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 Maintenance and Consolidation Regimens after a Second Autologous Transplant for Multiple Myeloma: A Decade of Experiences

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5700-5700
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Maire Okoniewski ◽  
Osama Diab ◽  
Siddhartha Ganguly ◽  
Al-Ola Abdallah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Standard Of Care ◽  
Advisory Board ◽  
Advisory Committees ◽  
Fda Approval ◽  
Novel Drugs ◽  
Significant Difference

Introduction: Autologous stem cell transplant (ASCT) followed by maintenance is the standard of care for eligible patients with multiple myeloma (MM). For patients that relapse, a second ASCT remains a viable option. However, the maintenance regimen to use for such patients remains an unanswered question, particularly in those with prior lenalidomide exposure. We retrospectively analyzed patients receiving two autologous transplants for a diagnosis of MM at our institution from 2008 to 2018 to determine maintenance strategies and outcomes upon completion of a second transplant. Methods: A total of 189 patients received two or more autologous transplants for MM at our institution from 2008 to 2018. Patients with planned tandem transplants, or those that proceeded directly to another transplant without interval progression were excluded. The remaining 135 patients were analyzed. Results: Patient characteristics are shown in Table 1. After first ASCT, 94 out of 135 patients (69.6 %) started maintenance therapy. The most commonly used maintenance regimen was lenalidomide in 63 patients, followed by bortezomib in 12 patients and thalidomide in 10 patients. Median time to initiation of maintenance from the date of transplant was 3.9 months. Overall median progression free survival (PFS) from transplant was 24.7 months with no significant difference between groups that received lenalidomide (median PFS: 21.2 months) or bortezomib (median PFS: 19.2 months, p:0.12). 10 (15.8%) patients discontinued lenalidomide due to toxicity, and 1 patient (8.3%) discontinued bortezomib due to toxicity. The median time from the onset of disease progression post first ASCT to time of second ASCT was 5.8 months. Strategies used post second ASCT includedconsolidation with triplet regimens followed by de-escalation (n=11) versus monotherapy (n=100). Table 2 highlights differing maintenance regimens used after the second ASCT. Median time from second ASCT to initiation of maintenance was 4.0 months. Median PFS post ASCT was 20.7 months. There was no statistically significant difference in PFS between the different regimens used (p=0.26), although there was a numerically higher discontinuation rate due to toxicity with older agents such as lenalidomide and bortezomib compared with newer agents such as daratumumab and pomalidomide. There was no statistically significant difference in the cytogenetic risk profile (p=0.21) or stage at diagnosis (p=0.36) between the groups that received different types of maintenance agents. However, patients receiving daratumumab as maintenance were more likely to have received more lines of therapy (median 5 for Daratumumab vs 3 for Lenalidomide, p=0.0001), and more likely to have previous exposure to daratumumab prior to second ASCT (92% vs 0% for other agents p=0.0001). Patients receiving daratumumab, carfilzomib or triple therapy were more likely to have been refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (p=0.0001). Despite stratifying for use of newer novel drugs (FDA approval after 2010- pomalidomide, daratumumab, carfilzomib) vs older novel drugs (FDA approval before 2010- lenalidomide, bortezomib, thalidomide), there was no difference in PFS ( 21.2 months vs 20.4 months, p= 0.92), between these groups when used as part of a maintenance strategy. Conclusions: Our data show a variety of maintenance and consolidation regimens are used for patients with MM after their second ASCT. In this single-center, retrospective analysis, there was no clear superiority of a consolidative strategy using triplet over monotherapy, and no superiority of newer agents compared to older agents. This suggests that toxicity, prior therapies and their tolerance may be the more important patient-related factors for consideration when selecting an agent/agents. Randomized, prospective data will be important to ascertain the standard of care in this situation. Disclosures Ganguly: Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. McGuirk:Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

