ALBERT

Description: Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile. Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity. Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a "by-default-delayed" ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background Autosomal dominant germline mutations in the phosphatidylinositol-3-OH kinase (PIK3CD) encoding for the PI(3)K catalytic subunit p110δ, lead to combined immunodeficiency with increased incidence of B-cell lymphomas. (Lucas CL et.al. Nature Immunology 2014). While p110δ is selectively expressed in leukocytes, it is critical for TCR and BCR signaling and lymphocyte homeostasis. Clinically, these patients may present with sinopulmonary infections, bronchiectasis, cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) viremia, lymphoproliferation and autoimmune cytopenias. Immune phenotype includes naïve CD4+ T cell lymphopenia, expanded terminally differentiated or exhausted T cells, increased circulating transitional B cells and reduced class-switched memory B cells. Herein we report immunophenotypic abnormalities in B-lymphoid maturation in the bone marrow (BM) of 5 patients with PIK3CD mutations. Methods BM from 5 patients with PIK3CD mutations (2 males, 3 females, age range: 4–15 years, median 11.5 years) were studied by flow cytometry (FC), morphology and immunohistochemistry (IHC). BM aspirate from 5 healthy age matched pediatric patients were used as controls for flow cytometric analysis of B-cell subsets and maturation. Antibodies against CD45, CD3, CD4, CD8, CD19, CD10, CD34, CD20, and surface kappa and lambda light chains were used for FC. B-lymphocyte subsets were defined as: early stage precursor B-cells (CD34+/CD19+/CD10+bright/CD20-); intermediate precursor B-cells (CD45+moderate/ CD19+/CD10+moderate/CD34-); and late stage and mature B cells (CD34-/CD10-/CD19+/CD45+bright/CD20+). The intermediate subset corresponds to transitional B cells (developmentally intermediate between immature and mature naive B cells). IHC and in situ hybridization staining were applied to biopsy sections using standard methods. Prism software was used for statistical analyses (Mann-Whitney test). Results There was no significant difference in the median percentage of early B-cell precursors (among all B-lymphocytes) between the PIK3CD patients and the age-matched controls (3.6% vs. 3.7%; p=0.8). However, all PIK3CD marrows showed expanded CD10+ intermediate precursor B-cells which were overall 2.5 times more abundant in PIK3CD marrows than in controls (94.6% vs. 37.4% of all B-cells; p

Description: Background Hairy cell leukemia (HCL) variant (HCLv) is considered a separate, more aggressive entity compared to classic HCL. HCLv responds poorly to single-agent purine analog with complete response (CR) rates below 10% and overall response rates under 50%. Rituximab combined with purine-analog can improve response rate and duration, but long-term data have not been reported for HCLv, particularly regarding minimal residual disease (MRD). We therefore update the results of a phase II trial with cladribine and concurrent rituximab in patients with HCLv, previously reported for 10 of the 20 patients enrolled. Methods Patients with HCLv with 0 to 1 prior courses of cladribine, and/or 0-1 prior courses of rituximab, received cladribine (0.15 mg/kg days 1-5), with 8 weekly doses of rituximab (375 mg/m2) beginning day 1. The primary endpoint was to determine CR rate and secondary endpoints included evaluating minimal residual disease (MRD) by blood and bone marrow aspirate flow cytometry, and bone marrow biopsy immunohistochemistry. Patients were able to receive a 2nd course of rituximab ≥ 6 months after the first, if and when MRD was detected in blood. Results Twenty patients were enrolled. Median age was 67 (range: 42-86) years. No patients had prior concurrent cladribine-rituximab. Eight were previously untreated, 1 had only splenectomy, 6 had prior cladribine, 1 had prior cladribine and splenectomy, 1 had prior rituximab, 1 had prior rituximab and splenectomy, 1 had cladribine, rituximab, and splenectomy, and 1 had combination rituximab-containing chemotherapy followed by cladribine. Out of 20 patients receiving concurrent cladribine-rituximab (CDAR), the CR rate was 95% (95% CI: 75-100%). This CR rate was superior to a historical control group of 3 of 39 HCLv patients who achieved CR to cladribine alone (p

