scholarly journals Research funding and price negotiation for new drugs

2020 ◽  
Vol 29 (S1) ◽  
pp. 83-96 ◽  
Author(s):  
Francesca Barigozzi ◽  
Izabela Jelovac
Keyword(s):  
Research Funding ◽  
New Drugs ◽  
Price Negotiation

Diffuse Large B-Cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP Or R-ICE Chemotherapy Included In The Coral Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 764-764 ◽  
Author(s):  
Eric Van Den Neste ◽  
Christian Gisselbrecht ◽  
Norbert Schmitz ◽  
Nicolas Mounier ◽  
Devinder S Gill ◽  
...  
Keyword(s):  
Research Funding ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
New Drugs ◽  
High Dose ◽  
Second Line ◽  
Line Therapy ◽  
Significant Difference ◽  
Third Line Therapy ◽  
Third Line

Abstract Introduction and Methods Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is the standard of care for relapsing/refractory DLBCL. In the CORAL study, there was no difference between two randomized second line regimens (R-DHAP or R-ICE) and only half of the patients (pts) eventually underwent per protocol ASCT (Gisselbrecht et al, JCO 2010 & 2012). Because outcome data are limited in DLBCL pts failing second-line strategy, 145 pts included in the CORAL study who failed R-DHAP or R-ICE and could not proceed to scheduled ASCT were herein reviewed. Results Median age was 56y (range 20-67, 31% > 60y), M/F ratio 91/54, IPI 0-1 in 30%, 2-3 in 56%, and 4-5 in 14%. Third-line therapy consisted of ICE-type (19%), DHAP-type (19%), gemcitabine-containing (16%), CHOP-like (8%), dexaBEAM (8%), and miscellaneous (31%) regimens with or without rituximab according to centre policy. Overall response rate to third-line chemotherapy was 43%, with 21% complete response (CR), 8% CR unconfirmed (CRu), and 14% PR. CR/CRu and PR rates among pts treated with ICE-type, DHAP-type, gemcitabine-containing, or CHOP-like regimens were 23 and 23%, 35 and 8%, 9 and 4%, 25 and 25%, respectively. Among the 145 patients, 64 (44%) could eventually be transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS), calculated from time of second failure until death, was 5.9 months (95% CI 4.6-7.5; min: 0.0-max: 68.8 months; median follow-up: 32.8 months) and was not influenced by the type of third-line regimen (p=.49). OS was statistically different (p<.0001) according to IPI at CORAL failure: IPI 0-2: 11.1 months (1-y OS 42.9%), IPI > 2: 3.7 months (1-y OS 7.7%, HR 3.021). OS in pts achieving CR/CRu, PR, or no response after third-line regimen was 63.6 m (1-y OS 72.1%, p<.0001), 12.8 m (1-y OS 53.5%, p=.04), and 4.4 months (1-y OS 9.2%), respectively. Median OS of pts who could eventually be transplanted was 11.1 months (1-y OS 41.6%), as compared to a median OS of 5.0 months in those who were not transplanted (1-y OS 19.2%) with a HR of 2.182 (1.41-3.38, p<.0001, Figure 1). Median OS of pts transplanted in CR after third-line regimen was not reached as compared to those in PR (11.8 months) or those with no response (4.4 months, p<.0001). There was no statistically-significant difference in median OS between ASCT and alloSCT, taking into account the low numbers. In multivariate Cox analysis, IPI at relapse (HR 2.409) and transplantation (HR 0.381) independently predicted for OS. Conclusions Outcome of DLBCL pts failing second-line R-DHAP or R-ICE is overall poor. However, response to third-line therapy occurs, and 44% of the pts can be further transplanted. Long-term disease control can be observed, especially in pts achieving CR after third-line. This approach (salvage chemotherapy aiming at achieving response followed by transplantation) should then be encouraged in these patients, although there is obviously an urgent need for new drugs improving salvage efficacy. Disclosures: Gisselbrecht: Roche: Consultancy, Research Funding; Baxter: Research Funding; Chugai Pharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Radford:Roche: Consultancy. Shpilberg:Roche: Consultancy, Honoraria, Research Funding. Dührsen:Roche Pharma: Honoraria, Research Funding. Moskowitz:Genentech: Consultancy, Research Funding. Glass:Roche: Honoraria, Research Funding.

