scholarly journals A Comprehensive Toxicity and Efficacy Analysis of Different Bridging Therapies Prior to Anti CD19-CAR-T Cell Therapy in Patients with DLBCL- a National Multi-Center Cohort Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1733-1733
Author(s):  
Ron Ram ◽  
Sigal Grisariu ◽  
Liat Shargian-Alon ◽  
Dana Yehudai-Ofir ◽  
Irit Avivi ◽  
...  
Keyword(s):  
Disease Control ◽  
Board Of Directors ◽  
Progression Free Survival ◽  
Bridging Therapy ◽  
Advisory Committees ◽  
Free Survival ◽  
Tumor Mass ◽  
Car T ◽  
Grade 3 ◽  
Bridging Strategies

Abstract Introduction - Data regarding efficacy and toxicity of different bridging strategies prior to CAR-T therapy are scanty. Tisagenlecleucel (Kymriah TM, Novartis) and axictagene ciloleucel (Yescarta TM, Kite/Gilead) were commercially approved for relapsed/refractory (R/R) DLBCL since 2019. We analyzed real-life data of CAR-T therapy among all consecutive patients who were treated in 4 different CAR-T centers in Israel. Methods - From May 2019, 144 R/R DLBCL patients underwent apheresis and continued to receive bridging therapy that included chemo/immunotherapy (n=78, 54%), radiation (n=11, 7.6%), chemoradiation (n=22, 15%), steroids only (n=5, 3.5%) and none (n=28, 19.4%). All patients were evaluated after bridging therapy and prior to CAR-T infusion by PETCT (96%) or CT scan (4%). Results - Median age was 68 (20-88) years and Median follow-up was 13 (4-26) months. All 144 patients underwent successful apheresis. Reasoning for choosing specific bridging therapy was based on low tumor mass (n= 23, 16%), high tumor mass (n=73, 51%), frailty of the patient (n=27, 19%), ongoing significant prior regimen's toxicities (n=14, 10%) and local disease (n=7, 4%). In patients given radiation therapy median dose was 23 (range, 8-30) Gy. In patients given chemo/immunotherapy or chemoradiation, sepsis was the main complications (9% of all patients) during bridging therapy. However, none of the patients had a fatal event. 14 patients (9.7%) did not proceed to CAR-T infusion; 6 (4.2%) had disease progression and died; 8 (5.6%) had manufacture failure). Among the 130 patients that received CAR-T infusion, PET-CT prior to preparative regimen demonstrated CR/PR status in 38%, 50%, 40%, 17%, and 16% of patients given chemotherapy, radiation, chemoradiation, steroids only, or no bridging therapy, respectively (p=.15), Figure 1. Any bridging therapy was associated with a better disease control compared to either steroids only or no treatment (p=.012). There were no differences in the incidences of overall CRS (p=.692), grade 3-4 CRS (p=.196), overall ICANS (p=.941), grade 3-4 ICANS (p=.281), acute kidney disease (p=.244), and liver dysfunction (p=.45) between the 5 different bridging strategies. Cardiovascular complications were more common after chemoradiation (36%), chemotherapy (19%) and radiation (13%), compared with steroids (0%) or no bridging therapy (4%), p=.05. Non-relapse mortality was 0 in all subgroups. PETCT at 1-month post CAR-T infusion demonstrated an increase in CR status percentage across all subgroups with no statistically significant difference in the incidence between the subgroups (p=.27), Figure 1. There was no difference in both progression-free survival (Figure 2) and overall survival between the 5 subgroups (p=.7, and p=.23). Cox regression model identified preinfusion lower ECOG status (HR=0.8, p=.04), preinfusion CR/PR status (HR=.46, p=.037) and 1-month post infusion CR status as a time dependent co-variate (HR=.14, p<.01) to be associated with better progression-free survival, while age and type of bridging therapy did not predict survival. Conclusions - Bridging to CAR-T should be tailored based on patient's and disease's characteristics with the aim to achieve the best disease control prior to CAR-T. However the chosen strategy per-se does not impact long-term outcomes. Intensive bridging therapy is associated with more cardiovascular events after CAR-T infusion. A prospective-controlled-trial allocating patients to different bridging strategies is needed to verify these results. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Yehudai-Ofir: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Zuckerman: Cellect Biotechnology: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; AbbVie: Honoraria. Yeshurun: Astellas: Consultancy; Janssen: Consultancy. Gurion: Medison; Gilead Sciences; Takeda Pharmaceuticals: Consultancy; JC Health CARE; Roche: Honoraria. Levi: AbbVie: Consultancy, Research Funding.

scholarly journals The Use of CEP (Lomustine, Etoposide and Prednisone), an All-Oral Palliative Chemotherapy Regimen, in Aggressive Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4131-4131
Author(s):  
Lakshman Vasanthamohan ◽  
Brent Parker ◽  
Joy Mangel ◽  
Selay Lam ◽  
Kang Howson-Jan ◽  
...  
Keyword(s):  
Disease Control ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Multivariate Analyses ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Advisory Committees ◽  
Free Survival ◽  
Aggressive Lymphomas

