scholarly journals Risk of Histological Transformation in Patients with Primary Refractory Follicular Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4145-4145
Author(s):  
Sara Alonso ◽  
Martina Manni ◽  
Clementine Sarkozy ◽  
Marielle Wondergem ◽  
Attilio Guarini ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Board ◽  
Critical Event ◽  
P Value ◽  
Advisory Committees ◽  
Increased Risk ◽  
Histological Transformation

Abstract INTRODUCTION There is a growing interest in analyzing the biological and clinical variables that might help in identifying patients at risk of histological transformation (HT), a critical event that can still lead to reduced survival in patients with follicular lymphoma (FL). As part of the Aristotle study, we have previously reported that the risk of HT as a first event has been significantly reduced by the use of rituximab (Federico et al, Lancet Hematology 2018). However, this incidence might still be unacceptable in some groups of patients. Thus, we investigated the risk of HT in patients with primary refractory FL, a subset of patients with poor prognosis. METHODS We carried out a retrospective analysis of cumulative incidence of HT in the 289 cases with primary refractory FL retrieved from the Aristotle Study, which included a total of 6970 FL cases (grade 1, 2 or 3a), diagnosed between 1997 and 2013 and treated with systemic therapy. Refractoriness was defined as progressive disease (PD) within the end of first-line therapy. Patients with PD were compared to patients with partial response (PR) or stable disease (SD) and to patients with complete response (CR) at the end of therapy. The cumulative incidence of HT was calculated using the Nelson-Aalen estimator, with a 95 confidence interval (CI). The estimate is in absolute value, and then multiplied by 100. The overall survival (OS) and survival after relapse/progression (SAR) were calculated using Kaplan-Meier estimation, with a 95% CI. RESULTS Six hundred and twenty-eight cases (9%) were excluded for incomplete data and 6,339 were considered for analysis. The five-year cumulative incidence of HT among patients with PD was 34.2% (95% CI: 26.9-43.4), whilst it was 7.1% (95% CI: 6.0-8.5) and 3.5% (95% CI: 3.0-4.2) in the 1,954 and 4,096 patients with PR+SD and CR at the end of induction therapy, respectively. The rate observed in PD group had a Hazard Ratio (HR) of 11.4 (95CI: 8.61-15.0) compared with CR patients, and 6.14 (95% CI: 4.6-8.2), when compared with PR+SD patients. All comparisons and estimations showed a p-value below 0.001. Cumulative incidences of HT according to response to initial therapy are represented in Figure 1. The five-year SAR was 33% (95% CI: 28-39) for the PD group, with a median SAR of 1.1 year (95% CI: 0.8-1.8). At the same time point, the SAR was 56% (95% CI: 53-60) in patients with initial PR/SD, with a median SAR of 6.3 years (95% CI: 5.7-8.6). Finally, in patients with initial CR who later relapsed, the 5 year SAR was 63% (95% CI: 66-72), with a median of 10.4 years (95% CI: 10-12.2). The difference among groups was statistically significant (p-value <0.001, Figure 2). HR for PD group was 3.39 (95% CI: 2.87-4.01) compared to CR, and 2.12 (95% CI: 1.8-2.5) compared to PR/SD group. CONCLUSIONS According to the results of the present study, primary refractory FL patients have not only an already known reduced SAR (Casulo et al, JCO 2015), but also a dramatically increased risk of HT, which probably contributes to patients' adverse outcome. These findings reinforce the need to develop combined diagnostic and therapeutic strategies aimed to eradicate the disease at the "first shot", reducing the risk of refractoriness and eventually further improving the outcome of FL patients. Disclosures Sarkozy: ROCHE: Consultancy. Wondergem:NOVARTIS: Other: advisory board, educational talk; SANOFI: Other: advisory board; GILEAD: Other: educational talk. Chamuleau:Genmab: Research Funding; BMS: Research Funding; celgene: Research Funding; Gilead: Research Funding. Gomes da Silva:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; Roche: Other: Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Zucca:CELGENE: Other: Grant to the Institution + Advisory Board; Janssen: Other: Grant to the Institution; ROCHE: Other: Grant to the Institution + Advisory Board; Celltrion Healthcare + Mei Pharma + Astra Zeneca: Other: Advisory Board; AbbVie + Gilead: Other: Travel Expenses; Gilead + Bristol-Myers Squibb + MDS: Other: Expert Statement + Meetings. Aurer:Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Marcheselli:Fondazione Italiana Linfomi (FIL) Onlus: Employment. Salles:Novartis: Consultancy, Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Morphosys: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Servier: Honoraria.

Defining the Impact of Tandem Autologous Stem Cell Transplantation in Multiple Myeloma: A Case-Match Analysis in the Total Therapy Trials

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3182-3182
Author(s):  
Sharmilan Thanendrarajan ◽  
Caleb K. Stein ◽  
Faith E Davies ◽  
Frits van Rhee ◽  
Maurizio Zangari ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
P Value ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Data Set ◽  
Baseline Characteristics ◽  
Total Therapy