Phase 2 Randomized Trial Comparing 6 Cycles of Standard RCHOP Chemotherapy Vs 6 Cycles of Brcap (bortezomib, rituximab, cyclophosphamide, adriamicine and prednisone) As First Line Treatment in Young Patients with Poor Prognosis Diffuse Large B-Cell Lymphoma (DLBCL): Interim Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1514-1514
Author(s):  
Eva González-Barca ◽  
Estrella Carrillo ◽  
Carlos Grande ◽  
Alejandro Martín ◽  
Mónica Coronado ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Research Funding ◽  
Young Patients ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
New Drugs ◽  
Hematological Toxicity ◽  
Early Evaluation ◽  
Grade 3 ◽  
Beta 2 Microglobulin

Abstract Background: survival of young patients with high IPI DLBCL treated with RCHOP chemotherapy needs to be improved. In this poor risk population the combination of RCHOP with new drugs is an attractive approach, along with performing an early evaluation with PET/CT after 2 to 4 cycles and change induction therapy if a complete response is not achieved. Bortezomib has been combined with RCHOP [1]. We present preliminary data of patients treated in a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib at a dose of 1.3 mg/m2 sc days 1, 8, and 15 of every 21 days cycle (NCT01848132). Methods: patients younger than 70 yrs diagnosed of DLBCL with aIPI 2-3 or aIPI 1 with elevated beta2microglobulin were eligible. The main objective was to evaluate the proportion of patients who survives free of event at 2 years. Central pathology review was performed in all cases, and samples were classified as GC vs non-GC subtypes by IHC (Hans algorithm). PET/CTs were performed at diagnosis, after 2, 4 and 6 cycles (PET2, PET4 , and PET6), and were reviewed by at least 3 experts of a central panel at real time. Response was analyzed following the visual method with the Deauville scale, and for PET2 and PET4 the semiquantitative method was used. Patients with persistent disease after 4 cycles were considered a failure of therapy and were dropped out from the trial. Results: data from the first 76 patients were analyzed. Diagnosis of DLBCL was confirmed in all except 3 pts, 36 pts were treated in the experimental arm and 37 in the control arm. Median age was 58.2 yo (range 23-70), 37 (50.7%) were males. Characteristics at diagnosis were: non-GC subtype 18/46 (39.1%), C-myc expression 35/43 (81.4%), bcl2 expression 43/49 (87.7%), double expression cmyc/bcl2 30/42 (71%), stage III-IV 64 (87.6%), ≥2 extranodal locations 27 (42.2%), ECOG 2-3 24 (33%), elevated LDH 43 (62.3%), elevated beta 2 microglobulin 47 (75.8%), aIPI 2: 42 (57.5%), aIPI 3: 21 (28.8%). Among 160 cycles of BRCAP chemotherapy, 5 (3.1%) on day 8, and 22 (13.7%) on day 15, were given without bortezomib due to a neutrophil count below 0.5 /L. The most common toxicities are shown in table 1 without significant differences between both arms. Twenty-one (32.8%) out of 64 patients had a positive PET2. Fifteen (26.8%) out of 56 patients who have finished the 4 cycles had a positive PET4 according to central review and were withdrawn of the trial. Table 1. Episodes of treatment-related adverse events Control arm: RCHOP n=166 Experimental arm: BRCAP n=160 Any grade Grade 3-4 Any grade Grade 3-4 Anemia 6 0 22 9 ( 5.6%) Neutropenia 31 26 (15.6%) 47 37 (23.1%) Thrombocytopenia 9 4 ( 2.4%) 16 5 ( 3.1%) Febrile neutropenia - 6 ( 3.6%) - 10 ( 6.2%) Fever 8 1 ( 0.6%) 8 0 Infection 4 1 ( 0.6%) 7 1 ( 0.6%) Nausea/vomiting 12 0 19 0 Peripheral neuropathy 7 1 ( 0.6%) 7 1 ( 0.6%) Diarrhea 4 0 8 0 Constipation 7 0 4 0 Hepatotoxicity 6 0 6 0 Conclusions: BRCAP regimen with bortezomib sc d1, 8, and 15 is feasible. Its main toxicity is hematological, and some patients cannot receive some doses of bortezomib due to neutropenia. Grade 3-4 non-hematological toxicity is rare, including peripheral neuropathy, and do not differ from RCHOP toxicity. 1.Ruan J et al, JCO 2011;29:690-7 Disclosures Sancho: CELLTRION, Inc.: Research Funding. Lopez-Guillermo:Roche, Celgene, Mundipharma, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Mobilization of Human Immature Hematopoietic Progenitors after Combinatory Use of Bortezomib and Immunomodulatory Drugs

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 316-316
Author(s):  
Taro Tochigi ◽  
Takatoshi Aoki ◽  
Yoshikane Kikushige ◽  
Tomohiko Kamimura ◽  
Takuji Yamauchi ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Research Funding ◽  
Time Course ◽  
Mononuclear Cells ◽  
Biological Effects ◽  
New Drugs ◽  
Immunomodulatory Drugs ◽  
Hematopoietic Progenitors ◽  
Cd34 Cells ◽  
Immature Cells

