Key Points A subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.
The CD20-directed monoclonal antibody rituximab established a new era in lymphoma therapy. Since then other epitopes on the lymphoma surface have been identified as potential targets for monoclonal antibodies (mAb). While most mAbs eliminate lymphoma cells mainly by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or direct cell death, others counter mechanisms utilized by malignant cells to evade immune surveillance. Expression of PD-L1 on malignant or stromal cells in the tumor environment for example leads to T-cell anergy. Targeting either PD-1 or PD-L1 via mAbs can indirectly eliminate cancer cells by unblocking the host intrinsic immune response. Yet another mechanism of targeted therapy with mAbs are bi-specific T-cell engagers (BiTE) such as blinatumomab, which directly engages the host immune cells. These examples highlight the broad spectrum of available therapies targeting the lymphoma surface with mAbs utilizing both passive and active immune pathways. Many of these agents have already demonstrated significant activity in clinical trials. In this review we will focus on novel CD20-directed antibodies as well as mAbs directed against newer targets like CD19, CD22, CD40, CD52 and CCR4. In addition we will review mAbs unblocking immune checkpoints and the BiTE blinatumomab. Given the success of mAbs and the expansion in active and passive immunotherapies, these agents will play an increasing role in the treatment of lymphomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0058-4) contains supplementary material, which is available to authorized users.
The development of single-cell subclones, which can rapidly switch from dormant to dominant subclones, occur in the natural pathophysiology of multiple myeloma (MM) but is often "pressed" by the standard treatment of MM. These emerging subclones present a challenge, providing reservoirs for chemoresistant mutations. Technological advancement is required to track MM subclonal changes, as understanding MM's mechanism of evolution at the cellular level can prompt the development of new targeted ways of treating this disease. Current methods to study the evolution of subclones in MM rely on technologies capable of phenotypically and genotypically characterizing plasma cells, which include immunohistochemistry, flow cytometry, or cytogenetics. Still, all of these technologies may be limited by the sensitivity for picking up rare events. In contrast, more incisive methods such as RNA sequencing, comparative genomic hybridization, or whole-genome sequencing are not yet commonly used in clinical practice. Here we introduce the epidemiological diagnosis and prognosis of MM and review current methods for evaluating MM subclone evolution, such as minimal residual disease/multiparametric flow cytometry/next-generation sequencing, and their respective advantages and disadvantages. In addition, we propose our new single-cell method of evaluation to understand MM's mechanism of evolution at the molecular and cellular level and to prompt the development of new targeted ways of treating this disease, which has a broad prospect.
Background DHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. Methods This study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. Results One hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P<0.0001) predicted for inferior OS. Consolidative SCT did not improve OS on MVA (P 0.13). Conclusions In this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population. ^Three patients untreated, one received multiple regimens Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.
Patient: Female, 57Final Diagnosis: Renal heavy chain amyloidosisSymptoms: Fatigue • proteinuriaMedication: —Clinical Procedure: Chemotherapy, consideration of autologous stem cell transplantSpecialty: HematologyObjective:Rare diseaseBackground:T-cell large granular lymphocytic leukemia (T-LGL) is a rare hematological malignancy that currently has no standard therapy. Immunoglobulin heavy chain amyloidosis (AH) involving the kidney is a rare condition and the pathology, diagnosis, clinical characteristics, and prognosis are becoming understood. This report is of a rare case of T-LGL associated with renal AH and discusses the approach to management.Case Report:A 57-year-old woman presented with symptoms of fatigue and she had proteinuria. A diagnosis of T-LGL associated with renal AH was made, which is an association that has not been previously reported in the literature. Given the dysregulation of her immune function due to her underlying T-LGL and her comorbidities, treatment options were limited. She was clinically stable and was initially observed. After one year, her symptoms of fatigue became worse, and her proteinuria increased. Treatment was initiated with the triple drug combination of bortezomib, cyclophosphamide, and dexamethasone (CyBorD) with consideration for future hematopoietic stem cell transplantation (HSCT). Her clinical condition improved, with a reduction in proteinuria.Conclusions:A rare case of T-LGL and renal AH is presented. Currently, there is no standard therapy for T-LGL and AH amyloidosis, and the approach, in this case, was to manage the patient initially with CyBorD triple chemotherapy.