Abstract Introduction The introduction of melphalan-based high-dose chemotherapy and autologous stem cell transplantation (MEL-ASCT) has markedly improved the survival of patients with multiple myeloma (MM). The initial clinical studies suggested conditioning with melphalan (MEL) 200 mg/m2 was optimum compared to MEL 140mg/m2 or MEL/TBI. Following on from the introduction of a single MEL-ASCT, the use of tandem transplantation was explored and highlighted the potential of this approach to improve outcome. With the introduction of consolidation and maintenance approaches, questions still remain regarding which patients are most appropriate for the tandem approach and what dose of melphalan should be delivered. The Total Therapy (TT) trials were initiated more than 25 years ago and have used tandem MEL-ASCT since their inception. Not all patients treated in our facility received a 2nd MEL-ASCT due to a number of reasons including adverse events during 1st MEL-ASCT or a lack of funding for 2nd ASCT thus limiting access to a tandem treatment approach. A dose-reduced MEL (140 mg/m2) was given to patients with renal impairment or advanced age at 1st and / or 2nd ASCT. Consolidation/Maintenance chemotherapy was introduced from TT2 onwards. This large data set therefore allows us to perform a retrospective pair-matched analysis to address a number of important clinical questions including the role of single versus tandem MEL-ASCT and standard versus dose-reduced tandem MEL-ASCT in the era of novel agents for induction and consolidation/maintenance therapy. Materials and Methods We have analyzed data from 1918 patients who were enrolled in Total Therapy 1 - 6 trials. Given the changing chemotherapy regimens within TT trials due to the introduction of novel agents coupled with diverse baseline characteristics, we designed a retrospective pair-matched analysis framework in order to account for differences in patient and treatment variables. This was achieved by generating identical treatment and control group subsets from within the full data set that are identical across key covariates including baseline characteristics of ISS stage, age, and creatinine; protocol anti-myeloma treatment regimens such as dexamethasone, thalidomide, bortezomib, and lenalidomide; and variations in transplantation such as melphalan dosage. The majority of the patients in the TT trials completed induction chemotherapy and received the 1st MEL-ASCT (TT1: 88.3%, TT2: 86.0%, TT3: 97.6%, TT4: 95.0%, TT5: 100% and TT6: 95.1%). Fewer patients received the 2nd MEL-ASCT (TT1: 66.7%, TT2: 68.2%, TT3: 85.0%, TT4: 70.0%, TT5: 74.0%, and TT6: 52.4%). MEL 200 mg/m2 was the predominant dose, administered with MEL 140 mg/m2 given to a smaller fraction of patients due to age and renal impairment restrictions. TT3 has the highest percentage of patients receiving a 2nd MEL-ASCT at 85.0% and most of those at standard dose (MEL 200 mg/m2). Results After balancing treatment and control groups with identical treatment, baseline characteristics, and dose of 1st ASCT (140 or 200 mg/m2), we found 289 tandem and 289 single transplant pairs with no significant differences across any of our balancing covariates (all paired Wilcoxon rank test p-values = 1.00). Analysis of these pair-matched cases strongly supported tandem transplantation as superior in outcome-cases with tandem transplantation had 5-year OS rate of 74.8% compared to 54.1% in single transplant cases (logrank p-value: 1.44e-06). For cases with tandem transplantation, we pair-matched 164 cases with tandem 200 mg/m2 transplants to 164 cases with either 140 mg/m2 received as 1st ASCT, 2nd ASCT, or both transplants. Analysis of these pair-matched cases strongly supported tandem 200 mg/m2 over 140 mg/m2 as the 5-year OS rates were 78.5% and 63.6%, respectively (logrank p-value: 1.23e-03). Conclusion MEL-ASCT is the backbone for treatment of MM. From our study, there is overwhelming evidence that application of tandem MEL-ASCT delivers superior clinical outcome compared to single MEL-ASCT. In order to achieve the best clinical results tandem MEL-ASCT should be performed using standard dose MEL 200 mg/m2; dose reduction (140 mg/m2) leads to unfavorable clinical outcome. Ongoing analysis aims to reveal the benefits of MEL-ASCT treatment across specific subgroups to better understand differential response and optimal therapy for patients across distinct molecular and risk subgroups. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Thanendrarajan: University of Arkansas for Medical Sciences: Employment. Stein:University of Arkansas for Medical Sciences: Employment. Davies:Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:Onyx: Research Funding; University of Arkansas for Medical Sciences: Employment; Millennium: Research Funding; Novartis: Research Funding. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Jethava:University of Arkansas for Medical Sciences: Employment. Weinhold:University of Arkansas for Medical Sciences: Employment; Janssen Cilag: Other: Advisory Board. Matin:University of Arkansas for Medical Sciences: Employment. Mathur:University of Arkansas for Medical Sciences: Employment. Mohan:University of Arkansas for Medical Sciences: Employment. Radhakrishnan:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; MMRF: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria.

scholarly journals Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 125-125 ◽  
Author(s):  
Loretta J. Nastoupil ◽  
Jason R. Westin ◽  
Fredrick B. Hagemeister ◽  
Hun Ju Lee ◽  
Luis Fayad ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Tumor Burden ◽  
Advisory Board ◽  
Advisory Committees ◽  
High Tumor Burden ◽  
Equity Ownership ◽  
Grade 3

Introduction: FL, the most common indolent non-Hodgkin lymphoma, is characterized by a defective immune microenvironment that suppresses normal T-cell and natural-killer (NK)-cell activity. The clinical course is often depicted by high initial response rates coupled with a prolonged natural history and repeated relapses with most patients (pts) succumbing to their disease. Effective, well tolerated therapies are desirable. Obinutuzumab (O) is a humanized, type II anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Lenalidomide (len) is an immunomodulatory agent that binds the cereblon E3 ubiquitin ligase complex resulting in recruitment, ubiquitination, and degradation of transcription factors Aiolos and Ikaros resulting in T-cell and NK-cell activation. Therefore, combining O with len is anticipated to be synergistic in augmenting the innate and adaptive immune response in FL. The combination has been shown to be well tolerated and effective in relapsed FL (Fowler ICML 2017). Therefore, we sought to explore the efficacy and safety of O-len in previously untreated, high tumor burden FL. Methods: We conducted as single-center, phase 2 study in previously untreated, stage II, III, or IV, high tumor burden (defined by GELF) FL (grade 1, 2 or 3A). Pts received 1000mg of O on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and day 1 of even numbered cycles, cycle 8-30. Cycle length was 28 days. Len was administered as 20mg on days 1-21 of cycles 1-6. Pts in a complete response (CR) after 6 cycles received reduced dose len (10mg on days 1-21) for cycles 7-18. Among pts in a partial response (PR) after 6 cycles, len was continued at 20mg for the next 3-6 cycles or until CR, whichever occurred first, len was then dose reduced to 10mg on days 1-21 for the remainder of 18 cycles. The primary endpoint was progression-free survival (PFS) at 2 years (according to Lugano 2014 criteria). Secondary endpoints included: safety, CR, PR, overall response (ORR), and overall survival (OS). Results: 90 pts with high tumor burden FL were enrolled. Median age was 58 years (range 33-84), 52% (N=47) were male, 67 (74%) had an ECOG performance status of 0, 9 (10%) had stage II, 23 (26%) stage III, and 58 (64%) had stage IV disease. The majority had grade 1/2 FL (80%). Twenty-one percent had low risk FLIPI scores, 37% intermediate risk, and 42% were high risk. With a median follow-up of 22 months (range 1-30 months), the 2-year PFS estimate is 96% (95% CI 92-100%) with only 2 pts experiencing progression to date. The ORR is 98% (85 CR, 1 PR), 92% achieved a CR at the first response assessment (cycle 4, day 1). Correlative studies are underway including serial circulating tumor DNA measurements. No deaths have been observed to date. Eleven pts (12%) discontinued therapy as a result of an adverse event (AE), upper respiratory infection was the most common reason (N=5). Other reasons included bradycardia with sick sinus syndrome, urinary tract infection, constipation, abdominal pain, fatigue, foot neuroma (N=1 for each instance). The most common grade 3 or higher AEs include neutropenia (16%, grade 3 N=5, grade 4 N= 9), rash (10%), lung infection (4%), neutropenic fever (1%). Conclusions: O-Len was associated with very high CR rates and 2-year PFS estimates in untreated, high tumor burden FL. The toxicity profile was manageable. Further study of this effective, immune therapy approach in untreated FL is warranted. Figure Disclosures Nastoupil: Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Allogene: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Poseida: Research Funding; Karus: Research Funding; Novartis: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding. Fowler:ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: 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; Novartis Pharmaceuticals Corporation: Consultancy. OffLabel Disclosure: Lenalidomide in untreated follicular lymphoma