Abstract Introduction: Combination of proteasome inhibitor (PI) bortezomib and immunomodulatory drugs (IMiDs), lenalidomide or thalidomide, have revealed superior outcomes in multiple myeloma (MM) over their single use. PI and IMiDs possess their direct anti-tumor activity as well as exert the indirect pleiotropic biological effects by modulating immune response, cytokine production, cell adhesion molecule, anti-apoptotic factors, cell cycle regulators. We recently found that circulating immature granulocytes and erythrocytes/megakaryocytes frequently appeared in peripheral blood (PB) in patients treated with bortezomib and IMiDs. In this study, we tested whether this effect is derived from PI, IMiDs or combination, and tried to understand its underlying mechanism to further understand their combinatory effects to normal hematopoiesis. Patients & Methods: 47 patients aged 37 - 81 years with newly diagnosed or relapsed/refractory MM were enrolled into this study. PB or bone marrow (BM) samples were collected from 7 patients treated with bortezomib/lenalidomide/dexamethasone (VRD), 15 with bortezomib/thalidomide/dexamethasone (VTD), 6 with bortezomib/dexamethasone (BD), 19 with lenalidomide/dexamethasone (RD) regimen. Clonogenic progenitor assay (CFU-C) was performed using PB samples. Change in expression level of adhesion molecules on mobilized immature cells was analyzed with flowcytometric (FCM) analysis. We counted 250 differential WBC in May-Giemsa-stained PB smears under the microscope every other day after start of chemotherapy. Result: In PB analysis, a significant fraction of immature myeloid or erythro-megakaryocyte cells was morphologically documented in 16 out of 22 (73%) patients treated with VTD/VRD, but never in the patients treated with BD or RD (n=22). During the time course, circulating immature hematopoietic cells gradually increased after the commencement of VRD or VTD therapy, and reached to a peak on a median of 12 days (range, 4 - 24 days), which was documented after 2nd or 3rd administration of bortezomib in the most patients. In these patients, a mean peak percentage of immature cells per WBC was 2.6% (0 - 6.5%) during VRD/VTD therapy. We also performed FCM analyses to confirm mobilization of immature hematopoietic progenitors in peripherally during VRD/VTD therapy. Number of mobilized CD34+ cells was statistically higher in the VRD/VTD group than that in BD/RD group (0.070% vs. 0.017%, p=0.041). We extended an analysis of change in expression of adhesion molecules on mobilized immature cells in PB mononuclear cells, since down-regulation of these molecules resulted in release of stem/progenitor cells from marrow and mobilization into the circulation. We found a significant decrease in mean fluorescence intensity (MFI) of CXCR-4 expressed on PB CD34+ cells in VRD/VTD group compared with that in BD/RD groups (11.1 vs 15.2, p=0.033). Number of CFU-cells (CFU-C) increased after 2nd or 3rd administration of bortezomib during VRD/VTD therapy compared to that before therapy (Figure), which was coincided with the appearance of immature cells in PB. A number of CFU-C derived from 100,000 PB mononuclear cells was increased up to 45 in VRD/VTD group compared to 11 in BD/RD group (p=0.021). Discussion: In this study, we unexpectedly found a transient mobilization of the immature hematopoietic progenitors in the majority of patients who received concurrently PI and IMiDs, but not in the patients treated with either alone. IMiDs promote degradation of IKZF1, which regulate GATA-1 and PU.1, critical transcription factors for erythroid and granuloid lineage, resulting in a suppression of erythropoiesis and granulocyte maturation arrest with accumulation of immature granulocyte progenitors in the BM. In contrast, PI downregulate expressions such as CXCL-12/CXCR-4 and VLA-4/VCAM-1 by which hematopoietic progenitors anchor to BM microenvironments. Therefore, we hypothesize that accumulated immature progenitors in marrow by treatment with IMiDs, can be quickly released into peripherally by concurrent administration of bortezomib. It is still unknown whether the mechanism of mobilization effect is linked to their anti-myeloma effect. Thus, our observations provided the unexpected biological effects of these drugs. Combinatory use of new drugs should be carefully evaluated to maximize their benefit or prevent possible adverse events. Figure 1. Figure 1. Disclosures Akashi: Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Age-Based Probability of Ten-Year Overall Survival (OS) of Acute Myeloid Leukemia (AML): A National Cancer Database (NCDB) Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Vijaya R. Bhatt ◽  
Valerie K Shostrom ◽  
Nabin Khanal ◽  
Chakra P Chaulagain ◽  
Fiona He ◽  
...  
Keyword(s):  
Older Patients ◽  
Research Funding ◽  
Clinical Trial Data ◽  
Older Age ◽  
New Drugs ◽  
Cell Transplant ◽  
Short Term ◽  
Hematopoietic Cell Transplant ◽  
Logistic Regression Models

