Minimal Residual Disease Measurement By Deep Sequencing Reflects Changes In Disease Load During Therapy In Diffuse Large B Cell Lymphoma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1785-1785
Author(s):  
Nina Wagner-Johnston ◽  
Nancy L. Bartlett ◽  
Kenneth R. Carson ◽  
Mary Anderson ◽  
Li Weng ◽  
...  
Keyword(s):  
B Cell ◽  
Peripheral Blood ◽  
Treatment Time ◽  
Residual Disease ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
End Of Treatment ◽  
Equity Ownership ◽  
Pre Treatment ◽  
Time Point

Abstract Background Assessment of prognosis in patients (pts) with diffuse large B cell lymphoma (DLBCL) is suboptimal. Pre-treatment clinical evaluations such as the International Prognostic Index (IPI) score are not useful in assessing response or tailoring therapy. Interim PET/CT, as an early indicator of response has a low positive predictive value and current guidelines recommend against its use, underscoring the need for improved predictive markers for early response assessment. The LymphoSIGHT™ platform is a high-throughput sequencing-based method for detecting lymphoid malignancies in peripheral blood that could potentially be used for detecting minimal residual disease (MRD) during and after treatment (Faham et al. Blood 2012). LymphoSIGHT™ has a sensitivity to detect one lymphoma cell per million leukocytes in peripheral blood and can be used to identify circulating tumor DNA in DLBCL (Armand et al., Brit J Haematol 2013). Here we assessed the ability of the sequencing method to detect lymphoma clones in pre-treatment tumor biopsy (bx) and peripheral blood samples obtained during and post-therapy from 33 DLBCL pts. Methods Fifty pts with DLBCL undergoing chemotherapy with curative intent were prospectively enrolled in a study to evaluate for clonal immunoglobulin (Ig) DNA in baseline tumor and peripheral blood samples collected pre-treatment, day 8, week (wk) 4, wk 7 and end of treatment. Using universal primer sets, we amplified Ig heavy chain (IGH) variable, diversity, and joining and Ig kappa chain (IGK) gene segments from genomic DNA. Amplified products were sequenced and analyzed using standardized algorithms for clonotype determination. Tumor-specific clonotypes were identified for each pt based on their high-frequency within the B-cell repertoire in the lymph node (LN) bx sample. The presence of the tumor-specific clonotype was then quantitated in plasma and serum samples obtained at pre-treatment time points. A quantitative and standardized measure of clone level per million leukocytes in each follow-up sample was determined using internal reference DNA. Results Paired tumor/plasma specimens were available from 41 pts. Of 33 LN bx samples screened, 30 had adequate DNA, and we detected a high-frequency clonal rearrangement in 25/30 (83%, CI 70-97%). In pts with an identified lymphoma specific clonotype in the bx sample, the clonotype was also detected in the plasma and/or serum compartment in 17 of 24 (71%) pts at the pre-treatment time point. We observed high qualitative and quantitative correlation (r2 = 0.89) between MRD levels measured in the matched plasma (median 0; average 53,036) and serum (median 0; average 111,496) samples. Three qualitative discordances were observed, in which the serum was negative and the plasma was positive at the same time point, all of which can be attributed to low amounts of lymphoma clone molecules that were detected in the positive samples. Pts who later relapsed tended to have higher levels of lymphoma-specific clones in their pretreatment samples compared to pts in sustained CR (t-test p=0.10).We also monitored MRD kinetics in response to therapy and observed a marked decline in MRD positivity over the course of treatment. Specifically, MRD positivity was observed in 4/5 (80%) pts at Day 8, in 6/19 (32%) at wk 4, in 1/21 (5%) at wk 7 and in 1/20 (5%) at the end of treatment (Figure 1). The average MRD level per million leukocytes was 261,681 at pre-treatment, 14,698 at wk 4, 0.35 at wk 7, and 74 at the end of treatment time point (Figure 1, horizontal lines). Thus, MRD levels demonstrated a substantial decline with treatment and reflected changes in disease load. Of note, the single pt that was MRD positive at the end of treatment was the only pt with refractory disease. Of 5/18 pts with a positive interim PET/CT following 2-3 cycles of chemotherapy, only 2 have relapsed. Three of the 5 pts (including one that relapsed) were tested for detectable clonal DNA at 7 wks, and none of the three was positive. Results of all 41 pts will be presented. Conclusions Our data demonstrate that circulating clonal tumor DNA can be detected in the blood of pts with DLBCL, and that MRD levels decline consistent with tumor burden. Further studies are warranted to better characterize the predictive value of this novel sequencing platform. Disclosures: Weng: Sequenta, Inc: Employment, Equity Ownership. Klinger:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership.

