scholarly journals High Dose Fractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (mHyperCVAD) Is an Active Regimen in Heavily Pretreated Relapsed/Refractory Multiple Myeloma, Enabling Access to Experimental Therapies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3784-3784
Author(s):  
Nicole Watts ◽  
Smith Giri ◽  
Kelly N. Godby ◽  
Gayathri Ravi ◽  
Luciano J. Costa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Control ◽  
Research Funding ◽  
Progressive Disease ◽  
Progression Free Survival ◽  
Free Survival ◽  
Car T Cells ◽  
Car T

Abstract Background Therapeutic advancements and deeper understanding of disease biology have helped improve the outcomes of multiple myeloma (MM). However, there is no consensus regarding the optimal management of patients whose disease becomes refractory to the three main class of drugs [proteasome inhibitors (PI), immunomodulatory drug (IMiD), and monoclonal antibodies (mab)] or among those presenting with complications secondary to rapidly progressive disease. While chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engagers have yielded high rates of durable responses, access to these therapies in clinical trials is often hindered by high disease burden compromising eligibility. We evaluated the use of a combination of cytotoxic agents (cyclophosphamide, doxorubicin, vincristine, and dexamethasone; mHyperCVAD) in this challenging population. Methods This is a retrospective, single center study evaluating the safety/tolerability and efficacy of mHyperCVAD in relapsed and refractory MM (RRMM). The regimen consists of cyclophosphamide 300 mg/m2 IV every 12 hours on D1-4 (total 2400 mg/m2), vincristine 0.4 mg/day IV continuous infusion D1-4 (total 1.6 mg), doxorubicin 9 mg/m2/day IV continuous infusion D1-4 hours (total 36 mg/m2) and dexamethasone 40 mg PO daily D1-4. Adult patients with RRMM were included if they received ≥1 cycle of mHyperCVAD between 2019-2021. Patients with primary plasma cell leukemia were excluded. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Patients were censored for progression free survival (PFS) at the last follow-up date if neither progression nor death occurred. All patients received growth factors, and infectious disease prophylaxis per institutional standard. Toxicities were graded using CTCAE v5.0 up to 30 days post therapy. Results Between 1/2019 and 7/2021, 39 patients met the inclusion criteria and received 44 courses of mHyperCVAD (four patients received mHyperCVAD at more than one timepoint). The median age was 54 years (range 32-71), 56% male. 36% patient had ISS stage III disease and 56% had high risk disease [t(4;14), t(14;16), del17p, +1q]. The median lines of therapy prior to mHyperCVAD were 3 (range 1-12) with 93% triple class refractory (refractory to PI, IMID and mab) and 64% penta-refractory (refractory to 2 PI, 2 IMiDs and mab) and 76% had received a prior autologous transplant. The median number of mHyperCVAD cycles per course was 1 (range 1-8). Baseline characteristics are summarized in Table. Eleven courses (25%) were administered as bridge after lymphocyte collection for the manufacture of CAR-T cells and prior to lymphodepletion chemotherapy (100% triple class refractory and 91% penta-refractory) with ORR 18% and DCR 72%. Thirty-three courses (75%) were used as salvage for rapid disease control. The most common toxicities with mHyperCVAD were hematologic (65% grade 3/4 toxicities) with 20% incidence of febrile neutropenia. Four patients died during mHyperCVAD therapy due to rapidly progressive disease and one patient died due to sepsis. For the entire cohort, the ORR is 50% (≥VGPR 30%) with a DCR 82%. Additionally, 39% could proceed with experimental CAR-T cells and/or bispecific T cell engagers. The median progression free survival is 3.6 months, and the median overall survival is 8 months from start of mHyperCVAD with 10.5 months median follow up. The most common cause of death was progressive disease (39%). Conclusion mHyperCVAD is an efficacious cytotoxic chemotherapy regimen which can achieve rapid disease control allowing patients an opportunity to proceed with additional therapies, including investigational agents on clinical trials. It can also be used as an effective bridging strategy among heavily treated, triple class and penta-refractory MM awaiting manufacturing of CAR-T cells with manageable and expected toxicities. Figure 1 Figure 1. Disclosures Giri: PackHealth: Research Funding; CareVive: Honoraria, Research Funding. Costa: Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau.