Reduced Intensity Delayed Intensification in Standard-Risk Patients Defined By Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: Results of an International Randomized Trial in 1164 Patients (Trial AIEOP-BFM ALL 2000)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4-4 ◽  
Author(s):  
Martin Schrappe ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
Georg Mann ◽  
Maria Grazia Valsecchi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Advisory Board ◽  
P Value ◽  
Advisory Committees ◽  
Childhood All ◽  
Standard Risk ◽  
Reduced Intensity

Abstract From 07/2000 to 06/2006, 4741 eligible pts with ALL (age range 1-17 years) were enrolled in the trial AIEOP-BFM-ALL 2000 (NCT 00430118 (BFM) and NCT 00613457 (AIEOP)). 1164 patients from Germany, Italy, Austria, and Switzerland entered the randomized comparison of protocol III (P-III) versus standard protocol II (P-II) for delayed reintensification in order to reduce treatment burden in the group of patients with best treatment response and lowest risk of relapse. P-III is shorter than P-II (duration 29 vs 49 days), the dose of dexamethasone in P-III is 30% less and the dose of vincristine, doxorubicine, and cyclophospamide 50% less than in P-II. The intention was to prove non-inferiority of the reduced intensity treatment as compared to standard treatment. Only patients who were defined as MRD standard risk (MRD-SR) being negative at both days 33 and 78 after start of induction therapy, using at least 2 molecular markers with sensitivity of at least 10-4, were eligible for the randomization. The main analysis was planned as a per protocol analysis of the 4-year disease free survival (4y-DFS). Stratification, induction and consolidation therapy and the results of a randomization in induction, dexamethasone at 10 mg/m2/d (DEXA) vs prednisone at 60 mg/m2/d (PRED), have been described earlier (A. Möricke et al, BLOOD 2016, M. Schrappe et al, BLOOD 2011, and V. Conter et al, BLOOD 2010). With a median follow-up of 8.6 years, 4y-DFS was 91.8% (SE 1.1%) and 95.8% (SE 0.8%) for patients who received P-III (N=584) or P-II (N=579), respectively (log-rank p=0.04). The lower limit of the one-sided 95% confidence interval for the DFS-rates was -6.4%, far below the non-inferiority range of -4%, (p-value on difference of the 4y-DFS estimates: 0.005). The 4-year cumulative incidence of relapse (CIR) was 6.3% (SE 1.0%) and 3.2% (SE 0.7%), for P-III and P-II, respectively (Gray p=0.09). The results at 8 years were 89.2% (SE 1.3%) and 92.3% (SE 1.2%) for DFS, and 8.7% (SE 1.2) and 6.4% (SE 1.1%) for CIR (P-III vs P-II). The 8-year overall survival (OS) was 96.1% (SE 0.8%) and 98.0% (SE 0.6%, p=0.06) and the 8-year cumulative incidence of secondary malignancies was 1.3% (SE 0.5%) and 0.6% (SE 0.4%) for patients who received P-III and P-II, respectively. An intent-to-treat analysis revealed almost identical results. There were no major differences of the treatment effect in clinical and biological subgroups and in the subgroups of the two induction regimens (DEXA vs PRED) with the exception of age at diagnosis. For patients below 10 years of age the 4-DFS was 90.7% (SE 1.0%) vs 92.5 (SE 1.2, p=0.26) and for patients 10 years or older 81.6% (SE 4.0%) vs 90.3 (SE 4.1%, p=0.04), for P-III vs P-II, respectively. The pattern of relapse was similar after P-III and P-II. The incidence of death in remission was comparable being 0.9% (SE 0.4%) and 0.7% (SE 0.3%) for P-III and P-II. The rate of grade III/IV infections used as an indicator for relevant toxicity was essentially the same in P-III and P-II. In conclusion, in childhood ALL patients with most favorable prognosis, as predicted by complete MRD response already by day 33, an attempt to reduce the burden of chemotherapy by lower intensity delayed intensification achieved by replacing the traditional BFM protocol II with protocol III, was not successful due to evidence of more relapses observed in patients treated less intensively. Interestingly, almost identical rates of 5-year DFS and CIR (91% and 8% in AIEOP-BFM ALL 2000 vs 93% and 6% in study DCOG 11) were observed. The DCOG authors considered the result of their non-randomized study sufficient to prove that therapy reduction is safely feasible in MRD negative patients defined identically (R. Pieters et al, JCO 2016). Our study underlines the importance of well-designed, sufficiently powered studies for prospective evaluation of treatment reduction in childhood ALL, a major challenge for developing future therapy strategies. Disclosures Möricke: JazzPharma: Honoraria, Other: Financial support of travel costs. Biondi:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board.

