TP53 and MYD88 Mutations As Detected By Liquid Biopsy in the Prediction of Progression-Free Survival in Patients with Diffuse Large B-Cell Lymphoma

Abstract Introduction: Liquid biopsy has been reported to be useful in predicting residual disease in patients with diffuse large B-cell lymphoma (DLBCL). Most of the studies focused on quantifying the level of circulating lymphoma-specific DNA. We explored the clinical relevance of the specific mutated genes in predicting progression in patients with DLBCL. Method: Peripheral blood samples were collected from patients with DLBCL based on their visit to clinic without other specific selection. Median age of patients is 69 (range 28-91), with 51% of the patients being male. These patients were treated on multiple protocols including R-CHOP, R-EPOCH, Magrath, HCVAD, CAR-T (#2 patients), and others. cfDNA was extracted and sequenced by next generation sequencing using 177 gene panel. The panel uses single primer extension (SPE) approach with UMI. Sequencing depth is increased to more than 2000X after removing duplicates. Low level mutations are confirmed by inspecting BAM file. Results: A total of 86 sample from 61 patients were collected post clinical remission at different time points (median 28 weeks, range: 1-994 weeks). Of these samples, 56 (65%) from 46 patients (75%) were positive. However, 6 of these samples from 4 patients had germline mutations or mutations in TET2, ASXL1, or DNMT3A that are consistent with CHIP (clonal hematopoiesis of indeterminate potential). The remaining 50 positive samples from 42 patients had 8 repeats on the same patients collected at different time points. Comparing the 19 negative patients with the 42 positive patients post-remission, patients with residual molecular disease were significantly older than patients without residual disease (P=0.01). However, there was no significant difference between the two groups in gender, ethnic background, LDH, cell of origin classification, or TP53 positivity by IHC. Patients with residual disease showed tendency for short progression-free survival (P=0.08). Focusing on patients with specific mutations detected in the cfDNA showed that 14 (23%) patients had mutations either in TP53 or MYD88. There was no significant difference in age between these two groups or any of the other clinical variables. However, patients with TP53/MYD88 mutations had significantly shorter survival (P=0.04). Conclusion: Post-remission residual disease as measured by circulating cfDNA is an independent predictor of potential relapse in patients with DLBCL. However, presence of it is important to determine the aggressiveness of the residual circulating clone. Residual circulating lymphoma DNA with TP53 or MYD88 mutations is a strong predictor of earlier relapse. Figure 1 Figure 1. Disclosures Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Goy: Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Honoraria, Other; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Acerta: Consultancy, Research Funding; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Michael J Hennessey Associates INC: Consultancy; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xcenda: Consultancy, Honoraria; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; LLC(Targeted Oncology): Consultancy; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Xcenda: Consultancy; Hoffman la Roche: Consultancy; Incyte: Honoraria; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Infinity/Verastem: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment.

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High Risk Diffuse Large B Cell Lymphoma: A Comparison of Aggressive Subtypes Treated with Dose Adjusted Chemotherapy-the University of Texas MD Anderson Experience

Blood ◽

10.1182/blood.v128.22.106.106 ◽

2016 ◽

Vol 128 (22) ◽

pp. 106-106 ◽

Cited By ~ 3

Author(s):

Vishwanath Sathyanarayanan ◽

Yasuhiro Oki ◽

Amir K Issa ◽

Mohamed Amin Ahmed ◽

Mansoor Noorani ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Time To Event ◽

Advisory Committees ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Md Anderson