Detection of Diffuse Large B-Cell Lymphoma in Peripheral Blood Using High-Throughput Sequencing Assay.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2666-2666
Author(s):  
Yasuhiro Oki ◽  
Malek Faham ◽  
Victoria Carlton ◽  
Sattva S. Neelapu ◽  
Anas Younes
Keyword(s):  
B Cell ◽  
Peripheral Blood ◽  
High Throughput Sequencing ◽  
B Cell Lymphoma ◽  
Lymph Node Biopsy ◽  
Employment Equity ◽  
Tumor Biopsy ◽  
Blood Samples ◽  
Large B Cell Lymphoma ◽  
Equity Ownership

Abstract Abstract 2666 Background: In patients with diffuse large B-cell lymphoma (DLBCL), circulating lymphoma cells in the bloodstream are rarely detected by conventional morphology or flow cytometry evaluation. We developed a high-throughput sequencing based platform, LymphoSIGHT, to detect evidence of lymphoid malignancies in peripheral blood samples, as this could potentially be used for detection of minimal residual disease after treatment. This sequencing method has a sensitivity to detect one lymphoma cell per million leukocytes in peripheral blood. We herein report the results of our pilot study assessing the ability of this method to detect the lymphoma clone in peripheral blood samples from 5 DLBCL patients at the time of diagnosis. Methods: This study has been approved by IRB and consent has been obtained from patients. Using universal primer sets, we amplified immunoglobulin heavy chain (IgH@) variable, diversity, and joining gene segments from genomic DNA in tumor biopsy and peripheral blood samples (plasma and peripheral blood mononuclear cell (PBMC) compartments) collected at initial diagnosis. Amplified products were sequenced to obtain >1 million reads (>10× sequencing coverage per IgH molecule), and were analyzed using standardized algorithms for clonotype determination. Tumor-specific clonotypes were identified for each patient based on their high-frequency within the B-cell repertoire in the lymph node biopsy sample. The presence of the tumor-specific clonotype was then quantitated in cell-free and PBMC compartments from the diagnostic blood sample. A quantitative and standardized measure of clone level among all leukocytes in the diagnostic sample was determined using internal reference DNA. Results: We detected a high-frequency IgH clonal rearrangement in all 5 lymph node biopsy samples. The lymphoma clonotype that was identified in the tumor biopsy was also detected in the plasma and/or PBMC compartment in all 5 patients at diagnosis. Specifically, the lymphoma clonotype was detected in the plasma compartment in 4 patients, while 3 patients demonstrated the presence of the lymphoma clonotype in the PBMC compartment (Table 1). We hypothesize that the positive lymphoma clone in the plasma is due to rapid proliferation and necrosis of the primary tumor, releasing the degraded component of lymphoma into the blood stream. However, in this small sample size, we did not observe an obvious correlation between the level of detection (PBMC or plasma) and clinical parameters (LDH, stage, size of tumor, tumor Ki67, cell-of-origin). All patients achieved complete response after initial treatment and four are being followed. We plan to analyze blood specimens while they are in remission. Conclusions: IgH clonal rearrangements were detected by sequencing in all tumor biopsy samples. Importantly, all peripheral blood samples showed signs of circulating lymphoma material in either the plasma or PBMC compartment at diagnosis. Analysis of diagnostic and post-therapy samples from additional DLBCL patients is ongoing. These data will determine whether the sequencing assay is a strong indicator for response to therapy and relapse monitoring. Disclosures: Faham: Sequenta, Inc.: Employment, Equity Ownership, Research Funding. Carlton:Sequenta, Inc.: Employment, Equity Ownership, Research Funding.

DNA Sequencing-Based Monitoring Of Serum Predicts Clinical Relapse Before CT Imaging in Diffuse Large B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1767-1767 ◽  
Author(s):  
Mark Roschewski ◽  
Stefania Pittaluga ◽  
Kieron Dunleavy ◽  
Katherine Kong ◽  
Margaret Shovlin ◽  
...  
Keyword(s):  
Lymph Node ◽  
Dna Sequencing ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Circulating Tumor Dna ◽  
Clinical Relapse ◽  
Serum Samples ◽  
Employment Equity ◽  
Equity Ownership ◽  
Pre Treatment

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma with >40,000 cases annually in the US. While most patients are cured by frontline immunochemotherapy, up to 20% recur and salvage therapy is poor. Relapse detection relies on CT imaging, which is hampered by radiation exposure, high costs, high false positive rates, and infrequently detects relapse prior to symptoms. Novel methods to detect early relapse may improve outcomes. The LymphoSIGHT™ platform is a high-throughput DNA sequencing method that can detect minimal residual disease (MRD) of lymphoid malignancies in peripheral blood (PB) (Faham et al. Blood 2012) with a sensitivity of one lymphoma cell per million leukocytes. We showed it can also detect circulating tumor DNA in the PB of DLBCL pts (Armand Br J Haematol 2013). We assessed the sensitivity and specificity of LymphoSIGHT™ to detect circulating tumor DNA in serum after frontline therapy in DLBCL. Methods All pts were newly diagnosed DLBCL undergoing frontline EPOCH-based chemotherapy. Post-therapy surveillance included clinic visits, PB samples, and contrast CT scans at 3, 4, 6, 12 and 12 mos intervals for the first 5 years, respectively. Pre-treatment lymph node biopsies and PB samples collected at initial diagnosis and during surveillance visits were sent for VDJ amplification and MRD sequencing assessment. Using universal primer sets, we amplified immunoglobulin heavy and kappa chain (IGH and IGK) variable, diversity, and joining gene segments from genomic DNA in tumor biopsy and PB samples. Amplified products were sequenced, and tumor-specific clonotypes were identified for each pt based on their high frequency within the B-cell repertoire in the lymph node. The presence of the tumor-specific clonotype was then quantitated in PB samples. Results Twenty-seven pts, treated between July 1996 and July 2005, had adequate DNA from pre-treatment FFPE lymph node biopsies, and 25 (92.6%) had a high-frequency clonal rearrangement (MRD) detected. The median pt age was 49 years (20-75) and an IPI risk groups included 8 low, 3 low-intermediate, 11 high-intermediate and 3 high. The pts had a median of 12 surveillance CT scans (range 1-13) and 221 serum samples analyzed for MRD. Two pts progressed early after cycles 1 and 6. The first pt had progressive disease by CT scan after cycle 1 and remained MRD positive. The second pt remained MRD positive at the end of cycle 6, at which time a CT showed CR-unconfirmed, and progressed one month later. In the remaining 23 pts who achieved CR, seven relapsed at a median of 20.3 (range 5.6-151.6) months. The 16 pts in sustained CR had a median follow-up of 99.7 months (range 3.0-136.3) and none were MRD positive post-treatment (specificity 100%; 88.9-100%). There were 0 false positives in 200 post-treatment samples tested (specificity 100%, 99-100%). Of 7 relapsing pts, 6 had serum samples within 1 year of recurrence. Of these, 5 pts had a positive MRD (range 3.2 to 11.2 months) (sensitivity 83%; 44-98%) at a median of 9.2 months (range 3.2 to 11.2 months) prior to a positive CT scan (Figure). One relapsing pt only had a serum sample obtained 18 mos before CT recurrence and it was MRD negative. Conclusions Our data suggest that a DNA sequencing-based MRD test of serum can predict clinical relapse with high sensitivity and specificity in DLBCL prior to CT progression. MRD assay detection may significantly reduce the cost, inconvenience and toxicity of surveillance. Importantly, early detection of recurrence may significantly improve pt outcomes. Additional pts are being analyzed and updated results will be available. This work was supported by the Intramural Research Program of NCI at NIH and Sequenta, Inc. Disclosures: Kong: Sequenta: Employment, Equity Ownership. Zheng:Sequenta: Employment, Equity Ownership. Willis:Sequenta: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Faham:Sequenta: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Minimal Residual Disease Detection By Next Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia (ALL) Patients Treated on SWOG Trial S0333