scholarly journals B Cell Maturation Antigen-Specific CAR T Cells for Relapsed or Refractory Multiple Myeloma: A Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3113-3113 ◽  
Author(s):  
Nico Gagelmann ◽  
Francis Ayuketang Ayuk ◽  
Djordje Atanackovic ◽  
Nicolaus Kroeger
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Overall Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background Cellular immunotherapies represent an enormously promising strategy for relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in early-phase clinical studies. Here, we summarize the current body of evidence on the role of anti-BCMA CAR T cell therapy for RRMM. Methods We performed a systematic literature review to identify all publicly available prospective studies. We searched Medline, Cochrane trials registry, and www.clinicaltrials.gov. To include the most recent evidence, meeting abstracts from international hematology congresses were added. A conventional meta-analysis was conducted using meta and metafor packages in R statistical software. Pooled event rates and 95% confidence intervals (CIs) were calculated using the inverse variance method within a random-effects framework. Main efficacy outcomes were overall response, complete response (CR), and minimal residual disease (MRD). Furthermore, relapse rates, progression-free survival, and overall survival were evaluated. In terms of safety, outcomes were cytokine release syndrome (CRS), neurotoxicity, and hematologic toxic effects. Results Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, stem cell transplantation) which included autologous stem cell transplantation in 90% of patients. The median age of patients was 59 years and median follow-up duration ranged from 1.1 to 11.3 months. Most studies used 4-1BB (or CD137), a member of the TNF receptor superfamily, as an activation-induced T-cell costimulatory molecule. Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide and one study used cyclophosphamide only. Most studies used the former Lee criteria for CRS grading. Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% CI, 74-88%). The pooled proportion of CR in all evaluable patients was 36% (95% CI, 24-50%). Within responders, the pooled proportion of MRD negativity was 77% (95% CI, 67-85%). Higher dose levels of infused CAR+ cells were associated with higher overall response rates resulting in a pooled proportion of 88% (95% CI, 78-94%). In addition, peak CAR T cell expansion appeared to be associated with responses.The presence of high-risk cytogenetics appeared to be associated with lower overall response rates resulting in a pooled proportion of 68% (95% CI, 47-83%). The presence of extramedullary disease at time of infusion did not influence outcome and was associated with similar response rates compared with RRMM patients who did not have extramedullary disease, resulting in a pooled proportion of 78% (95% CI, 47-93%). The pooled relapse rate of all responders was 45% (95% CI, 27-64%) and the median progression-free survival was 10 months. In terms of overall survival, pooled survival rates were 84% (95% CI, 60-95%) at last follow-up (median, 11 months). In terms of safety, the pooled proportion of CRS of any grade was 69% (95% CI, 51-83%). Notably, the pooled proportions of CRS grades 3-4 and neurotoxicity were 15% (95% CI, 10-23%) and 18% (95% CI, 10-31%). Peak CAR T cell expansion appeared to be more likely in the setting of more severe CRS in three studies. Most hematologic toxic effects of grade 3 or higher were neutropenia (85%), thrombocytopenia (70%), and leukopenia (60%). Conclusion Anti-BCMA CAR T cells showed high response rates, even in high-risk features such as high-risk cytogenetics and extramedullary disease at time of CAR T cell infusion. Toxicity was manageable across all early-phase studies. However, almost half of the patients who achieved a response eventually relapsed. Larger studies with longer follow-up evaluating the association of response and survival are needed. Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Kroeger:Medac: Honoraria; Sanofi-Aventis: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding.

scholarly journals Sequential CD19- and CD22-CART Cell Therapies for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2126-2126 ◽  
Author(s):  
Shuangyou Liu ◽  
Biping Deng ◽  
Yuehui Lin ◽  
Zhichao Yin ◽  
Jing Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Car T Cells ◽  
Car T

Abstract With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Chimeric antigen receptor (CAR) T cell therapy targeting at CD19 has demonstrated a significant efficacy on refractory/relapsed (r/r) B-ALL, but single-target CART could not maintain a long-term remission. Recently, CD22-CART has also shown an exciting result in r/r B-ALL. Here we sequentially applied CD19- and CD22-specific CART cells to treat relapsed B-ALL post-HSCT and observed the therapeutic effect. From June 30,2017 through May 31,2018, twenty-four B-ALL patients (pts) relapsing after allo-HSCT with both antigens CD19 and CD22 expression on blasts were enrolled, the median age was 24 (2.3-55) years. Seventeen pts had hematologic relapse, 6 with both bone marrow and extramedullary (EM) involvements and 1 with EM disease (EMD) only. Fourteen pts had failed to previous therapies including chemotherapy, donor lymphocyte infusion, interferon and even murinized CD19-CART in other hospitals. Recipient-derived donor T cells were collected for producing CAR-T cells, which were transfected by a lentiviral vector encoding the CAR composed of CD3ζ and 4-1BB. Eighteen pts were initially infused with murinized CD19-CART, then humanized CD22-CART; while 6 pts (5 failed to prior murinized CD19-CART and 1 had bright CD22-expression) were initially infused with humanized CD22-CART, then humanized CD19-CART. The time interval between two infusions was 1.5-6 months based on patients' clinical conditions. The average dose of infused CAR T cells was 1.4×105/kg (0.4-9.2×105/kg) for CD19 and 1.9×105/kg (0.55-6.6×105/kg) for CD22. All patients received fludarabine with or without cyclophosphamide prior to each infusion, some pts accepted additional chemo drugs to reduce the disease burden. Treatment effects were evaluated on day 30 and then monthly after each CART, minimal residual disease (MRD) was detected by flow cytometry (FCM) and quantitative PCR for fusion genes, EMD was examined by PET-CT, CT or MRI. Sixteen patients finished sequential CD19- and CD22-CART therapies. Three cases could not undergo the second round of CART infusion (1 died, 1 gave up and 1 developed extensive chronic graft-versus-host disease (GVHD)). The rest of 5 pts are waiting for the second CART. After first T-cell infusion, 20/24 (83.3%) pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), MRD-negative was 100% in CR or CRi pts, 3 (12.5%) cases with multiple EMD obtained partial remission (PR), and 1 (4.2%) died of severe cytokine release syndrome (CRS) and severe acute hepatic GVHD. Sixteen patients (15 CR and 1 PR) underwent the second CART therapy. Before second infusion, 3/15 pts in CR became MRD+ and others remained MRD-. On day 30 post-infusion, 1 of 3 MRD+ pts turned to MRD-, 1 maintained MRD+ ( BCR/ABL+) and 1 had no response then hematologic relapse later. The PR patient still had not obtained CR and then disease progressed. As of 31 May 2018, at a median follow-up of 6.5 (4-10) months, among 16 pts who received sequential CD-19 and CD-22 CART therapies, 1 had disease progression, 2 presented with hematological relapse and 2 with BCR/ABL+ only, the overall survival (OS) rate was 100% (16/16), disease-free survival (DFS) was 81.3% (13/16) and MRD-free survival was 68.8% (11/16). CRS occurred in 91.7% (22/24) pts in the first round of T-cell infusion, most of them were mild-moderate (grade I-II), merely 2 pts experienced severe CRS (grade III-IV). The second CART only caused grade I or no CRS since the leukemia burden was very low. GVHD induced by CART therapy was a major adverse event in these post-HSCT patients. After the first CART, 7/24 (29.2%) pts experienced GVHD, of them, 4 presented with mild skin GVHD, 2 with severe hepatic GVHD (1 recovered and 1 died), and 1 developed extensive chronic GVHD. No severe GVHD occurred in the second infusion. Our preliminary clinical study showed that for B-ALL patients who relapsed after allo-HSCT, single CD19- or CD22- CART infusion resulted in a high CR rate of 83.3%, sequentially combined CD19- and CD22-CART therapies significantly improved treatment outcome with the rate of OS, DFS and MRD-free survival being 100%, 81.3% and 68.8%, respectively, at a median follow-up of 6.5 months. The effect of CART on multiple EMD was not good and CART induced GVHD needs to be cautious. Disclosures No relevant conflicts of interest to declare.