Background: Clinical trial data suggest excellent short-term outcomes for younger patients and a subset of fit older patients. Translating findings of clinical trials into the real-world practice has challenges, and longer-term data are often not available. Hence, we utilized NCDB to determine age-based probability of ten-year OS of unselected cohorts of adults with AML. Methods: NCDB captures about 70% of all new diagnosis of cancer. We utilized NCDB to analyze ten-year OS of 15,646 patients aged ≥18 years, who were diagnosed with AML during the years 2004-2007. Univariate and multiple logistic regression models were used to determine factors associated with ten-year OS. Kaplan Meier curves were generated for OS analysis. Results: Ten-year OS was 12.7% for patients aged 18-59 years treated with chemotherapy without hematopoietic cell transplant (HCT) (Table 1, Fig. 1). Older age, male, Charlson-Deyo comorbidity score &gt;0, insurance other than private, subtypes other than core-binding factor AML were associated with lower ten-year OS. Ten-year OS was 24.3% for patients aged 18-59 years treated with chemotherapy and HCT (Fig 2). Older age, male, and insurance other than private were associated with lower ten-year OS. Ten-year OS was 16.1% and 2.2% for patients older than 60 years and treated with and without HCT, respectively; multivariate analysis was not performed for older patients because of low sample size (HCT group) or low survival (non-HCT group). Detailed analysis will be presented. Conclusions: Long-term OS of adults with AML is low with less than a quarter of patients being alive at ten years. Ten-year OS is particularly poor for older patients who are treated with chemotherapy alone. Whereas recent advances and approval of eight new drugs will likely improve short-term OS at 2-3 years, innovative strategies are necessary to improve long-term OS and cure. Further study to identify the cause of death will be insightful. Disclosures Bhatt: Takeda: Consultancy; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero: Research Funding; Rigel: Consultancy; Agios: Consultancy; Omeros: Consultancy. Chaulagain:Sanofi Genzyme: Honoraria. Gundabolu:BioMarin: Consultancy; Bristol Myers Squibb pharmaceuticals: Consultancy.

Consolidation with Bortezomib, Thalidomide and Dexamethasone After High Dose Therapy Is Feasible, Safe and Effective In De Novo Multiple Myeloma Patients Who Already Received New Drugs Containing-Induction Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3041-3041 ◽  
Author(s):  
Murielle Roussel ◽  
Gaëlle Dörr ◽  
Willy Vaillant ◽  
Anne Huynh ◽  
Michel Attal
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
New Drugs ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Therapy ◽  
Induction Regimen ◽  
Immunophenotypic Analysis

Abstract Abstract 3041 High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is a standard treatment option for frontline myeloma patients (pts). However, after a single or a double transplantation, almost all pts ultimately relapse. Thus, new strategies are required to control the residual disease after HDT. Consolidation therapy, given early after HDT, could enhance the depth of response and further improve progression free survival (PFS) and overall survival (OS). The IFM (Intergroupe Francophone du Myélome) previously reported that either Thalidomide or Lenalidomide, administered after HDT, was able to reduce this residual disease (IFM 99-02 and 2005-02 trials, Attal M et al. Blood 2006 and ASCO 2010). Ladetto M et al. (JCO 2010) also reported a major shrinking of residual tumor cell burden in myeloma pts undergoing early consolidation with Bortezomib, Thalidomide and Dexamethasone (VTD) after ASCT. None of these pts had previously received treatment with Thalidomide and/or Bortezomib during induction. The aim of this study was to evaluate the feasibility, safety and efficacy of early consolidation therapy in pts who had received new drugs containing-induction therapies before ASCT. Patients and Methods: In this prospective monocenter study,patients were eligible if they had the following: 1) at least partial response (PR) after HD melphalan (HDM), 2) no grade ≥ 2 peripheral neuropathy (PNY). The consolidation therapy with vTD had to be started within 3 months from ASCT for a total of 2 cycles. Each 4-week cycle consisted of: a) Bortezomib: 1mg/m2 as an IV injection twice weekly (on days 1, 4, 8, 11); b) oral Thalidomide: 100 mg/day; c) oral Dexamethasone 40 mg/day once a week (on days 1, 8, 15 and 22). Pts did not receive maintenance therapy after vTD consolidation. A systematic prophylactic anticoagulation therapy was given either by aspirin or low molecular weight heparin. Pts also received systematic anti herpes zoster prophylaxis with valacyclovir. Toxicities were graded according to the CTAECv4 at each cycle. Response was assessed according to modified European group for Blood and Marrow Transplantion criteria including very good partial response (VGPR), 1 month after the last cycle of vTD. As no immunophenotypic analysis was available routinely in our institute, we did not evaluate stingent complete response. Results: From August 2008 to May 2010, 90 newly diagnosed multiple myeloma pts under 65 received HDM followed by ASCT in the Toulouse's hospital bone marrow transplant unit, FRANCE. Forty-six pts were eligible for this study and started on consolidation. Two pts are ongoing their treatment and 41 received the whole planned treatment. Two pts withdrawn thalidomide and 1 pt did not receive the second cycle of consolidation because of toxicities. Forty-four pts were excluded mainly because of PN (27%). Initial characteristics were: age=58 years (range,44-65); ISS: 1= 50%, 2= 23%, 3=18%, NA= 9%; DS stage: I=4,5%, II=4,5%, III=91%; median beta-2microglobulin=2,9 mg/l (1,3-11,3); FISH analysis: t(4-14) and/or del 17p= 4/29 evaluable pts. The induction regimen was: Bortezomib/Dexamethasone (82%), vTD (11%), or another regimen (7%). Before consolidation therapy, response rates were: PR=16%, VGPR=48%, near complete response (nCR)=14% and CR=23%. In an Intend to treat basis, 17 pts (39%) improved their responses after consolidation with vTD: 3 pts (7%) from PR to VGPR, 8 pts (18%) from VGPR to nCR, and 6 pts (14%) from VGPR to CR. Response improvement was also reported in the 5 pts who already received induction therapy with vTD; three pts (60%) improved their response: 1 pt from PR to VGPR and 2 pts from VGPR to nCR. As immunophenotypic analysis was not avalaible, response improvement might be underestimate for CR pts. Overall, consolidation therapy with 2 cycles of vTD was efficient; 16 pts (36%) acheived CR, 30 pts (68%) CR+nCR and 40 pts (91%) VGPR or better. Considering the safety profile, there was no toxic death or grade 3/4 hematological toxicity. Non-hematological toxicities reported were: fatigue=18%, PNY (all grades)= 9%, pneumonia=7%, vertigo= 7%, constipation= 6%, and deep-vein thrombosis= 4,5%. Conclusions: Early consolidation with vTD in pts who already received Thalidomide and/or Bortezomib as induction therapy is feasible, safe and effective. Response rates improved in almost 40% of pts. Disclosures: Roussel: Janssen: Consultancy, Research Funding, orator; celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib and thalidomide as consolidation therapy after High Dose Melphalan. Attal:celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding.