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2399-2399 ◽  
Author(s):  
Olga Sala Torra ◽  
Megan Othus ◽  
David W Williamson ◽  
Brent L. Wood ◽  
Ilan Kirsch ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Next Generation ◽  
Employment Equity ◽  
Equity Ownership ◽  
Generation Sequencing ◽  
Minimal Residual

Abstract We used next generation sequencing (NGS) of the immunoglobulin genes to evaluate minimal residual disease (MRD) in 153 specimens from 32 patients with newly diagnosed adult B cell ALL enrolled in the phase II SWOG S0333 multi-center study. We used the clonoSEQTM assay developed by Adaptive Biotechnologies that detects 1 leukemic cell in a background of 1 million nucleated cells and focuses in the B cell receptor (Ig). Initially, a set of pre-study specimens was sequenced in order to identify the precise sequence of the VDJ or DJ fragments. Clones representing more than 5% of the total repertoire of IgH molecules profiled were considered potentially leukemic. The follow-up specimen IgH repertoire sequences were compared to the diagnostic clonal ones and the leukemic marker sequence(s) previously identified were searched for explicitly. At least one Ig clonotype was detected in 29/32 (91%) cases analyzed. The 3 remaining cases were reviewed, and in 2 cases the specimens available for NGS had been reported as having no blasts by morphology. The leukemic clonal sequence was a complete VDJ rearrangement in 17/32 patients (53%), an incomplete DJ rearrangement in 8/32 patients (25%), and in 3/32 cases both VDJ and DJ rearrangements coexisted. One patient had a kappa light chain rearrangement. 17/32 (53%) cases contained more than one IgH rearrangement at diagnosis (median=2, range: 1 - 4). One of our patients is a potential case of therapy driven clonal selection. He presented at diagnosis with two related clones, one representing 75% of VDJ sequences and the second one 18%. At relapse, the second clone was responsible for most of the VDJ sequences (95%). The NGS results were compared to the MRD results detected by multiparameter flow cytometry (MFC) in 66 specimens analyzed by both methods. The concordance between the methods in the qualitative determination of the presence or absence of leukemia was 82% (54/66). In 12 specimens (18%) MRD was detected by sequencing but not by MFC. One specimen had MRD detected at very low levels by MFC and was negative by NGS. Our study includes 54 paired bone marrow (BM) and peripheral blood (PB) specimens. The median values of leukemia detected by NGS were 6-fold higher in BM than PB (range: 0.38 - 821-fold). Twenty-five pairs show no detectable MRD in either specimen. MRD was still detectable in 20 of the remaining 29 PB cases (for one of the pairs the BM specimen was negative). In 6/9 (67%) pairs of samples with disease detectable in BM but not in PB by NGS, no MRD was detected by MFC in the BM specimen. Lastly, outcome analysis was conducted in 21/32 patients with specimen available for MRD studies at the time of registration to second induction. Patients without MRD by NGS had a 5-year relapse free survival (RFS) of approximately 80%, while patients with MRD positive by both NGS and flow have the poorest outcome (p = 0.003) (see Figure). Patients with MRD detectable only by NGS have and intermediate RFS (p = 0.078, and p = 0.04 when compared to patients with MRD negative by both techniques, and patients with leukemia detected both by NGS and flow respectively). These results suggest that MRD detection by immunoglobulin gene sequencing is a very sensitive technique, and may identify patients with an excellent survival. Moreover, the increased sensitivity of the method may allow peripheral blood testing to supplement routine marrow sampling for MRD determination. Figure 1 Figure 1. Disclosures Williamson: Adaptive Biotechnologies: Employment, Equity Ownership. Kirsch:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership.

