there were five grade 3 hematologic AEs (leukopenia [1], neutropenia [1], lymphopenia [3]) and no grade 3+ non-hematologic AEs. At DL2, three grade 3 hematologic AEs (anemia [2], lymphopenia [1]), four grade 4 hematologic AEs (neutropenia [1], leukopenia [1], lymphopenia [1] and thrombocytopenia [1]). There was 1 event of grade 2 CRS at DL2, two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). At DL3, there was one grade 4 hematologic AE (neutropenia [1]), three grade 3 hematologic AEs (lymphopenia [2], leukopenia [1]), and one grade 3 non-hematologic AE (vasovagal reaction [1]). One grade 2 and grade 1 CRS by Lee criteria were observed. At DL4, there were three grade 3 hematologic AEs (lymphopenia [1], neutropenia [1], thrombocytopenia [1]), and three grade 3 non-hematologic AEs (AST increase [1], skin infection [1], soft tissue infection [1])and two grade 2 CRS. There were no dose limiting toxicities. There was one partial response (DL2) and one complete response (DL4); 3 pts had stable disease, 7 pts progressed. The MM pts receiving VSV-IFNβ-NIS at DL4 had stable disease. Six of the 7 MM pts demonstrated transient reduction in serum level of involved free light chain (LC) after VSV-IFNβ-NIS infusion, with median 20.4% reduction of the involved LC within 48 hrs. Viremia was detectable in all pts at the end of infusion, to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hrs post infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. The IFN levels were detectable within 30 minutes of infusion and peaked between 4 and 48 hrs. The pts with a diagnosis of TCL mounted higher hIFNβ levels within 48 hrs. Remarkably, the TCL pt with CR (DL4) mounted a peak hIFNβ response of 18213.3pg/ml at 48 hrs post infusion, approximately 15-fold higher than any other pt enrolled in the study; and highest neutralizing antibody titer (1:40960). Conclusion: VSV-IFNβ-NIS can be safely administered by intravenous infusion in pts with hematological malignancies, up to a dose level of 1.7 x 1011 TCID50, without dose limiting toxicities and no CRS higher than grade 2. In this small phase 1 study, pts with T-cell lymphoma demonstrated the strongest signal of response, with one confirmed partial response at DL2 and one complete response at DL4. IFNβ is an early biomarker of tumor susceptibility; the magnitude of IFNβ elevation appears to correlate with treatment response. There were no confirmed responses in pts with MM, but the 20.4% transient reduction in LC suggests that combination strategies with VSV-IFNβ-NIS may result in deeper and sustained responses in MM. Future trials investigating combination strategies with immune modulatory drugs are being planned. Disclosures Peng: Imanis: Other: Equity Ownership. Witzig:Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Incyte: Consultancy; Acerta: Research Funding; MorphSys: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Dispenzieri:Intellia: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Gertz:Celgene: Consultancy; Annexon: Consultancy; Sanofi: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; NCI SPORE MM: Research Funding; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; Ionis/Akcea: Consultancy; Spectrum: Consultancy, Research Funding; Prothena: Consultancy; DAVA oncology: Speakers Bureau; i3Health: Consultancy; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; International Waldenstrom Foundation: Research Funding. Dingli:Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Genecentrix: Consultancy; Tenebio: Other, Research Funding. Russell:Imanis: Other: Equity Ownership. OffLabel Disclosure: This describes of administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and human interferon, in Patients with Relapsed or Refractory Hematologic malignacies

AbstractBackgroundMultiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle).MethodsThe patient underwent magnetic resonance imaging (MRI) and whole body 18F‐florbetapir positron emission tomography (PET)/MRI.ResultsWhole body 18F‐florbetapir PET/MRI revealed abnormal low‐level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis.Conclusions 18F‐florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

AbstractThe role of quantitative magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) techniques continues to grow and evolve in the evaluation of musculoskeletal tumors. In this review we discuss the MRI quantitative techniques of volumetric measurement, chemical shift imaging, diffusion-weighted imaging, elastography, spectroscopy, and dynamic contrast enhancement. We also review quantitative PET techniques in the evaluation of musculoskeletal tumors, as well as virtual surgical planning and three-dimensional printing.