Differences in Patterns of Treatment and Outcome Among Patients with Relapsed Refractory Myeloma From United States, Europe and Asia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3989-3989
Author(s):  
Shaji Kumar ◽  
Jae Hoon Lee ◽  
Juan Jose Lahuerta ◽  
Gareth J Morgan ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Initial Therapy ◽  
New Drugs ◽  
Advisory Committees ◽  
The Us ◽  
Before And After ◽  
The Mean ◽  
To Receive ◽  
Different Parts

Abstract Abstract 3989 Background: Treatment patterns of multiple myeloma (MM) vary across the globe, mostly dictated by the availability and patient access to different drug therapies. The outcomes of patients with MM, especially relapsed myeloma can be significantly affected by the availability of newer treatments, as well as potential biological differences related to ethnicity. We have previously shown that the outcome of patients relapsing after therapy with bortezomib (Bz) and one or more of the IMiDs remain poor with the currently available treatments and represent a difficult group of patients to treat. We undertook the current analysis on a set of patients from United States, several European countries and South Korea. Methods: We designed a multicenter, retrospective study that enrolled 294 patients with relapsed MM, from 14 sites (122 from Europe, 107 from US, and 65 from Korea). Patients were refractory to Bz, defined as no response to prior Bz-containing regimen or disease progression within 60 days of a Bz-containing regimen. Patients were also relapsed, refractory, intolerant, and/or ineligible, to treatment with an IMiD (thalidomide or lenalidomide). The date patients satisfied the above entry criteria was defined as time zero (T0). Clinical and laboratory data from diagnosis and individual relapses were collected along with details of all MM drug therapies before and after T0. Responses were assessed by IMWG or EBMT criteria. The goal of the study was to compare the characteristics of patients who satisfy the above inclusion criteria, the therapies employed prior to and after T0 and clinical outcome among these patients from different parts of the world. Results: The mean (median, range) time to reaching T0 from diagnosis was 4.5 (4.0, 12.8), 4.2 (3.2, 18.6), and 3.2 (2.8, 9.6) years from diagnosis for patients from US, Europe and Korea, respectively, P=0.021. The mean (median, range) number of therapies for the three groups were 8 (8, 13), 4 (4, 10), 5 (4, 7), respectively; P<0.001. The response rates (>=PR) to the initial therapy at diagnosis were 56%, 77% and 49% respectively for the US, European and Korean cohorts. Overall 220 patients had at least one therapy after T0, and 114 (52%) had a novel agent (Bz, len or thal) containing regimen as their first treatment after T0. Patients in US were more likely to receive additional therapies after the first post-T0 therapy; 62%, 32%, and 12% of patients from US, Europe and Korea, respectively, began a second post-T0 regimen within 2 years following time zero. The median number of therapies post T0 was 2, 1, and 1 for patients in US, Europe and Korea respectively. The response rates to the first regimen after T0 were 15%, 33% and 19% for the US, European and Korean cohorts, and were similar between those receiving a regimen with one of the novel drugs compared to rest. Patients younger than 60 years and those with prior transplants were more likely to respond to post T0 regimens. The median time to progression or death from T0was similar for the three patient cohorts, 5 months (Figure 1A). The median overall survival (95% CI) from T0 was 13 months (10, 16), 7 (5,9) and 8 (4,9) respectively for the US, European and Korean cohorts (Figure 1B). Conventional prognostic factors, especially the ISS stage was predictive of OS post T0. Additionally, presence of extramedullary disease was associated with a shorter overall survival. Conclusion: The results of the current study demonstrate significant differences between different parts of the world in terms of the treatment patterns both in the setting of initial therapy as well as treatment of relapsed disease. Patients in the US were more likely to receive multiple regimens both before and after T0. This is likely a reflection of increasing numbers of new drugs that have gone into clinical trials and thus enhancing options. The study further highlights the poor outcome of patients who have relapsed after the new drugs, irrespective of the geographical location. Disclosures: Kumar: Merck: Consultancy, Honoraria; Genzyme: Consultancy; Celgene: Consultancy. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Sonneveld:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Merck: Honoraria; Millenium: Honoraria, Research Funding, Speakers Bureau. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Identification of Novel Therapeutic Targets in the Clinically Predictive Vk*MYC Mouse Model of Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 415-415 ◽  
Author(s):  
Marta Chesi ◽  
Victoria Garbitt ◽  
P. Leif Bergsagel
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Mouse Model ◽  
Nuclear Export ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Single Agent ◽  
New Drugs ◽  
Common Mutation ◽  
Activating Mutations