Description: Background Hodgkin lymphoma (HL) is mainly composed of reactive cells. Lymphocytes, macrophages, eosinophils, mast cells, plasma cells, and other stromal cells constitute these supportive or reactive cells. In-situ glycolytic and oxidative phosphorylation metabolism of reactive cells and cancer cells is unknown in HL. We interrogated HL specimens (N=24) to examine the metabolic compartments in-situ in this disease. Introduction High glycolytic activity is seen in the majority of HL on the basis of high uptake of 2-[18] fluoro-2-deoxy-glucose (FDG) on positron emission tomography (PET). The advent of FDG-PET in HL has revealed that these tumors as a unit are glycolytic and staging and assessment of response to treatment has improved. However, it is unknown if cancer cells and reactive cells share a metabolic phenotype. Purpose To study mitochondrial and glycolytic metabolism in HL cancer and reactive cells. Methods/Materials Two immunohistochemical biomarkers of metabolism were employed on HL tumor sections. Translocase of the Outer Mitochondrial Membrane 20 (TOMM20) protein expression is a biomarker of functional mitochondrial mass and oxidative phosphorylation. Monocarboxylate transporter 4 (MCT4) is a biomarker of glycolysis and lactate export. We selected 24 consecutive cases of classical HL based on morphology and immunohistochemical (IHC) staining for CD30, CD15 and CD45. We recorded FDG-PET standard uptake values (SUV) where available for all tumors studied. Immunohistochemical stains were performed on 5-micron thick, formalin-fixed, paraffin-embedded tissue sections using the horseradish peroxidase method. The primary antibodies used were TOMM20 and MCT4 (Santa Cruz). The immunostaining was graded on a scale of 0 to 2+ according to the intensity and percentage of immunoreactive cancer and reactive cells. Results Reed Sternberg and Hodgkin cells (RS/H) had high TOMM20 expression and low MCT4. In fact, the highest TOMM20 expression out of all cells analyzed was found in the RS/H cells in 20 of the 24 samples. In the other 4 samples, cancer and reactive lymphocytes (RL) had similar expression of TOMM20. The tumor stroma or stromal cells in proximity to cancer cells which includes histiocytes (TS/H) had low TOMM20 expression and high MCT4 expression in all 24 samples analyzed. Higher than baseline FDG-PET uptake is a measure of glycolysis and was found in all tumors where FDG-PET was performed. High MCT4 expression was not found in normal stroma or stroma at a distance from cancer cells. Histiocytes always had low TOMM20 expression but MCT4 expression was high in proximity to cancer cells and low at a distance from cancer cells. Conclusion Glycolysis and lactate export occurs in cancer-associated stroma (TS/H) that is spatially linked to mitochondrial metabolism in cancer cells (RS/H) in HL. This suggests that the most FDG-PET avid cells within HL are the reactive cells and not the cancer cells. Also, normalization of FDG-PET uptake when assessing response to treatment suggests reversal to a metabolically normal stroma. Representative images, 60x: Disclosures: No relevant conflicts of interest to declare.

Description: TAR is a rare bone marrow failure syndrome comprised of thrombocytopenia and a spectrum of bony abnormalities, the most common being bilateral radial aplasia in the presence of thumbs. Recent research has implicated alterations in the RBM8A gene in the pathogenesis of this disorder. Diffuse LCH is a neoplasm of mature Langerhans cells, a subset of dendritic cells, that has now been demonstrated to be clonal in nature. The co-occurrence of these two rare disorders has only been reported twice (Ingram, BMT 2006; Guastadisegni EJMG 2012). We report the third case of a patient with TAR and LCH and present the molecular and genetic characterization of this patient. A 52 year woman with TAR presented with abdominal mass, splenomegaly and left axillary adenopathy. CT scan showed a right pelvic mass measuring 11.5 x 8.6 cm, retroperitoneal lymphadenopathy, enlarged spleen and patchy areas of radiolucency throughout the spine, pelvis and left femoral head. Excisional biopsy of the left axillary lymph node revealed complete effacement of the normal lymph node architecture by an atypical proliferation of Langerhans cell histiocytes. Bone marrow involvement was documented as well. On immunohistochemistry, these cells were positive for CD1a (membrane staining) and S-100 (nuclear and cytoplasmic staining). As part of the diagnostic evaluation, CGH microarray (Signature Genomics) was performed. A diagnosis of diffuse LCH was made. She was treated with vinblastine and prednisone for a year and remains in complete remission from her disease 14 months later. Genomic DNA was extracted from peripheral blood (normal mononuclear cells) and paraffin-embedded tumor tissue, with written informed consent following the approval of the Institutional Review Board of Thomas Jefferson University. The CGH result on the patient's uninvolved tissue as well as the tumor sample showed a hemizygous deletion of 1q21.1 encompassing the RBM8A gene, consistent with recent TAR literature (Albers, Nat Genet 2012). Sequence analysis of the other RBM8A allele revealed minor allele A at SNP rs139428292 at position chr1:145,507,646 (hg19) in the 5'UTR of RBM8A and nt G at chr1:145,507,777 in the first intron (int1 +44). The coding sequence was normal. Minor allele A at the 5'UTR SNP has been associated with TAR syndrome, along with minor allele C at intronic SNP (rs 201779890, int1 +32) which was major allele G in our patient. However, nt G at intron 1 +44 is a novel variant that has not been reported before in dbSNP137, HapMap or 1000 Genomes (UCSC