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

scholarly journals Development of Novel Second Generation DC/Tumor Fusion Vaccine in Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 392-392 ◽  
Author(s):  
Shira Orr ◽  
Marzia Capelletti ◽  
Haider Ghiasuddin ◽  
Dina Stroopinsky ◽  
Jessica Liegel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Research Funding ◽  
Second Generation ◽  
Advisory Board ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Cells Cultured

Introduction: We have pioneered a personalized cancer vaccine in which patient derived tumor cells are fused with autologous dendritic cells (DCs) such that a broad array of shared and neo-tumor antigens is presented in the context of DC mediated co-stimulation, limiting the risk of antigen escape. In clinical trials of patients with hematologic malignancies, vaccination with DC/tumor fusions induced an expansion of tumor-specific T cells, and resulted in prolonged remissions in a subset of patients. In the current study, we have developed a novel second generation vaccine, whereby a DC/lymphoma fusion vaccine is presented in the context of a unique biomatrix that expresses high levels of the 41BB costimulatory molecule, to further accentuate T cell activation and prevent the establishment of tumor tolerance. In this study, we demonstrate efficacy of DC/lymphoma fusion cell vaccination in a preclinical lymphoma model, and show enhanced potency of the second-generation vaccine. Methods/Results: We first demonstrated the potency of the DC/tumor fusion vaccine in generating anti-tumor immunity in the A20 lymphoma model. Murine DC/A20 fusions were generated from bone marrow derived mononuclear cells cultured with GM-CSF and IL-4 then fused to syngeneic A20 lymphoma cells. DC/A20 fusion cells effectively induced tumor specific immunity as manifested by potent lysis of A20 T cells in vitro as compared to unstimulated T cells in a standard CTL assay. Consistent with this observation, vaccination with DC/A20 fusions effectively induced lymphoma specific immunity in an immunocompetent murine model. Balb/C mice (30 animals) underwent IV inoculation with 750,000 syngeneic, luciferase and mCherry transduced, A20 cells. 24 hours after tumor cells challenge, 15 mice were treated subcutaneously with 105 DC/A20 fusions. Tumor burden was detected using BLI imaging. 