scholarly journals Performance-based Institutional Research Funding in Flanders, Belgium

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Marc Luwel
Keyword(s):  
Research Funding ◽  
Institutional Research

scholarly journals Secreted Factors Determine Resistance to Idelalisib in Marginal Zone Lymphoma Models of Resistance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2569-2569
Author(s):  
Alberto J Arribas ◽  
Sara Napoli ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Alessandra Di Veroli ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Advisory Board ◽  
Institutional Research ◽  
Rna Seq ◽  
Scientific Advisory Board ◽  
Scientific Advisory ◽  
Erbb Signaling ◽  
Travel Grant

Background . PI3Kδ is expressed in B-cells and has a central role in the B-cell receptor signaling in B-cell derived malignancies. Idelalisib was the first-in-class PI3Kδ inhibitors and several second-generation compounds are undergoing clinical investigation as single agents and in combinations. To identify modalities to overcome the resistance that develops to this class of agents, we have developed two idelalisib-resistant models derived from splenic marginal zone lymphoma (SMZL) cell lines. Materials and Methods. Cells were kept under idelalisib (IC90) until acquisition of resistance (RES) or with no drug (parental, PAR). Stable resistance was confirmed by MTT assay after 2-weeks of drug-free culture. Multi-drug resistance phenotype was ruled out. Cells underwent transcriptome and miRNA profiling by RNA-Seq, whole exome sequencing (WES), lipidomics profiling, pharmacological screening (348 compounds), and FACS analysis. Cytokines and growth factor secretion was performed by ELISA. Results. Two RES models were obtained from VL51 and Karpas1718 with 7-10 fold times higher IC50s than PAR counterparts. In both models, conditioned media from RES cells transferred the resistance in the PAR cells. While WES did not identify somatic mutations associated with resistance, RNA-Seq and lipidomics analyses showed that the two cell lines had developed resistance activating different modalities. The VL51 RES model showed an enrichment in BCR-TLR-NFkB (TLR4, CD19, SYK), IL6-STAT3 (IL6, CD44), chemokines (CXCL10, CXCR4, CXCR3) and PDGFR (PDGFRA, PRKCE) signatures, paired with increased p-AKT and p-BTK levels, decreased cardiolipins and sphingomyelins levels, and increased levels of specific triacylglycerols and glycerophosphocholines. In particular, there was an over-expression of surface expression of PDGFRA and secretion of IL6 in the medium. Silencing of both IL6and PDGFRA by siRNAs reverted the resistance, while the silencing of the individual genes had only a partial effect. These data were paired with the acquired sensitivity to the PDGFR inhibitor masitinib, identified in the pharmacologic screening. In the Karpas1718 model, we observed an increased p-AKT activity with an enrichment for B-cell activation signatures (RAG1, RAG2, TCL1A), proliferation (E2F2, MKI67), ERBB signaling (HBEGF, NRG2, ERRB4), increased levels of some triacylglycerols and repressed levels for specific glycerophosphocholines. HBEGF secretion was confirmed by ELISA. The addition of recombinant HBEGF to the medium induced resistance in the PAR cells. Combination with the pan ERBB inhibitor lapatinib was beneficial in the K1718 RES. Recombinant HBEGF also induced resistance to the BTK inhibitor ibrutinib in the PAR cells and in the mantle cell lymphoma SP-53 cell line. Specific members of the let-7 family of miRNAs were repressed in the RES lines derived from both cell lines, indicating the involvement of miRNA deregulation in the mechanism of resistance. Indeed, let-7 members are known to directly target IL6-STAT3 and cytokine signaling cascade, as well PI3K-AKT network. In solid tumors, let-7 members are also expressed at low levels in tumors with constitutive active ERBB signaling, in accordance with the activation of ERBB pathway and p-AKT we observed in our Karpas1718model. Experiments with a LIN28B inhibitor are now on-going. Finally, we validated the findings across a panel of 34 B-cell lymphoma cell lines, in which IL6, PDGFRA, HBEGF and LIN28 expression levels were negatively correlated with idelalisib sensitivity, while the latter was positively correlated with let-7 levels (P <0.05). Conclusions. We developed two distinct models derived from MZL of secondary resistance to the PI3Kδ inhibitor idelalisib. We identified treatments that might overcome resistance to idelalisib and are worth of further investigations. The two models, driven by different biologic processes, will allow the evaluation of further alternative therapeutic approaches. Disclosures Stathis: PharmaMar: Other: Renumeration; ADC Therapeutics: Other: Institutional research funding; Abbvie: Other: Renumeration; Bayer: Other: Institutional research funding; Novartis: Other: Institutional research funding; MEI-Pharma: Other: Institutional research funding; Roche: Other: Institutional research funding; Pfizer: Other: Institutional research funding; Merck: Other: Institutional research funding. Stuessi:Gilead: Speakers Bureau. Zucca:Gilead: Honoraria, Other: travel grant. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Bertoni:Nordic Nanovector ASA: Research Funding; Acerta: Research Funding; Jazz Pharmaceuticals: Other: travel grants; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding; NEOMED Therapeutics 1: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants.