scholarly journals Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib

2017 ◽  
Vol 35 (26) ◽  
pp. 3010-3020 ◽  
Author(s):  
Cameron J. Turtle ◽  
Kevin A. Hay ◽  
Laïla-Aïcha Hanafi ◽  
Daniel Li ◽  
Sindhu Cherian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor–modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 × 105, 2 × 106, or 2 × 107 CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib. Six patients were venetoclax refractory, and 23 had a complex karyotype and/or 17p deletion. Results Four weeks after CAR-T cell infusion, the overall response rate (complete response [CR] and/or partial response [PR]) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24). Twenty patients (83%) developed cytokine release syndrome, and eight (33%) developed neurotoxicity, which was reversible in all but one patient with a fatal outcome. Twenty of 24 patients received cyclophosphamide and fludarabine lymphodepletion and CD19 CAR-T cells at or below the maximum tolerated dose (≤ 2 × 106 CAR-T cells/kg). In 19 of these patients who were restaged, the overall response rate by IWCLL imaging criteria 4 weeks after infusion was 74% (CR, 4/19, 21%; PR, 10/19, 53%), and 15/17 patients (88%) with marrow disease before CAR-T cells had no disease by flow cytometry after CAR-T cells. Twelve of these patients underwent deep IGH sequencing, and seven (58%) had no malignant IGH sequences detected in marrow. Absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progression-free survival and overall survival (median 6.6 months follow-up) after CAR-T cell immunotherapy. The progression-free survival was similar in patients with lymph node PR or CR by IWCLL criteria. Conclusion CD19 CAR-T cells are highly effective in high-risk patients with CLL after they experience treatment failure with ibrutinib therapy.

scholarly journals Clinical Responses to CAR.CD30-T Cells in Patients with CD30+ Lymphomas Relapsed after Multiple Treatments Including Brentuximab Vedotin

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 681-681 ◽  
Author(s):  
Natalie S Grover ◽  
Steven I Park ◽  
Anastasia Ivanova ◽  
Paul Eldridge ◽  
Kathryn McKay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Level ◽  
Research Funding ◽  
Brentuximab Vedotin ◽  
Car T Cells ◽  
Car T ◽  
Post Infusion ◽  
Phase 1B