10 days post inoculation, within the untreated cohort all 15/15 mice had detectable tumor whereas within the treated group, 5 mice did not demonstrate any evidence of disease and 5 mice demonstrated minimal disease. We subsequently demonstrated that patient derived autologous DC/lymphoma fusions stimulated T cell mediated lysis of primary lymphoma cells. DC were generated from patient derived peripheral blood mononuclear cells cultured with GM-CSF and IL-4 and matured with TNFa. Primary lymphoma cells were isolated from resected tumor and fused with DC at a ratio of 10:1. Fusion stimulated T cells potently lysed autologous tumor cells as compared to unstimulated T cells (25.7% as compared to 12.66%) in a standard CTL assay. To further enhance vaccine potency, we developed a biomatrix substrate expressing the costimulatory molecule 41BB. Using carbodiimide chemistry we covalently bonded RGD peptide and 41BBL protein to an alginate (Alg)-based scaffold. The Alg/RGD/41BBL scaffold can serve as a supporting microenvironment for the co-culture of T cells and fusion vaccine. We cultured syngeneic T cells with DC/A20 fusion vaccine within a scaffold with or without bound 41BBL and examined the T cells cytotoxicity by a CTL assay as described above. Vaccine mediated stimulation of T cells in the context of the Alg/RGD/41BBL scaffold demonstrated higher levels of tumor lysis as compared to the percent T cells cultured within an Alg/RGD scaffold (22.95% and 13.95% respectively). Conclusion: In the current study we assessed the efficacy of the DC/Lymphoma fusion vaccine to elicit a tumor specific immune response. We succeeded in demonstrating the capacity of DC/Lymphoma fusion vaccine to generate tumor specific T cell cytotoxicity in vitro as well as in vivo in an immunocompetent murine model. Accordingly, we presented patient derived primary tumor results supporting the applicable nature of the DC/Lymphoma vaccine in lymphoma patients. In addition, we developed a second-generation fusion vaccine comprised of the original DC/Tumor vaccine presented to the T cells in an Alg/RGD/41BBL scaffold acting as a nurturing microenvironment for T cell immune specific response against the tumor cells. Our initial results exhibit promising potential and an in vivo experiment with the second-generation fusion vaccine is ongoing. Disclosures Arnason: Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Kufe:Nanogen Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Genus Oncology: Equity Ownership; Reata Pharmaceuticals: Consultancy, Equity Ownership, Honoraria; Hillstream BioPharma: Equity Ownership; Victa BioTherapeutics: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees; Canbas: Consultancy, Honoraria. Rosenblatt:Dava Oncology: Other: Education; BMS: Research Funding; Partner Tx: Other: Advisory Board; Merck: Other: Advisory Board; Parexel: Consultancy; Imaging Endpoint: Consultancy; Celgene: Research Funding; BMS: Other: Advisory Board ; Amgen: Other: Advisory Board. Avigan:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexel: Consultancy; Takeda: Consultancy.