Background: There is no current standard of care therapy for the management of patients with aggressive lymphomas in the relapsed or refractory (R/R) setting who are not candidates for intensive salvage chemotherapy and/or autologous stem cell transplant (ASCT). The combination of lomustine (CCNU), etoposide and prednisone (CEP) is an oral chemotherapeutic regimen that is modified from CCEP used in Hodgkin Lymphoma (CCNU, chlorambucil, etoposide and prednisone). CEP consists of alternating A & B cycles as follows (Figure 1): 'A' cycles contain lomustine 80 mg/m2 on day 1 as well as etoposide 100 mg/m2 and prednisone 100 mg on days 1-7. 'B' cycles contain only the etoposide and prednisone. Cycles are given every 21 days apart. To date there has been no published data on CEP's efficacy and tolerability in aggressive R/R lymphoma. In this study, we describe our institutional experience with CEP at the London Regional Cancer Program (LRCP) in London, Ontario for patients with R/R aggressive lymphomas unable to tolerate intensive chemotherapy. Methods: We conducted a retrospective review of patients who received CEP at LRCP between January 2014 and May 2018 for R/R aggressive lymphomas. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse effects related to CEP. Kaplan-Meier survival curves modeled PFS and OS. We also performed univariate and multivariate analyses to assess whether pre-specified variables (age, IPI score at diagnosis, LDH at time of treatment, and the number of prior lines of therapy) were independently associated with response to CEP (using linear regression) or progression-free survival (using the Cox proportional hazards model). IPI score (0-2 vs. 3-5) and the number of prior lines (1-2 vs. ≥ 3) were analyzed as binary variables due to the overall sample size. Results: 46 patients received CEP at LRCP during the study period. Diffuse large B-cell lymphoma was the most common diagnosis (70%) with Hodgkin lymphoma (6.5%) and peripheral T-cell lymphoma (6.5%) being the next most common. The median age of patients starting CEP was 76, with the median number of prior therapies being 2 (range 1-6). The primary outcome was ORR, which was 41% in our population, with a median time to response of 23 days. The median PFS was 2 months while the median OS was 4 months (Figure 2). The 2-year PFS and OS were both 8.7%. The median CEP treatment period was 1.5 full cycles while the longest CEP treatment period was 21 consecutive cycles. Univariate analysis revealed that lower IPI score (p=0.037) was significantly associated with ORR, while lower LDH (p=0.029) was significantly associated with PFS. Multivariate analyses revealed no factors associated with ORR, while lower LDH (p=0.017) and lower IPI (p=0.037) were associated with PFS. Toxicities were manageable with 48% with cytopenias of any grade and the most common grade 3-4 toxicity was febrile neutropenia in 13%. Conclusions: CEP is a safe, and convenient, all-oral palliative regimen for R/R aggressive lymphoma who are not eligible for intensive salvage chemotherapy or ASCT. The median OS in our population is comparable to pooled clinical trial and academic center data from non-transplant eligible patients with R/R DLBCL (Crump et al, Blood, 2017). Some patients even in spite of low performance statuses were able to tolerate many cycles of CEP with a long period of disease control, suggesting it is a reasonable treatment option for frail patients to balance disease control with an acceptable side-effect profile. Disclosures Lam: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Other: Education Grant; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Phua:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 74-74 ◽  
Author(s):  
Jatin J. Shah ◽  
Edward A. Stadtmauer ◽  
Rafat Abonour ◽  
Adam D Cohen ◽  
William I. Bensinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 74 Background: Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an immunomodulatory agent (IMiD), have both demonstrated promising activity as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma. IMiD+PI combinations including lenalidomide, bortezomib, dexamethasone and lenalidomide, carfilzomib, dexamethasone have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly active in patients with relapsed/refractory multiple myeloma. Here, we report the first findings from the Phase I dose-escalation and expansion portions of the first phase I/II trial of Car-Pom-d in patients with relapsed/refractory multiple myeloma (NCT01464034). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pom-d. Secondary objectives included determination of overall response rate, time to progression, progression free survival, and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have been relapsed/refractory to their most recent therapy. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1–21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22. Dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Carfilzomib was initiated at 20 mg/m2for Cycle 1, days 1–2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: In the Phase I dose-escalation portion of the trial, a total of 12 patients were enrolled from 6 centers. The median age was 61 years (range 44–78), 67% were male. The median number of prior regimens was 6 (range 2–15), and median time from diagnosis was 5.1 years. Four (33%) patients had prior stem cell transplant, 11 (92%) had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 5 patients with del(17p), 2 patients with t(4;14), and 1 patient each with del(13), t(11;14), and t(14;16). In these first 12 patients, drug-related AEs occurring in >20% of patients included fatigue (42%), anemia (33%), pneumonia (33%), dyspnea (25%), and thrombocytopenia (25%). Six (50%) patients experienced grade ≥3 AEs including 2 incidence each of neutropenia and febrile neutropenia. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). At this dose, 1 of 6 patients experienced a protocol-defined DLT of febrile neutropenia. At dose level 2 (carfilzomib 20/36 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg), 2 of 6 patients experienced DLTs, consisting of grade 4 thrombocytopenia and grade 3 rash. All 12 patients were response evaluable with 2 very good partial response (VGPR), 4 partial response (PR), 2 minor response (MR), 2 stable disease (SD), and 2 progressive disease (PD) for a ≥ MR rate of 67%. The 6 month progression free survival was 70% (95% CI: 37 to 90%). Of the 5 patients with del(17p), 1 achieved VGPR, 2 achieved PR, 1 achieved SD. We then enrolled an expansion cohort of 20 patients from 8 centers resulting in a total study population of 32 patients, with 25 still receiving treatment. Three patients have died, all from progressive multiple myeloma. Early response assessments in 27 out of 32 patients show 2 VGPR, 7 PR, 6 MR, 8 SD, and 4 PD for a ≥MR rate of 56%. Conclusions: The Car-Pom-d regimen is well tolerated and achieves a high response rate in a heavily pre-treated, lenalidomide-refractory population with prior bortezomib exposure. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p). We are beginning enrollment in a larger phase 2 cohort, and updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Array: Consultancy. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Onyx: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Lentzsch:Celgene: Consultancy, Research Funding. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Durie:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Amgen: Consultancy.