Abstract Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non Hodgkin lymphoma (NHL).Nearly 50% of high-risk DLBCL patients are not cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). High risk DLBCL may be defined as double hit lymphoma (DHL, translocation of MYC and BCL2 or BCL6), double expressor lymphoma (DEL, over expression of MYC and BCL2), high risk international prognostic index (IPI) of 3-5, high Ki-67, and non-germinal center subtype (non-GCB). The majority of DHL cases occur in the GCB subtype, as opposed to the majority of DEL cases which occur in non-GCB. Hence we sought to compare different high risk subsets treated with dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab (DA) EPOCH-R. In single arm phase II clinical trials, dose adjusted (DA) EPOCH-R has shown promising results, with potential greater efficacy in the GCB subtype in subset analyses (Wilson et al, Hematologica 2012). A randomized phase III study comparing RCHOP with (DA) EPOCH-R in newly diagnosed DLBCL has completed accrual, with highly anticipated results due in late 2016. Methods: We conducted a retrospective reviewof all consecutive, newly diagnosed DLBCL patients treated with (DA) EPOCH-R at MD Anderson Cancer Center from 2010 to 2014. Eligible patients were 18 years or greater, had high-risk DLBCL as determined by the treating physician, and had available data of treatment and response. The cell of origin subtype was determined by immunohistochemistry using Hans algorithm, and MYC and BCL2 positivity were defined as BCL2 positive in at least 70% and MYC positive in at least 40% of cells. DHL was defined as rearrangement of MYC and BCL2 or BCL6 by fluorescent in situ hybridization. The objectives were to analyze demographic, prognostic, and treatment variables in comparison with clinical response and survival outcomes in three sub groups which included 1. DHL (GCB) 2. DLBCL without MYC and BCL2 expression (GCB), and 3. DEL (GCB and non GCB). Complete response (CR), overall survival (OS) and progression free survival (PFS) were calculated using standard methods. Statistical analysis was done using Fishers exact test or Chi-square test / Kruskal-Wallis test. Kaplan-Meier method was used for time-to-event analysis including overall survival and progression free survival. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Results: We identified 233 high risk DLBCL patients treated with (DA) EPOCH-R. After filtering the data to identify patients which were included in our three groups, we identified 22 patients with DHL (GCB), 46 patients with non DEL (GCB), and 16 with DEL. The demographic features and outcomes are mentioned in the table 1 below. The DHL group had more frequent bone marrow (BM) involvement, and the DHL and DEL groups were more frequently age >60 years and high IPI in comparison to the non DEL GCB group. The CR rate, OS and PFS at 1 year were not significantly different between these three groups. Figure 1 highlights the OS (A) and PFS (B) results of each group. Conclusions: (DA) EPOCH-R is highly effective in patients with subsets of patients with high-risk DLBCL and may be able to overcome prognostic factors which have been shown to be adverse with RCHOP therapy. The results of this retrospective study suggest that OS in DHL, DEL and non DEL (GCB) are not statistically different. Hence, intensive chemotherapy with (DA) EPOCH-R could be considered as a frontline treatment option for patients with high risk DLBCL, pending further confirmation in randomized trials. Disclosures Oki: Novartis: Research Funding. Fowler:Infinity: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding. Wang:Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Kite Pharma: Research Funding; Onyx: Research Funding; Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding. Westin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees.

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Making Clinical Decisions to Change Therapy Using Measurable Residual Disease Improves the Outcome in Multiple Myeloma

Blood ◽

10.1182/blood-2020-140352 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Joaquin Martinez Lopez ◽

Rafael Alonso Fernández ◽

Sandy W. Wong ◽

Rafael Rios ◽

Nina Shah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Progression Free Survival ◽