scholarly journals The Prognostic Significance of Acquired 1q22 Gain in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Hadiyah Y. Audil ◽  
Joselle Cook ◽  
Patricia Greipp ◽  
Prashant Kapoor ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Significance ◽  
Advisory Board ◽  
Control Group ◽  
First Line ◽  
Advisory Committees

Background: Within the heterogeneous genomic landscape of multiple myeloma (MM), clonal evolution including the acquisition of risk-defining mutations and chromosomal abnormalities is a recurrent event and can be detected by fluorescence in situ hybridization (FISH). The effects of acquired abnormalities on clinical outcomes have not been well defined. We previously reported that patients who acquired 17p deletion [del(17p)] during the course of their disease had a significantly reduced overall survival (OS) by 38 months compared to patients who did not acquire del17p (Lakshman et al 2019). Similarly, while de novo gain of the long arm of chromosome 1 (1q22 gain) is a known high-risk aberration associated with significantly shorter OS and progression-free survival (PFS) in MM, the prognostic significance of acquired 1q22 gain has not been described. The primary objective of this study was to analyze factors predictive for acquired 1q22 gain and determine its impact on survival. Methods: We identified MM patients from the Mayo Clinic Dysproteinemia Database who had at least one follow up FISH performed ≥6 months from diagnosis. The clinical characteristics, concomitant cytogenetic abnormalities, first line treatments administered, and OS were compared between patients with acquired 1q22 gain and patients who did not acquire this abnormality. The Mayo Clinic IRB approved this study. Results: A total of 1041 MM patients met the inclusion criteria. Of these, 63 patients (6.1%) had acquired 1q22 gain, defined as being negative for 1q22 gain on initial FISH at diagnosis and having this abnormality detected on subsequent FISH. Median age at diagnosis was 59 years and 56% were male. Median time to acquisition of 1q22 gain was 60 months (range 8-140 months). We identified one control patient for each case who was diagnosed within one year of the case and had a subsequent FISH performed at a similar duration from diagnosis. Patients with acquired 1q22 gain had similar baseline characteristics except for a higher proportion of high-risk (HR) FISH at diagnosis [t(4;14), t(14;16), t(14;20), and del(17p13)] when compared to controls (27% HR FISH versus 6% HR FISH; P<0.01). 1q22 gain was concomitantly present with trisomies in 33 patients (54%), monosomy 13 in 24 patients (39%), t(4;14) in 8 patients (13%), and del(17p13) in 7 patients (12%). All patients received treatment prior to acquisition of 1q22 gain. Of the 63 patients, first line induction therapy consisted of proteasome inhibitor (PI) with steroid in 43%, immunomodulatory drugs (IMiD) with steroid in 40%, and PI + IMiD with steroid in 17% of patients. 54 patients (85%) received upfront stem cell transplant (SCT) (median 5.9 months to SCT), compared to 50 patients (79%) in the control group who received SCT. The median follow up of all 126 patients was 6.8 years. There was a statistically significant reduction in median OS from diagnosis in patients with acquired 1q22 gain compared to the control group (10.8 years versus 13.0 years; P = 0.02; Figure 1). Predictors of acquisition of 1q22 gain were identified using a case-control method. Age ≥70 at diagnosis and presence of HR FISH at baseline appeared to increase the risk of acquiring 1q22 gain. Conclusion: Acquisition of 1q22 gain is a relatively uncommon occurrence, but notably reduced OS by 2.2 years compared to patients who did not acquire 1q22 during the course of their disease (P = 0.02). Older age and the presence of HR FISH at diagnosis increased the risk of acquisition of 1q22 gain. The presence of high-risk translocations at baseline suggests that acquisition of 1q22 gain occurs in the context of more aggressive disease biology. Disclosures Kapoor: Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Dispenzieri:Alnylam: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Intellia: Research Funding; Janssen: Research Funding. Gertz:Prothena: Consultancy; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Amgen: Consultancy; Appellis: Consultancy; Annexon: Consultancy; Spectrum: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Dingli:Apellis: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Sanofi-Genzyme: Consultancy; Alexion: Consultancy; Janssen: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Legend BioTech: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Kumar:Cellectar: Other; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Carsgen: Other, Research Funding; Tenebio: Other, Research Funding.