scholarly journals Biomarkers for Predicting Long-Term Disease Control in Transplant-Ineligible Multiple Myeloma Patients: The Presence of an MGUS- like Signature Is the Most Relevant Predictor

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4503-4503
Author(s):  
Paula Rodriguez Otero ◽  
Maria-Victoria Mateos ◽  
Joaquin Martinez Lopez ◽  
Miguel-Teodoro Hernández ◽  
Enrique M. Ocio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Control ◽  
Board Of Directors ◽  
Research Funding ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Disease Free

Abstract Introduction: Disease control at five years would be a desirable endpoint for elderly multiple myeloma (MM) patients; however, the percentage of cases reaching this objective as well as the biomarkers to predict it, are not well defined. Objective and design: In order to gain further insight about long-term disease control (>5 years progression-free) in elderly MM we have analyzed a homogeneous population of 435 newly-diagnosed transplant-ineligible (TNE) patients enrolled in two consecutive Spanish clinical trials (GEM2005MAS65, GEM2010MAS65), that included both proteasome inhibitors and immunomodulatory drugs. Results: Amongst the 435 patients included in this post-hoc study, only 18.8% remained alive and progression-free after five years of initiating treatment. Noteworthy, in these patients the overall survival (OS) rate at 10-years was 69.4%, as compared to 11.4% for those patients progressing during the first five years (p< 0.001). Baseline variables significantly associated with long-term progression free survival in the univariate analysis were younger age, ISS 1, R-ISS 1, hemoglobin ≥ 12g/dl, normal LDH, and standard-risk cytogenetic abnormalities and the presence of a monoclonal gammopathy of unknown significance (MGUS)-like immunophenotypic profile in the bone marrow. Complete responses (CR) and minimal residual disease (MRD) negativity were also associated with long-term progression free survival. In the multivariate analysis, an hemoglobin level ≥12g/dl (OR 2.61; 95% CI 1.47 - 4.61, p=0.001) and a MGUS-like immunophenotypic profile in the bone marrow (OR 3.33; 95% CI 1.30 - 8.54, p=0.002) were the two baseline variables significantly and independently associated with a higher probability of long-term disease-free survival. When the depth of response (including MRD) was included in the logistic regression model, Hb level ≥12g/dl (OR 2.18; p=0.010) and the MGUS-like signature (OR 4.99, p<0.001) retained their independent predictive value along with the achievement of MRD-negativity (OR 4.09, p<0.001). Focusing on the 24 patients with an MGUS-like signature (based on the automated immunophenotyping analysis of the relative frequency of BM plasma cells (PCs) plus the percentage of clonal and normal PCs within the whole BM PC compartment), 50% percent of these patients displayed a long-term disease-free survival, as compared to only 17.5% of the remaining MM patients. The median OS for patients with MGUS-like signature was 90.2 months as compared to 62.6 for the MM-like patients. Most MGUS-like patients (90.5%) achieved a favorable response (10 complete response (CR) and 9 very good partial response (VGPR)). No differences in outcome were observed between VGPR and CR cases (p-value for OS 0.87) among MGUS-like patients. Conclusions: This study revealed that despite the usage of former novel agents, the probability of disease control at five years is still restricted to a small fraction (18.8%) of transplant-ineligible patients that achieve remarkable rates of long-term OS. Here, we identify that the combination of three biomarkers (normal Hb, MGUS-Like signature and MRD negativity) can help todefine elderly MM patients achieving long-term disease control. Our results highlight the presence of an MGUS-like signature in the bone marrow at diagnoses as the most powerful predictor for long-term disease free survival, and could be incorporated in clinical practice in order toimprove the prognostic information given to our patients. Disclosures Rodriguez Otero: Clínica Universidad de Navarra: Employment; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Research Funding. Mateos:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau. Ocio:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Puig:Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bladé:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Lahuerta:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

scholarly journals Peak Absolute Lymphocyte Count Post CAR-T Is Associated with Clinical Response and Survival Outcome in Aggressive Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3856-3856
Author(s):  
Radhika Bansal ◽  
Anatilde Gonzalez Guerrico ◽  
Henan Zhang ◽  
Zuoyi Shao ◽  
Elham Babadi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Progression Free Survival ◽  
Absolute Lymphocyte Count ◽  
Advisory Board ◽  
Advisory Committees ◽  
Free Survival ◽  
Car T Cells ◽  
Car T