Cytomegalovirus Reactivation Does Not Increase Subsequent Risk for Acute Graft-Versus-Host Disease, Malignant Disease Relapse, or Infection Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3409-3409
Author(s):  
Jeffery J Auletta ◽  
Monica I Ardura ◽  
Sumithira Vasu ◽  
Ying Huang ◽  
Qiuhong Zhao ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Malignant Disease ◽  
Hematopoietic Cell Transplantation ◽  
Incidence Rates ◽  
Disease Relapse ◽  
Advisory Committees ◽  
Increased Risk ◽  
Subsequent Risk

Abstract Background: Identifying factors that influence donor-derived immune response may ultimately enable its therapeutic redirection, lessening risk for complications following allogeneic hematopoietic cell transplantation (alloHCT) like acute graft-versus-host disease (aGvHD) and promoting protection against infection and malignant disease relapse. Viral reactivation seems poised to influence donor-derived immune response, potentially disrupting the balance between immune surveillance in eradicating malignancy and infection and immune tolerance in preventing aGvHD. Cytomegalovirus (CMV) is a clinically-significant virus with immunomodulatory capabilities. However, studies interrogating such effects are limited in the modern transplant era. The primary study aim was to estimate the cumulative incidence of initial CMV reactivation (RA) and aGvHD in alloHCT patients and to assess reciprocal influence between CMV RA and aGvHD. The secondary study aim was to define whether CMV RA predisposed alloHCT patients to infection or increased relapse risk. Methods: Consecutive adult patients (n=324) with acute lymphoblastic leukemia, acute myelogenous leukemia or myelodysplasia whom received initial matched sibling or unrelated donor (MUD) bone marrow (n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center comprised the study cohort. Patient-, transplant-, and infection-related data were retrospectively analyzed (Table 1). Initial CMV RA was defined as plasma quantitative CMV PCR≥1000 viral copies/ml for which CMV-directed antiviral therapy was started. Microbiologically-documented infections were recorded for the first year after alloHCT and categorized as bacterial blood stream infection, invasive fungal infection, human herpes virus 6 viremia, and respiratory viral infection. Cumulative incidences of CMV RA and aGvHD were estimated accounting for competing risks (death from any cause). Association between CMV RA and incidence of aGvHD was evaluated in a proportional sub-distribution hazards model, where CMV RA was treated as a time-dependent covariate with competing risk as death from any cause. Similarly, influence of aGvHD on incidence of CMV RA was evaluated where development of aGvHD was treated as the time-dependent covariate and CMVR RA as the end point of interest. Associations between CMV RA and subsequent infection or disease relapse were similarly analyzed. To evaluate impact of CMV and aGvHD on long-term outcomes, landmark analysis (LMA) at D100 and D365 were compared among four distinct patient groups: (1) No CMV RA, no aGvHD; (2) CMV RA, no aGvHD; (3) No CMV RA, aGvHD; and (4) CMV RA and aGvHD. Results: Most transplant patients had AML in CR1, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Patients who developed aGvHD grades 2 (HR=1.93, 95% CI 1.15-3.23, p=0.013) or grades 3 and 4 (HR=3.36, 95% CI 1.76-6.45, p<0.001) had higher risk for developing subsequent CMV RA. In contrast, patients with initial CMV RA did not have increased risk for developing future aGvHD. Similarly, CMV RA did not have a significant impact on future infection, regardless of infection type, nor impact subsequent risk of malignant disease relapse. Overall survival (OS) at 1, 2, and 3 years post-transplant were 63%, 53%, and 45%, respectively. Cumulative incidence rates for non-relapse mortality (NRM) at 1, 2, and 3 years were 16%, 19%, and 23%, respectively; for infection-related mortality (IRM), cumulative incidence rates were 10%, 13%, and 16%, respectively. OS, NRM and IRM were stratified by initial CMV RA and aGvHD status at D100 and D365 (Table 2). Among patients who were alive, patients whom had initial CMV RA and aGvHD by D100 were at higher risk for NRM (HR=2.85, 95% CI 1.24-6.56, p=0.014) and IRM (HR=3.65, 95% CI 1.39-9.57, p=0.008) than patients who experienced neither CMV RA nor aGvHD. D365 LMA did not reveal any statistically significant differences in OS, NRM, and IRM between groups. Conclusion: aGvHD associated with increased risk for CMV RA, but initial CMV RA did not associate with subsequent aGvHD risk. Furthermore, initial CMV RA did not associate with increased risk for disease relapse or infection, but did increase NRM and IRM, particularly in combination with aGvHD. Disclosures Auletta: Shire Pharmaceuticals: Consultancy. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding. Hofmeister:Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Arno Therapeutics, Inc.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

scholarly journals Comparing the Efficacy of Aspirin or Low Molecular Weight Heparin or Vitamin K Antagonists in the Risk of Thromboembolic Events in Patients with Multiple Myeloma Treated with Lenalidomide-Based Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1121-1121
Author(s):  
Martha L Louzada ◽  
Maria-Victoria Mateos ◽  
Lenicio Siqueira ◽  
Jose-Maria B Bermejo ◽  
Enrique M Ocio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Expert Opinion ◽  
Research Funding ◽  
Low Dose ◽  
Vitamin K Antagonists ◽  
Advisory Board ◽  
Low Molecular Weight ◽  
Advisory Committees ◽  
Increased Risk