Sequencing-Based Minimal Residual Disease Assessment In T-Cell Malignancies: T-Cell Prolymphocytic Leukemia Case Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1392-1392
Author(s):  
Katherine Sutherland ◽  
Katherine Kong ◽  
Aaron C. Logan ◽  
Malek Faham ◽  
David B. Miklos
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Cell Receptor ◽  
Employment Equity ◽  
Prolymphocytic Leukemia ◽  
Blood Samples ◽  
Leukemia Cutis ◽  
Equity Ownership

Abstract Background The prognostic significance of minimal residual disease (MRD) quantification in the post-transplant setting has been demonstrated in multiple lymphoid malignancies, including acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Previous studies support the clinical utility of molecular MRD quantification of tumor burden after allogeneic hematopoietic cell transplantation (allo-HCT) (Logan et al, Leukemia 2013). We have developed the ClonoSIGHT™ test, which is based on the deep sequencing of immunoglobulin and T-cell receptor rearrangements and has a detection limit of one cancer cell per million leukocytes in peripheral blood or bone marrow (Faham et al, Blood 2012; Armand et al, Brit J Haematol 2013). In this report, we will discuss the technical performance of the ClonoSIGHT test for routine MRD quantification after allo-HCT and present a case study on a patient with T-cell prolymphocytic leukemia (T-PLL). Methods A 55 year old female presented with T-PLL including symptomatic CNS disease, received 12 weeks of Alemtuzumab therapy and then 12 weeks following her last Alemtuzumab treatment received an unrelated donor myeloablative allo-HCT using Fludarabine, BCNU and Melphalan conditioning with antithymoglobulin, Mycophenolate mofetil and cyclosporine primary immune prophylaxis. Peripheral blood samples were collected for MRD assessment before and serially after allo-HCT. Using universal primer sets, we amplified T-cell receptor beta (TRB), delta (TRD) and gamma (TRG) variable, diversity, and joining gene segments from genomic DNA isolated from peripheral blood mononuclear cells (PBMC). Amplified products were sequenced and analyzed using standardized algorithms for clonotype determination, and leukemia-specific clonotypes were identified based on their frequency within the T-cell repertoire (>5%). The leukemia-specific clonotype was then quantified in serial peripheral blood samples and reported as the absolute number of leukemic-specific clones among total leukocytes. Results A single clonal TRG gene rearrangement accounting for 26.1% WBC in the pre-transplant sample was identified and quantified in serial peripheral blood samples. A 4-log decline in MRD levels occurred post allo-HCT (Figure 1) thru 56 days following graft infusion; however, serial MRD monitoring demonstrated increasing levels of leukemia-specific clonotypes in the peripheral blood over time (Figure 1). Immunosuppression tapering strategies were employed in response to clinical events and MRD levels. Specifically, the patient developed an EBV+ post-transplant lymphoproliferative disease (PTLD) 60 days post allo-HCT, and cyclosporine was tapered in addition to instituting anti-CD20 rituximab treatment. As per institutional practice, a bone marrow biopsy 84 days post-HCT showed full donor engraftment with normal cellularity and no evidence of PLL was detected by flow cytometry when ClonoSIGHT detected 0.013% PLL in the patient's blood. Unfortunately, in the setting of immune suppression taper at 100 days post allo-HCT, the patient developed Grade II skin GVHD and was treated with 0.5mg/kg prednisone daily and tapered as indicated. At 160 days post allo-HCT, the patient presented with new skin papules suspected to be leukemia cutis. The PLL clonotype was detected in the skin biopsy; however, it was present at lower frequency in the TRG repertoire than in the blood, thus not supporting a diagnosis of leukemia cutis. In agreement, skin pathology revealed Verruca Vulgaris (warts). However, the patient's MRD continued to increase in the blood while immunosuppression was tapered and stopped completely 6 months post-HCT. Conclusions MRD assessment can be used to monitor a patient's disease progression after immune cellular therapy and aids immune suppression management following allo-HCT. Further, as presented in this case study, ClonoSIGHT detection of the leukemia clone in the blood compared with other tissues can sensitively and specifically assess extramedullary relapse. Disclosures: Kong: Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

TGR-1202, a Novel Once Daily PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1984-1984 ◽  
Author(s):  
Howard A. Burris ◽  
Manish R. Patel ◽  
Danielle M. Brander ◽  
Owen A. O'Connor ◽  
Changchun Deng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Employment Equity ◽  
Previous Formulation ◽  
Equity Ownership