INTRODUCTION : Despite advances in therapy, patients with relapsed AL amyloidosis die of resistant disease. New therapies are needed. siRNA directed at the constant regions of Ig light chains (LC) reduces LC mRNA and protein from patient cells, from human myeloma and AL cell lines, and in a flank plasmacytoma model with in vivo electroporation (Blood 2014;123:3440; Gene Ther 2016;23:727). To deliver siRNA in vivo, we first tested a series of biodegradable lipidoid nanoparticles (LPN) generated through Michael addition of aliphatic acrylates containing disulfide bonds responsive to intracellular glutathione that enhance siRNA transit from endosome to cytoplasm, and identified the 8B-3 LPN as safe and active in vitro. To provide an in vivo model, we tested RPMI8226, ALMC-1, NCI929 and JJN3 human myeloma reporter cell lines stably expressing FFL and GFP in NOD scid γ (NSG) mice using different routes of inoculation. We sought an optimal xenograft model that would provide reliable tumor-take, brief latency for circulating LC, rapid short-term increase in LC levels, measurable β2-microglobulin (β2M) levels and ease of administration of multiple injections of LPN. The NSG JJN3 intraperitoneal (IP) model met these standards. This model not only enables timely testing of this siRNA approach but also provides the significant challenge of rapid tumor growth. We now report the results in this model of delivery by the 8B-3 LPN of siIGKC targeting κ LC production. MATERIALS AND METHODS: LPN/siRNA are formulated using a microfluid based mixer (NanoAssemblr, Precision Nanosystems, Inc), and are controlled for size by varying the relative flow rates of lipid and solvent. For in vivo delivery, cholesterol, DOPE and PEGylated co-lipids are used to form stable LPN with siNT or siIGKC (Dharmacon). Standard QA metrics are applied to each lot of 8B-3/siRNA and lot-to-lot checks for cell viability and in vitro FFL knockdown are performed. Coated loaded 8B-3 LPN are ~100nM in diameter and were tested in vitro at 8B-3:siRNA ratios of 10:1, 5:1 and 1.5:1. The 1.5:1 ratio was superior; cell viability was unaffected and κ LC reduction was 84%. NSG mice with JJN3 tumor implants (107 cells IP on day 1) are injected IP with 200μL 8B-3:siRNA (1.5:1 ratio) mixed with 400μL PBS once daily on days 5, 6 and 7. Luciferin imaging is obtained on day 5 and blood is obtained on day 5 (pre-injection) and on day 8 for ELISA for human κ LC and β2M. RESULTS : Current JJN3 cells make only κ LC without IgA (Br J Haematol 1999;106:669) and in vitro at 48 hours after a single exposure to 8B-3/siIGKC we see reductions of 84% and 25% in κ LC and β2M secretion with no change in cell viability. Neither κ LC nor β2M reductions are seen with 8B3/siNT. The NSG JJN3 IP model has a 90% tumor-take and a 5-day LC latency. IP xenograft CD138+ cells are found in liver (subcapsular) and spleen. On day 5, the mice have median serum levels (Q1-Q3) of κ LC and β2M of 2.37μg/mL (1.68-3.32) and 1.56ρg/mL (0.58-5.38), values that strongly correlate (r=0.76, P<<0.01), as do the day 5 κ LC and FLUX values (r=0.88, P<<0.01). In 3 cohorts of 10 mice each, 5 siNT and 5 siIGKC per cohort, there were no differences in day 5 κ LC, FLUX and β2M, or in day 8 β2M, between the siNT and siIGKC groups (Table 1). On day 8 after 3 IP injections, the ratio of the medians of κ LCday 8/κ LCday 5 x 100% was lower in siIGKC mice (161% versus 264%) and trends towards significant reductions in κ LC with siIGKC were observed (Table 1). In a paired comparison of the means of the groups in the 3 cohorts the 33% reduction in κ LC with siIGKC was significant (Table 1). On day 8 there were no differences in the weights or behaviour of the mice. CONCLUSIONS : We have previously shown that siIGKC, a pool of siRNA directed at consensus sequences in the κ LC constant region gene, can significantly reduce κ LC production in clonal plasma cells from patients, in human myeloma cell lines, and in vivo in a flank plasmacytoma xenograft model. In this work, we show that 8B-3 is a promising LPN for delivery of siRNA to human plasma cells and, when loaded with siIGKC, can with relative safety significantly reduce circulating κ LC in the NSG JJN3 IP model after 3 daily IP injections despite rapid tumor growth. We also show the utility of the NSG JJN3 IP model for the study of κ LC directed therapies. Extensive work lies ahead to identify and optimize a lead candidate for delivery of siRNA to human bone marrow plasma cells in vivo and to begin systematic pre-clinical safety studies. Disclosures Ma: Tufts Medical Center: Patents & Royalties: Patent: 9593332. Wang:Tufts University Medical School: Patents & Royalties: Patent: 9765022. Xu:Tufts University School of Medicine: Patents & Royalties: Patent: 9765022. Comenzo:Tufts Medical Center: Patents & Royalties: Patent: 9593332.