Abstract Background: Infusion of chimeric antigen receptor modified T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) in the absence of lymphodepleting chemotherapy has been shown to be safe with responses seen in patients (pts) with relapsed/refractory (r/r) CD30+ lymphomas (Ramos et al., JCI 2017). We present here the results of a phase 1b/2 trial of CD30.CAR-Ts administered after lymphodepleting chemotherapy in pts with r/r CD30+ Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). Methods: The primary objective of the phase 1b portion of the study was to determine the recommended phase 2 dose level (RP2DL) of CD30.CAR-Ts using a standard 3+3 design. Two dose levels were tested: 1 x 108 CAR-Ts/m2 (DL1) and 2 x 108 CAR-Ts/m2 (DL2). For lymphodepletion, the first 8 pts (including the first 3 pts treated at DL1) received 2 days of bendamustine (benda) 90 mg/m2, while the 10 remaining pts received 3 days of benda 70 mg/m2 and fludarabine (flu) 30 mg/m2, except for one pt who received only 1 day of benda and flu due to possible benda toxicity. Inclusion criteria were age ≥ 18 years, CD30+ disease, and r/r HL or NHL having failed ≥2 prior therapies. Results: At the time of data cut off (7/1/2018), 18 pts with a median age of 40.5 years (range: 23-70) had received CD30.CAR-Ts and undergone response assessment. Sixteen pts had HL, 1 had enteropathy associated T cell lymphoma, and 1 had Sezary syndrome. All pts were heavily pre-treated with a median of 8.5 prior therapies (range: 4-17). All pts had received prior brentuximab vedotin and 13 had prior checkpoint inhibitor therapy. Fourteen pts had prior autologous stem cell transplant (SCT) and 7 had prior allogeneic SCT. Treatment was well tolerated with no dose limiting toxicities; as a consequence, the highest dose level of CAR-T cells (2 x 108 CAR-Ts/m2) was given as the RP2DL. Three pts developed cytokine release syndrome (CRS) (grade 1: 2 pts and grade 2: 1 pt). Grade 1 CRS resolved spontaneously, while the pt with grade 2 CRS responded to tocilizumab. No neurotoxicity was observed. Out of the 18 pts, 4 were in a complete response (CR) before infusion due to bridging chemotherapy and remained disease free at 6 wk follow up. Two of these pts have since relapsed with PFS of 3.8 months and 11.9 months while the other 2 pts are still in CR after 1 year of follow up. The 14 pts with evidence of disease pre-lymphodepletion were included in efficacy analysis. Of these 14 pts, 6 had a CR (43%, all in the benda/flu cohort), 1 had partial response (7%), 2 had stable disease (14%) and 5 had progressive disease (35%) at disease assessment. No responses occurred in the 3 pts treated at DL1. At median follow up of 138 days, the median PFS was 129 days. The median PFS for the 3 evaluable pts who received benda at DL1 was 55 days vs 172 days for the 9 pts who received benda/flu at DL2 (p = 0.039). The median PFS for the 2 evaluable pts at DL2 who received benda lymphodepletion was 85.5 days but this was not included in the comparison due to small sample size. Two out of 14 evaluable pts remain in CR at 1 year. Using PCR on peripheral blood, CD30.CAR-Ts were found to be increased in the circulation of all pts, peaking at wk 2 post infusion, with increasing CAR-T cells in pts receiving greater number of CAR-T cells or more robust lymphodepletion (3.4x103 ± 2.9x103 copies/ug of DNA for DL1-beda vs. 61x103 ± 41x103 for DL2-benda vs. 59x103 ± 22x103 for benda/flu). These differences were confirmed by flow cytometry (CD3+CAR+ cells = 13%±9% for DL1-benda vs 21%±10% for DL2-benda vs 35%±8% for benda/flu). Persistence was also related to dose level and lymphodepletion (0.06x103 ± 0.01x103 vs 0.44x103 ± 0.41x103 vs 28x103 ± 15x103/ug of DNA at wk 4 for DL1-benda, DL2-benda, and benda/flu, respectively). Although both lymphodepletion regimens reduced the lymphocyte counts, only the combination of benda/flu was found to have a significant increase in IL-15 and IL-7 cytokines (13 fold, p<0.01 and 3 fold, p=0.016, respectively) that was sustained for 2 wks post infusion. Conclusions: We show that CD30.CAR-Ts combined with lymphodepletion with benda/ flu are safe and at 2 x 108 CAR T cells/m2 demonstrate excellent antitumor activity for pts with r/r CD30+ lymphomas. We also find that the addition of flu is critical for enhancing cytokines important for T cell growth and persistence. Finally, we demonstrate a significant PFS advantage in pts with r/r CD30+ lymphoma who received the highest dose level combined with benda and flu. Disclosures Grover: Seattle Genetics: Consultancy. Park:G1 Therapeutics: Consultancy; Gilead: Speakers Bureau; Seattle Genetics: Research Funding; Teva: Research Funding; Rafael Pharma: Consultancy; BMS: Consultancy; BMS: Research Funding; Seattle Genetics: Speakers Bureau; Teva: Consultancy; Takeda: Research Funding. Dittus:Seattle Genetics: Consultancy. Serody:Merck: Research Funding.

scholarly journals Repeat Infusions of CD19 CAR-T Cells: Factors Associated with Response, CAR-T Cell In Vivo Expansion, and Progression-Free Survival

2020 ◽  
Vol 26 (3) ◽  
pp. S267-S268 ◽  
Author(s):  
Jordan Gauthier ◽  
Evandro Dantas Bezerra ◽  
Alexandre V. Hirayama ◽  
Barbara S. Pender ◽  
Aesha Vakil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progression Free Survival ◽  
Free Survival ◽  
Factors Associated ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