Abstract Background: TGR-1202 is a novel oral, next generation PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients with advanced hematologic malignancies (ASCO 2014). Herein we present updated results from this Phase I, first in human study of TGR-1202 in patients with relapsed and/or refractory CLL and B-cell lymphoma. Methods: TGR-1202 is administered orally once daily following a 3+3 dose escalation design. Previously treated patients with an ECOG PS ≤ 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 49 patients have been enrolled to date of various lymphoma subtypes including CLL, follicular lymphoma (FL), Hodgkin’s lymphoma (HL), DLBCL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Demographics: 76% male, ECOG 0/1/2: 17/31/1, median age of 59 yrs (range: 22-85), median prior treatment regimens: 3 (range: 1-14), and 43% were refractory to prior treatment. 35 patients have been treated at doses ≥ 800 mg of a previous formulation where a threshold effect in activity was observed, and 6 have been treated with an improved micronized formulation (≥ 200 mg). TGR-1202 was well tolerated and no MTD has been reached to date. The only Gr≥3 AE occurring in >5% of patients was neutropenia (8%). AE’s of all grades occurring in >20% of patients were limited to diarrhea (24%), cough (22%), fatigue (20%), and nausea (20%). Notably, in comparison to other PI3Kδ inhibitors, no hepatotoxicity and no cases of colitis have been observed to date. Rates of infection and pneumonia have also been low (12% and 6%, respectively), and no cases of febrile neutropenia have been reported. Of the 41 patients treated at ≥ 800 mg of the previous formulation or with the micronized formulation, 32 are evaluable for efficacy (6 too early to evaluate, 2 non-compliant, 1 did not meet I/E criteria). Responses have been limited in patients with aggressive lymphoma and HL. Of the 9 evaluable CLL patients, 8 (89%) achieved a nodal PR (median nodal reduction of 71%), of which 5 achieved a PR per Hallek 2008 criteria with the remaining 4 having persistent lymphocytosis. The 1 CLL patient with SD had a >40% nodal reduction and remains on study. Of the 7 evaluable FL patients, all have shown clinical benefit with a reduction in tumor burden with 2 having achieved a PR, and the remaining 5 patients in SD. Additionally 2 MZL patients each achieved SD with >25% nodal reductions and remain on study. Notably, no patient with CLL or indolent lymphoma (FL & MZL) treated at ≥800 mg has progressed to date (median time on study of 20 weeks, range 6 – 73+), and no patient who achieved >50% reduction in tumor burden (including patients with CLL, FL, and HL) has progressed, with median time on study of 34 weeks (range 7 – 68+). Pharmacodynamic analysis in CLL patients indicates rapid suppression of pAKT at doses of 400 mg QD of the previous formulation. Conclusions: TGR-1202 is well tolerated in patients with relapsed and/or refractory hematologic malignancies with no reported hepatotoxicity or events of colitis and promising clinical activity. Enrollment continues in expansion cohorts and with the micronized formulation. Disclosures Brander: Celgene: Mentor received research funding Other. O'Connor:Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Flinn:Infinity Pharmaceuticals: Consultancy.

CC-122 Degrades the Lymphoid Transcription Factor Aiolos (IKZF3) By Modulating Cereblon and Shows Clinical Activity in a Phase Ib Study of Subjects with Relapsed or Refractory Non-Hodgkin’s Lymphoma and Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3500-3500 ◽  
Author(s):  
Vincent Ribrag ◽  
Silvia Damien ◽  
Mecide Gharibo ◽  
Mercede Gironella ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Single Dose ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background: CC-122 is a novel non-phthalimide analog of the IMiDs® immunomodulatory drugs (lenalidomide and pomalidomide) and a first in class PPMTM (Pleiotropic Pathway Modifier) compound with multiple biological activities including potent anti-proliferative activity against B-lineage cells (10-fold greater than lenalidomide), anti-angiogenic activity (100-fold greater than lenalidomide) and immunomodulatory effects (10-fold greater than lenalidomide). The molecular target of CC-122 is cereblon (CRBN), a substrate receptor of the Cullin ring E3 ubiquitin ligase complex (CRL4CRBN). CC-122 promotes ubiquitination of lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) in a CRBN-dependent manner, leading to their subsequent degradation. Following establishment of 3mg once daily (QD) as the maximum tolerated dose (Blood 122:2905 2013), patients with advanced aggressive non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable patients. CC-122 was dosed at 3 mg QD in 28-day cycles until disease progression. Results: As of May 1, 2014, 93 total patients were enrolled in the expansion phase of the study. The NHL cohort included 21 patients with diffuse large B-cell lymphoma (DLBCL) and 1 patient with mantle cell lymphoma, and twenty-four patients were enrolled in the MM cohort. Results in solid tumor cohorts will be reported separately. All patients were ECOG performance status 0-2, the median number of prior systemic therapies was 4 (NHL) and 6 (MM). The most common (> 20%) adverse events (AEs) (grades 1-4) included neutropenia (69.6%), anemia (52%), asthenia (50%), pyrexia (35%), diarrhea (30%), cough (30%), thrombocytopenia (28%), and constipation (22%). Grade 3/4 AEs occurring in more than one patient were neutropenia (52%), anemia (26%), febrile neutropenia (13%), and thrombocytopenia (7%). CC-122 dose reduction was required in 36.4% of patients with NHL and 63% of patients with MM, the majority of which was due to neutropenia and occurred during cycle 1 or 2. CC-122 systemic exposure in NHL and MM patients was generally comparable after administration of single and multiple doses. Peak concentrations were observed between 30 minutes and 2 hours (median Tmax concentration = 1.5 h). Four treated patients with DLBCL had objective responses; one patient with complete response (CR) and 3 with partial responses (PR). Responses were observed in patients with germinal center B cell (GCB), non-GCB and Myc/Bcl2 over-expressing DLBCL. Four treated patients with MM had PR, and two of these responders were progression free beyond 10 cycles. A single dose of CC-122 3mg resulted in decreased Aiolos protein expression at 1.5 and 5 hours compared with baseline in peripheral B cells (median 38% and 53%) and T cells (median 31% and 54%) in the combined NHL (n = 16) and MM (n = 19) cohorts. Decrease in expression of Aiolos protein from baseline was also observed in lymph node biopsies of patients with DLBCL. Furthermore, CC-122 treatment decreased CD19+ B cells (median = 57% of baseline), expanded CD4-/CD8+/CD45RA-/CD45RO+ cytotoxic memory T cells (median = 320% of baseline), and expanded CD4+/CD8-/CD45RA-/CD45RO+ helper memory T cells (median = 154% of baseline) in peripheral blood samples from patients with MM (n = 9) and NHL (n = 3-12) subjects. Additionally, ex vivo activation of T cells after a single dose of CC-122 compared with baseline, as measured by IL-2 production, increased by a median of 776% (NHL n = 3 and MM n = 7). Conclusions: CC-122 shows promising initial clinical and pharmacodynamic activity in heavily pretreated relapse/refractory NHL and MM patients. Biomarker analysis indicates that the 3 mg QD dose of CC-122 results in rapid CRBN target engagement and Aiolos degradation in the peripheral blood lymphocytes of patients with NHL and MM patients and in NHL tumor tissue. Exploration of an intermittent dosing to mitigate neutropenia-related dose reductions and interruptions is ongoing and clinical studies exploring drug combinations with CC-122 are underway. Disclosures Ribrag: Celgene Corp: Consultancy. Rasco:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Wei:Celgene Corp: Employment, Equity Ownership. James:Celgene Corp: Employment. Hagner:Celgene Corp: Employment, Equity Ownership. Gandhi:Celgene Corp: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership. DiMartino:Celgene Corp: Employment, Equity Ownership. Pourdehnad:Celgene Corp: Employment, Equity Ownership. Stoppa:Celgene Jansen: Honoraria.