scholarly journals Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-14
Author(s):  
Alexander Coltoff ◽  
Joseph G. Jurcic ◽  
Peter Campbell ◽  
Daniel J. Lee ◽  
Mark L Heaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Residual Disease ◽  
Institutional Research ◽  
Negative Group ◽  
Advisory Committees ◽  
Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

A Comparison of the Outcomes of Early Versus Delayed Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Therapies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1993-1993
Author(s):  
Siyang Leng ◽  
Erin Moshier ◽  
Douglas Tremblay ◽  
Noa Biran ◽  
Naman Barman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retrospective Study ◽  
Stem Cell Transplantation ◽  
Research Funding ◽  
Institutional Research ◽  
Novel Therapies ◽  
Time To Progression ◽  
Landmark Analysis ◽  
Group 1

Abstract Background: In phase 3 studies comparing high dose melphalan (mel) with autologous stem cell transplantation (ASCT) to conventional chemotherapy, ASCT improves progression free survival (PFS) and, in some studies, overall survival (OS). However, these studies were performed before the use of potent, novel induction therapies such as bortezomib (V), lenalidomide (R), and dexamethasone. The optimal timing and benefit of ASCT in the era of novel therapies is unknown. In our program, upon completion of stem cell harvest (SCH), some patients elect to delay ASCT after discussion of risks and benefits. The aim of this retrospective study is to compare the time to progression (TTP) and OS of patients who proceeded to ASCT early as consolidation of initial therapy, versus ASCT delayed until relapse. While data from prospective studies are eagerly awaited, this retrospective study has the advantage of a long follow up. Methods: In this IRB approved, retrospective case series, electronic medical records of all patients with symptomatic MM who had SCH at Saint Vincent's Medical Center or Mount Sinai Hospital between 1/1/2005 to 6/30/2014 were reviewed. Patients were divided into the following groups: Time to progression (TTP) is calculated using Kaplan-Meier analysis. OS is calculated using a landmark analysis at 2 and 3 years after diagnosis. Results: 572 consecutive patients were identified. 18 were excluded for incomplete data. Baseline characteristics are shown in Table 1. The groups did not differ significantly in terms of stage (either Durie Salmon or International Staging System), disease isotype, or high risk disease features (defined by cytogenetics or FISH as amp 1q, t(14;16), t(14;20), del 17p13). The median follow-up for the entire group was 47.5 months. Not surprisingly, the median TTP after ASCT diminished with delay of ASCT, from 28.4 mo for early ASCT to 12.2 mo for delayed (p < 0.001). That said, when comparing groups 1 and 2, there was no difference in the median time from diagnosis to progression after mel 200 mg/m2 ASCT Ð 39.1 vs 43.6 mos (p = 0.945). Using landmark analysis starting at 2 years from diagnosis, the median OS was 61.3, 37.4, 18.9, and 116.7 for groups 1, 2, 3, and 4 respectively (p = 0.087 for group 1 vs 2; p < 0.001 for group 1 vs 3; Figure 1). Landmark analysis at 3 years from diagnosis showed median OS of 50.3, 56.5, 13.9, and not reached (p = 0.41 for group 1 vs 2; p < 0.001 for group 1 vs 3). Conclusions: There are three findings of interest. 1) TTP in those who underwent early ASCT was 15 months longer than those who underwent ASCT at relapse. 2) TTP after SCT was comparable in groups 1 and 2, which may be attributable to the preferential use of maintenance chemo either pre or post ASCT, respectively. 3) The rank ordering of median OS by landmark analysis suggests an interplay between therapy and disease biology Ð many patients may do very well without SCT, perhaps due to durable remissions with novel regimens. The remaining groups demonstrate a striking decrease in OS as the number of relapses in a given time period increases, indicating the need for novel approaches to MM that behaves in clinically aggressive manner. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Biran: Celgene: Speakers Bureau. Jagannath:Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria. Chari:Onyx: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding.

Towards a Network-Based Molecular Taxonomy of Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 840-840
Author(s):  
Alessandro Lagana ◽  
Ben Readhead ◽  
Deepak Perumal ◽  
Brian Kidd ◽  
Hearn Jay Cho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Somatic Mutations ◽  
Molecular Taxonomy ◽  
Network Biology ◽  
Cellular Systems ◽  
Biological Processes ◽  
Institutional Research ◽  
Newly Diagnosed ◽  
Integrative Network