scholarly journals Simultaneous Targeting of CD19 and CD22: Phase I Study of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Pediatric Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL): Amelia Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 279-279 ◽  
Author(s):  
Persis J Amrolia ◽  
Robert Wynn ◽  
Rachael Hough ◽  
Ajay Vora ◽  
Denise Bonney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Research Funding ◽  
Advisory Board ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Abstract Introduction CAR T-cell therapies directed against CD19 or CD22 antigens have shown significant activity in pediatric patients with r/r B-ALL. Whilst complete response (CR) rates of 70‒90% have been observed, relapse due to target antigen downregulation or loss is the major cause of treatment failure. This Phase I/II study evaluates the safety and efficacy of AUTO3, a CAR T-cell therapy designed to target CD19 and CD22 simultaneously in order to reduce the likelihood of relapse due to antigen loss. Methods & Patients We constructed a novel bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. Antigen binding domains were humanized and both CARs are in "2nd generation" format (incorporating an OX40 co-stimulatory domain for the CD19 CAR and a 41BB for the CD22 CAR). The performance of the CD22 CAR was optimized by incorporating a novel pentameric spacer. The cell product was manufactured on a semi-automated and closed process using CliniMACS® Prodigy (Miltenyi Biotec). Patients (1‒24 years of age) with high risk relapse (IBFM criteria) or relapse post-allogeneic stem cell transplant (SCT), adequate performance score/organ function, and an absolute lymphocyte count ≥0.5 x 109/L are eligible. Patients with CNS 3 disease, active graft versus host disease, and clinically significant infection or serious toxicity from prior CAR T-cell are excluded. Patients receive lymphodepletion with 30 mg/m2/day fludarabine x 4 days and 500 mg/m2/day cyclophosphamide x 2 days prior to AUTO3 infusion. Three dose levels are being explored (1 x 106, 3 x 106, and 5 x 106 transduced CAR+ T cells/kg) and CAR T cells are infused as a single (for <25% blasts) or split (for >25% blasts) dose based on leukemia burden. Bridging therapy is allowed during the manufacturing period. The primary endpoint of Phase I is the frequency of dose-limiting toxicities (DLTs) and key secondary endpoints include proportion of patients achieving a morphological/minimal residual disease (MRD) negative CR, disease-free survival, overall survival, as well as biomarker endpoints including AUTO3 levels and persistence in blood and bone marrow. Results As of the data cut-off date (July 16, 2018), 9 patients have been enrolled and 8 have received AUTO3. It was possible to generate a product in all patients and the median transduction efficiency was 16% (range 9‒34%). Median age was 7.5 years (range 4‒16 years) and 5 (63%) patients had prior SCT. One patient (13%) had prior anti-CD19 CAR-T cells and blinatumomab. The disease burden at Day ‒7 ranged from 0% to 90% leukemic blasts. Eight patients had a minimum of 4 weeks' follow up and were evaluable for safety and efficacy analysis. Three patients received ≤1 × 106 CAR T cells/kg as single dose, 1 patient received 2 × 106/kg as split dose, and 4 received 3 × 106 CAR cells/kg (3 single infusions, 1 split). No AUTO3 related deaths and no DLTs were observed. The most common grade (Gr) ≥3 adverse events were neutropenia (63%), febrile neutropenia (50%), pyrexia (25%), and anemia (25%). Five patients (63%) had Gr 1 cytokine release syndrome (CRS); no Gr 2 or higher CRS was seen. Five patients (63%) experienced neurotoxicity: 4 had Gr 1 and 1 patient (13%) had Gr 3 encephalopathy that was considered likely related to prior intrathecal methotrexate. No patients required ICU admission. Six of 8 patients achieved MRD negative CR, giving an objective response rate of 75% (95% CI 34.9‒96.8%) at 1 month. In patients treated at doses <3 x 106/kg, 3 responded but subsequently relapsed. Importantly, no loss of CD19 or CD22 was noted in patients that relapsed. All 4 patients treated at the higher dose of 3 × 106 CAR T cells/kg had an MRD negative CR with ongoing remission and B-cell aplasia, with the longest follow up of 4 months. CAR T-cell expansion was enhanced in patients receiving 3 x 106/kg (median 79,282 copies/µg DNA in blood at peak) compared to those receiving lower doses (median 10,243 copies/µg DNA). Conclusion This interim data analysis demonstrates for the first time the feasibility and safety of simultaneous targeting of CD19 and CD22 with AUTO3. Promising efficacy was demonstrated at a dose level of 3 × 106 CAR T cells/kg, as 4/4 patients achieved MRD complete remission with no antigen negative escape at this early stage. The study continues to enrol and updated follow up and additional patient data at higher dose levels, as well as cellular kinetics and additional biomarker analysis, will be presented. Disclosures Wynn: Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Hough:University College London Hospital's NHS Foundation Trust: Employment. Vora:Amgen: Other: Advisory board; Medac: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board; Jazz: Other: Advisory board. Veys:Servier: Research Funding; Pfizer: Honoraria; Novartis: Honoraria. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Al-Hajj:Autolus Ltd: Employment; Autolus Ltd: Equity Ownership. Cordoba:Autolus Ltd: Employment; Autolus Ltd: Equity Ownership; Autolus Ltd: Patents & Royalties. Onuoha:Autolus Ltd: Employment, Equity Ownership, Patents & Royalties. Kotsopoulou:Autolus Ltd: Equity Ownership; Autolus Ltd: Employment. Khokhar:Autolus Ltd: Employment; Autolus Ltd: Equity Ownership. Pule:Autolus Ltd: Employment, Equity Ownership, Other: Salary contribution paid for by Autolus, Research Funding; University College London: Patents & Royalties: Patent with rights to Royalty share through UCL. Peddareddigari:Autolus Therapeutics plc: Equity Ownership; Autolus Therapeutics plc: Patents & Royalties; Autolus Therapeutics plc: Employment.