Abstract Introduction Chimeric antigen receptor T cell (CAR-T) expansion has been consistently identified as a predictor of clinical response. However, there are no clinically available test to measure CAR-T presence after infusion for the FDA approved CAR-T therapy. We hypothesize that the lymphocyte expansion which can be readily measured as absolute lymphocyte count (ALC) in blood count differential could be a clinically accessible surrogate for CAR-T expansion in patients who receive FDA approved CD19 CAR-T to treat aggressive B-cell non-Hodgkin lymphoma (NHL). We examined the ALC levels in the first 2 weeks after CAR-T infusion and correlation with clinical outcomes in NHL patients who received CAR-T at our institution. Methods Records were reviewed for patients who received CAR-T between 6/2016 and 1/2021 at Mayo Clinic, Rochester. CAR+ T cells were identified by flow cytometry using an anti-FMC63 antibody. Receiver operator curve was generated using nominal logistic regression to predict complete response (CR) as best response. Progression-free survival and overall survival were calculated using Kaplan-Meier method and between-group differences were assessed using log-rank test. Continuous variables were compared using wilcoxon text and categorical variables were compared using chi-square test. Results Among the 87 patients who received CAR-T for NHL, majority of the pts received axicabtagene ciloleucel (86, 99%). The highest ALC level (ALC peak) in the first 15 days were identified for all patients and median ALC peak was 0.44 X10 9/L (range, 0 - 2.55x10 9/L). The median time to ALC peak was 10 ±3 days. Increasing ALC peak levels correlated with increased CAR+ T cells in blood measured by flow cytometry (n=16, R=0.63, p=0.0008). Using ROC analysis, an ALC peak level of 0.67 was identified as the cut point for best association with CR (AUC=0.68, p=0.0004). Baseline demographics were similar between the high ALC peak (N=35) and low ALC peak (N=52) groups, as shown in Table 1. There was no difference in the incidence, high grade, or duration of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) between the two groups (Table 2). Patients who received a higher cumulative dose of steroid for management of CRS and ICANS had lower ALC peak. A higher ALC peak was associated with an increased CR rate and durable CR at month 6. Similarly, a higher ALC peak was associated with increased progression-free survival (PFS, 6.4 months vs. 2.7 months, p=0.004) and overall survival (OS, 31 months vs. 12 months, p=0.04), as shown in figure 1. Conclusion Given the typical CAR-T expansion seen in the first 2 weeks post infusion, ALC peak in the first 15 days is a clinically accessible, reliable surrogate for CAR-T expansion and predicts durable CR and longer PFS, OS. This study was supported in part by the Mayo Clinic Center for Individualized Medicine, Bernard E. and Edith B. Waterman, Henry J. Predolin Foundation and other generous benefactors of Mayo Clinic. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Research Funding; Merck: Research Funding; Sorrento: Consultancy; Juno: Consultancy.

A Phase II Multi-Center Trial Of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) In Older Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4177-4177 ◽  
Author(s):  
Marco Montillo ◽  
Davide Rossi ◽  
Marina Motta ◽  
Giulia Quaresmini ◽  
Marianna Rossi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade 3 ◽  
Anti Cd20

Abstract Introduction The seminal phase 3 trial conducted by the German CLL Study Group demonstrated that the addition of the anti-CD20 monoclonal antibody [mAb] rituximab to the FC platform (FCR) improved response rates, progression free survival and also overall survival. However, FCR showed considerable hematologic toxicity, particularly among patients over age 70. Pentostatin demonstrated similar response frequency to other purine analogues in CLL. Furthermore, its relative lack of myelotoxicity has allowed to use it with improved tolerability particularly when administered in combination with myelotoxic agents such as cyclophosphamide. Ofatumumab is a fully human anti-CD20 mAb with clinical activity as a single agent in patients with fludarabine-refractory CLL. Ofatumumab appears to have greater single agent clinical activity than rituximab in patients with previously treated CLL and also has activity in rituximab-refractory patients. Given the reported efficacy of chemo immunotherapy [CIT] in CLL and the activity and toxicity profile of pentostatin combinations, we designed a trial of pentostatin, cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) aged ≥ 65 years and ECOG PS of 0-2 were enrolled to receive Pentostatin 2 mg/sqm and Cyclophosphamide 600 mg/sqm both as intravenous infusions at day 1 of each 21 day cycle and Ofatumumab administered as intravenous infusions (Cycle 1: 300 mg day 1 and 1000 mg day 2, subsequent cycles: 1000 mg at day 1). Ofatumumab premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was of 6 cycles. The primary endpoint was overall response rate (ORR) including detection of minimal residual disease (MRD) and secondary endpoints included, progression-free survival (PFS) overall survival (OS) and safety. Patients 49 patients from 12 centres from the italians regions of Lombardy and Piedmont were included. Baseline demographics were: Median age 72.8 years with 64% aged over 70, among them 32 were males (65%). Disease characteristics in 32 patients evaluable at this point were: 76% Binet stage B and 24% C; 45% of patients had unmutated IGVH, 7 % showed 17p deletions. Results ORR was 93.7% with 41% CR(11)/CR(2) with incomplete marrow recovery [CRi]. All six intended courses of treatment were administered to 30 (94%), and 90% of these patients received full-dose treatment. The reason for discontinuing treatment before completing six courses was myelosuppression occurring in 2 patients. The primary reason for dose reduction was again myelosuppression. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 62% of patients receiving PCO with the most common being neutropenia [Total number of patients with at least one Grade 3 or 4 event: 19 patients] while anemia and thrombocytopenia were detected only as grade 1 to 2 in 41% and 25% of cases respectively. Of the grade 1 to 2 toxicities, fever occurred in 2 patients (6%), hypotension occurred in 2 patients (6%), nausea and vomiting occurred in 3 patients (9%), skin rash of grade 1 occurred in 2 patients. Grade 3 infusion-related AEs were reported in 12% of patients. There were no grade 4 toxicities associated with any Ofatumumab infusion. Grade 3 infection was reported in 1 patient (3%) being a pneumonia. No deaths during treatment occurred in these 32 subjects. Conclusion Ofatumumab added to Pentostatin and Cyclophosphamide demonstrated clinically important results and is well tolerated in patients with previously untreated CLL. In this preliminary report the efficacy of this ofatumumab-based CIT compares favorably to the historical rituximab-based CIT using the same chemotherapeutic agents with a more manageable side effect profile in this older population. Further data in a higher number of enrolled patients and including MRD detection will be presented at the Meeting. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