Abstract Recent advances in computational biology have led to the development of novel and sophisticated methods to model large datasets measured from complex organisms based on integrative network biology. Networks can provide valuable insight into key biological processes and allow for a deeper understanding of the complexity of cellular systems and disease mechanisms. We developed and applied a network biology approach to infer an improved molecular model and understanding of newly diagnosed multiple myeloma (MM). We constructed the first co-expression network of MM based on RNA-seq data from the current release (IA4) of the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study dataset. The data set consists of 92 samples from newly diagnosed MM patients. Whole Exome Sequencing (WES) data available for 77 out of 92 samples allowed the integration of somatic mutations into the network. Our analysis organized 23,033 genes into 50 co-expression modules. We then evaluated the molecular activity of co-expression modules for concordance with molecular traits. We performed module enrichment analysis against Gene Ontology terms, pathways, chromosome locations, protein-protein interaction networks, MM-associated gene sets and drug-target databases. Analysis of the newly diagnosed multiple myeloma network model (MMNet) revealed known and novel molecular features of multiple myeloma. The integration of MMNet with somatic mutations data unveiled a significant association between mutation burden and the activation of several modules. Fundamental biological processes such as DNA repair, cell cycle, signal transduction, NK-kappaB cascade and MAPK signaling characterized such modules. Interestingly, a number of mutated genes demonstrated pluripotent associations with co-expression module activity. For example, FGFR3 was correlated with expression of several modules, including one enriched for RNA processing and translation-related processes and included the known MM-associated genes FRZB and CCND3. Similarly, the frequently mutated gene DIS3 was significantly associated to five different modules, including the translation-related module and a module enriched for the 1q locus. Our results have identified novel key driver genes that may inform therapy prioritization. The MMNet topology revealed a far greater molecular heterogeneity in primary MM underscoring opportunities to improve the molecular taxonomy of this disease. We identified several modules associating with previously described MM classes, including a module enriched for genes up regulated in the UAMS MS class characterized by spiked expression of WHSC1 and FGFR3. Module connectivity confirmed the central role of both genes, WHSC1 being the top hub gene, i.e. the most connected gene in the module, and FGFR3 being among the top 10 hubs. Consistent with previous findings, this module was characterized by negative correlation with aneuploidy. We found other modules enriched for genes dysregulated in other UAMS classes, such as MF, CD1 and CD2. We also identified several modules associating with relevant biological processes such as apoptosis, cell communication, Wnt and Toll-like receptor signaling. Correlation of modules expression with clinical traits identified insights into genetic subgroups of MM that are not previously described. For examples, we found a module positively correlated to the African American ethnicity. This module was also characterized by enrichment for genes in the fragile regions 5q31 and 6q21. These findings may provide important and exciting insights into the biology of MM among African Americans as they are at increased risk for MM. Our integrative network analysis of the CoMMpass dataset uncovers novel and complex patterns of genomic perturbation, key drivers and associations between clinical traits and genetic markers in newly diagnosed MM patients. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:BMS: Honoraria; MERCK: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Dudley:Ayasdi, Inc: Other: Equity; Personalis: Patents & Royalties; NuMedii, Inc: Patents & Royalties; GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals: Consultancy; Ecoeos, Inc: Other: Equity.

scholarly journals A Phase II Study of Sequential Pembrolizumab (PEM) Followed By AVD for Frontline Treatment of Classical Hodgkin Lymphoma (CHL): Quantifying Response Following PEM Monotherapy with FDG-PET-Derived Metabolic Tumor Volume and Total Lesion Glycolysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1651-1651 ◽  
Author(s):  
Hatice Savas ◽  
Pamela Allen ◽  
Andrew M. Evens ◽  
Barbara Pro ◽  
Gary Dillehay ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Early Stage ◽  
Residual Activity ◽  
Metabolic Tumor Volume ◽  
Institutional Research ◽  
Research Support ◽  
Advisory Committees ◽  
Early Stage Disease ◽  
Advisory Role