Abstract A genetic rearrangement of the MYC locus, resulting in dysregulated expression of MYC, is the most common mutation in human multiple myeloma (MM). The genetically engineered Vk*MYC mouse model is based on dysregulation of MYC, and has been extensively validated as a clinically and biologically faithful model of untreated MM. We previously reported 9 drugs or classes of drugs (DNA alkylators, glucocorticoids, proteasome inhibitors, IMiDs, nab-paclitaxel, histone deacetylase inhibitors, TACI-Ig, perifosine and SNS-032, a CDK2,7,9 inhibitor) with more than 20% partial response (PR) rate in Vk*MYC MM. Among those, the first 5 also have more than 20% PR in patients with MM for a positive predictive value of 56%. Although the HDACi did not show single agent activity in relapsed/refractory MM patients, the PANORAMA phase 3 study of panobinostat in combination with bor+dex has shown superior PFS compared to bor+dex, suggesting the possibility that HDACi may have shown single agent activity if tested in a less advanced clinical setting. In contrast, 11/12 drugs that have less than 20% PR in Vk*MYC MM also have less than 20% PR in patients with MM for a NPV of 92%. Confident that drugs with activity in Vk*MYC mice will likely be effective in the treatment of MM, we have used this model to study novel drugs for prioritization in clinical trials. Pim kinases are constitutively active serine/threonine kinases identified using retroviral mutagenesis as potent suppressors of MYC induced apoptosis and can be inhibited by the pan-PIM kinase inhibitor LGH447. KPT-276 is a selective inhibitor of nuclear export CRM1/XPO1 inhibitor. Both drugs are active in Vk*MYC MM and are showing early evidence of promising clinical activity, increasing the PPV of the Vk*MYC model of MM to 64% (or 73% if HDACi are considered clinically active). Also active in the Vk*MYC model were the bromodomain inhibitors GSK I-BET151, CPI-203, CPI-456, OTX-015, which, like JQ1, compete with acetylated histones for the binding to BRD4, inhibiting super-enhancer activity and MYC transcription. The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) induces transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3) at the promoter of silenced genes. Activating mutations in the SET domain of EZH2 are prevalent in germinal center DLBCL and follicular lymphoma but have not been identified in MM, where the frequent dysregulation of MMSET by t(4;14) translocation or biallelic deletion of UTX are thought to play a tumorigenic role equivalent to EZH2 activation. EZH2 inhibitors have demonstrated activity against lymphoma with EZH2 activating mutations. Interestingly, we found the EZH2 inhibitor CPI-169 active against Vk*MYC MM, identifying EZH2 as a promising new epigenetic target in MM. EDO-S101 is a novel drug resulting from the fusion of a molecule of bendamustine with a molecule of vorinostat, with the aim of increasing the efficacy of the alkylator through the HDACi-mediated chromatin relaxation that would make DNA more accessible to the damaging effect of bendamustine. It induced a high rate of response in Vk*MYC MM that was sustained for more than 3 months in mice receiving only 2 doses, one week apart. Remarkably EDO-S101 is the only drug we have identified with single agent activity in the very aggressive, multi-drug resistant Vk12653 transplant model of relapsed/refractory MM. Finally, 2 agents (anti-murine PD-L1 and LCL161) that primarily modulate the immune microenvironment, with little to no direct anti-MM activity, also induced responses. Anti-PD-L1 blocks immunosuppressive signaling from MM cells to PD1 on T cells. LCL161 is an IAP antagonist that leads to constitutive activation of the alternative NFkB pathway with direct stimulation of the innate and adaptive immune systems. Although antibodies to CD38 are among the most exciting new agents for the treatment of MM, they cannot be evaluated in Vk*MYC MM since murine normal or malignant plasma cells do not express CD38. In contrast while SLAMF7 is expressed in Vk*MYC MM, there is no murine equivalent of elotuzumab. In summary, we report 7 new drugs with single agent activity in Vk*MYC MM, nearly doubling the number of drugs or classes of drugs with promising anti-MM activity. Two (LGH447 and KPT-330) are already beginning to demonstrate clinical efficacy in MM. All of these agents should be prioritized for rapid evaluation in clinical trials of patients with MM. Disclosures Bergsagel: Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding.