Abstract Background Malignancy is a well-recognized risk factor for venous thromboembolism (VTE). In multiple myeloma the incidence of VTE varies between 3% and 10%. Immunomodulatory drugs (IMiDs) play a crucial role in the treatment of myeloma and are known to be associated with an increased risk of arterial and venous thromboembolic events (TE). It appears that patients with newly diagnosed multiple myeloma (NDMM) are at higher risk for TE compared to patients with relapsed or refractory myeloma (RRMM) at the start of IMiD therapy. Lenalidomide is a second-generation IMiD which in combination to dexamethasone has shown to be an effective and well-tolerated therapy for patients with NDMM or RRMM. However, studies have consistently demonstrated the need for TE prophylaxis in patients receiving the combination lenalidomide-dexamethasone which leads to a 4.4-fold increased risk for VTE compared to dexamethasone alone in the absence of prophylactic anticoagulants. Panel consensus from the International Myeloma Work Group has agreed that the choice of thromboprophylaxis depends on the individual risk of TE, as determined by patient and treatment-related factors, such as obesity, prior VTE, central venous catheter, immobilization, recent surgery, comorbidities, use of erythropoietin stimulating agents and myeloma therapy. Aspirin (ASA) is recommended for patients with one or no risk factors, and LMWH for those with more than one risk factor. However, the optimal approach to thromboprophylaxis has not yet been established. In this study we sought to compare the efficacy of ASA or low molecular weight heparin (LMWH) or vitamin K Antagonists (VKA) in the prevention of VTE or arterial thromboembolism (ATE) in patients with myeloma using lenalidomide-based therapy. Methods We performed a retrospective chart review in 2 centres (London, Canada; and Salamanca, Spain) on patients with NDMM or RRMM multiple myeloma receiving lenalidomide-based therapy. We collected data from january 2010 to December2014. We included adult patients diagnosed with NDMM or RRMM receiving lenalidomide-based therapy. We did not include who received lenalidomide but refused or had contra-indication to thromboprophylaxis; or used single agent lenalidomide. Results We included 168 patients with multiple myeloma receiving lenalidomide-based therapy. 14 (8%) were NDMM and 154 (92%) had RRMM. Median age was 68 (31-89) and 106 (63%) were males. On average patients with RRMM had 1.6 previous treatments (range:1-11). 104 (62%) patients were low risk and 64 (38%) were high risk for TE. 140 (83%) patients received prophylaxis with ASA, 32 (19%) LMWH and 6 (4%) VKA. 10 patients started with prophylactic LMWH for an average of 2 months then were empirically switched over to ASA. In total, there were 18 (10.7%) TE of which, 16 (9.5%) were VTE: 3 PE, 12 DVT, 1 both. The relative risk for TE was the same regardless of risk stratification [RR=1.27 (95%CI 0.524 - 3.059; p=0.599)]. At TE diagnosis, 16 patients were on ASA, 1 on LMWH and 1 on VKA. The relative risk of TE was significantly higher for patients on ASA compared to LMWH or VKA [RR= 2.17 (0.522 - 9.03; p= 0.286). After the TE, all patients changed anticoagulation strategy: 15 of 16 (94%) patients with VTE switched to therapeutic LMWH and 1 who was on VKA had ASA added. In the 2 patients with ATE, 1 started on full dose LMWH and the other one continued on ASA. 16 of 18 patients with a TE continued on lenalidomide-based therapy. There was no recurrent arterial or venous TE within the first 6 months of anticoagulation after the TE. Univariate analysis suggested that BMI, use of ASA and sex could be potential predictors of TE; but the logistic regression was not statistically significant (Table). Conclusions In patients with multiple myeloma on lenalidomide-based therapy the preferred TE prophylactic approach is low dose ASA irrespective of patients' risk assessment for thromboembolism. However, VTE risk in these patients is not negligible (9.5%) and low dose ASA may not be the best prophylactic strategy for them. It appears that patients on ASA, obese and males are at higher risk for TE. Future studies are needed to confirm these assumpations. Table 1. Multivariate Analysis of the TE risk for patients with myeloma on lenalidomide-based therapy Odds Ratio Variable Point Estimate 95% CI p -value Sex 2.316 0.854 6.278 0.0989 BMI 1.705 0.501 5.804 0.3935 ASA 3.870 0.486 30.796 0.2010 Disclosures Louzada: Celegene: Consultancy, Other: advisory board and expert opinion; pfizer: Consultancy, Other: advisory board and expert opinion; janssen: Consultancy, Other: advisory board and expert opinion. Mateos:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ocio:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Porras:Celgene: Consultancy, Honoraria.

scholarly journals Follicular Lymphoma Grade 3A Exhibits Pathological and Cytogenetic Diversity, but Similar Prognosis Compared to FL Grade 1-2: Pooled Analysis of 1757 Follicular Lymphomas from the PRIMA and Relevance Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 778-778
Author(s):  
Camille Laurent ◽  
Danielle Canioni ◽  
Bettina Fabiani ◽  
Véronique Meignin ◽  
Catherine Chassagne-Clément ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Research Funding ◽  
Statistical Difference ◽  
Prognostic Significance ◽  
Advisory Board ◽  
Genomic Diversity ◽  
Advisory Committees ◽  
Significant Difference