A Phase II, Single-Center, Open-Label Study of Oral Panobinostat in Combination with Lenalidomide and Weekly Dexamethasone in Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3486-3486 ◽  
Author(s):  
Ajai Chari ◽  
Hearn J. Cho ◽  
Samir Parekh ◽  
Amishi Dhadiwal ◽  
Katarzyna Garcia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Progression Free Survival ◽  
Additional Patient ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade 3 ◽  
Dose Modifications ◽  
Triplet Regimen

Abstract Background: Treatment options for patients with multiple myeloma (MM) refractory (ref) to immunomodulatory drugs and proteasome inhibitors are urgently needed. A promising strategy is the use of epigenetic agents such as the pan histone deacetylase inhibitor (HDACi) panobinostat (pan) to modulate the acetylation of histones and proteins involved in oncogenesis. Pre-clinical studies with pan demonstrate synergy against MM cells when combined with dexamethasone (dex), lenalidomide (len), and bortezomib (btz) (Ocio EM et al. Haematologica 2010). Interim data from the phase 3 PANORMA 1 study of 768 patients randomized to receive IV btz and dex with either pan or placebo revealed a 3.9 month increase in PFS with pan along with an increase in CR rates. However, this was accompanied by 25% grade 3/ 4 diarrhea versus 8% in the placebo arm. The safety and preliminary efficacy of the pan-len-dex triplet regimen was assessed in a phase 1b study of relapsed (rel) or rel/ref MM patients (Mateos et al, ASCO 2010) but was complicated by high dose dex toxicities. The maximum tolerated dose of pan and dex in that study are the doses selected for this phase 2 study. However we investigated a modified schedule (table 1) of this triplet regimen. Here, pan is given thrice weekly only every other week (instead of weekly) and dex is given weekly (instead of three 4 day pulses). Patients and Methods: Inclusion criteria were patients with rel or rel/ref MM, measurable disease, adequate performance status, organ function, and hematologic parameters. Patients previously treated with a HDACI or currently receiving medications with a risk of prolonging the QTc interval were excluded. The primary objective was to evaluate the best overall response rate (ORR). Secondary objectives were to evaluate safety, response duration, and overall and progression-free survival. Each drug was administered at the doses and schedule shown in Table 1. Results: Overall, 13 evaluable patients with progressive disease (PD) at screening have been enrolled, including 9 len-refractory (2 also pomalidomide refractory) and 4 len sensitive with a median of 4 and 3 lines of prior therapy respectively (range 1–10). High-risk molecular findings were present in 9 patients, including 6 with gain of 1q21 by FISH and 3 with del p53. Three of the patients with gain of 1q21 also had t (4;14). Of the 13 patients, there have been 3 very good partial responses (VGPR), 2 partial responses (PR), 3 minimal responses (MR), 4 stable diseases (SD), and 1 PD, for an ORR of 38% and clinical benefit rate (CBR i.e. MR or greater) of 61 %. With a median follow up of 4.5 months the median progression free survival and duration of response have not been reached. Of the 9 patients who were len refractory, there were 2 VGPR, 2 MRs, 4 SD, and 1 PD for a 22% ORR and 44% CBR. Notably, 3 len refractory patients remain on treatment for 11, 16, and 16 months including 2 with gain of 1q21 that have attained VGPRs. Grade 3/4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia, thrombocytopenia, lymphopenia, and anemia noted in 7, 4, 1, and 1 patients respectively. Grade 3/4 nonhematologic AEs included infections in 4 (with 1 one occurring while neutropenic), and 1 patient with each of the following: pulmonary embolus, neck pain, QTc prolongation, and weight loss 1. Dose modifications for neutropenia were required in 4 patients for len and in 2 patients for pan. 1 additional patient required pan dose reduction for asymptomatic T wave inversions. Nausea was noted in 2 patients and diarrhea in 3 with 2 additional patients experiencing both – however these were transient, Grade 1/2, and did not require dose modifications. Importantly, no patients discontinued therapy for toxicity. Conclusions: In rel/ref MM patients, pan in combination with len and dex demonstrates durable responses, even in len-refractory patients with high-risk molecular findings, indicating the essential role of pan in attaining a response. These results suggest that pan modulates expression of genes to restore sensitivity to len, In notable contrast to the PANORMA 1 results, this completely oral regimen is well tolerated with no Grade 3/4 GI toxicities and primarily expected hematologic toxicities. Updated results, including correlative studies, will be presented at the annual meeting. Table 1: Study Drug Doses Panobinostat Lenalidomide Dexamethasone 20 mg po Day 1, 3, 5, 15, 17,19 25 mg po Day 1-21 40 mg po Day 1, 8, 15 Disclosures Chari: Array Biopharma: Membership on an entity's Board of Directors or advisory committees; Millenium : Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