Clinical Decision ◽

Clinical Decisions ◽

Advisory Committees ◽

Free Survival ◽

New Treatment ◽

Positive Results

Background Measurable residual disease (MRD) testing in multiple myeloma (MM) is increasingly being utilized in clinical trials for the assessment of disease response and as a prognostic tool for predicting response duration. However, there is only limited evidence to date for the use of MRD to make clinical decisions, a serious barrier to its potentially important role in the management of MM patients. This retrospective review analyzes the results of making clinical decisions to change therapy based on MRD assessments in MM patients. Methods We reviewed 373 patients with MM from 3 health centers through a retrospective search. Patients included in the study had at least one MRD assessment. Clinical decisions to change therapy based on MRD were made in 3 directions: 1. Stop or reduce treatment after MRD negative results; 2. Increase intensity of treatment after MRD positive results; 3. Start a new treatment line after MRD positive results. We gathered all the available data on clinical and biological parameters, induction treatment and response monitoring. MRD was assessed by flow cytometry or next-generation sequencing (Clonoseq) with sensitivity from 10-5to 10-6Statistical analyses were performed with SPSS software version 21.0 (SPSS, Inc., IBM, Armonk, NY). Results In 58 out of 373 (16%) patients a clinical decision to change therapy was made. Treatment was reduced or stopped in 24 cases (group 1). Intensity of treatment was increased in 20 cases(group 2) and a new treatment was started in 13cases(group 3). Most of these decisions were implemented during the post-ASCT maintenancephase, although in 3 cases ASCT was avoided based on the MRD result. For all 373 patients, the median progression-free survival (PFS) was 80 months. Of the 58 cases where a clinical decision was made to change therapy, 33 cases were MRD positive and 25 were MRD negative at the time the decisions were made. 33 patients in this group either remained MRD negative or eventually achieved MRD negativity. Patients in which a clinical decision was made to change therapy based on MRD (n=58) had a prolonged progression free survival versus those in which therapy remained the same (n=312) (median PFS 97 vs. 75 months, p=0.006) (Figure 1). Moreover, we once again confirmed that patients who achieve MRD negativity demonstrate a prolonged PFS vs those who don't achieve negativity (median PFS 97 vs. 57 months, p=0.0001). Conclusion Clinical decision-making to change therapy based on MRD in MM patients can improve patient outcomes. These results support the integration of MRD assessment in the management of MM patients. Disclosures Wong: Fortis: Research Funding; GSK: Research Funding; Roche: Research Funding; Janssen: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Barrio Garcia:Altum sequencing: Current Employment. Martin:GSK: Consultancy; Sanofi: Research Funding; AMGEN: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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A Multi-Institutional Outcomes Analysis of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Ibrutinib

Blood ◽

10.1182/blood.v128.22.1115.1115 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1115-1115 ◽

Cited By ~ 1

Author(s):

Allison Marie Winter ◽

Daniel J. Landsburg ◽

Francisco J. Hernandez-Ilizaliturri ◽

Nishitha Reddy ◽

Stephen Smith ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

De Novo ◽

Molecular Subtype ◽

Single Agent ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Free Survival ◽

Large B Cell Lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with distinct survival differences according to molecular subtype with superior outcomes in patients with the germinal center B cell-like (GC) subtype as compared to those with the activated B cell-like (ABC) subtype. Efficacy data for single-agent ibrutinib in patients with relapsed/refractory (r/r) DLBCL are limited to a single clinical trial of 80 patients. In that study, higher response rates were observed for r/r ABC-DLBCL compared to GC-DLBCL (37% vs. 5%), when assigned by gene expression profiling (GEP). The response rate of those with unknown/unclassifiable DLBCL was 22%. Despite biologic rationale for selective cytotoxicity of ibrutinib for ABC-DLBCL, it is not clear that such preferential activity will be observed when subtyping based on immunohistochemical (IHC) staining is used, as the correlation with subtype determined by GEP and IHC is imperfect. Furthermore, GEP is time consuming and expensive so IHC is used in clinical practice to differentiate GC from non-GC, the latter of which includes both ABC and unclassifiable DLBCL. We retrospectively analyzed outcomes of patients with r/r DLBCL treated with ibrutinib at a number of large academic medical centers. Methods: We reviewed medical records of all patients with DLBCL treated with ibrutinib at five U.S. tertiary-care cancer centers from 2013 to 2016. We included patients with de novo DLBCL as well as those transformed from indolent lymphoma if the ibrutinib was given for the DLBCL histology. Patients were excluded if they received ibrutinib for ≤ 14 days. Molecular subtype (GC vs non-GC) was determined by local pathology findings and/or the investigator's application of the Hans algorithm. Categorical variables were compared between groups using the Chi-square test. Outcomes were calculated from the date of initiation of ibrutinib. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Thirty five patients met inclusion criteria (27 de novo and 8 transformed DLBCL). The median age at diagnosis was 61 years (range 38-88) with 66% men.By Hans IHC criteria, there were 21 cases of non-GC, 9 GC and 5 were unknown.The median number of treatments prior to ibrutinib was 3 (range 1-8). 30% of patients had undergone prior autologous stem cell transplant. Characteristics including age, gender, transformed versus de novo, relapsed versus refractory, number of prior therapies, and prior use of transplant did not significantly differ between subgroups. The overall response rate (ORR) to ibrutinib was 29% with 4 patients achieving a complete response (CR) and 6 achieving a partial response (PR). When evaluated by subtype assigned by IHC, GC-DLBCL patients had an ORR of 44% and non-GC-DLBCL patients had an ORR of 19%. There was no significant difference in the rates of CR, PR, stable disease, or progressive disease between the subtypes (p=0.185) or between de novo ortransformed disease (P = 0.114). The median progression-free survival (PFS) was comparable for patients with the GC, non-GC, and unknown subtype (3.9, 2.2, and 4.1 months, respectively, P = 0.382, Figure). The median overall survival (OS) was longer for patients with the GC subtype (10.5 months) compared to 5.5 months for patients with the non-GC subtype, and 9.7 months for those with unknown subtype but this difference was not statistically significant (P=0.564). Figure: Progression Free Survival of r/r DLBCL Patients Treated with Ibrutinib, based on Hans Algorithm Subtype Conclusions: Responserates to single agent ibrutinib in the GC and non-GC subtypes of r/r DLBCL do not appear different when using Hans algorithm to assign subtypes. PFS and OS were modest in both groups and not statistically different. In conclusion, until GEP or other molecular technologies such as Nanostring are in more widespread use for routine subtyping of DLBCL, caution is advised when selecting patients for subtype-specific therapy, as clinical outcomes for patients receiving ibrutinib may not differ by cell of origin as determined by IHC. Figure Figure. Disclosures Reddy: celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees. Shadman:Pharmacyclics: Honoraria, Research Funding. Smith:Spectrum: Honoraria; Celgene: Honoraria; Abbvie: Research Funding; Genentech: Honoraria.