Abstract Introduction: Follicular lymphoma (FL) is graded as 1, 2, 3A and 3B based on the number of centroblast cells. Although FL grade 3A is considered as a low-grade lymphoma, its prognostic significance compared to FL grade 1-2 remains controversial, especially for particular morphological variants with large cleaved cells or blastoid features, which are not recognized as a specific entity. Method: In order to clarify these points, FL grade 3 patients (pts) were selected from a large series of 2247 untreated pts enrolled in two LYSA trials: PRIMA (evaluating rituximab (R) maintenance after R-chemotherapy) and RELEVANCE (evaluating lenalidomide plus rituximab (R2) followed by R2 maintenance versus R-chemotherapy). FL3B pts were excluded from both trials. Sufficient material and clinical informations were available for 1757 out of 2247 pts. Among them, 161 pts including 88 of 950 PRIMA pts (9.2%) and 73 of 734 RELEVANCE pts (9.2%) were classified as FL3A. Among these FL3A cases, a panel of 7 expert hematopathologists identified 48 cases (2.7% of 1757 analyzed FL cases) which contained a significant component of large cleaved cells or medium-sized blastoid cells but did not meet grade 3B criteria. These cases were called FL3 "unclassified" (FL3U) as compared to classical FL3A (cFL3A) cases. We then analyzed the correlations between the histologic grade, phenotypic/cytogenetic features and clinical outcome. Results: FL3U were characterized by: i) proliferation of large cleaved tumor cells with moderately coarse to fine chromatin and absent or inconspicuous nucleoli (n=30) or predominance of medium-sized blastoid tumor cells with fine chromatin and small nucleoli (n=18) and ii) expression of CD20 and at least one germinal center marker. Mean of MYC and MUM1 protein expression in FL3U were 18% [from 3 to 25%] and 14.8% [3-35%], respectively, with no significant difference with cFL3A. Ki67 expression was higher in FL3U than in cFL3A (55.6% [20-90%] vs 41.3% [2-85%]) (p=0.008). Expression of p53 protein was slightly higher in FL3U than in cFL3A (37% [10-80%] vs 34.9% [8-90%] (p=0.052). FL3U had a tendency to harbor less frequent BCL2 rearrangements than cFL3A (74% vs 95%) (p=0.0620), whereas BCL6 rearrangements were significantly higher in FL3U than in cFL3A (29% vs 0%) (p=0.0034). The frequency of MYC rearrangements and 1p36 deletions in FL3U (9.6% and 6% of FL3Us, respectively) showed no significant difference with cFL3A. No detectable alteration in IRF4 locus was seen in both FL3U and cFL3A. The median age of FL3U pts was 58 years with 1:1 ratio of males to females and most pts had advanced stage at diagnosis with frequent marrow infiltration and intermediate to high FLIPI score. Outcome of pts with FL3U was not significantly different to that of cFL3A pts in Cox multivariate analyses. After a median follow-up of 117 months for PRIMA and 38 months for RELEVANCE, 89.6% of FL3U and 85.2% of cFL3A were alive with no significant difference between the 2 groups (p=0.4507). There was also no statistical difference in progression free survival (PFS) between the 2 groups (p= 0.1479). Similarly, we did not found any statistical difference in PFS between FL3U and FL1-2 and between FL1-2 and cFL3A (p=0.9210 and p=0.5375, respectively); as well as in overall survival (OS) (p=0.6223 and p=0.0960, respectively). Finally, the outcome of the whole group of FL3A pts including cFL3A and FL3U variants was similar to FL1-2 pts. Conclusion: FL grade 3A exhibits pathological and genomic diversity due to FL3U variants characterized by higher amounts of medium-sized blastoid or large cleaved cells, higher Ki67 proliferative index and p53 expression, together with increased frequency of cytogenetic BCL6 alterations and lower frequency of BCL2 rearrangements. However, in both PRIMA and RELEVANCE trials, FL3U pts showed no significant difference in terms of PFS or OS as compared to both FL1-2 and cFL3A pts. These results indicate that FL3A represents a spectrum of proliferations with variable maturity, proliferative activity and genomic alterations that may be intermediate points of progression toward FL3B/transformation. They suggest that the distinction between cFL3A and FL3U variant, as well as between FL1-2 and FL3A may not have any prognostic significance using modern rituximab- or lenalidomide-based treatments, although this has to be confirmed with different drug combinations. Disclosures Cartron: Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Morschhauser:Epizyme: Consultancy; Janssen: Other: Scientific Lectures; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Salles:Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria, Other: Advisory Board; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Gilead: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Merck: Honoraria; Takeda: Honoraria; Servier: Honoraria. Xerri:Janssen: Other: Travel.

scholarly journals Metabolic PET/CT Analysis of Aggressive Non-Hodgkin Lymphoma Prior to Axicabtagene Ciloleucel CAR-T Infusion: Predictors of Progressive Disease, Survival, and Toxicity

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2518-2518
Author(s):  
William Breen ◽  
Jason R. Young ◽  
Matthew Hathcock ◽  
Roman O. Kowalchuk ◽  
Radhika Bansal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk ◽  
Pet Ct ◽  
Car T ◽  
Grade 3

Abstract Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion. Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use. Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD. Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p&lt;0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p&lt;0.05 for each). While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p&lt;0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2). Additional patients and follow-up will be presented. Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. 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; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: 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: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

scholarly journals Immunomodulatory Interventions Based on Minimal Residual Disease before and after Transplantation for Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3480-3480
Author(s):  
Adriana Balduzzi ◽  
Lucia Di Maio ◽  
Daniela Silvestri ◽  
Simona Songia ◽  
Giulia Prunotto ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Advisory Board ◽  
P Value ◽  
Advisory Committees ◽  
Post Transplant ◽  
Risk Of Failure ◽  
Increased Risk ◽  
Additional Chemotherapy ◽  
Risk Of Relapse