Lenalidomide (LEN) and Epstein-Barr Virus (EBV) Reactivation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5372-5372
Author(s):  
Melinda Mezo ◽  
Chad C. Bjorklund ◽  
Lilia Weiss ◽  
Neil Minton ◽  
John Freeman
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Safety Database ◽  
Barr Virus ◽  
Ebv Infection ◽  
Ebv Reactivation ◽  
Equity Ownership ◽  
Epstein Barr

Abstract Background: EBV is a common infection that can be reactivated from latency by exposure to chemotherapy and immunosuppressants. The EBV-positive prevalence rate in the adult population is ≈ 80% to > 90% (Serraino et al, J Biol Regul Homeost Agents, 2005). A recent report suggested that Ikaros is an indirect repressor of the immediate-early EBV genes, BZLF1 and BRLF1 (Iempridee et al, J Virol, 2014). Ikaros has also been demonstrated as a LEN-inducible substrate of the cereblon-dependent E3-ubiquitin ligase complex CRL4ACRBN, therefore targeting it for degradation (Chamberlain et al, Nat Struct Mol Biol,2014). These data suggest that both BZLF1 and BRLF1 could be activated by LEN. However, no data suggest that LEN treatment (Tx) leads to activation of EBV lytic replication in patients (pts). In contrast, the downregulation of c-Myc and IRF4, which is facilitated by LEN-induced degradation of Ikaros, may disrupt the c-Myc/IRF4-dependent EBV transcriptional program (Bjorklund et al, Blood, 2014). Thus, LEN could possibly suppress EBV reactivation. Several observations have linked the presence of viral activation and/or the presence of EBV during multiple myeloma (MM) Tx regardless of therapy, suggesting that EBV reactivation could be from a therapy-induced stress response and not from any particular Tx. Additionally, many commonly used therapies in MM have also been shown to reactivate EBV, including glucocorticoids and melphalan (Yang et al, Brain Behav Immun, 2010). Objective: Our study investigated the impact, if any, of LEN on EBV reactivation in LEN-treated pts by identifying and analyzing all EBV reactivation/infection reports in the Celgene global safety database. Methods: The overall occurrence of EBV infection during LEN Tx was determined by searching for the MedDRA High-Level Term of "Epstein-Barr viral infection" and Preferred Terms of "Epstein-Barr virus antibody positive," "Epstein-Barr virus antigen positive," and "Epstein-Barr virus test positive" from all sources in the Celgene global safety database. The occurrence of EBV reactivation was derived from all EBV infections and laboratory findings of EBV positivity identified in the database. Results: Overall, the review of the Celgene global safety database identified 42 pts with EBV infection during LEN Tx, of whom 8 pts were considered to have EBV reactivation. Thirty-four pts were identified with EBV infection that lacked any information regarding preexisting EBV infection. Therefore, the occurrence of EBV reactivation and impact of LEN could not be ascertained. Of the 42 pts, 14 reported EBV infection with B-cell malignancies (Hodgkin disease [9 pts] and 1 pt each with B-cell lymphoma, diffuse large B-cell lymphoma, lymphomatoid granulomatosis, lymphoma, and post-transplant lymphoproliferative disorder), of which one (Hodgkin lymphoma) was in a pt with EBV reactivation. With a cumulative LEN pt exposure of 428,373, the reporting rate for EBV infection was 0.01% (42/428,373) and for EBV reactivation was 0.002% (8/428,373). Most (73.8%; 31/42) of the reports were identified in the clinical trial setting, and over half (54.8%; 23/42) of the pts received LEN in the MM indication. Approximately half (52.4%; 22/42) of all pts with EBV infection/reactivation were aged < 65 yrs and 71.4% (30/42) were male. There were 5 reports with a fatal outcome, of which 4 were EBV-associated lymphomas. The median time to onset of all EBV infection/reactivation was 318.5 days (range, 3-1670 days), and median time to onset of EBV infection with B-cell malignancies was 791.5 days (range, 128-1430 days) from start of LEN therapy. The event seriousness, outcome, causality, and action taken with LEN were not available for > 50% of the reports. Review of the 42 pts with EBV infection/reactivation revealed confounding factors that may have contributed to or predisposed pts to develop EBV infection, including immunosuppression, multiple chemotherapies, concomitant use of dexamethasone, and stem cell transplantation. Conclusions: Immunomodulatory agents have been reported to potentially reactivate the lytic cycle in B cells latently infected with EBV due to effects on Ikaros. However, observations suggesting that EBV reactivation is the result of a therapy-induced stress response, as well as the very low reporting rates of EBV infection/reactivation, do not substantiate an increased risk of EBV infection/reactivation in LEN-treated pts. Disclosures Mezo: Celgene Corporation: Employment, Equity Ownership. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Weiss:Celgene Corporation: Employment, Equity Ownership. Minton:Celgene Corporation: Employment, Equity Ownership. Freeman:Celgene Corporation: Employment, Equity Ownership.