Genome Browser, August 1, 2013). The CGH result on the patient's tumor sample showed a 1.82 Kb deletion within the MAF gene. We identified in normal and tumor DNA one intact MAF gene and one deleted of all of the coding sequences of MAF isoform 1 (alternatively, complete deletion of exon 1 of MAF isoform 2). In addition, a copy loss in the 14q32.2 region was found in the tumor sample but not in the uninvolved tissue. This region contains the BCL11b gene. Finally, we identified a tumor-specific missense mutation (GTG to GAG) resulting in a change in amino acid from valine to glutamine at codon 600. This is the BRAF V600E mutation previously described in LCH and other malignancies. In summary, we report the third ever reported case of the co-occurrence of two rare disorders, TAR and LCH, in a single patient and identify novel molecular changes. We have found the patient to have the recently reported RBM8A genetic alterations of TAR (microdeletion of 1q21 for one allele, minor 5’UTR SNP on the other allele), plus a novel RBM8A intronic SNP. We found a somatic MAF deletion in our patient, possibly a predisposing factor towards LCH. In addition, BRAF V600E mutation is a tumor-specific mutation in our patient. Whether BRAF inhibitors will be of therapeutic benefit in primary or relapsed LCH is currently unknown. Future research is needed to elucidate the function, if any, of the novel RBM8A SNP, the mechanism(s) by which the identified SNPs lead to reduced Y14 levels, and the potential contribution of Y14 deficiency in tumorigenesis. The authors wish to acknowledge the invaluable role of Dr. Elena Gitelson in the care of this patient. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Identifying the causes of adult-onset rheumatic diseases remains a challenge, and limits diagnosis, prognosis, and targeted treatment. We hypothesized that mutations in genes regulating the post-translational modification ubiquitin, previously implicated in two autoinflammatory diseases, may define new rheumatic disorders. Methods: We analyzed peripheral blood exome sequence data from 2,560 individuals with inflammation-related diagnoses for deleterious mutations in 〉800 ubiquitin-related genes. After discovering three patients with novel UBA1 mutations, we identified additional cases based on clinical similarities through screening multiple independent cohorts. Clinical evaluation of all patients combined with Sanger sequencing, digital droplet PCR, immunoblotting, immunohistochemistry, flow cytometry, and transcriptome/cytokine profiling were performed. CRISPR/Cas9 edited zebrafish provided an in vivo model to assess UBA1 gene function. Results: Twenty-eight adult males were identified with somatic mutations at methionine 41 in UBA1, an X-linked gene, encoding the major E1 enzyme that initiates ubiquitylation. Methionine 41 is highly conserved in UBA1, and these mutations were not observed in exome sequences from over 80,000 healthy controls. Among affected individuals, mutations were found in more than half of hematopoietic stem cells, exclusively in peripheral blood myeloid cells, and not in lymphocytes or fibroblasts. The variant allele fraction of UBA1 p.Met41 mutations in peripheral blood ranged from 20-95%. Patients developed an often fatal, treatment-refractory inflammatory syndrome in late adulthood, with fever, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis and some individuals met clinical criteria for relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, or giant cell arteritis. In addition, the majority of subjects developed myelodysplastic bone marrow with cytopenias, characteristic vacuoles in myeloid and erythroid precursors cells, progressive bone marrow failure and thromboembolic disease, and some fulfilled clinical criteria for myelodysplastic syndrome or plasma cell dyscrasia. Transformation into MDS with excess blasts or acute myeloid leukemia did not occur in any case. Mutations at p.Met41, the initiation start site of the canonical cytoplasmic isoform, caused loss of this protein and expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral blood cells exhibited decreased ubiquitylation and activated innate immune pathways. Knockout of the zebrafish cytoplasmic UBA1 isoform homologue, but not the nuclear isoform, caused systemic inflammation. These results identify somatic mutations in UBA1 as the cause, and not the consequence, of this inflammatory disease. Conclusions: We have defined a novel disorder, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), which connects seemingly unrelated adult-onset inflammatory and hematologic diseases. Our work also reveals somatic mutations in a hematopoietic stem cell as a cause of adult-onset rheumatic syndromes that overlap with hematologic conditions. Identification of UBA1 mutations as a cause of these diseases has important implications for classification, prognosis, and treatment of patients, and for the role of somatic mutations of hematopoietic origin in multi-organ pathophysiology. Figure Disclosures Young: Novartis: Research Funding.