scholarly journals New Era in Chronic Lymphocytic Leukemia: Consequences of the Arrival of New Drugs

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4696-4696
Author(s):  
Jorge Labrador ◽  
Covadonga Garcia Diaz ◽  
Beatriz Cuevas ◽  
Maria Victoria Cuevas ◽  
Rodolfo Alvarez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Statistical Significance ◽  
Young Patients ◽  
Complete Response ◽  
Cell Receptor ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
New Drugs ◽  
First Line

Abstract Introduction In the last decade, the incorporation of anti-CD20 monoclonal antibodies (MoAb) (rituximab, obinutuzumab), bendamustine, B-cell receptor inhibitors (ibrutinib) and Bcl-2 antagonists (venetoclax) have changed the paradigm of chronic lymphocytic leukemia (CLL) treatment, improving overall survival (OS). Methods We conducted a retrospective observational study of patients diagnosed with CLL between 2003 and 2016 at our center to evaluate: i) the influence of date of diagnosis, before or after 2010; ii) having received new drugs (MoAb or target therapies) in first line or not. Results A total of 182 patients were evaluated: 104 men (57%) and 78 women (43%); median age 74 years (39 - 97), 132 patients were &gt;65 years (72.5%). At diagnosis, 135 (74%), 19 (10%), 15 (8%), 4 (2%) and 9 (5%) were diagnosed as stages 0, I, II, II, III and IV of the Rai classification. While 154 (84%) 15 (8%) and 14 (8%) were classified as Binet's stages A, B and C. Regarding the presence of comorbidities, the median CIRS scale score was 4 (0 - 15). 71 patients (39%) were diagnosed before 2010 and 111 (61%) from 2010 onwards. With a median follow-up of 76 months (range, 20-212), 77/182 (42%) patients had received ≥1 line(s) of treatment: 1: 53%, 2: 26%, 3: 8%, ≥4: 13%. 20 patients (26%) received the first line of treatment before 2010, and 56 (74%) from 2010 onwards. Half of the patients received new drugs in 1st line (n=39), 92% of them from 2010 onwards. 32 patients (41.5%) achieved complete response after 1st line, and 24 (31%) at least a partial response. The median OS of patients diagnosed before 2010 was 66 months (35.32 - 96.68) vs 143 months (95% CI 90.5 - 195.5) (p=0.032) as of 2010. In those ≤ 65 years median OS has not been reached, being 80.5% at 10 years: 65% for those diagnosed before 2010 and 97% after 2010, p=0.036. The median OS of patients &gt; 65 years was 6 years (95% CI 4.17 - 7.83), and increased from 82 months for those diagnosed before 2010, to 110 months in those diagnosed after 2010, p=0.744. Patients treated with new drugs in 1st line increased the median OS from 76 months and 13% at 10 years to a median not reached and OS of 77% at 10 years, p=0.000. This difference was more evident in those ≤ 65 years: 20% vs 100% at 10 years (p=0.012), while it was not statistically significant for those &gt; 65 years (11% vs 50% at 10 years, p=0.181) (Figure 1). However, in a multivariate model including age, sex, CIRS&gt;6 and year of diagnosis (before or after 2010), treatment with new drugs retained statistical significance (HR 0.414; 95% CI 0.183 - 0.935) along with age ≤ 65 years (HR 0.256; 95% CI 0.085 - 0.771) and CIRS ≤ 6 (HR 0.247; 95% CI 0.111 - 0.551). Conclusions In our experience, the introduction of new drugs in the first line has led to an increase in OS, especially in young patients. Figure 1 Figure 1. Disclosures Gonzalez-Lopez: Grifols: Other: Advisory board honoraria; Sobi: Other: Advisory board honoraria; Amgen: Other: Advisory board and speakers honoraria, Research Funding; Novartis: Other: Advisoryboard and speakers honoraria, Research Funding.