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Prolonged Progression-Free Survival Is Possible in Patients with Diffuse Large B-Cell Lymphoma Receiving > 1 Salvage Therapies before Autologous Stem Cell Transplant

Blood ◽

10.1182/blood.v128.22.5825.5825 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5825-5825

Author(s):

Abigail G Kettle ◽

Jeffrey Switchenko ◽

Oscar Calzada ◽

Anh Thuy Phan ◽

Monique Farone ◽

...

Keyword(s):

Radiation Therapy ◽

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Salvage Treatment ◽

Cell Transplant ◽

Advisory Committees ◽

Free Survival

Abstract Introduction While 50-60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with initial chemoimmunotherapy such as R-CHOP, many patients will relapse and require additional therapy. Historically, autologous stem cell transplant (ASCT) has been utilized in chemo-sensitive patients with relapsed DLBCL although the role of ASCT in patients who require > 1 salvage treatment to achieve remission is less defined due to concerns about the likelihood of long-term remission in that population. We evaluated the outcome of ASCT in patients who required >1 salvage therapy. Methods We included all patients undergoing ASCT for relapsed/refractory DLBCL at our site between 2005-2016 who received > 1 salvage treatment before transplant, with radiation therapy considered a salvage treatment if given after relapse but before ASCT. We collected demographic, clinical, laboratory and pathologic data on all patients. We defined progression-free survival (PFS) as time from ASCT to date of progression or death from any cause and overall survival (OS) as time from ASCT to date of death from any cause. Living patients were censored at the time of their last follow up. Univariate Cox proportional hazards models of PFS and OS were fit and Kaplan-Meier plots were developed to estimate the impact of variables of interest on survival. Results Out of 259 patients undergoing ASCT for DLBCL, 43 received > 1 salvage treatment, the median age was 51 years and 23 patients were male. Twenty patients had stage III/IV disease at diagnosis. The median time to relapse from the time of diagnosis was 9.3 months, and 42% of patients experienced a relapse > 12 months after diagnosis. Twenty-six patients (60%) received radiation as one of their salvage therapies, 25 patients (58%) received R-ICE as their first salvage therapy and 10 (23%) patients received R-ICE as their second salvage treatment. All patients received either 2 (n=39) or 3 (n=4) salvage therapies before ASCT, and the response to the initial salvage therapy received was CR in 4 patients, PR in 14 patients, SD in 1 patient, and PD in 14 patients, with initial response to salvage therapy missing in 10 patients. The median PFS for all patients was 15.9 months and the median OS was 57.2 months (Figure 1a). Receipt of radiation and having disease sensitive to treatment at the time of ASCT were the only factors associated with prolonged PFS and OS. Median PFS has not been achieved in patients who received radiation while patients who did not receive radiation had a median PFS of 4.2 months (HR = 0.36, p = 0.014; Figure 1b). Patients who had a chemo sensitive disease status at transplant had a median PFS of 22.6 months; however, patients with refractory disease at transplant only achieved a median PFS of 3.6 months (HR = 0.30, p=0.008). Remaining factors including conditioning regimen, time to relapse, and number of salvage therapies were not significantly associated with PFS or OS. Conclusions ASCT can result in prolonged PFS/OS in patients requiring > 1 salvage therapy especially in the case of sensitive disease. Radiation as an additional line of therapy is associated with improved PFS/OS, suggesting this can be included to induce remission in patients who fail to achieve CR with initial salvage treatment. While uncommon, patients with chemo-refractory disease can also have durable survival and should not be excluded from transplant. Figure 1a Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy. Figure 1a. Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy. Figure 1b Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy based on receipt of radiation therapy. Figure 1b. Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy based on receipt of radiation therapy. Disclosures Calzada: Seattle Genetics: Research Funding. Flowers:Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Celgene Corporation: Consultancy, Honoraria; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Clinical Relevance of MYC/BCL2 and Cell of Origin in Patients with Relapsed Diffuse Large B-Cell Lymphoma Treated with Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-126719 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2021-2021