Abstract Background: Pembrolizumab (PEM), a PD-1 inhibitor, is US FDA approved for the treatment of relapsed/refractory cHL based on results of a pivotal trial demonstrating an overall response rate of 69% and complete response (CR) rate of 22%. We hypothesized that PEM monotherapy would result in a higher CR rate (50%) in previously untreated patients owing to greater immunocompetence. Consequently, we initiated a phase 2 clinical trial of upfront sequential PEM and AVD (Adriamycin, Vinblastine, Dacarbazine) chemotherapy. While several of the initial patients had dramatic responses to PEM x's 3 on PET2, they only met Lugano criteria for partial responses. In an attempt to better reflect and quantify the response to checkpoint inhibition, we amended our protocol to include additional analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) which have been investigated as predictors of response in cHL and DLBCL. Herein, we report an interim analysis of toxicity and efficacy, measured by Deauville score, MTV and TLG in the first 13 patients to complete PEM monotherapy. Methods: Patients ≥ 18 years of age with newly diagnosed cHL stages I-IV, including unfavorable early stage disease with at least one risk factor according to the NCCN criteria, were eligible. Patients had a pre-therapy PET-CT, followed by 3 cycles of PEM at 200 mg every 3 weeks and interim PET-CT (PET2) after single agent PEM for primary analysis. Subsequently, patients received 4-6 cycles of AVD chemotherapy based on initial stage. MTV representing the total volume of the metabolically active tumor in a volume of interest (VOI) was calculated using the fixed 41% SUVmax threshold corresponding to the dimensions of the tumor. TLG, combining the volumetric and metabolic information of FDG-PET, was calculated by multiplying the SUVmean of the segmented VOI and the MTV. These measurements were performed using SyngoVia software, Multi-foci segmentation tool (Siemens). Blinded central review of the visually assessed Deauville score was performed, and if different from the report by one of four nuclear medicine radiologists, a second central review was performed to adjudicate. Correlative studies include serum and biopsy samples pre/post PEM to assess immune biomarkers of response. Results: Fifteen patients were enrolled from September 2017, through a data cut off of July 10, 2018, at Northwestern University. Thirteen patients have completed lead-in PEM monotherapy and have undergone PET2. Median age was 30 years (range, 23-77). Eight patients had unfavorable early stage disease and 7 had advanced stage. Early stage risk factors included bulky disease (n=8), B-symptoms (n=5), and elevated ESR (n=5). Overall, therapy was well tolerated. Grade 3 events included lymphopenia (n=1) and diarrhea (n=1). Only one grade 4 immune-related adverse event (transaminitis) occurred, which resolved with steroid therapy and a delay in therapy. PET2 was scored as Deauville 2 or 3 in six cases including three with large mediastinal masses, and as D 4 or 5 in 7 cases with residual activity (Figure 1). PET2 MTV and TLG could be calculated for 12 of 13 cases, (MTV: 42 - 774 cm2, median 134 cm2; TLG: 257 - 5924; median 814). All 12 patients who completed a subsequent scan (PET3) after 2 cycles of AVD are now in a metabolic CR (Deauville 1-3), including all 7 cases with residual activity after PET2. Conclusion: These interim data suggest that upfront PEM x's 3 is highly active in previously untreated cHL. PEM monotherapy resulted in complete metabolic responses in some patients including those with large mediastinal masses, and near complete responses, best represented by the decline in MTV and TLG compared with Deauville scores or Lugano criteria. Our preliminary data suggest that MTV and TLG are useful additional interim indicators of biologic activity when assessing response after PD-1 inhibitor therapy. Disclosures Allen: Merck: Research Funding; Bayer: Consultancy. Evens:Bayer: Consultancy; Janssen: Consultancy; Affimed: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Abbvie: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Pro:kiowa: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; portola: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding. Advani:Millenium: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support. Winter:Merck: Honoraria, Research Funding.

scholarly journals A Phase II, Open-Label Study of Bortezomib (Velcade®), Cladribine, and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1790-1790
Author(s):  
Abhijeet Kumar ◽  
Jose Guillen-Rodriguez ◽  
Jonathan H. Schatz ◽  
Lora Inclan ◽  
Alfonso E Ayala ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Advisory Board ◽  
Institutional Research ◽  
Prior Therapy ◽  
Mantle Cell ◽  
Indolent Lymphomas