scholarly journals P16, c-Myc, SOX11, P53, ki67 and CD71Protein Expression in Aggressive Morphological Variants of Mantle Cell Lymphomas Compared to Classical Morphological Mantle Cell Lymphomas in Multiple Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2820-2820
Author(s):  
Barbara Burroni ◽  
Anne Moreau ◽  
Mathieu Baldacini ◽  
Antoine Martin ◽  
Steven Le Gouill ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Who Classification ◽  
Progression Free Survival ◽  
Advisory Board ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Significant Difference ◽  
Mantle Cell ◽  
Scientific Advisory

On behalf of the Lymphoma Study Association (LYSA) Introduction: Aggressive Mantle Cell Lymphoma variant (A-MCL), including blastic and pleomorphic morphological variants, is a rare subtype of MCL whose frequency varies around 10-15% of all newly-diagnosed MCL patients. According to 2017 World Health Organization (WHO) classification, the diagnosis of A-MCL is based on morphology. A high proliferation rate on Ki-67 staining is not sufficient to be classified as a blastoid or pleomorphic subtype. This might induce diagnostic confusion. The aim of the present retrospective study is to investigate whether or not the CD71, c-Myc, SOX11, P53, ki67 and P16 expressions assessed by immunohistochemistry (IHC) can distinguish A-MCL from classical MCL (C-MCL). We also investigate the prognostic value of these markers in A-MCL patients. Methods: We re-investigated all MCL patients presented with A-MCL (n=110) at diagnosis and who have been enrolled in six prospective clinical trials. At time of inclusion, a centralized pathological review was performed to confirm the diagnosis of MCL. Cases were initially classified according to the 2008 WHO classification (LYMA, MCL-SA, MCL-SJ, RIBVD and RIPAD trials) or according to the 2017 WHO classification (MCLR2-ELDERLY trials). For the present study, we performed a supplemental pathology review by a panel of 5 hematopathologists experts from the LYSA group according to 2017 WHO classification. We identified 75 cases (out of 110) of A-MCL (8 blastic and 67 pleomorphic variants) which represent 15% of all MCL enrolled in these six trials. We have compared A-MCL characteristics to C-MCL who had specimens available for TMA (n=412 C-MCL out of 487 patients enrolled). IHC was performed on TMA, using the six selected antibodies and were scored by quantifying the percentage of cells stained on each spot. Patients available for survival analysis (53 A-MCL and 312 C-MCL) were drawn from all studies (except from the MCLR2-Elderly study that is ongoing). Different cut-offs were considered for progression free survival (PFS) and overall survival (OS) for each variable. The proliferation index was evaluated with Ki67 classical determination eyeballing and Ki67 reading by grid counting. Cut-offs for each of these markers were determined using X-tile software, which determines the optimal value for classifying patients into groups based on overall and progression-free survival. Results: At baseline, the aggressive forms were similar to classical forms in terms of demographic characteristics (age at diagnosis, localization and sex). p53 protein expression was significantly higher in A-MCL patients than in C-MCL (p<0.001) like p16 (p=0.002), c-MYC (p<0.001), CD71 (p<0.001) and Ki67 index (both classical and by grid) (p< 0.001). There was no statistically significant difference in SOX11 expression. In univariate analyses, elevated levels of P16 (>10%), c-MYC (>30%) Ki67 (>40%) were associated with poorer OS and PFS in the cohort of A-MCL and C-MCL patients. There was no significant difference in survival both for OS and PFS regarding P53 (>30%). In multivariate analysis stratified by trial, Ki67 by grid>40% (HR=2.303[1.479-3.585] ; p =0.0002) and c-MYC >30% (HR=1.865 [1.060-3.279] p =0.0305) were predictive for OS whereas only Ki67 by grid >40% (HR=2.055 [1.434, 2.944], p<0.0001) was a significant prognostic factor for PFS. Conclusion: CD71, c-Myc, P53 and P16 expression levels assessed by IHC are higher in A-MCL as compared to C-MCL. These markers could therefore be recommended in routine practice to distinguish between A-MCL and C-MCL. We also found that patients with Ki67 count by grid >40% had significantly shorter PFS and OS and patients with high Myc expression >30% had a significantly poorer OS. Thus, MYC expression and Ki67 by IHC is a suitable test for routine diagnostic practice to assess A-MCL prognosis. Disclosures Le Gouill: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Ribrag:argenX: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dreyling:Novartis: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Hermine:Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding.

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.

scholarly journals Polatuzumab Vedotin Use before Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Aggressive Lymphoma: A US Single Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3842-3842
Author(s):  
Arushi Khurana ◽  
Radhika Bansal ◽  
Matthew Hathcock ◽  
Adrienne Nedved ◽  
Yucai Wang ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Single Center ◽  
Infection Rates ◽  
Bridging Therapy ◽  
Advisory Committees ◽  
Single Center Experience ◽  
Significant Difference ◽  
Car T