INTRODUCTION : Currently patients with systemic AL amyloidosis (AL) are not identified until they are sick due to end-organ damage, usually a result of elevated clonal Ig free light chains (FLC) produced by λ clones in 75% of cases. Delays in diagnosis put patients at risk of developing irreversible organ damage making AL much harder to treat. Only about 25% of newly diagnosed AL patients are eligible for melphalan (MEL) based stem cell transplant (SCT). To extend the overall survival and quality of life of AL patients, early diagnosis is critical. A retrospective study of AL λ-type patients using the US Department of Defense serum repository showed that 100% of patients had a monoclonal FLC present for up to 4 years preceding diagnosis, 92% of whom had a difference between the pathologic and non-involved FLC (dFLC) of >23 mg/L (J Clin Oncol 2014;32:2699). Progression to AL from precursor states such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) is well described but often not clinically appreciated. SAVE is an internet-based diagnostic trial (NCT02741999) for patients with λ MGUS or SMM with a κ:λ ratio < 0.26 and dFLC > 23mg/L. Using peripheral blood and, when available, marrow aspirates, we try to identify each patient's λ germline variable region (IGLV) donor gene. Five IGLV genes account for 75% of AL λ-type (IGLV1-44. 1-51, 2-14, 3-1, 6-57) (Blood 2017;129:299). Based on data in AL-Base, relative risk of AL versus myeloma with these clonal genes can be significantly high (7.3, 6-57; 2.5, 1-44), intermediate (1.6, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1). MATERIAL S & METHODS : Patients provide written consent to be screened by medical records review. Eligible patients ship peripheral blood (PB) or marrow (BM) samples to us obtained only at times of routine clinical testing. We select CD138+ cells from PBMNC or BM for whole-cell RNA preparation (RNeasy Mini Kit, QIAGEN, Valencia, CA) and cDNA synthesis (ThermoScript RT-PCR System, Invitrogen Life Technologies, Carlsbad, CA) for storage at -80o C. Primer sets are degenerate FR1 and 5' CR primers for the Vλ1, Vλ2, Vλ3 and Vλ6 families (Blood 2001;98:714). Three RT-PCR products of appropriate size per clone are sent to our core facility for sequencing. We then use the sequences to search for the corresponding IGLV germline gene in IMGT (ImMunoGene-Tics, www.imgt.org). Patients and their MDs are notified of the results and, if the germline donor is associated with AL with high or intermediate risk, further evaluation for AL is discussed and pursued. RESULTS : Twenty asymptomatic λ patients from 13 states thus far have consented to be screened for SAVE, and 19 enrolled (3M, 16F). Twenty-three PB and 4 BM specimens have been obtained. Median months from diagnosis to receipt of first specimen was 15, involved FLC 107mg/L and κ:λ ratio 0.09. Median PBMNC and CD34-selected cells were 8x106 (2.6-24) and 3x105 (0-6) respectively. Twelve patients had IGLV genes identified by PCR with the first specimen; 5 sent additional specimens including 3 BM. There were no differences in CD34-selected cell numbers or λ light chain levels between first-specimen PCR successes and failures. Seventeen patients have had IGLV genes identified: four 2-14, three 1-44, two 3-1 and eight others. Increased risk of AL was identified in 7 patients who were screened with abdominal fat pad studies. One of the 7 (with IGLV2-14) had a positive fat pad and was then diagnosed with AL λ-type with GI involvement. She was induced with 4 cycles of bortezomib-based therapy and is now 3 months status post an uncomplicated MEL 200 SCT. Two SMM patients (of 19) have proceeded to symptomatic myeloma requiring therapy. CONCLUSIONS : The SAVE trial may enable early appreciation of risk of AL λ-type based on the variable region germline gene used by the clonal plasma cells. In λ MGUS and SMM patients with elevated lambda FLC, below normal ratios, and dFLC > 23mg/L, the clonal gene can be identified by RT-PCR with CD138-selected cells from a single peripheral blood specimen 70% of the time. Close follow up of patients at risk may reduce the likelihood of eventually being diagnosed with advanced organ involvement. Earlier diagnosis may permit prompt induction therapy if required and expanded application of MEL 200 SCT, a preferred treatment for patients with < 10% clonal marrow plasma cells at diagnosis or after induction (Biol Blood Marrow Transplant 2016;22:1729). Disclosures No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.