e20068 Background: FL grade 3B (FL3B) is an aggressive subtype of FL with a distinct morphologic, cytogenetic and immunohistochemical profile that is associated with higher mortality compared to other subtypes of FL. FL3B is a rare disease, and data regarding its prognostication beyond grading is lacking. Recent data suggests that spleen and extranodal (EN) involvement on PET/CT predict early clinical failure in FL grades 1-3A[1]. We aimed to determine the incidence of spleen and EN involvement on PET/CT in FL3B, and whether these can predict EFS. Methods: Patients with untreated FL3B diagnosed between 2003-2016, with available pre-treatment PET/CT, were identified using the Mayo Clinic Lymphoma Database and the University of Iowa/Mayo Clinic Lymphoma SPORE database. 27 patients were included in this analysis. All but two patients received treatment with immunochemotherapy. Associations with outcomes were assessed using EFS, defined as disease progression, relapse, transformation, or death. Results: 11/27 (40.7%) of patients had EN involvement on PET/CT. The most common EN site was bone, in 8/27 (29.5%) of patients. Soft tissue involvement was present in 4/27 (14.8%) of patients. Liver, brain, and endometrial involvement were each noted once. 11/27 (40.7%) of patients had spleen involvement on PET/CT. Presence of bone involvement as detected on PET/CT was associated with lower EFS (p = 0.02). EN involvement was associated with a trend toward a lower EFS but statistical significance was not reached likely secondary to low numbers in this cohort. Results in the table are compared to results obtained from our analysis in patients with FL grade 1-3A[1]. Conclusions: Bone involvement on pre-treatment PET/CT in FL3B was associated with early clinical failure in this small cohort of 27 patients. EN involvement at diagnosis may also be associated with poorer outcomes. These findings are similar to our analysis of a large (n = 613) cohort of patients with FL grade 1-3A. These findings may aid in the prognostication of patients with newly diagnosed FL3B, to guide therapy in select higher risk patients. [Table: see text]

AbstractWith rapid advancements in the diagnosis and treatment of multiple myeloma (MM), imaging has become instrumental in detection of intramedullary and extramedullary disease, providing prognostic information, and assessing therapeutic efficacy. Whole‐body low dose computed tomography (WBLDCT) has emerged as the study of choice to detect osteolytic bone disease. Positron emission tomography/computed tomography (PET/CT) combines functional and morphologic information to identify MM disease activity and assess treatment response. Magnetic resonance imaging (MRI) has excellent soft‐tissue contrast and is the modality of choice for bone marrow evaluation. This review focuses on the imaging modalities available for MM patient management, highlighting advantages, disadvantages, and applications of each.

AbstractBackgroundStandard bone marrow biopsy (BMB) and bone involvement with follicular lymphoma (FL) on positron emission tomography (PET)/computed tomography (CT) both predict early clinical failure in FL. The key clinical question is whether PET/CT findings can obviate the need for BMB. The goal of this study was to determine the value of PET/CT in determining bone involvement in FL, using posterior iliac crest BMB as the gold standard.Materials and MethodsA total of 548 patients with newly diagnosed grade 1–3A FL were included. The presence, pattern, and location of bone involvement, spleen involvement, and standardized uptake values (SUVs) in the L3 vertebral body were recorded for all patients and compared with the BMB report.ResultsExcluding patients with focal bone lesions on PET/CT, the sensitivity and specificity of PET/CT in detecting bone or marrow involvement, compared with BMB, were 53% and 88%, respectively. The sensitivity and specificity of spleen involvement on PET/CT in predicting a positive BMB were 55% and 86%, respectively. An L3 SUVmax of less than 2.0 resulted in a negative predictive value (NPV) of 96% for marrow involvement on BMB; an L3 SUVmean below 1.4 resulted in an NPV of 100%.ConclusionIn newly diagnosed FL, PET/CT-detected bone and splenic involvement is highly specific for a positive BMB, and very low SUV values (<2.0 SUVmax and < 1.4 SUVmean) in the lumbar spine have a high NPV for a negative BMB. Routine BMB may be obviated in these patients. BMB remains necessary to definitively exclude bone marrow involvement in a large majority of patients with a negative PET.Implications for PracticePredicting early clinical failure in follicular lymphoma (FL) is important but difficult. Bone marrow involvement by FL is associated with early clinical failure, and determining this involvement is a key component of the initial staging. This study highlights that in certain patients, positron emission tomography/computed tomography is sufficient in determining bone or marrow involvement, without the need for a confirmatory bone marrow biopsy (BMB). An algorithm is provided based on these findings to help clinicians determine which patients would benefit from BMB and when it can be avoided.