Abstract Background: Mantle cell lymphoma (MCL) is characterized by initial sensitivity to both chemotherapy and radiation but also by an invariable relapse and eventual resistance to treatment. Bortezomib (Velcade) is a proteasome inhibitor and is approved as a single agent for relapsed MCL and in combination therapy as part of initial therapy (Goy et al, JCO 2005; Robak et al, NEJM 2015). Cladribine is a purine nucleoside analog effective in indolent and mantle cell lymphomas (Inwards et al, 2008; Rummel et al, 1999), with 52% durable CR rate reported in MCL in combination with rituximab, and it shows CR rates of up to 20% in relapsed and up to 32% in untreated indolent lymphomas (Kay et al, 1992; Fridrik et al, 1998). The median age at diagnosis for these lymphomas is approximately 65 years which precludes many patients from receiving combination therapies which have significant toxicities, representing an unmet need for novel combinations with high efficacy, good tolerability and non-overlapping toxicities. We investigated a combination of bortezomib, cladribine and rituximab(VCR) in both front line and relapsed/refractory (R/R) settings with a primary objective to determine 2-year progression free survival(PFS) in patients with MCL, marginal zone, lymphoplasmacytic, small lymphocytic, and relapsed follicular lymphomas (NCT00980395). Methods: Adult patients with histologically confirmed mantle cell, marginal zone, lymphoplasmacytic, small lymphocytic lymphoma (both frontline and relapsed), or follicular lymphoma (relapsed/refractory), platelet counts ≥100,000, absolute neutrophil count >1000, creatinine clearance >20 ml/min who met treatment criteria were eligible. Prior treatment with bortezomib and/or rituximab was acceptable. Patients with grade 2 or greater peripheral neuropathy, myocardial infarction in the last 6 months or other active cardiac ailments were excluded. Rituximab 375 mg/m2 IV day 1, Cladribine 4 mg/m2 IV over 2 hours days 1-5, Bortezomib 1.3 mg/m2 IV days 1 and 4 were administered every 28 days, which constituted a cycle, for a maximum of 6 cycles. Results: Twenty-four patients were enrolled with planned follow-up of two years from end of treatment. Eleven patients had mantle cell lymphoma (MCL) and rest was indolent lymphomas; 42% received the treatment as frontline. All patients received at least one cycle. Median age was 65 years, 75% were male, 96% were Caucasians, 54% of patients had bulky disease (>5cm), and 75% of patients had bone marrow involvement. Fifty eight percent of patients had grade 3 or greater adverse events and 67% of patients did not receive all 6 cycles, with median number of cycles being 5. Most common grade 3/4 adverse events were leukopenia (33%), thrombocytopenia (25%), fatigue (21%) and anemia (4%). There were no deaths due to adverse events. Overall response rate was 92% and another 4% had stable disease. The overall CR rate was 33%, and duration of response for those in CR was 41.5 months. After a two year minimum follow-up, median progression free survival (PFS) was 42 months and median time to progression was 33 months. The overall 2 year PFS was 63%. The 2 year PFS in patients with no prior therapy and prior therapy were 78%, and 54% respectively. In patients with no prior therapy, median OS was not reached. Conclusion: This study shows VCR is an effective regimen in indolent and mantle cell lymphomas. This combination has better response rates that better than both single agent bortezomib and cladribine (Kay et al, 1992; Fridrik et al, 1998; Goy et al, JCO 2005). In combination, VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) was reported to have a complete response rate of 53 % and a median PFS of 24.7 months (Robak et al, NEJM 2015), and rituximab-cladribine-vorinostat had similar response rates (100%) but a CR rate of 69%(Spurgeon et al, ASH annual Meeting 2012). Rituximab-Cladribine combination is reported to have a response rate of 87% and a median PFS of 37.5 months (Spurgeon et al; Leuk Lymphoma 2011) which is slightly lower than our study. This regimen is associated with significant cytopenias leading to majority of patients not receiving all of the 6 planned cycles but has significant activity in mantle cell and indolent lymphomas. Figure 1 Figure 1. Disclosures Anwer: Seattle Genetics: Other: Advisory Board Participant; Incyte: Speakers Bureau. Persky:Gilead: Speakers Bureau; Merck: Research Funding; Spectrum: Research Funding. Puvvada:Spectrum: Other: Institutional Research Funding; Gilead: Speakers Bureau; Takeda: Other: Institutional Research Funding; Pharmacyclics: Other: Advisory Board participant; Seattle Genetics: Other: Advisory Board participant, Institutional Research Funding; Abbvie: Other: Advisory board participant.

Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 816-816 ◽  
Author(s):  
Shaji Kumar ◽  
William I Bensinger ◽  
Craig B. Reeder ◽  
Todd M. Zimmerman ◽  
James R. Berenson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
20S Proteasome ◽  
Institutional Research ◽  
Advisory Committees ◽  
Investigational Agent

Abstract Abstract 816 Background: Proteasome inhibition is a very effective therapeutic strategy in multiple myeloma (MM). The investigational agent MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome that has shown antitumor activity in solid tumor and hematologic malignancy xenograft models. Phase 1 trials are evaluating both intravenous and oral formulations using different dosing schedules in a variety of tumor types. Here we report the findings from the dose-escalation portion of a phase 1 trial of once-weekly, orally administered MLN9708 in patients with relapsed and/or refractory MM (NCT00963820). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of MLN9708. Secondary objectives included determination of response rate, and characterization of the pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (PD, 20S proteasome inhibition in blood) of once-weekly oral MLN9708. Patients with MM who had received ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. Treatment consisted of MLN9708 administered orally on days 1, 8, and 15 of a 28-day cycle. Dose-escalation proceeded from 0.24 mg/m2 using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v3. Response was assessed by modified EBMT/IMWG criteria. Blood samples were collected after dosing on days 1 and 15 of cycle 1 for PK and PD analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: A total of 28 patients have been enrolled to date (data cut-off: June 29, 2011), including 3 each at dose levels of 0.24, 0.48, 0.80, and 1.20, 4 at 1.68, 3 at 2.23, 4 at 2.97, and 5 at 3.95 mg/m2. The median age was 63.5 years (range 40–76); 54% were male. The median number of prior regimens was 5 (range 2–15), and median time from diagnosis was 4.6 years. Nineteen (68%) patients had prior stem cell transplant, and 16 (59%) were refractory to their last prior therapy, including 7 (26%) to bortezomib and 11 (41%) to lenalidomide or thalidomide. The MTD has not been reached; the current cohort is receiving 3.95 mg/m2. No DLTs have been observed among 21 DLT-evaluable patients. Patients have received a median of 2 treatment cycles (range 1–11; mean 2.8). Four patients remain on treatment; discontinuation was mainly due to progressive disease (71%). All 28 patients are evaluable for toxicity; 26 (93%) experienced at least one AE, including 22 (79%) who experienced at least one drug-related AE. Drug-related AEs occurring in >20% of patients included fatigue (39%), thrombocytopenia (36%), nausea (32%), and diarrhea (29%). Two (7%) patients had drug-related peripheral neuropathy (PN, both grade 2); both had grade 1 PN at baseline. Ten (36%) patients experienced grade ≥3 AEs, 4 (14%) had AEs resulting in MLN9708 dose reductions, and 3 (11%) discontinued due to AEs. No on-study deaths have occurred. In 16 response-evaluable patients, one partial response has been seen, in a patient treated at 2.97 mg/m2 (who had three prior lines of therapy, thalidomide–dexamethasone, lenalidomide–dexamethasone –perifosine, and bortezomib–dexamethasone, to which the patient responded and relapsed); duration of response is 3.7 months, and the patient remains in response at cycle 8. A further five patients had a best response of stable disease, durable for up to 9.5 months. PK analyses showed that MLN9708 was rapidly absorbed, with MLN2238 Tmax of 0.5–2.0 hours and a terminal half-life after multiple dosing of approximately 7 days based on limited data (n=5). MLN2238 exposure appeared to increase proportionally with increasing MLN9708 dose over the range 0.8–2.97 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that MLN9708 on a once-weekly schedule is generally well tolerated and has early signs of anti-tumor activity in this heavily pre-treated population with prior exposure to lenalidomide/thalidomide and bortezomib. To date, toxicity has been manageable, and no significant neuropathy signal has been observed. Updated data will be presented, with the MTD anticipated to be reached. Data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708 will also be presented. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Reeder:Celgene: Institutional research funding; Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding. Zimmerman:Novartis: Expert witness; Celgene: Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Research Funding.