Author(s):

Yingjun Wang ◽

Ken H. Young ◽

Denái R. Milton ◽

Celina Ledesma ◽

Elias Jabbour ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Board ◽

Cell Of Origin ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

Bcl2 Expression

Purpose: Dual expression of MYC and BCL2 proteins (Double Expressor Lymphoma-[DEL]) and MYC, BCL2 and /or BCL6 translocations (Double Hit Lymphoma-[DHL]) as well as the cell-of-origin (COO) are important prognostic factors in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who are treated with standard chemo-immunotherapy. Data are limited regarding the prognostic impact and interdependence of these biomarkers on outcomes in pts with relapsed DLBCL treated with autologous stem cell transplantation (ASCT). Methods: Data from Pts with relapsed DLBCL who underwent ASCT at our center and in whom archived tumor material was available were analyzed. Cutoff values of 40% for MYC and 70% for BCL2 were established by immunohistochemistry (IHC). FISH cases for MYC and BCL2 were considered for evaluation if at least 200 tumor cell nuclei per core displayed reliable signals in the sections. COO classification was achieved by IHC methods according to both the Visco-Young and Choi algorithms. The majority of pts (81%) underwent chemo-mobilization of stem cells with rituximab for in-vivo purging; rituximab was also given on days+1 and +8 with BEAM conditioning (J Clin Oncol 2005; 23:2240-7; Clin Cancer Res 2018; 24:2304-11). The study was IRB-approved at our center. Results: 303 pts were evaluated; 169 (56%) met the criteria for DEL and 3 (1%) for DHL; 8 (3%) met criteria for both (DEL/DHL) and 97 (32%) for neither (non-DEL/non-DHL). Because of small size, the 3 pts with only DHL were excluded from this analysis. In addition, 8 pts (3%) had atypical DHL and their outcomes were analyzed separately. GCB classification was successful in 269 pts, and 119 pts (44%) were of the GCB subtype. Median age of the whole group was 60 years (range, 18-80); the male gender predominated (65%). The median number of prior lines of therapies was 2. At ASCT, 90% of pts had chemo-sensitive disease (64% CR, 26% PR), and 6% had small volume SD; IPI was ≥ 2 in 17% of pts and PET was positive in 26%. There were no statistically significant differences in pt characteristics between the subgroups of non-DEL/non-DHL, DEL, or DEL/DHL, with the exception of GCB distribution: 46% and 41% of non-DEL/non-DHL and DEL, respectively, were classified to be of the GCB subtype, whereas all 8 DEL/DHL were classified as non-GCB (P=0.002). With a median follow-up time among survivors of 50 months (range, 4-217 months), the 4-year overall survival (OS) rates of non-DEL/non-DHL, DEL and DEL/DHL subgroups were 65%, 59%, and 25%, respectively. There was no significant difference in OS between non-DEL/non-DHL and DEL subgroups (P=0.39), however a significant difference in OS was observed between the two subgroups compared to the DEL/DHL pts (P=0.034; Figure 1). Progression-free-survival (PFS) rates were higher for the non-DEL/non-DHL (4-year rate: 51%) and DEL (4-year rate: 49%) compared to DEL/DHL (4-year rate: 25%) subgroups, though not statistically different (P=0.22). A higher risk of non-relapse mortality was observed in the DEL/DHL group compared to the other 2 groups (hazard ratio [HR]=3.8, P=0.017). The 4-year OS and PFS rates for the atypical DHL were 67% and 33%, respectively. We also evaluated the interaction of COO with BCL-2 protein expression; we found that pts who had BCL2 (+) expression, had worse OS (HR=1.82; P=0.049) and a trend for worse PFS (HR=1.58; P=0.08) compared to BCL2 (-) pts. This interaction was more prominent however in GCB pts. The 4 year OS rates of GCB/BCL2(-) and GCB/BCL2(+) were 87% and 56%, respectively (P=0.030). The 4-year PFS rates were 88% and 47%, respectively (P=0.007) (Figure 2). The OS and PFS rates within non-GCB subgroups were similar regardless of BCL2 expression. Conclusions: Our study shows that pt subgroups who have both DEL/DHL DLBCL have inferior survival. Interestingly, we also found that pts who have DEL and non-DEL/non-DHL have similar outcomes after ASCT. BCL2 expression is an important prognostic factor in GCB lymphoma. Investigational studies combining targeted therapies in this setting are warranted. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding. Qazilbash:Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Genzyme: Other: Speaker. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