Abstract INTRODUCTION: Adult mature T- and NK-cell neoplasms are a heterogeneous group of aggressive lymphomas comprising approximately 10% to 20% of all non-Hodgkin lymphomas (NHL) with an estimated 5-year overall survival of 40%. Staging and treatment strategies are guided by malignant involvement on PET/CT scan and bone marrow (BM) biopsy. The Lugano Criteria, established in 2014, suggested that focal FDG uptake within the bone marrow was highly sensitive for both Hodgkin (HL) and diffuse large B-cell lymphoma (DLBCL) potentially obviating the need for a bone marrow biopsy if no lesions were seen. Limited data exist regarding the sensitivity of PET for BM involvement in T-cell lymphoma. This study compares PET/CT scans and repeat BM biopsy in patients who have undergone treatment for peripheral T-cell lymphomas (PTCL) by evaluating BM avidity on PET scans. METHODS: This is a single institution study using the Mayo Clinic Lymphoma Database between January 1, 2001 and January 1, 2015. We retrospectively identified all patients with a diagnosis of PTCL, biopsy proven BM involvement at diagnosis, and a concomitant PET for staging. Patients were then reviewed to assess completion of induction therapy and availability of both PET/CT and bone marrow results post-therapy. Evaluation for concordance and discordant BM involvement were then determined using BM biopsy as the gold standard. RESULTS: Sixteen patients had both PET/CT and BM biopsy after completing induction therapy. Median age at diagnosis was 63 years (range 34-72) and 69% were male. PTCL subtype was peripheral T-cell lymphoma, not otherwise specified in seven patients; ALK negative anaplastic large cell lymphoma in one patient; and angioimmunoblastic in 8 patients. Pre-treatment PET/CT scans demonstrated eight patients (50%) with false negative scans. Post-treatment biopsy results demonstrated that ten (62.5%) had biopsy proven residual bone marrow involvement after induction. Eight patients (50%) were found to have BM biopsy proven disease with a negative PET scan. Two patients (12.5%) had both positive BM biopsy and PET scans; 5 patients (31.3%) had negative BM biopsies and PET scans. One patient (6.25%) had a negative BM biopsy, but had a PET scan that revealed positive disease. This patient was considered to have had a false positive PET scan and indeed has remained in remission since April 2009 without any further relapse or treatment. Sensitivity of PET for BM involvement was very poor at 20% (2/10) with a specificity of 50% (2/4) (Table 1 and 2). CONCLUSIONS: This study in PTCL indicates that PET scans at the completion of therapy have a 50% false negative rate. These patients should not be assumed to have negative bone marrow involvement based solely on PET/CT scans. A bone marrow biopsy at the end of therapy is necessary in PTCL patients to confirm complete response. Table 1. Bone Marrow Involvement Pre-Therapy PET Scan Imaging PET Negative PET Positive Total Patients Bone Marrow Negative NA NA NA Bone Marrow Positive 8 8 16 Total Patients 8 (50%) 8 (50%) 16 Abbreviations: NA, not applicable. The study defined that all patients had to have a positive bone marrow at baseline to be eligible for the study. Table 2. Bone Marrow Involvement PET Negative PET Positive Total Patients Bone Marrow Negative 4 2 6 (37.5%) Bone Marrow Positive 8 2 10 (62.5%) Total Patients 12 (75%) 4 (25%) 16 Table 1 and 2. Involvement of bone marrow with peripheral T-cell lymphoma based on evaluation by PET scans versus bone marrow biopsy. Disclosures Maurer: Kite Pharma: Research Funding.