scholarly journals CD19-CAR Therapy Using Naive/Memory or Central Memory T Cells Integrated into the Autologous Stem Cell Transplant Regimen for Patients with B-NHL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 610-610 ◽  
Author(s):  
Leslie Popplewell ◽  
Xiuli Wang ◽  
Suzette Blanchard ◽  
Jamie Wagner ◽  
Araceli Naranjo ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Memory T Cells ◽  
Central Memory ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Autologous stem cell transplantation (ASCT) remains an important consolidative therapy for patients with recurrent non-Hodgkin lymphoma (NHL), but is limited by the high incidence of NHL relapse. We report a Phase I clinical trial of ASCT followed by CD19-specific CD28-costimulatory chimeric antigen receptor (CD19:28z-CAR) T cells, with the goal of reducing NHL relapse rates. Safety and feasibility were the primary objectives, with CAR T cell persistence and expansion in the myeloablative ASCT setting as secondary objectives. This study examines safety and feasibility for two manufacturing platforms that differed in the T cell subset composition used for CAR engineering. Initially, the T cell population for CAR transduction was central memory (Tcm)-enriched: participants' peripheral blood mononuclear cells (PBMC) were depleted for CD14+ monocytes, CD25+ Tregs, and CD45RA+ naïve and stem-memory T cells, after which they were selected for CD62L+ Tcm (Wang et al. Blood;127:2980). Based on comparative preclinical data, a second arm was added to the trial to evaluate a Tn/mem-derived manufacturing platform that enriched central memory, naïve, and stem memory T cells (no CD45RA+ depletion). Either Tcm- or Tn/mem-enriched T cells were activated with CD3/CD28 beads, transduced with lentiviral vector encoding the CD19:28z-CAR, and expanded ex vivo. This phase I trial used the toxicity equivalence range design (Blanchard and Longmate. Contemp Clin Trials; 32;114) with an equivalence range for DLTs of 0.20-0.35 and a target toxicity rate of 0.25. The first 3 participants on each arm were followed one at a time, with later accrual in cohorts of 3. Twenty-three participants underwent ASCT and received CD19:28z-CAR T cells 2 days post stem cell infusion at the assigned dose level (DL): 17 on the Tcm arm (DL 50 million [M] CAR+ T cells [n=3], 200 M [n=5], 600 M [n=9]); 6 on the Tn/mem arm (DL 200 M). Participants were followed for dose limiting toxicity (DLT) for 28 days. Table 1 shows results by arm and DL. Both arms demonstrated safety and feasibility. There was no delayed hematopoietic reconstitution on either arm. On the Tcm arm, the only DLT was at DL 600 M (1 of 9 at 600 M). The Tn/mem arm was opened at 200 M and 6 participants were treated with no DLTs. The dose was not escalated as the protocol management team had seen activity at the 200M level in 2 other trials using the Tn/mem product. Tcm Arm: Fourteen of 17 participants (82%) had a diagnosis of diffuse large B-cell lymphoma (DLBCL) and 3 had mantle cell lymphoma. The mean age of the participants on the Tcm arm was 57 (35-75). The median number of prior chemotherapy regimens was 2 (1-5). The median progression-free survival (PFS) was 34.6 months 95% CI [21.8, undefined]. Seven of 17 participants (41%) have progressed, 1 died in remission of unrelated intracranial hemorrhage (6%), 7 (41%) remain in CR and are still in follow-up, and 2 are lost to follow-up (12%). All 17 participants achieved a CR or a continuing CR after ASCT and T cells. Tn/mem arm: Five of 6 participants (83%) had a DLBCL diagnosis, and 1 was NHL not otherwise specified. The mean age of the participants was 50 (40-72). The median number of prior chemotherapy regimens was 2.5 (1-3). The median follow-up time for the Tn/mem arm was 12 months, with median PFS not yet reached. One of 6 (17%) has progressed, 4 (66%) remain in CR and are still in follow-up, and 1 is lost to follow-up (17%). Five of 6 (83%) participants achieved a best response of CR or continuing CR after therapy. Several differences were observed between the manufacturing platforms. Since the Tn/mem production platform has fewer depletion steps, it resulted in a higher product yield, which shortened the ex vivo expansion period by 4.1 days (95% CI [1.5%, 6.6%]) from 18.9 days (15-24) for Tcm to 14.8 days (12-18) for Tn/mem (P<0.005). Notably in the ASCT minimal disease burden setting, the Tn/mem-derived CD19:28z-CAR T cell products exhibited significantly higher in vivo CAR T cell expansion compared to Tcm products at the 200M DL (Figure 1). We conclude that although both Tcm- and Tn/mem-enriched CD19CAR T cell therapies are safe, the Tn/mem product is more promising due to its 1) shorter production time, 2) higher cell yield, and 3) better in vivo expansion, despite the low antigen drive in these patients post-salvage and ASCT therapy. Longer follow-up for the 2-year PFS secondary objective will indicate if improved Tn/mem expansion impacts tumor control. Disclosures Wang: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Budde:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Safety and efficacy of optimized tandem CD19/CD20 CAR-engineered T cells in patients with relapsed/refractory non-Hodgkin lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
Yajing Zhang
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Progression Free Survival ◽  
Free Survival ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Engineered T Cells ◽  
Grade 3