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Interim or End of Treatment FGD-PET Complete Response Does Not Have Adequate Predictive Value in Mature T/NK Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1813.1813 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1813-1813

Author(s):

Tatyana Feldman ◽

Larysa Sanchez ◽

Patrick Toth ◽

David Panush ◽

Lori A Leslie ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Nk Cell ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Significant Difference

Abstract Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: 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, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial

Blood ◽

10.1182/blood.v128.22.3028.3028 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3028-3028

Author(s):

Mathias Witzens-Harig ◽

Andreas Viardot ◽

Ulrich Keller ◽

Christian Buske ◽

Anne Crombé ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Free Survival ◽

Multicenter Phase

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels of 25, 50, 75 and 100 mg for Temsirolimus were predefined. Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. Results. We here report on 46 patients (pts), 15 from part I and 31 from part II. Seven pts were not evaluable for response. Of the evaluable 39 patients, median age was 63 and median number of prior regimen was 1. Temsirolimus dose was 50 mg on day 1 and 8 in 7 pts from the part I of the trial and 25 mg in the remaining 39 pts. The overall response rate was 82% (32/39pts) with 22 partial and 10 complete responses. After a median follow up of 10 months for the total study population, median PFS and OS have not been reached (Figure 1A and 1B). Early safety analysis includes preliminary data of 22 pts. The most frequent non-hematologic side effects were nausea (14 pts, 64%), epistaxis (11 pts, 50%), fatigue (12 pts, 55%), fever (11 pts, 50%) and diarrhea (11 pts, 50%). Frequent grade 3/4 events (n>2) included leukopenia (21 pts, 95%), thrombocytopenia (20 pts, 91%), lymphopenia (11pts, 50%), anemia (8 pts, 36%), neutropenia (10 pts, 45%), renal failure (3 pts, 20%) and infections (7 pts, 32%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Two therapy-related deaths occurred (one patient died from sepsis during neutropenia, another from cerebral bleeding, both events occurring after cycle 3). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Figure 1 Progression free survival Figure 1. Progression free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures Witzens-Harig: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Viardot:Pfizer: Honoraria; Takeda: Other: travel support; Roche: Honoraria; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buske:Celltrion, Inc.: Consultancy, Honoraria. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Teva: Other: Travel Support; Celgene: Other: Travel Support. LaRosee:Pfizer: Honoraria. Marks:Pfizer: Honoraria. Hess:Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.

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

Blood ◽

10.1182/blood-2020-135999 ◽

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

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

Blood ◽

10.1182/blood.v116.21.2406.2406 ◽

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.

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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 ◽

10.1182/blood.v116.21.41.41 ◽

2010 ◽

Vol 116 (21) ◽

pp. 41-41 ◽

Cited By ~ 3

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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