Description: Background: HR-SMM is a plasma cell disorder with a 5-year risk of progression to symptomatic multiple myeloma (MM) of ~75% without therapy. Early treatment with novel therapies, may decrease the risk of progression and prolong survival as evidenced by studies (Quiredex and ECOG E3A06) comparing lenalidomide ± dexamethasone to observation. Randomized studies in MM have demonstrated that triplet are superior to doublet regimens and whole exome sequencing in HR-SMM suggests a more treatment-sensitive biology. Together, these support our initial pilot study (Korde et al, JAMA Onc 2015) in using effective therapy with KRd-R as early intervention. Given the favorable initial results of our pilot in terms of minimal residual disease (MRD) negativity rates, we designed a single-arm, phase 2 study with the primary objective of determining the rate of MRD negative complete remissions. Herein, we show that rates of MRD negativity are high and they are sustained with the use of KRd-R. Methods: Patients with HR-SMM (Mayo Clinic or PETHEMA models) received eight 28-day cycles of carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after 4 cycles of KRd and then resumed treatment without an intent for early high-dose melphalan with stem cell support (HDM-ASCT). After 8 cycles of KRd, patients transitioned to receive maintenance therapy with lenalidomide 10 mg PO days 1-21 for 24 additional cycles. Prophylactic antiviral and anticoagulation was mandated for all. MM laboratory evaluations were performed at the start of every cycle during KRd and every 3 cycles during -R and every 3 months during indefinite follow up. Bone marrow biopsies and PET/CTs were performed by the end of cycle 8 induction and then annually indefinitely. The primary objective was to determine the rate of MRD negative remissions by validated multi-color flow cytometry (≤10-5 sensitivity). Key secondary objectives included progression free survival (PFS) to symptomatic myeloma and biochemical progression per IMWG, duration of MRD negativity, overall response rate (ORR), and duration of response. Results: As of 7/15/2020, 52 patients meeting eligibility criteria were enrolled and their demographics and disease characteristics are shown in Table 1. With a median potential follow up of 27.3 months, the primary objective of MRD negative CR rate was 70.2% and the MRD negative ≥VGPR rate was 80.9%, Table 2. The median duration of MRD negativity was 5.5 years with 2 and 5 -year rates of 78% and 55%, respectively. The median time to progression to MM and time to biochemical progression was not reached with 90-month rates of 90% and 78%, respectively - 2 patients progressed to symptomatic MM and 4 patients biochemically. The ORR was 100% and 78% achieved a best response of stringent CR. No deaths occurred. All grade and Grade 3-4 treatment-related adverse events occurred in 90% and 33% of patients, respectively. Grade 3-4 toxicities occurring in 〉1 patient included neutropenia (19%), lymphopenia (13%), thromboembolism (12%), anemia (8%), rash (8%), leukopenia (6%), lung infection (6%), ALT increase (4%), diarrhea (4%), hyperglycemia (4%), hypophosphatemia (4%), and thrombocytopenia (4%). Other Grade 3-4 adverse events of interest occurring in ≤1 patient included atrial fibrillation, creatinine increase, dyspnea, febrile neutropenia, heart failure, hypertension, and neoplasm. Treatment discontinuation occurred in 4 patients; 3 due to toxicity and 1 due to patient withdrawal. Conclusions: Treatment of HR-SMM with KRd-R to prevent symptomatic MM resulted in an MRD negative CR rate of 70% with a median duration of 5.5 years. At the 5-year landmark, only 10% of patients developed MM which is favorable compared to historical rates with no treatment of ~75%. Alternative approaches using monotherapy lenalidomide (Lonial et al, JCO 2019) resulted in no CRs and a 5-year progression rate of 22% with a treatment discontinuation rate of 51% compared to 7% in our study. More aggressive approaches include GEM-CESAR (Mateos et al, ASH 2019) incorporating HDM-ASCT with KRd-R. Importantly, the rate of MRD negativity reported in GEM-CESAR was 56% compared to 70% in this study. Overall, the benefit compared to risk with KRd in SMM is very favorable. Future randomized trials will be needed to lock in this conclusion. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Manasanch:Quest Diagnostics: Research Funding; Sanofi: Research Funding; JW Pharma: Research Funding; Merck: Research Funding; Takeda: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Research Funding. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Landgren:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Seattle Genetics: Research Funding. OffLabel Disclosure: carfilzomib, lenalidomide, and dexamethasone are not approved for smoldering myeloma.