3034 Background: Chimeric antigen receptor T (CAR T) cells targeting CD19 have been used to achieve breakthroughs in the treatment of hematological malignancies, however, a high recurrence rate is the main obstacle to durable remission following CAR T cell therapy. Methods: As an open-label and single-arm phase I/IIa trial (ClinicalTrials.gov number, NCT03097770), we screened 99 patients with r/r B-NHL—including DLBCL, PMBCL, CLL/SLL, MCL, TFL and FL—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue, and a total of 87 patients received an infusion of one dose tandem CD19/CD20 CAR-engineered T cells on day 0 in the range of 0.5×106-10×106 cells per kilogram of body weight after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of CAR T cells. Efficacy, progression-free survival (PFS) and overall survival (OS) were evaluated as secondary objectives. Our clinical trials is registered with ClinicalTrials.gov, NCT03097770. Safety was assessed by CTCAE Version 5.0, and clinical response by PET-CT referred to standard international criteria. The trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Results: Between May 11, 2017, and Jan 31, 2020, 99 patients were enrolled and 87 received tandem CD19/CD20 CAR-engineered T cells across phases I/IIa. As of the cutoff date, 74 assessable patients were followed up for a median of 13.5 months (IQR 33.2 - 3.3), 62 (84%) had an objective response, and 55 (74%) had a complete response. The median progression-free survival and overall survival were all not reached. Cytokine release syndrome (CRS) occurred in 62 patients (71%), with 61% grade 1 or 2 and 10% grade 3 or more. CAR-T-cell-related encephalopathy syndrome (CRES) of grade 3 occurred in 2 patients (2%) . Three treatment-related deaths (2 in pulmonary infection and 1 in deposition of CART cells in pulmonary alveoli). Conclusions: In this study, optimized tandem CD19/CD20 CAR-engineered T cells induced a potent and durable anti-tumour response with controllable CRS and CRES. Clinical trial information: NCT03097770 .

scholarly journals Phase 1 Study of on Site Manufactured Anti-CD19 CAR-T Cells: Responses in Subjects with Rapidly Progressive Refractory Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4074-4074 ◽  
Author(s):  
Paolo F Caimi ◽  
Jane Reese ◽  
Folashade Otegbeye ◽  
Dina Schneider ◽  
Kristen Bakalarz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Progressive Disease ◽  
Hematologic Toxicity ◽  
Bulky Disease ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Background: Salvage regimens for chemorefractory aggressive lymphoma achieve response rates of approximately 30%. Anti-CD19 CAR-T cells have demonstrated anti-lymphoma activity, but patients (pts) with rapidly progressive disease and urgent need for therapy have worse prognosis and many are not able to receive CAR-T cells in time. Decreasing the time from apheresis to infusion can make CAR-T cells available to pts with rapid progression of their disease. We present the results of a phase I clinical trial using on-site CAR-T manufacture for treatment of relapsed / refractory (r/r) B cell non Hodgkin lymphoma (NHL). Methods: Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc, LTG1563) encoding an anti-CD19 binding motif, CD8 linker and tumor necrosis receptor superfamily 19 (TNFRS19) transmembrane region, and 4-lBB/CD3z intracellular signaling domains. GMP-compliant manufacture was done using CliniMACS Prodigy, in a 12-day culture. Dose escalation was conducted according to a 3+3 design. Lymphodepletion was done with cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m2/d x 3). Cytokine release syndrome (CRS) and CAR-T related encephalopathy syndrome (CRES) were graded using the Lee and CARTOX criteria, respectively. Results: As of July 30, 2019 , 12 pts were enrolled and treated. Baseline characteristics are listed in table 1. 10/12 pts were refractory to the prior line of therapy, 5 had bulky disease and 9 had symptomatic disease at the time of lymphocyte collection. CAR-T cell product manufacture was successful in all pts. Median transduction rate was 48% [range 29-62] with and median culture expansion of 43-fold [range 30-79]. High dimensional flow cytometry showed the infused CD4 and CD8 CAR-T cells express a central memory and transition to memory - like profile, with enrichment for CD27 and high CCR7 expression. In addition, a subset of CD4 and CD8 CAR-T cells expressed effector transcription factors T-BET and GATA3 while CD4 CAR-T clusters express low levels of immune checkpoint blockers PD-1 and BTLA. All enrolled pts received their infusion of anti-CD19 CAR-T cells. CAR-T cell doses were 0.5 x 106/kg (n = 4) and 1 x 106/kg (n = 8). Median apheresis to infusion time was 13 days [range 13-20], 10 products were infused fresh. CAR-T persistence, based on vector sequence, peaked in peripheral blood MNCs between days 14-21. All responding subjects have had CAR-T persistence on follow up PCR measurements (range 1 - 12 months). CAR-T cell dose did not have an impact in the time to peak in vivo CAR-T cell expansion or in the rate of CAR-T cell persistence. Five pts experienced CRS. Grade 1 - 2 CRS was observed in 4 pts; whereas 1 pt died as a consequence of severe CRS in the context of bulky disease. Pharmacologic interventions for CRS included tocilizumab (n = 5), siltuximab (n = 2) and corticosteroids (n = 2). Two subjects presented grade 4 CRES with resolution after corticosteroids, no other grade ≥3 non-hematologic toxicity was observed. The most common all grade non - hematologic toxicity was fatigue, observed in 6 subjects. Hematologic toxicity was common, with grade ≥ 3 neutropenia observed in all subjects, with 4 subjects presenting grade 3 neutropenia without fever beyond day 30. Among 11 pts evaluable for response, 8 pts have achieved complete response (CR) and one had partial response (PR). Two pts did not respond. For the intention to treat population (n=12), the CR rate was 67% and overall response rate (ORR) was 75%. Overall response rates were equal between both dose levels (75%), but CR rates were higher in pts treated with 1 x 106 CAR-T cells (75% vs. 50%). Two pts have died, causes of death include progressive disease (n=1) and CRS (n=1). After a median follow up 3 months (range 1 - 12) all responding pts are alive; 1 subject relapsed 6 months after treatment with CD19+ disease and entered CR after anti-CD19 antibody drug immunoconjugate treatment. Conclusions: In this phase 1 study, second generation anti-CD19 CAR-T cells with TNFRS19 transmembrane domain have potent clinical activity. The short manufacture times achieved by local CAR-T cell manufacture with the CliniMACS Prodigy enables treatment of a very high risk NHL population that would otherwise not be able to receive CAR-T products due to rapidly progressive disease. Disclosures Caimi: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Genentech: Research Funding. Schneider:Lentigen Technology, A Miltenyi Biotec Company: Employment. Bakalarz:Genentech: Speakers Bureau. Kruger:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Worden:Lentigen Technology, A Miltenyi Biotec Company: Employment. Kadan:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Malek:Adaptive: Consultancy; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. Dropulic:Lentigen Technology, A Miltenyi Biotec Company: Employment. OffLabel Disclosure: Clinical Trial of on - site manufactured CAR-T cells. This manufacturing process is under research.