Evaluating Gvhd Outcomes Using Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil As Gvhd Prophylaxis Compared with Methotrexate/Tacrolimus in Matched-Related and Matched-Unrelated Hematopoietic Stem Cell Transplant in Relation to the Haplo-Identical Setting: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Mindy Hsiao ◽  
Preet M. Chaudhary ◽  
George Yaghmour
Keyword(s):  
Stem Cell ◽  
Mycophenolate Mofetil ◽  
Board Of Directors ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
End Points ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade 3 ◽  
Haplo Group

Background: The use of post-transplant cyclophosphamide (PTCy)/tacrolimus/mycophenolate mofetil (MMF) for GVHD prophylaxis has improved outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT). PTCy is now being evaluated in matched-related (MRD) and matched-unrelated (MUD) allo-HCT. Previous studies demonstrated improved GVHD-free/relapse-free survival (GRFS) when PTCy was combined with two immunosuppressive agents and PTCy has also been associated with better relapse-free survival (RFS) as demonstrated in De Jong et al 2019, though only one immunosuppressive agent was used. Currently, there is limited published data comparing outcomes using PTCy/tacrolimus/MMF to standard MRD/MUD GVHD prophylaxis of methotrexate (MTX)/tacrolimus. The importance of studying this comparison may help to improve GVHD outcomes in MRD and MUD allo-HCT. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 19) who received allo-HCT from 2018 to 2020. The primary end-points assessed were incidence and severity of 1-year aGVHD and cGVHD. Secondary end-points included day+100 mortality, 1-year overall survival (OS), 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HCT period. Results: A total of 65 adult MRD and MUD allo-HCT recipients and 53 haplo-HCT patients were reviewed. Of the MRD/MUD patients evaluated, approximately 51% (n = 33) were female and 49% (n = 32) were male. The age range was 20-69 years old (median = 46), and the most common diseases included ALL (46%), AML (31%), MDS (11%), and others (i.e. lymphoma, aplastic anemia (AA), myelofibrosis) (12%). 34% (n = 22) of patients received PTCy on D+3 and D+4 with tacrolimus/MMF/ on D+5 as GVHD prophylaxis and 66% (n = 43) of patients received MTX/tacrolimus on D+1, +3, +6, and +11 as GVHD prophylaxis. All haplo-HCT patients received standard PTCy/tacrolimus/MMF. Stem cell source was primarily PBSC except in HLH and AA patients. The PTCy group had more MUD allo-HCT (64%), degree of antigen mismatch (56%), and median age of 50.5 years compared with the MTX group at 44%, 47%, and 44 years respectively. 70% in the MTX group received MAC compared with 45% in the PTCy group. The haplo group had similar demographics to the MTX group. The mean CD34 cell doses in the PTCy, MTX, and haplo groups were 4.87, 5.36, and 7.24x106 cells/kg respectively. Incidences of total GVHD, aGVHD, and aGVHD grade 3 or 4 in the PTCy group were 55%, 50%, and 4.5% respectively compared with 65%, 35%, and 7% in the MTX group, though not significant. The haplo group had 68%, 55%, and 1.9% respectively. Incidence of total cGVHD and cGVHD requiring systemic therapy in the PTCy group was 4.5% and 0% respectively compared with 30% (p = .02) and 23% (p =.01). The haplo group had 13% and 1.9% respectively. Day+100 mortality, 1-year OS, 1-year RFS, 1-year TRM, and 1-year GRFS in the PTCy group were 0%, 80%, 60%, 0%, and 64% respectively compared with 7%, 88%, 90%, 7.3%, and 59%. The haplo group had 3.8%, 86%, 89%, 14%, and 66%. In a univariate analysis, factors significantly associated with GVHD were disease status (p = .0.12) and CD34 dose (p = 0.015) and antigen mismatch (p = 0.04) was associated with increased mortality. Discussion: Our results demonstrate improved overall and extensive cGVHD outcomes in the PTCy group and thus an improvement in 1-year GRFS. Furthermore, incidence and severity of 1-year cGVHD in this group are improved when compared with previously reported outcomes. 1-year GRFS reported in De Jong et al 2019 was 45% and 1-year GRFS reported for all groups in our study is higher at 66%, 64%, and 59% for the haplo, PTCy, and MTX groups respectively. Although this was not significant, it may be clinically meaningful given the significant improvement in extensive GVHD and improvement in all other secondary end-points except 1-year OS and RFS. Furthermore, the PTCy group had a higher percentage of mismatched antigens yet demonstrated superior outcomes. 1-year OS and RFS were superior in the MTX group however this is likely due to sample size differences. The improved extensive cGVHD and GRFS outcomes observed using PTCy/tacrolimus/MMF in the MRD/MUD setting should continue to be evaluated and currently there is an ongoing prospective, randomized study to further investigate. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Long-Term Efficacy and Safety (27 months) of the Biosimilar CT-P10 in Patients with Low Tumor Burden Follicular Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Larry W Kwak ◽  
Juan Manuel Sancho ◽  
Seok-Goo Cho ◽  
Hideyuki Nakazawa ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Advisory Committees ◽  
Free Survival ◽  
Travel Costs ◽  
Single Transition ◽  
Second Year