Abstract Background: Polatuzumab vedotin (Pola), an antibody drug conjugate targeting CD79b received FDA approval in combination with bendamustine and rituximab (Pola-BR) in June 2019. With CAR-T as destination therapy, the option of Pola-BR appears appealing with its superior efficacy and lack of potential interference with CAR-T due to different target antigens. However, clinical concerns remain regarding prolonged lymphopenia associated with benda and CAR-T manufacturing if used before apheresis. We reviewed the single center experience of all patients with exposure to polatuzumab around CAR-T for R/R aggressive NHL treated at Mayo Clinic Rochester. Methods: A review of patients that received at least one dose of Pola with the intent to proceed to CAR-T between July 1, 2019 and March 31st, 2021 at Mayo Clinic, Rochester were included. Response to therapy was based on 2014 Lugano criteria. Overall survival (OS) was defined as the time from CAR-T infusion to death, and event-free survival (EFS) as the time from CAR-T infusion to disease progression, next treatment, or death. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results: A total of 22 patients were identified during the study period. Of these 18 (82%), made it to CAR-T infusion (17 axi-cel, and 1 -tisa cel). 3 patients died due to progressive disease (PD) before CAR-T and one achieved complete remission (CR). In the pre-CAR-T Pola cohort (n = 22), the median age was 65.5 years (39-73), 50% were males, 96% had advanced stage and IPI ≥ 3. Median prior lines of treatment were 4.5 (2-6), 73% had primary refractory disease and 50% had myc rearrangement. 19 (86%) patients received Pola as bridging therapy and 8 were exposed to Pola before T-cell apheresis. Bendamustine was included in the treatment for 79% (15/19) for bridging therapy and 63% (5/8) with exposure pre-apheresis. For those in the bridging group, the overall response rate (ORR) was 26% (5/19), with one patient achieving CR with Pola-BR. Disease control (defined as those in a partial response [PR] or stable disease [SD]) was seen in 47% (9/19) patients. One of the 8 patients with pre-apheresis exposure to Pola, required an additional attempt at CAR-T manufacturing after the initial failure. At a median follow up of 48 weeks, the EFS and OS in 18 patient cohort with pre-CAR-T Pola exposure were 6.7 weeks (95% CI, 4.3-not reached [NR]) and 15 weeks (95% CI, 9.7-NR), respectively. At the data cut off (7/25/2021), 78% patients had died. As traditional chemo for bridging is a particularly poor prognostic group, we compared Pola-BR bridging group (n = 15), to other traditional chemo bridge group (n = 16) in our CAR-T database. Both groups had comparable baseline characteristics as shown in Table 1 except for higher proportion of patients with B-symptoms in the Pola-BR group at time of CAR-T. There was also no difference in the inflammatory markers (CRP and ferritin) at LD or peak level after CAR-T. Table 2 shows outcomes between the 2 groups with comparable any grade CRS, neurotoxicity, pre and post CAR-T infection rates. Best response ORR to CAR-T was higher in the other chemo group vs. Pola BR (81.2% vs. 33%, p = 0.027). There was a significant difference in the 6-month OS rate (other 81.3% [95%CI, 54.5-96] vs. pola 33.3% [95%CI, 11.8- 61.6], p = 0.007) but no significant difference in the 6-month EFS rate (other 37.5% [95%CI, 15.2-64.6%] vs. pola 13.3% [95%CI, 1.7-40.5%] p = 0.12) between the 2 groups (figure 1). On univariate analysis within the chemo type bridging cohort (Pola-BR + other traditional chemo, n = 31), presence of B-symptoms (HR 4.72, p = 0.002), ECOG PS &gt; 2 at CAR-T (HR 6.75, p = 0.0008), and type of bridge therapy (pola HR 6.57, p = 0.009) were associated with worse OS whereas a response to bridge (PR+SD, HR 0.39, 0.031) was favorable. On MVA, association was maintained for bridge type (pola, p &lt;0.001) and response to bridge (p &lt;0.001). Discussion: Pola based bridge was feasible in this US based cohort without significant issues with CAR-T manufacturing or increased infection rates. However, in this retrospective analysis, use of Pola-BR was associated with inferior outcomes compared to other traditional chemotherapy options. Future studies are required to elucidate whether these difference in outcomes stem from a biological basis versus bias in patient selection. Figure 1 Figure 1. Disclosures Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Incyte: 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; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; InnoCare: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Legend: Consultancy; Sorrento: Consultancy.

scholarly journals 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 ◽  
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.

scholarly journals A Multicenter, Real World Analysis of Primary Central Nervous System Lymphoma in Those with and without Human Immunodeficiency Virus

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1457-1457
Author(s):  
Christopher Dittus ◽  
Natalie S Grover ◽  
Tarsheen Sethi ◽  
Jonathon B. Cohen ◽  
Alfredo Voloschin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Performance Status ◽  
Advisory Board ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Genetics Research ◽  
Significant Difference ◽  
To Receive