scholarly journals Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients Relapsing after Autologous Stem Cell Transplantation (ASCT): An Analysis of Patients Included in the Coral Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 517-517 ◽  
Author(s):  
Eric Van Den Neste ◽  
Norbert Schmitz ◽  
Nicolas Mounier ◽  
Devinder Gill ◽  
Marek Trneny ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
New Drugs ◽  
Late Relapse ◽  
High Dose ◽  
Third Line

Abstract Introduction and Methods: Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is standard care for relapsed/refractory DLBCL. In the CORAL study, 477 patients were assigned to one of two salvage regimens (R-DHAP or R-ICE). Only the 240 responding patients underwent per protocol ASCT and were randomly assigned to rituximab or observation. The four-year event-free survival (EFS) post ASCT were 52 and 53% for the rituximab and observation groups, respectively (p=.7). Secondary IPI (sIPI) independently predicted EFS, PFS and OS after ASCT (Gisselbrecht et al, JCO 2010 & 2012). Outcome data are limited in DLBCL patients who relapse after ASCT, with reported overall survival (OS) of 9.9 months in rituximab-pretreated patients (Nagle et al, AJH 2013). To shed more light on outcome and prognostic factor in this population, 75 patients included in the CORAL study who relapsed after scheduled BEAM/ASCT were reviewed. Results: Median time between ASCT scheduled in CORAL and relapse was 7.1 months (range 3.1-61.9) with 32.9% relapsing > 12 months. Median age was 56.1y (range 20.9-67.7), M/F ratio 51/24, sIPI 0-2 in 71.6%, >2 in 28.4%. 49.3% were in the rituximab and 45.3% in the observation arm of the CORAL. All patients had previously received rituximab. Third-line therapy consisted of ICE-type (17.3%), DHAP-type (24%), gemcitabine-containing (28%), CHOP-like (13.3%), and miscellaneous regimens (17.3%). Overall response rate to third-line chemotherapy was 44%, with 32% complete response (CR)/CR unconfirmed (CRu), and 12% PR. Among the 75 patients, 16 (21.6%) could eventually be transplanted 3 ASCT and 13 allogeneic SCT with conditioning regimens including fludarabine. Median OS, calculated from time of relapse until death, was 10.0 months (95% CI 6.6-12.6; min: 0.9-max: 55.2 months; median follow-up: 32.8 months) with an estimated 1-y OS of 39.1%. Median OS was statistically different (p=.0007) according to sIPI at CORAL failure: sIPI 0-2: 12.6 months (1-y OS 51.3%), sIPI > 2: 5.3 months (1-y OS 21.6%, HR 2.805). Median OS in patients achieving CR/CRu, PR, or no response after third-line regimen was 37.7 m (1-y OS 90.5%, p<.0001, HR 0.132), 10.0 m (1-y OS 44.4%, p=.03, HR 0.375), and 6.3 months (1-y OS 13.4%), respectively. Median OS of patients who could eventually be transplanted was 17.4 months (1-y OS 68.2%), as compared to a median OS of 8.0 months in those who were not transplanted (1-y OS 31.2%) with a HR of 0.575 (p=.11). Median OS was particularly dismal among patients who relapsed < 6 months after CORAL-scheduled ASCT (5.7 months, n=28), as compared to those relapsing either > 6 and < 12 months (11.3 months, n=21) or > 12 months after ASCT (12.6 months, p=0.01, fig. 1)). In multivariate Cox analysis (with the following variables entered: age, sex, sIPI, response to third line and time between CORAL ASCT and relapse), sIPI >2 (HR 2.464, p=0.01), achievement of CR (HR 0.1, p<.0001) or PR (HR 0.242, p=0.02), and post-ASCT remission lasting < 6 months (HR 2.270, p=0.05) independently predicted for OS. Conclusions: Overall, the outcome of DLBCL patients relapsing after second-line R-DHAP/R-ICE followed by ASCT is poor. However, prognostic factors predicting better outcome in this group are late (> 6 months) relapse, lower sIPI and achieving at least PR after third-line salvage followed by transplantation. In the transplanted patients (allo SCT or second ASCT) a 2-year OS of 50% was observed. Thus, new salvage regimens can be a bridge to transplantation in patients with late relapse and/or low sIPI,. New drugs improving salvage efficacy are urgently needed, especially for patients relapsing < 6 months following ASCT. Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Disclosures Schmitz: Roche, Takeda, Gillead, Riemser und ctilifesciences: Other: Advisory board, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding. Milpied:Celgene: Honoraria, Research Funding. Briere:St. Louis Hospital, Paris, France: Employment. Thieblemont:St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Gisselbrecht:roche: Research Funding, Speakers Bureau.

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