Description: Somatic mutations in UBA1 in hematopoietic stem cells and myeloid cells have recently been described and are associated with adult-onset severe autoinflammatory diseases including relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, and giant cell arteritis. This newly defined syndrome is named VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic). We performed clinicopathologic, cytogenetic, flow cytometric and molecular bone marrow assessment of 15 patients diagnosed with VEXAS and peripheral cytopenias. All patients were male, with a median age of 64y (IQR 45-80) and all had somatic missense mutations affecting the p.Met41 residue in UBA1 with variant allele frequencies (VAF) over 20% from peripheral blood or bone marrow samples and with lineage restriction to mature myeloid cells. Germline mutations at this residue are not reported in any public databases. Peripheral blood findings included macrocytic anemia in all patients (100%), thrombocytopenia in 9/15, and neutropenia in 1/15. All bone marrow aspirates (15/15; 100%) showed prominent vacuolization of both myeloid and erythroid precursors with few vacuoles noted in mature cells. Of the 9 patients tested for serum copper levels all were normal or borderline low. Marrow was hypercellular with granulocytic and megakaryocytic hyperplasia in 12/15 (80%). Definitive WHO criteria for MDS was met in 5/15 (40%) with 3 cases of MDS-MLD, and 2 of MDS-SLD. The remaining cases were suspicious for MDS with low or borderline levels of dyspoiesis that did not exceed greater than 10% of cells in respective lineages meeting criteria for clonal cytopenia of undetermined significance (CCUS). Of the MDS cases, dysplasia was seen in megakaryocytes (5/5), myeloid (2/5) and erythroid (1/5) precursors. Cytogenetic abnormalities were detected in 2/5 MDS patients involving t(3;12)(q21;q13) in one case, and del (5q)/del (13q) in another case. Next generation sequencing analyses were performed in 9/15 patients and showed mutations in DNMT3A in 2/5 MDS cases (VAF 43% and 44%), CSF1R in 1/5 MDS (VAF 3.1%), GNA11 in 1/5 MDS (VAF3.3%) and EZH2 mutation (VAF 22%) in one of the patients without overt MDS. Clonal plasma cell or B-cell populations were diagnosed in 6/15 patients with 3 plasma cell dyscrasias, and 2 cases of monoclonal B-cell lymphocytosis. The most common abnormalities detected by bone marrow flow cytometry analysis were severely reduced or absent B-cell precursors, inverted CD4:CD8 ratios and abnormal expression of CD56 on monocytes. In summary, hematologic disorders were identified in 10/15 VEXAS patients, including both myeloid and lymphoid clonal disease comprising MDS, plasma cell dyscrasias, and monoclonal B cell lymphocytosis. Based on the presence of UBA1 somatic mutations in hematopoietic cells of all VEXAS patients, the patients without evidence of overt neoplasia in this study met criteria for CCUS. Importantly, all patients had characteristic vacuoles in myeloid and erythroid precursors in the marrow without evidence of copper deficiency. These findings suggest that vacuolization of hematopoietic precursors in marrow of cytopenic patients, particularly in male patients and in the setting of systemic inflammation and normal copper levels, should prompt evaluation for somatic UBA1 mutations. In addition to severe autoinflammatory disease manifestations, VEXAS patients appear to confer increased risk for development of both myeloid and lymphoid/plasma cell neoplasia and require surveillance for disease progression. Figure Disclosures Young: Novartis: Research Funding.

Description: CAR T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T-cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Amongst 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase and occasionally hemophagocytosis. Development of carHLH was associated with pre-infusion NK-cell lymphopenia and higher bone marrow T/NK-cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK-cell lymphopenia amplified pre-infusion differences in those with carHLH without evidence for defects in NK-cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.