Abstract Introduction: Representing 4% of central nervous system (CNS) tumors, primary CNS lymphoma (PCNSL) is a rare type of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, spinal cord or cerebrospinal fluid without evidence of systemic disease. High-dose methotrexate (HD-MTX)-based regimens that incorporate consolidation with reduced dose whole brain radiation therapy (WBRT) or autologous stem cell transplant have shown 2-year overall survival (OS) rates ranging from 69% to 81% (Morris, JCO, 2013; Omuro, Blood, 2015). Although these data are encouraging, patients whose CNS deficits are too severe to receive treatment will die within the first months of diagnosis. HIV PCNSL has been associated with a poorer performance status and worse OS compared to non-HIV PCNSL. With the advent of combination antiretroviral therapy (ART), HIV PCNSL has become less common and by incorporating HD-MTX into HIV PCNSL treatment, outcomes have improved (Gupta, Neuro Oncol, 2017). In this study, we report the real world survival of PCNSL at 3 large academic centers, including those who received HD-MTX versus those who did not. We also compare survival of HIV PCNSL relative to non-HIV PCNSL. Methods: Adult patients (&gt;18 years of age) with PCNSL at 3 medical centers (UNC Chapel Hill, Vanderbilt Medical Center, Emory University) were included in this analysis. Patients were diagnosed between January 2004 and July 2020. Only the diffuse large B-cell lymphoma (DLBCL) histology was included. Cases were excluded if there was any disease outside of the CNS or if they previously had systemic DLBCL. Demographic information was collected from the medical record, as well as disease-related information, HIV status, HD-MTX treatment (defined as &gt;3g/m2) with or without other chemotherapeutic agents, imaging to determine progression, and survival data. Data were analyzed for the entire cohort as well as compared between HIV and non-HIV subjects. Demographic variables were summarized using appropriate statistics (frequencies, mean and standard deviation) and compared between HIV and non-HIV patients using Fisher's exact tests or Wilcoxon rank sum tests. Progression free survival (PFS) and OS were also compared between HIV and non-HIV patients using log-rank tests. Results: We identified 158 cases of PCNSL. The median PFS for the entire cohort was 1.17y and the median OS was 3.24y. Patients who received HD-MTX had an improved PFS (1.69y vs 0.25y; p=0.0016) and an improved OS (4.01y vs 1.05y; p=0.00075) over those who did not receive HD-MTX. Twenty-six of the 158 cases were HIV positive. Table 1 reports clinical features in HIV versus non-HIV PCNSL patients. Patients with HIV PCNSL were significantly younger than those with non-HIV PCNSL (44y vs 75y), and had a worse performance status (PS&gt;2: 57.7% vs 26.8%). Notably, patients with HIV were less likely to receive HD-MTX compared to patients without HIV (53.8% vs 83.3%). Receiving frontline WBRT trended towards significance in favor of the HIV PCNSL group. Other factors such as gender, deep structure involvement, elevated cerebrospinal fluid protein, and elevated lactose dehydrogenase (LDH) were not significantly different between groups. When comparing HIV to non-HIV PCNSL, there was not a statistically significant difference in PFS (0.30y vs 1.34y; p=0.34), but there was a statistically significant difference in OS (0.30y vs 3.65y; p=0.0023) (Figure 1). When comparing those who received HD-MTX in the HIV group vs non-HIV group, there was not a statistically significant difference in PFS (3.39y vs 1.66y; p=0.45) or OS (3.6y vs 4.0y; p=0.43) (Figure 2). Conclusions: Our analysis shows that real-world survival for PCNSL is modest compared to reported outcomes from clinical trials. Patients who are able to receive treatment with HD-MTX had a significantly improved outcome. HIV PCNSL has worse OS than non-HIV PCNSL, and the median PFS and OS were both several months in the HIV PCNSL group, suggesting an unmet need for both frontline and salvage therapies. The survival difference between HIV PCNSL and non-HIV PCNSL decreased when evaluating only those patients who received HD-MTX. Importantly, fewer patients received HD-MTX in the HIV PCNSL group; and these patients had worse PS. These real-world data may serve as the benchmark for survival outcomes in PCNSL and provide valuable information for designing future trials in patients with PCNSL. Figure 1 Figure 1. Disclosures Dittus: Genentech: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; BeiGene: Other: Advisory Board. Grover: Kite: Other: Advisory Board; ADC: Other: Advisory Board; Novartis: Consultancy; Tessa: Consultancy; Genentech: Research Funding. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Park: G1 Therapeutics: Consultancy; Takeda: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Seattle Genetics: Research Funding, Speakers Bureau; Gilead: Speakers Bureau.