Characterization of B12 Deficiency in Patients with Plasma Cell Disorders

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5330-5330 ◽  
Author(s):  
Caitlyn Braschi ◽  
John Doucette ◽  
Ajai Chari
Keyword(s):  
Multiple Myeloma ◽  
Vitamin B12 ◽  
Plasma Cell ◽  
Negative Correlation ◽  
Research Funding ◽  
Rank Order ◽  
Institutional Research ◽  
Strong Negative Correlation ◽  
B12 Deficiency ◽  
Total P

Abstract Background: Although vitamin B12 deficiency has been reported in patients with plasma cell dyscrasias (PCDs), no mechanism has been identified. Excess free light chains (FLCs), readily measurable by the serum FLC assay since 2001, could disrupt the renal proximal tubule receptors megalin and cubulin where B12 is reabsorbed. We sought to identify risk factors for B12 deficiency in PCD patients to elucidate a possible mechanism. In particular, we hypothesized that rates of B12 deficiency would be higher in PCD patients with higher FLC burdens. Methods: Of 1482 patients with ICD9 codes for PCDs, 530 met the inclusion criteria of having both serum B12 and FLC values. We reviewed the electronic medical records to obtain clinical data collected in the time preceding the patient's lowest B12 level. Patients were excluded if the lowest B12 was elevated in the setting of known concurrent vitamin B12 replacement therapy. Data from eligible patients were analyzed using chi-square, Student's independent t test, and Spearman's rank-order correlation to identify associations between B12 insufficiency (defined as <250 pg/ml or <350pg/ml and B12 treatment history) and PCD characteristics. This retrospective study was approved by the Mount Sinai IRB. Results: Overall, 26.6% patients were found have vitamin B12 insufficiency. Other than an IgG isotype PCD (P=0.025) there were no significant differences in age, gender, or PCD diagnosis between patients with and without B12 insufficiency (see Table 1). As expected, there was a strong negative correlation between eGFR and involved FLC, r(248) = -0.277, p < 0.001. However, unexpectedly, there was also a significant negative correlation between B12 level and eGFR, rs(487) = -0.106, p = 0.019 such that insufficient B12 was associated with normal eGFR (p = 0.001). There was no correlation between B12 level and involved FLC (p = 0.948) nor B12 level and Bence Jones proteinuria (p = 0.302). Discussion: While our data do not appear to support the proposed mechanism of FLC disruption of renal receptors, B12 deficiency was more common in our sample (26.6%) than the previously reported 13.6% prevalence among PCD patients (Baz et al Cancer 2004). While B12 deficiency and PCDs are both associated with higher age, the prevalence of B12 deficiency among older adults is only 10-15% (Baik et al Annu Rev Nutr 1999). Therefore, prospective studies are needed to explore other characteristics of PCD patients, such as chemotherapy treatment (Tandon et al Indian Pediatr 2015) or aspirin use (van Oijen et al Am J Cardiol 2004), contributing to a high prevalence of B12 deficiency in this population. Detection and treatment of B12 deficiency among PCD patients remains clinically important to reduce ensuing sequelae of neurologic dysfunction and cytopenias, which are complications of PCDs and their treatments. Table 1. Demographics and disease characteristics by B12 status. Vitamin B12 Status Insufficient B12 Normal B12 Total p Gender N %a N %a N %b Male 78 30.2 180 69.8 258 48.7 0.066 Female 63 23.2 209 76.8 272 51.3 Total 141 26.6 389 73.4 530 Age at PCD Diagnosis (median) 61 62 0.857 PCD N %a N %a N %b Multiple myeloma 60 35.9 107 64.1 167 78.4 0.488 Non-multiple myeloma 14 30.4 32 69.6 46 21.6 Total 74 34.7 139 65.3 213 Isotype N %a N %a N %b IgG 50 44.2 63 55.8 113 53.3 0.025 IgA 9 22.5 31 77.5 40 18.9 IgM 3 30.0 7 70.0 10 4.7 Kappa only 4 16.0 21 84.0 25 11.8 Lambda only 8 33.3 16 66.7 24 11.3 Total 74 34.9 138 65.1 212 Renal Function (KDOQI stages) N %a N %a N %b Stage 1-2 52 36.9 89 63.1 141 29.0 0.001 Stage 3 67 29.1 163 70.9 230 47.2 Stage 4 12 16.7 60 83.3 72 14.8 Stage 5 8 18.2 36 81.8 44 9.0 Total 139 28.5 348 71.5 487 a row percent, b column percent Table 2. Light chain burden and relevant labs by B12 status. Vitamin B12 Status Insufficient B12 Normal B12 Total p FLC Burden* N %a N %a N %b Normal FLC 12 34.3 23 65.7 35 16.4 0.354 Not measurable FLC, abnl ratio 23 40.4 34 59.6 57 26.8 Measureable FLC, nl BJP 18 26.1 51 73.9 69 32.4 Measurable FLC, elevated BJP 15 44.1 19 55.9 34 16.0 Massive BJP (>3g/24hr) 6 33.3 12 66.7 18 8.5 Total 74 34.7 139 65.3 213 Labs (medians) Folate, serum 14.0 14.6 0.919 MCV 91.3 92.4 0.055 Hemoglobin 10.9 10.6 0.940 LDH 186 199 0.145 Albumin 3.8 3.9 0.958 *normal = (sFLC<100mg/l), k/l ratio 0.26-1.85; measureable = sFLC ³100mg/l; abnl ratio = k/l ratio<0.26 or >1.85; elevated bence jones protein (BJP) = M-spike or BJP>200mg/24hr arow percent, b column percent Disclosures Chari: Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Biotest: Other: Institutional Research Funding; Millennium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Flow Cytometry Based Detection of MRD in Bone Marrow of Patients with Multiple Myeloma: A Comparison Between Fluorescent-Based Cytometry Versus Cytof