7554 Background: Predicting early clinical failure in patients with untreated FL is important but difficult. Lymphoma involvement of EN sites is better detected by FDG-PET/CT than CT alone, but PET parameters are not part of the usual predictive indices. We aimed to determine the incidence and patterns of spleen and EN disease using PET/CT, and learn if they are useful in predicting early clinical failure. Methods: PET/CT images from 613 cases of newly diagnosed FL between 2003 – 2016 were retrospectively reviewed. The location, pattern, and number of EN sites, as well as splenic involvement, were recorded. Associations with outcomes were assessed using event-free survival (EFS) and overall survival (OS). Results: 49% (301/613) of patients had PET/CT-detected EN involvement, and 28% (171/613) had spleen involvement. Presence of ≥2 EN sites, spleen, bone, or soft tissue involvement, as well as a multifocal on diffuse pattern of bone involvement by imaging, were univariate predictors of EFS; presence of ≥2 EN sites and bone involvement pattern were also predictive of OS. In a multivariate analysis with FLIPI-2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (Table). When the multivariate analysis was performed using PRIMA-PI factors, the presence of ≥2 EN sites was an adverse independent prognostic factor for OS (HR 2.28; 95% CI 1.01-5.18; p=0.05). Conclusions: Baseline PET/CT identifies EN and spleen sites of disease that can predict early clinical failure of FL. These results may be useful to better identify high-risk patients and guide appropriate therapy. [Table: see text]

Background: FDG PET/CT and bone marrow biopsy (BMB) are considered standard procedures for the staging of patients with new, untreated FL. A key issue in FL is the early identification of patients who will fail early. We recently reported (Am J Hematology 2019) that the presence of ≥2 EN sites, spleen, bone or soft tissue involvement as detected by PET all predicted failure to achieve EFS24. In Hodgkin lymphoma and diffuse large B-cell NHL, PET has replaced the routine need for a staging BMB. However, there is no such evidence in FL. The goal of this study was to determine the value of FDG PET/CT in determining bone involvement in FL using BMB as the gold standard. Methods: Patients were identified using the Mayo Clinic Lymphoma Database. 548 patients with newly diagnosed FL grades 1-3A between years 2003-2016, available BMB results, and PET/CT imaging at diagnosis, were included in the analysis. The presence of bone and spleen involvement on PET/CT, SUVmax and SUVmean of the axial skeleton at L3, and BMB results were recorded and compared. Results: In all, 36% (197/548) of patients had a positive BMB, and 34% (189/548) had bone involvement detected on PET/CT. Compared to BMB, the sensitivity and specificity of PET/CT in detecting bone involvement as determined by BMB were 60% and 80%, respectively. We noted that 59 patients had focal bone involvement on PET/CT rather than a diffuse component, and found that 47% (28/59) of these patients had a negative BMB obtained in the posterior iliac crest. Excluding these patients, the sensitivity and specificity of PET/CT in detecting bone involvement were 53% and 88%, respectively (Table 1). With respect to the spleen, 29% (157/548) of patients had evidence of splenic FL involvement on PET/CT, and of these, 69% (109/157) also had a positive BMB. The sensitivity and specificity of spleen involvement on PET/CT in predicting bone involvement on BMB were 55% and 86%, respectively (Table 2). We recorded SUV data at L3 in the 439 patients who had either a diffuse pattern of bone involvement on PET/CT, or a PET/CT read as negative. We analyzed the positive and negative predictive values (PPV and NPV) of SUVmax and SUVmean at several cut-off points to determine whether axial bone SUV is reliable at determining patients with a positive or negative BMB. The NPV for an SUVmax of less than 2.0 was 96% (n=25 patients classified as negative). For SUVmean, the best cut-off point was at less than 1.4, where NPV was 100% (n=15 patients classified as negative). There was no logical cut-off point for a significant PPV > 95%. Conclusion: In newly diagnosed FL, the sensitivity and specificity of bone involvement on PET/CT are insufficient for PET/CT to routinely replace BMB. However, in patients where the need for BMB at staging is being debated, certain factors on PET/CT can help facilitate this decision. The detection of focal bone lesions, especially those that may be missed on posterior iliac crest BMB, can make BMB unnecessary. If both the spleen and bone appear involved on PET/CT, this confers a relatively high chance that BMB will be positive. If SUVmax at L3 is less than 2.0, or if SUVmean is less than 1.4, the BMB will likely be negative, with a NPV > 95%. This decision-making algorithm is outlined in Figure 1 and may serve as a useful guideline for clinical trials and routine practice. Disclosures No relevant conflicts of interest to declare.