We assessed long-term safety and efficacy of CT-P10 and rituximab in patients with newly diagnosed low-tumour-burden follicular lymphoma (LTBFL), and following a single transition from rituximab to CT-P10. This double-blind, parallel-group, active-controlled phase 3 trial randomized patients with CD20+ LTBFL to receive CT-P10 or US-sourced rituximab (375 mg/m2 intravenous). Induction therapy (weekly for 4 cycles) was followed by a 2-year maintenance period for patients achieving disease control (CR, CRu, PR and SD). During the maintenance, CT-P10 or rituximab were administered every 8 weeks (6 cycles) in the first year and additional CT-P10 was administered every 8 weeks (6 cycles) in the second year. Secondary endpoints (reported here) were overall response rate during the study period, progression-free survival, time-to-progression, and overall survival. Safety and immunogenicity were also evaluated over the study period. Between Nov 9, 2015 and Jan 4, 2018, 258 patients were randomised (130 CT-P10; 128 rituximab). Over the study period, 115 (88%; CT-P10) and 111 (87%; rituximab) patients achieved overall response. At a median follow-up of 29·2 months (IQR: 26·1-33·7), median progression-free survival, time-to-progression, and overall survival were not estimable. The KM estimates (95% CI) for OS at 36 months were 98% (93-99) and 97% (89-99) in the CT-P10 and rituximab groups, respectively. Corresponding values for PFS were 80% (70-87) and 68% (54-79), while results for TTP were 82% (72-88) and 68% (54-79) in the CT-P10 and rituximab groups, respectively. (Figure A. OS; Figure B. PFS and Figure C. TTP) Over the study period, 114 (88%) and 104 (81%) patients in the CT-P10 and rituximab groups, respectively, experienced at least one treatment-emergent adverse event (TEAE) and 14 (11%) patients in each group experienced TE-serious adverse events (TESAEs). There were no unexpected safety findings observed during the second year of the maintenance period after single transition from rituximab to CT-P10. Figure 1 Disclosures Kwak: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Sancho:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gelgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Jurczak:Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Trneny:Gilead: Consultancy, Honoraria, Other: Travel Expenses; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses. Ogura:Cellgene: Honoraria; Chugai: Honoraria; Denovo Biopharma: Membership on an entity's Board of Directors or advisory committees; MejiSeika Pharma: Membership on an entity's Board of Directors or advisory committees; Mundi Pharma: Membership on an entity's Board of Directors or advisory committees; SymBio: Membership on an entity's Board of Directors or advisory committees; TevaTakeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees. Kim:Pfizer: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; F. Hoffmann-La Roche: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding. Lee:Celltrion, Inc.: Current Employment. Kim:Celltrion, Inc.: Current Employment. Ahn:Celltrion, Inc.: Current Employment. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. OffLabel Disclosure: Rituximab monotherapy to LTBFL patients

Progressive but Previously Untreated CLL Patients with Greater Array CGH Complexity Exhibit A Less Durable Response to Chemoimmunotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2406-2406
Author(s):  
Neil E. Kay ◽  
Jeanette Eckel Passow ◽  
Esteban Braggio ◽  
Scott Van Wier ◽  
Tait Shanafelt ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Genomic Complexity ◽  
Duration Of Response ◽  
Gains And Losses