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4195-4195 ◽  
Author(s):  
Arnab Ghosh ◽  
Nicole Carreau ◽  
Alessandra Moscatello ◽  
Adeeb Rahman ◽  
Jingjing Qi ◽  
...  
Keyword(s):  
Heavy Metal ◽  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Metal Ions ◽  
Research Funding ◽  
Heavy Metal Ions ◽  
Residual Disease ◽  
Response To Therapy ◽  
Institutional Research ◽  
Highly Sensitive

Abstract The introduction of novel agents for the treatment of multiple myeloma (MM) has shifted the emphasis towards achieving a molecular complete remission (CR). Traditional methods to detect malignant plasma cells (PC) in minimal residual disease (MRD) utilize multicolor flow cytometry (MFC) to detect aberrant phenotypes. However fluorescent-based MFC assays are limited by the number of markers, difficulty in standardization of assays and overlap of signal between the fluorescent channels. These limitations can be overcome by cyTOF, a flow cytometry assay based on time-of-flight mass spectrometry using antibodies labeled with heavy-metal ions, permitting simultaneous assessment of large panels of markers. We have developed a novel highly sensitive mass cytometry protocol for the detection of MRD. BM from 5 MM patients and 1 non-myeloma control were RBC-lysed and labeled with MM markers for MFC and cyTOF. cyTOF is a flow cytometry based on mass spectometry where antibodies are labeled with heavy-metal ions, permitting utilization of more markers without concern for spillover. The MFC panel included CD38, CD138, CD45, CD56, CD19, CD117. Labeled cells for MFC were acquired by BD LSR Fortessa.. The panel for cyTOF comprised markers for cells across the hematopoietic spectrum and those specific for MM. Labeled cells acquired with cyTOF were analyzed using SPADE. Limits of detection (LOD) and quantification (LOQ) for MFC are based on prior reports. The results were compared with an independent commercial MFC-based assay (Genoptix). Malignant PC could be detected by MFC and cyTOF based assasys (See Figure). We were able to detect MRD in three subjects that had no detectable disease by an independent commercial MFC based assay (Genoptix). This can be attributed to acquiring at least 1x106 for our assays leading to a lower LOD and LOQ (greater sensitivity). Using cyTOF and SPADE, we could detect MRD in 4/5 patients. Overall our panel with cyTOF has a lower LOD than MFC for detection of MRD. Early detection of MRD in MM patients using a highly sensitive flow cytometry like cyTOF will help in risk stratification, predicting relapse and studying response to therapy. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Biotest: Other: Institutional Research Funding; Novartis: Consultancy, Research Funding. Jagannath:Bristol Myers Squibb: Honoraria; Janssen: Honoraria; Merck: Honoraria; Novartis: Honoraria; Celgene: Honoraria.