Next Generation Sequencing (NGS) Based Minimal Residual Disease (MRD) Testing Is Highly Predictive of Overall and Progression Free Survival in the Total Therapy Trials and Shows Different Prognostic Implications in High Vs Standard Risk Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2064-2064
Author(s):  
Carolina Schinke ◽  
Shayu Deshpande ◽  
Hongwei Wang ◽  
Victoria Carlton ◽  
Katherine A. Kong ◽  
...  
Keyword(s):  
Residual Disease ◽  
Focal Lesions ◽  
Employment Equity ◽  
Pet Ct ◽  
Significant Difference ◽  
Equity Ownership ◽  
Next Generation Sequencing Ngs ◽  
Standard Risk ◽  
Generation Sequencing ◽  
Time Point

Abstract Introduction Achieving complete remission (CR) improves outcomes in multiple myeloma (MM). We have shown that 50% of patients enrolled in Total Therapy (TT) trials achieve CR within one year of enrollment irrespective of risk as defined by the GEP70 risk signature. Nevertheless, the majority of patients with high risk (HR) MM show an early relapse with grim prognosis, while most standard risk (SR) patients tend to relapse late, most often years after completion of maintenance therapy. Evaluation of minimal residual disease (MRD) has been shown to be of prognostic relevance in patients in CR with MRD negativity being associated with better outcomes. Here we report the impact of next generation sequencing (NGS)-based MRD assessment in TT patients who have achieved at least a very good partial response (VGPR) at two different time points during their treatment protocol: first after auto stem cell transplant (ASCT at 4-8 months of enrollment) and secondly during maintenance therapy (12-24 months). Materials and methods In brief, our TT protocols incorporate induction therapy consisting of Velcade and Thalidomide in conjunction with chemotherapy (Cisplatin, Doxorubicin, Cytoxan, Etoposide) followed by ASCT, consolidation and three years of maintenance with Velcade, Revlimid and Dexamethasone. HR and SR were assigned using the GEP70 risk signature. For MRD testing, we included 119 patients who were treated on our TT3b -TT6 protocols and who achieved at least VGPR and had bone marrow samples available at 4-8 months post ASCT and 12-24 months into maintenance. Thirty-eight patients had HR MM (32%), 75 patients had SR MM (63%) and no GEP70 data was available for 6 patients (5%). For NGS-based MRD assessment (Adaptive Biotechnologies Corp), genomic DNA was amplified using locus-specific primer sets for immunoglobulin heavy-chain complete (IGH-VDJH) and incomplete (IGH-DJ) as well as for immunoglobulin κ locus (IGκ). The amplified products underwent sequencing and clonal gene rearrangements were analyzed. MRD levels were calculated at a sensitivity level of 1 x 10-5. PET-CT and/or MRI were obtained at same time point as MRD assessment to evaluate presence of focal lesions. Results Using MRD status post-ASCT and during maintenance as a predictor, there were significant differences for PFS and OS in HR and SR MM. In HR disease, MRD positivity post ASCT was associated with significantly worse clinical outcomes with 2 year PFS/OS at 33% and 52% for MRD positive patients compared to 82%and 83% in MRD negative patients. Further 5 year PFS and OS for the same patient group were 11% and 24% for MRD positivity compared to 45% and 75% for HR patients that had achieved MRD negativity. In contrast to the HR group, there was no significant difference between MRD positivity and negativity in SR patients at the time point post ASCT we have investigated. In this latter patient group a significant difference only became obvious later during maintenance with 5 year PFS and OS at 55% and 63% for MRD positive patients compared to 83% and 93% for MRD negative patients. Of the 54 SR patients that were MRD positive post ASCT, 25 (46%) became negative later during maintenance, while in HR disease only 4 of 21 MRD positive patients post ASCT became negative during maintenance (19%). Importantly, a stratified analysis of our MRD data showed that even during maintenance the majority of cases in the favorable CD-2 subgroup were MRD positive, indicating that MRD results should further be interpreted in the context of patients' molecular subgroup. Conclusions Our data suggest that HR patients that do not achieve MRD negativity after their first ASCT have a very high likelihood of disease progression and death within 24 months. In contrast, SR patients that are still MRD positive post ASCT tend to have continuing response to treatment and MRD testing only becomes prognostic during maintenance. Of interest is that a high proportion of HR patients that achieve MRD negativity post ASCT and a smaller proportion of MRD negative SR patients still relapse within 5 years of enrollment suggesting that remaining residual MM cells are not detected by molecular MRD testing. Imaging studies with PET-CT and MRI could further stratify these patients as they detect any residual focal lesions that are not assessed by molecular MRD testing. We have combined PET-CT/MRI data for all of the 119 patients that were included in this study and analyzed data will be presented at ASH 2016. Disclosures Carlton: Adaptive Biotechnologies: Employment, Equity Ownership. Kong:Adaptive Biotechnologies Corp: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies: Employment. Barlogie:Signal Genetics: Patents & Royalties. Davies:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Morgan:Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding.