scholarly journals Comparison of Fixed Dose, Reduced-Intensity Conditioning with Busulfan and Fludarabine to Reduced PK-Guided Busulfan AUC Conditioning in Patients Undergoing Hematopoietic Stem Cell Transplant for AML/MDS

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5715-5715
Author(s):  
Brendan Rasor ◽  
Tyler Dickerson ◽  
Qiuhong Zhao ◽  
Jonathan E Brammer ◽  
Karilyn Larkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
Hazard Ratio ◽  
Cell Transplant ◽  
Research Support ◽  
Advisory Committees ◽  
Significant Difference

Background: Consolidation therapy with allogeneic hematopoietic stem cell transplant (HSCT) is recommended to prevent relapse and improve survival in patients with intermediate and poor risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Due to toxicity, older patients with comorbidities were historically not candidates for HSCT. The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to proceed to HSCT by reducing toxicities associated with myeloablative conditioning (MAC).The cornerstone of reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). This can be achieved by the use of patient-specific pharmacokinetic targets. Previous studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day x 4 days in a subset of patients to balance reduced toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. Methods: To compare the two regimens, a retrospective, IRB-approved cohort study was conducted. The inclusion criteria were as follows: age 18-89 years, HSCT for a diagnosis of AML or MDS, and fludarabine + busulfan conditioning regimen ± antithymocyte globulin. In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to neutrophil recovery; time to platelet recovery; incidence of acute and chronic graft vs host disease (GVHD); sinusoidal obstructive syndrome; febrile neutropenia; graft failure; and grade 3-5 mucositis, acute kidney injury, or hepatic dysfunction. The log-rank test was used to compare RFS and OS, and Cox proportional hazard regression model was used to estimate the hazard ratio. Gray's test was used for competing risks analysis of relapse, acute GVHD, and chronic GVHD. Fine and Gray regression models were used to estimate the hazard ratio. Results: Seventy-four patients who received conditioning from 2015-2018 with either AUC 4,000 or RIC were identified. Disease type was similar between groups with 61.8% AML in the AUC 4,000 group and 52.5% in the RIC group. There were no significant differences in disease risk status. In the AUC 4,000 group, 17.6% had either AML with myelodysplastic changes or therapy-related AML/MDS, compared to 17.5% in the RIC group. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different, at 66.9% with AUC 4,000 compared to 57.5% with RIC (p=0.37) (A). Eighteen-month overall survival was also not significantly different with 66.9% alive in the AUC 4,000 group and 60% in the RIC group (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not significantly different (p=0.82, p=0.18, respectively) (C,D). There was, however, a statistically significant difference in the cumulative incidence of relapse over 18 months in favor of the AUC 4,000 regimen (hazard ratio 4.08, 95% confidence interval 1.15-14.5) (E). Grade 2-4 mucositis was more common in the AUC 4,000 group (85.3% vs 30%, p<0.01), but there were no significant differences in transaminitis, kidney injury, neutropenic fever, sinusoidal obstructive syndrome, or graft failure. Discussion: Though no significant difference existed in disease risk between the groups, choice of regimen was driven by physician judgement, perceived fitness, and ability to tolerate potential adverse effects. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower cumulative incidence of relapse. Adverse effects other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed. Figure Disclosures Brammer: Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. William:Guidepoint Global: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.

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