scholarly journals Outcomes and Management of Red Blood Cell Transfusions in Multiple Myeloma Patients Treated with Daratumumab

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3571-3571 ◽  
Author(s):  
Ajai Chari ◽  
Toshihisa Satta ◽  
Amit Tayal ◽  
Sundar Jagannath ◽  
Hearn Jay Cho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Single Agent ◽  
Cell Phenotype ◽  
Institutional Research ◽  
Panel Testing ◽  
Antiglobulin Test ◽  
Positive Direct ◽  
The Impact ◽  
Transfusion Reactions

Abstract Background Daratumumab (DARA) is a human IgG1 kappa monoclonal antibody that targets cells expressing CD38, which is highly expressed in multiple myeloma (MM) cells. In the phase 2 MMY2002 (Sirius) trial, treatment with single agent DARA resulted in a 29% overall response rate, with a median PFS of 3.7 months in heavily pretreated MM patients (Lonial S. J Clin Oncol. 2015; 33(suppl): abstrLBA8512). However, CD38 is also expressed on red blood cells (RBCs) and DARA binding to RBCs results in pan-reactivity on RBC panel testing using an indirect antiglobulin test (IAT). Recently, it was reported that treating RBCs with dithiothreitol (DTT) removes DARA to allow for accurate antibody testing (Chapuy CI, et al. Transfusion. 2015;55(6pt2):1545-1554) but also denatures Kell antigen in the process. To date, little is known about the impact of DARA interference with IAT on the outcomes of patients requiring packed RBC (PRBC) transfusions. Methods The frequencies of PRBC transfusions and any transfusion-related adverse events from all 124 patients treated on the Sirius study were obtained from the clinical database as of the data cut off of January 9th, 2015. Although details of transfusions were not prospectively collected, surrogate outcomes of transfusion reactions within 4 weeks of the transfusion were analyzed including change in hemoglobin (Hb), elevated bilirubin, fever, and hypotension. In addition, we evaluated IAT results and transfusion outcomes of the 8 patients treated at our institution. Results During the study, 47 patients received 147 transfusions with a total of 235 units of PRBCs. To date, no transfusion-related reactions were noted. Of the 47 patients, 8 patients were treated at our institution. One patient showed multiple alloantibodies (anti-E, -K, -Jkb, -Fya, -Fy3, -S, Knops) on IAT prior to DARA. This individual and 6 others agglutinated all RBCs on panel testing with weak reactivity at the antihuman globulin phase of testing. Reactivity was enhanced by gel testing compared to reactivity in low ionic strength saline and was unaffected by enzymatic treatment with ficin. Six out of 7 patients had a negative autocontrol. The one patient with a positive autocontrol had a weakly positive direct antiglobulin test with IgG. Six out of these 7 patients with panagglutinin had a positive result on the first IAT after initiation of DARA, ranging from 7 to 175 days (median 49). One patient did not have an IAT after initiation of DARA. A total of 9 leuko-reduced, irradiated, phenotypically matched RBCs were given to 3 patients during DARA treatment, and additional 9 units were given to 3 patients after DARA completion while their IATs remained positive. All transfusions resulted in an appropriate rise in Hb (median 1.0 g/dL, range 0.5-2.7) without any associated transfusion reactions. None of the patients made new unexpected RBC alloantibodies while receiving phenotypically matched RBCs. Conclusion For the 7 patients at our site with IAT testing after DARA treatment, all demonstrated pan-reactivity on RBC panel testing. Treatment with DTT removes this interference but also denatures Kell antigen in the process. Most hospitals do not use DTT as part of routine immunohematology workups; therefore, we recommend obtaining a red cell phenotype prior to initiating DARA treatment and providing phenotypically matched blood thereafter to avoid resultant difficulties in new alloantibody identification and delays in providing compatible PRBCs. Based on a database query of all 124 patients as well as all patients at our site, PRBC transfusions did not appear to be associated with complications. In a MM patient population that will frequently require PRBC transfusion, blood bank and hematologist/oncologist awareness of these findings is important to minimize errors or delays in providing compatible PRBCs. Disclosures Chari: Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding. Jagannath:Celgene: Honoraria; BMS: Honoraria; MERCK: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Janssen: Honoraria. Catamero:Celgene: Honoraria, Other: Lecturer; Onyx: Other: Lecturer; Millennium/Takeda: Other: Lecturer. Verina:Celgene: Other: Lecturer. Doshi:Janssen: Employment. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Voorhees:Millennium/Takeda and Novartis: Honoraria; Array Biopharma, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Celgene, GlxoSmithKline, and Oncopeptides: Research Funding.

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