Abstract INTRODUCTION. Pre- and post-transplant MRD strongly affects transplantation outcome in ALL. To which extent any MRD-driven intervention may lower its impact is still to be assessed. PATIENTS AND METHODS. One-hundred-and-seventeen children and adolescents who underwent allogeneic transplantation for ALL in remission (period 2001-2015) had been assessed for MRD by RQ-PCR before and at 1,3,6,9 and 12 months after transplantation. Four MRD-driven interventions were prospectively planned throughout the years. According to pre-transplant MRD ³1x10-4, chemotherapy intensification before transplant and early (2nd month) immunosuppression discontinuation after transplant, if no GVHD, were planned, since 2007; according to any level of post-transplant MRD, sudden immunosuppression discontinuation, since 2003, and donor lymphocyte infusions, since 2010, for MRD levels above 1x10-3, and, since 2013, for any level, were planned, if no GVHD. RESULTS. Five-year-EFS and CIR were 75.6% (SE5.0) and 13.8% (SE4.1), respectively, for patients with pre-transplant MRD<1x10-4 (65%), versus 50.4% (SE 7.9) (p-value<0.001) and 44.3% (SE 7.8) (p-value<0.001), respectively, for those with MRD³1x10-4 (35%). Pre-transplant MRD³1x10-4 was associated with a 4.8-fold risk of relapse (CI 2.18-10.51; p-value <0.001) and a 3.2-fold risk of any event (CI 1.64-6.10; p-value <0.001), compared with patients with MRD negative or <1x10-4. Patients who experienced any post-transplant MRD positivity did not necessarily relapse (5-year-EFS 53.8%, SE 7.7), but had a 3.7-fold risk of failure (CI 1.37-9.90; p-value 0.01) if any level was first detected after 6 months or later; a positivity detected in the first 100 days was not significantly associated with outcome, after adjusting for pre-transplant MRD and disease phase. Pre-transplant MRD positivity remained highly significantly associated with lower EFS in patients experiencing any MRD positivity in the first 3 months post-transplant (HR 2.8, CI 1.33-5.71; p-value 0.006), but no significant association could be detected in those experiencing their first post-transplant positivity after 6 months or later. The presence of any acute GVHD was significantly associated with a lower risk of failure, both in patients with pre-transplant MRD positivity (HR 0.20; CI 0.12-0.49; p-value <0.001) and with early post-transplant first MRD positivity, (HR 0.27; CI 0.12-0.60; p-value 0.001), but not in those with late post-transplant first MRD positivity. Patients who received pre-transplant additional chemotherapy, in the attempt to reduce MRD, had a non significant 2-fold reduction of the risk of failure (hazard-ratio 0.41, 95% CI 0.14-1.22, p-value=0.11). Out of the 41 patients with pre-transplant MRD positivity, of the 39 patients evaluable in the second month, immunosuppression could be tapered early in 12 of the 14 patients who had no GVHD; 6 of the 12 who could taper immunosuppression are in long-term remission, compared with 0 of the 2 who did not taper and 15 of the 25 who could not taper due to ongoing GVHD. Of the 45 patients who experienced any post-transplant MRD positivity, 10 patients received DLI, 7 of whom are in long-term remission, compared with 18 of the 35 who did not receive them. All those patients achieving a MRD level 5x10-4 ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion the risk of relapse was strongly associated with pre-transplant MRD level and relapse did not necessarily occur after post-transplant MRD positivity, especially if detected early and at levels <1x10-4. Reduction of MRD burden before transplant by additional chemotherapy and post transplant immunomodulation might reduce the risk of relapse associated with high pre-transplant MRD. Immunosuppression discontinuation and DLI might revert the increased risk of relapse associated with post-transplant MRD positivization and improve ultimate outcome. Disclosures Biondi: Cellgene: Other: Advisory Board; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board.

Early Relapse of Follicular Lymphoma after Rituximab-Based Biologic Doublet Upfront Therapy Is Associated with Increased Risk of Death: A Combined Analysis from CALGB Studies 50402, 50701 and 50803 (Alliance)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2953-2953 ◽  
Author(s):  
Frederick Lansigan ◽  
Ian Barak ◽  
Brandelyn Nicole Pitcher ◽  
Sin-Ho Jung ◽  
Bruce Cheson ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Entry ◽  
Multivariate Logistic Regression ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Increased Risk ◽  
Male Sex

Abstract Background: In follicular lymphoma (FL) patients treated with first-line R-CHOP, early progression of disease (POD) within 2 years after diagnosis is associated with high risk for death (hazard ratio 6.4) and a 50% 5-year overall survival (Casulo et al. JCO 2015). Whether these observations hold for patients treated without chemotherapy is unknown. The Alliance for Clinical Trials in Oncology conducted three frontline rituximab-based non-chemotherapy-containing biologic immunotherapy doublet clinical trials: R-Galiximab (Anti-CD80, CALGB 50402), R-Epratuzumab (Anti-CD22, CALGB 50701) and R-Lenalidomide (CALGB 50803). We performed a retrospective analysis of 174 patients to determine outcomes of early progressors after initial biologic, non-cytotoxic treatment and risk factors for early POD. Methods: CALGB 50402 (n=60), CALGB 50701 (n=57), and CALGB 50803 (n=57) had similar eligibility criteria: previously untreated follicular lymphoma, grade 1, 2 or 3a with stage III, IV or bulky (single mass >7 cm) stage II disease, and ECOG PS 0 to 2. Early POD was defined as progression within 24 months from study entry. Univariate and multivariate logistic regression modeling using forward selection was performed to identify predictors of early POD. Kaplan-Meier (KM) method was used to estimate 2-year and 5-year overall survival probability. Hazard ratios (HR) and 95% CI were calculated using a univariate and multivariate Cox regression model adjusting for FLIPI. Results: Twenty-seven percent (48/174) of patients had early POD. Median survival follow-up time from study entry was 5.5 years (2.1 to 10.1 years) and median time from diagnosis to enrollment was 2 months (0.2 to 115 months). Median age was 54 (range: 22-90), 49% were male and 24% had low-, 52% intermediate- and 24% high-risk FLIPI (Table 1). Early POD from study entry conferred a worse OS [HR=4.86 (95% CI 1.90-12.4), p < 0.001]. After adjusting for FLIPI, patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years [HR=4.77 (95% CI 1.70-13.4), p=0.003]. For early POD, the 2-year survival probability was 89% (76-95%) vs. 100% for non-early POD, and the 5-year survival was 76% (60-86%) vs. 99% (95-99%), respectively (Figure 1). When the 2-year early POD interval was taken from time of diagnosis, similar findings were noted (n=171, HR for OS 5.27 (95% CI 1.98-14.0), p 0.0009) [Table 2]. Univariate analysis revealed age >60 (p=0.019), male sex (p=0.002), higher FLIPI (p<0.001), hemoglobin <10 (p=0.021), number of nodal sites >4 (p=0.010), elevated LDH (p=0.004), nodal size >7 cm (p=0.002), albumin <3.5 (p=0.030) and CD10 positivity (p=0.015) were associated with early POD, while grade and bone marrow involvement were not. Histologic biomarkers PD1 and Ki67 were not associated with early POD in this analysis. A multivariate logistic regression model showed that male sex, albumin <3.5, low absolute monocyte count, interfollicular CD10 expression and high-risk FLIPI were predictors of early POD. Conclusions: Early relapse within 2 years after diagnosis in patients receiving front-line rituximab-based biologic non-cytotoxic therapy is associated with an increased risk of death. These data are similar to previous findings in patients treated with R-CHOP from the National LymphoCare study, suggesting that the adverse survival of patients with early POD may be independent of systemic treatment modality. Novel clinicopathological approaches are needed at diagnosis to identify patients who are likely to have unfavorable outcomes, and for whom biologic doublets are efficacious. Support: U10CA180821, U10CA180882.ClinicalTrials.gov Identifier: NCT00117975 (CALGB 50402), NCT00553501 (CALGB 50701), and NCT01145495 (CALGB 50803) Disclosures Lansigan: Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Czuczman:Celgene: Employment. Martin:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Teva: Research Funding; Acerta: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Other: travel, accommodations, expenses. Hsi:Eli Lilly: Consultancy; Abbvie: Consultancy; Cellerant Therapeutics: Consultancy; Seattle Genetics: Honoraria; HTG molecular diagnostics: Honoraria. Bartlett:Gilead: Consultancy.