scholarly journals Comparison of Pharmacokinetics and Pharmacodynamics of Two Anti-CD20 Monoclonal Antibodies (Candidate Biosimilar DRL-Rituximab and Innovator Reference Product Rituximab (Mabthera®) in a Randomised, Multi-Centre, Double-Blind, Parallel Group Study of CHOP with Rituximab Chemotherapy in Patients with CD20-Positive Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5391-5391
Author(s):  
Auro Viswabandya ◽  
Asis Mukhopadhyay ◽  
Sandip Shah ◽  
Rajnish Vasant Nagarkar ◽  
Sonica Sachdeva Batra ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Similarity Criterion ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Double Blind ◽  
Large B Cell Lymphoma ◽  
Parallel Group ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: DRL-Rituximab (T) is a proposed biosimilar of rituximab. The similarity of DRL-Rituximab andtheinnovator reference products(USA: Rituxan®; European Union: Mabthera® [R]) has been demonstrated in physicochemical analyses and nonclinical studies. This study was undertaken to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T with R sourced from the European Union. Methods: Multiple-center, randomized, double-blind, two-arm, parallel-group study conducted in patients of both genders, aged 18-60 with a centrally confirmed newly diagnosed CD20 positive diffuse large-B-cell lymphoma (DLBCL) in their first line of treatment. Patients were randomized to receive 6 cycles of 21 days either T or R at an initial dose of 375 mg/m2 along with chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone (CHOP). The primary objective of this study was to compare the PK of T and R. One of the secondary objectives was to establish the similarity of T and R in the pharmacodynamic parameters - as B-cell depletion and repletion in peripheral blood using counts of CD19+ positive cells determined by flow cytometry. The PK similarity criterion was that the 90% confidence intervals (CI) of the geometric mean ratios of AUC0-21days, and Cmax in Cycle 1 were within 80.00% - 125.00%. Cycle 1 PK, PD and summary safety results are reported here. Other PK parameters were evaluated as secondary endpoints. Results: A total of 151 patients were randomized to the study (76 to T, 75 to R). After exclusion of 2 patients with very low exposure (results confirmed to be outliers by a z-score higher than 3 and currently under further investigation), both products met the preset Cycle 1 PK similarity criterion (Table 1), with these 2 patients included the Cmax criterion was met, but for AUC the lower limit of the CI was 78.36% (Table 2). PK parameter values were generally comparable (Table 3). For PD both products appear comparable regarding both B-cell depletion and B-cell repletion, both in terms of proportion of patients as well as median time to depletion/repletion. (Table 4 & Figures 1A and 1B) Safety was also comparable between both products. Grade 3/4 Adverse Events (AEs) showed a similar trend in incidence across the two treatment arms [overall: 121 (80.1%); T: 57 (75.0%); R: 64 (85.3%)]. Neutropenia was the most frequently reported of the grade 3/4 AEs, followed by febrile neutropenia, leukopenia, and anaemia. The most commonly reported TEAEs related to the study drug were neutropenia [overall: 48 (31.8%); T: 29 (38.2%); R: 19 (25.3%)] and leukopenia [overall: 24 (15.9%); T: 16 (21.1%); R: 8 (10.7%)]. A total of 5 deaths are reported in the study amounting to 3.3% fatality rate. Conclusion: DRL-rituximab has equivalent PK profile to Mabthera in Cycle 1 when given in combination with standard CHOP chemotherapy for the treatment of CD20 positive DLBCL. PD and safety results are also similar. While awaiting results of further PK/PD data as well as outcomes from this trial, these results are highly encouraging and provide further impetus to development of DRL-rituximab as a candidate rituximab biosimilar. Acknowledgment: We thank all the Principal Investigators for their participation in conducting this study: Dr. Randeep Singh, Dr. Chiramana Haritha, Dr. Asis Mukhopadhyay, Dr. Anup Majumdar, Dr. Shailesh Bondarde, Dr. Rajnish Vasant Nagarkar, Dr. Vijay Ramanan, Dr. Chetan Dilip Deshmukh, Dr. MVT Krishna Mohan, Dr. SVSS Prasad, Dr. Nalini Kilara, Dr. Poonam Patil, Dr. Shekhar Patil, Dr. Neelesh Reddy, Dr. Suresh Sudalaiandi, Dr. Krishnan Srinivasan, Dr. Sundar Subramanian, Dr. VP Gangadharan, Dr. Auro Viswabandya, Dr. Alok Srivastava, Dr. Sharat Damodar, Dr. Rajesh Grover, Dr. Reena Nair, Dr. Bhausaheb Bagal, Dr. Kasi Viswanathan, Dr. Minish Jain, Dr. Jitendra Singh, Dr. Dipti Samanta, Dr. Sudha Sinha, Dr. Lakshmaiah Kuntegowdanahalli, Dr. Rajendersingh Arora, Dr. Sandip Shah, Dr. Shashikant Janardhan Apte, Dr. Mukul Goyal, and Dr. Prasanth Ganeshan. Disclosures Batra: Dr. Reddy's Labs: Employment, Equity Ownership. Lazaro:Dr. Reddy's Labs: Employment, Equity Ownership. Kankanwadi:Dr. Reddy's Labs: Employment, Equity Ownership.

Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1637-1637 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
Stefan W. Krause ◽  
Stefan Kallert ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

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