Abstract Abstract 2406 The outcome for a given CLL patient is difficult to predict. While there are promising models, they require collation of multiple clinical and laboratory parameters, and it remains to be seen whether they will apply to typical CLL patients in the community. To further dissect out explanations for this dramatic clinical heterogeneity, we sought to understand genomic complexity of clonal B-cells as a possible explanation of clinical variability with specific application to genomic complexity as a predictor of therapeutic response and clinical outcome in CLL. Thus we wished to identified global gains and losses of genetic material in order to define copy-number abnormalities (CNA) in 48 clinically progressive CLL patients who were about to be treated on a chemoimmunotherapy protocol. This protocol was previously reported by us (Blood. 109:2007) and had an induction phase with pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 3 weeks for 6 cycles and then responding patients were followed ever three months until relapse. In order to estimate CNA, we employed array-based comparative genomic hybridization (aCGH) using a one-million oligonucleotide probe array format on the leukemic B-cells from the 48 patients entering this trial. In those same patients, the aCGH data were compared to a) FISH detecxtable data using a panel for the common recurring genetic defects seen in CLL and b) to their clinical outcome on this trial. With aCGH we found that 288 CNA were identified (median of 4 per patient; range 0–32) of which 215 were deletions and 73 were gains. The aCGH method identified most of the FISH detected abnormalities with a complete concordance for 17p13.1- deletion (17p-) between aCGH and FISH. We also identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14 and 17. We found that CLL patients with ≥15 CNA had a significantly worse progression free survival (PFS) than patients with <15 CNA (p=0.004)(figure). Patients with ≥15 CNA also had a shorter duration of response than those with <15 CNA (p=0.0726). Of interest, more complex genomic features were found both in patients with a 17p13.1 deletion and in more favorable genetic subtypes such as 13q14.1. Thus, for 5 patients with >15 CNAs the following FISH patterns were seen: +12/13q14.1-x1/13q14.1 -x2, 13q14.1 ×1 (n=2), and 17p13.1 (n=2). In addition, a 17p- by FISH was positively associated with the number of CNA and total deletion size. The odds of having an overall response decreased by 28% (95% CI: 5–55%; p=0.015) with each additional CNA for the 17p13.1- patients. In addition to defining genomic complexity as the total number of CNA for each patient, we also defined complexity as the sum of the lengths of all interstitial chromosomal gains and losses. When defined as the total size of chromosomal gains or losses, genomic complexity was significantly associated with 17p13.1 and worse overall clinical response. In summary, this analysis utilized the global assessment of copy number abnormalities using a high-resolution aCGH platform for clinically progressive CLL patients prior to initiation of their treatment. One outcome was that we found higher genomic complexity was associated with shorter progression-free survival, reduced duration of response and predicted a poor response to treatment. In addition since we did find genomic complexity in more traditionally favorable FISH categories, such as 13q14.1 type defects, this may explain why some of the latter patients do not fare as well as might be expected even with aggressive chemoimmunotherapy approaches. This study adds information on the association between inferior trial response and increasing genetic complexity as CLL progresses. Disclosures: Off Label Use: Pentostatin. Kipps: GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) with or without Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched Sibling Non- Myeloablative Allogeneic HCT (auto-allo) for Patients with Standard Risk (SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 41-41 ◽  
Author(s):  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edward A. Stadtmauer ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Advisory Committees ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Matched Sibling

Abstract Abstract 41 AuHCT improves survival in patients with MM, but disease relapse and progression remain a challenge. Both tandem AuHCT and post transplant maintenance therapy improve progression-free survival (PFS). Alternatively, allogeneic HCT has the potential to reduce disease progression through a graft-versus-myeloma effect. Use of nonmyeloablative conditioning regimens allows the latter approach to be used with reduced treatment-related mortality (TRM). BMT CTN 0102 was a multicenter phase III trial that biologically assigned patients with MM to auto-auto using melphalan 200mg/m2 (MEL 200) conditioning or an auto-allo approach using MEL 200 followed by alloHCT with 2 Gy total body irradiation. Graft-versus-disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled. Patients were assigned to the auto-allo arm based on availability of an HLA-matched sibling donor at time of enrollment. Patients in the auto-auto arm were further randomized to thalidomide and dexamethasone (Thal-Dex) for 1 year or observation (obs). Among 625 patients with SR MM (absence of chromosome 13 deletion by metaphase karyotyping and β-2 microglobulin ≤ 4mg/L), 436 were assigned to auto-auto (217 Thal-Dex, 219 obs) and 189 to auto-allo. Compliance with Thal-Dex was poor, with 84% of patients not completing prescribed therapy. PFS and overall survival (OS) between the Thal-Dex and obs cohorts were equal and these arms were pooled for the primary analysis. The auto-auto and auto-allo groups differed in age (median 55y vs. 52y, p =0.01) and time between first and second transplants (median 98d vs 105d, p =0.02), but were otherwise balanced. Complete and near complete (CR+nCR) response rates at study entry were 24% for both groups. Three-year PFS was 46% and 43% (p=0.67) and 3-year OS was 80% and 77 % (p=0.19) for the auto-auto and auto-allo groups, respectively. Corresponding probabilities for 3-year progression/relapse were 50% and 46% (p=0.8) and for 3-year TRM were 4% and 11% (p=0.04). Among auto-allo patients, probabilities of grade III-IV acute and chronic GVHD were 9% and 47%, respectively. Eighty-two percent of patients in each arm received the assigned second transplant. Among 522 patients who received their second transplant, 3-year PFS was 47% and 44% (p=0.89) with auto-auto and auto-allo, respectively. Disease response rates at day 56 after second HCT were: 50% very good partial response (VGPR) or better and 40% CR+nCR in the auto-auto group; and 49% (VGPR or better, p=0.8) and 48% (CR+nCR,p=0.12) in the auto-allo group. In conclusion, there were no differences in 3-year PFS and OS between patients receiving auto-auto or auto-allo. Potential benefits of graft-versus-myeloma to reduce disease progression or relapse were offset by increased TRM. Thal-Dex maintenance did not improve PFS or OS, likely due to poor tolerability of this regimen. At 3 years, the auto-allo approach for SR MM had no added benefit compared to tandem AuHCT. Disclosures: Krishnan: Celgene: Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Comenzo:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding. Hari:Celgene: Research Funding. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

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