scholarly journals Clinical Outcomes of Relapsed/Refractory Multiple Myeloma Patients Following Treatment with Bispecific Antibodies (BiAbs)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 821-821
Author(s):  
Tarek H. Mouhieddine ◽  
Oliver Van Oekelen ◽  
Darren Pan ◽  
Sarita Agte ◽  
Adolfo Aleman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Bispecific Antibodies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Heavily Pretreated

Abstract Background: Bispecific antibodies (BiAbs) are a novel off-the-shelf class of drugs currently being investigated in clinical trials for patients with relapsed/refractory multiple myeloma (RRMM) with promising efficacy in heavily pretreated patients. BiAbs simultaneously bind two antigens, thereby engaging CD3+ T cells with myeloma cells expressing specific antigens such as BCMA, GPRC5D, FcRH5 or CD38. However, the outcome of myeloma patients after relapse on BiAbs is unknown and effective approaches for salvage therapy are needed. Methods: Demographics, disease characteristics and post-clinical trial outcomes were collected retrospectively on RRMM patients who relapsed after BiAb therapy at the Tisch Cancer Institute (The Mount Sinai Hospital, New York). We identified a total of 116 patients who were enrolled on trials with BiAbs targeting either BCMA or GPRC5D. Of these, 69 patients were no longer enrolled on the trials due to disease progression (including 5 patients who died on the trial). Clinical data was collected up until July of 2021. This retrospective study was approved by the institutional review board (IRB) and follows the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice (IRB: GCO#: 11-1433). Survival and response duration were calculated by Kaplan-Meier estimation. Results: The 64 RRMM patients had a median age of 58.5 years (range: 46-82) at time of disease progression following BiAbs therapy, and 48% were male. Median time from diagnosis to initiation of BiAbs therapy was 5 years (range: 1.6-16.3) and patients had a median follow-up of 24.9 months from time of relapse from BiAb therapy. Fifty patients (78%) had high-risk cytogenetics, including gain1q21, del17p, t(4;14), t(14;16) and t(14;20). Most patients were highly pretreated with a median of 7 prior lines (range: 3-17) and 54 patients (84%) had received an autologous stem cell transplant (ASCT) prior to receiving BiAbs. Three patients were treated with chimeric antigen receptor (CAR) T cell therapy prior to BiAb and 5 patients were exposed to a BCMA antibody-drug conjugate prior to the BiAb. Furthermore, 89% of patients were triple-class refractory while 44% were penta-refractory. Following treatment with a BiAb, 2 patients were lost to follow up, 1 patient decided to be monitored off treatment and 61 patients received a median of 2 lines of therapy (range: 1-8). Most common therapies included a second BiAb (n=20; 33%), CAR T cells (n=15; 26%) or intensive chemotherapy (n=36; 59%) such as melphalan, carmustine or VDPACE with stem cell rescue (n=13) or DCEP (n=23). Best response to initial treatment following the BiAb varied widely and included 12 complete responses, 5 very good partial responses, 17 partial responses, 2 minimal responses, 10 stable disease and 13 progressed disease for an overall response rate (ORR) of 58%. Encouraging responses were seen in 10 patients who directly transitioned from one BiAb to another and 8 patients who directly transitioned to CAR T cell therapy. The progression-free survival of those 18 patients who directly transitioned to a T cell directed therapy was 28.9 months (95% CI: 21.6-NE) and their median overall survival was not reached. Furthermore, the overall survival for the whole cohort of patients was 17.6 months (95% CI: 12.0-NE). Conclusion: Our data suggests that heavily pretreated, predominantly triple-class refractory, patients relapsing after BiAbs may still have good outcomes when sequentially treating with other immunological/T cell-directed therapeutics such as BiAbs and CAR T cells. Studying the appropriate sequence of these treatments is of paramount importance as BiAbs are expected to become part of the standard of care for RRMM patients. Disclosures Richard: Karyopharm, Janssen: Honoraria. Richter: Celgene: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Janssen: Speakers Bureau; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Chari: Janssen Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceutical Company: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

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