scholarly journals Treatment and Lifestyle Risk Factors for Cardiovascular Disease Post Lymphoma Diagnosis: A Prospective Study in the Modern Treatment Era

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 422-422
Author(s):  
Nicholas J Boddicker ◽  
Matthew J. Maurer ◽  
Melissa C Larson ◽  
Cristine Allmer ◽  
Susan L. Slager ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Medical Records ◽  
Research Funding ◽  
Cardiac Risk ◽  
Advisory Committees ◽  
Increased Risk ◽  
Modern Treatment ◽  
New Onset

Background With lymphoma survival rates increasing and a growing population of long-term survivors, the development of cardiovascular disease (CVD) in this patient population is of increasing importance. Anthracyclines are critical in the management of many lymphoma subtypes. However, there is a risk of developing anthracycline-induced CVD. Here, we estimate the cumulative incidence of CVD in adult lymphoma survivors and investigate risk factors associated with post diagnosis CVD. Methods Participants were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). From 2002-2015, the MER offered enrollment to all patients with newly diagnosed lymphoma who are US residents and age &gt;18 years. Participants completed a risk factor questionnaire, and clinical and treatment data were abstracted from medical records. Patients were contacted every 6 months for the first 3 years after diagnosis and annually thereafter to assess disease status, re-treatment and new onset morbidity including CVD. CVD events, including congestive heart failure (CHF), coronary artery disease (CAD), valvular heart disease (VHD), and arrhythmia were identified and validated against medical records. CHF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. CAD, arrhythmia, and VHD were validated using clinical definitions. We calculated the cumulative incidence of CVD, with death modeled as a competing risk. The association of risk factors and treatments with risk of CVD was estimated using hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression with a competing risk of death. Risk factors included age, sex, diabetes, smoking, body mass index (BMI), and treatment with anthracyclines or radiation therapy. Results The study consisted of 3,063 lymphoma patients after excluding those with chronic lymphocytic leukemia and CVD prior to lymphoma diagnosis. The median age at diagnosis was 59 years (range 18-95), and 56% were males. At a median follow-up was 6.9 years (range 0.8-17.1), 640 patients (21%) had died without CVD and 485 patients self-reported CVD post lymphoma diagnosis, of which 280 (57.7%) were validated. Cardiovascular events included 86 CHF, 78 CAD, 40 VHD, and 164 arrhythmias. The cumulative incidence of CVD (Figure 1) at 5 and 10 years was 6.0% (95% 5.2%-7.0%) and 10.7% (95% CI 9.5%-12.1%), respectively. In multivariable analysis, increasing age (HR=3.93 per 5 years, p&lt;0.001), male sex (HR=1.33, p=0.03), former smoker (HR=1.04, p=0.77), current smoker (HR=1.96, p&lt;0.001), BMI&gt;30 kg/m2 (HR=1.50, p=0.01), and anthracycline treatment (HR=1.49. p&lt;0.001) were all significantly associated with risk of overall CVD, while there was no association with diabetes (HR=0.92, p=0.70) or radiation therapy (HR=1.05, p=0.78) in the multivariable model. Anthracycline use was significantly associated with increased risk of CHF (HR=2.64, p&lt;0.001) and arrhythmia (HR=1.51, p&lt;0.01), but not VHD (HR=0.83, p=0.56) or CAD (HR=1.23, p=0.31) after adjustment for the cardiac risk factors. The number of anthracycline cycles ranged from 0 to 12. 63.2% of individuals that received anthracyclines received 6 cycles. The 5-year cumulative incidence of CVD for 0, 1-5, 6, and &gt;6 anthracycline cycles was 5%, 6.9%, 7.4%, and 7.7%, respectively. Adjusting for cardiac risk factors, the number of anthracycline cycles was significantly associated with increased risk of CVD (1-5 cycles HR=1.34, p=0.11; 6 cycles HR=1.51, p&lt;0.01; &gt;6 cycles HR=2.04, p=0.03). Furthermore, the number of anthracycline cycles was associated with CHF (1-5 cycles HR=2.82, p&lt;0.001; 6 cycles HR=2.46, p&lt;0.001; &gt;6 cycles HR=5.33, p&lt;0.001) and arrhythmia (1-5 cycles HR=1.31, p=0.27; 6 cycles HR=1.60, p&lt;0.01; &gt;6 cycles HR=1.65, p=0.27). Conclusions In the modern treatment era, the risk of new onset CVD in patients with lymphoma without a history of CVD is approximately 1% per year after diagnosis. Arrhythmia and CHF were the most commonly occurring CVD events in this cohort. Both traditional CVD risk factors and treatment with anthracyclines was associated with an increased risk of developing CVD, and anthracyclines were a risk factor for arrhythmia and CHF in particular. Prevention of CVD in lymphoma patients will need to address both treatment and traditional lifestyle factors. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Celgene: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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