Final Results of a Phase 1/2a, Dose Escalation Study of Pvx-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)

Abstract Introduction: PVX-410 Multi-Peptide Vaccine (OncoPep, Inc.) is being developed for the treatment of SMM. PVX-410 consists of 4 human leukocyte antigen-A2 (HLA-A2), synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US184-192; XBP1 SP367-375; CD138260-268; and CS1239-247) emulsified in Montanide® ISA-720 VG (Seppic). Adults with SMM at high risk of progression to active MM who were HLA-A2-positive were eligible. The primary objective was to determine the tolerability of PVX-410, initially as monotherapy and then in combination with lenalidomide (len). Immune and disease response also were assessed. Methods: All patients received 6 bi-weekly subcutaneous injections of PVX-410, initially at the low-dose of 0.4 mg (0.1 mg/peptide or 0.4 mg total) and then at the target dose of 0.8 mg (0.2 mg/peptide or 0.8 mg total). In the PVX-410+len cohort, patients received 3 standard cycles of len (25 mg orally on Days 1-21 every 28 days, without dexamethasone). All patients also received 0.5 mL (1 mg) Hiltonol® (poly-ICLC) (2 mg/mL) via intramuscular injection at the time of PVX-410 administration. Patients were followed for 12 months post-treatment. Blood samples for immune response evaluation were collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 weeks during treatment and at Months 1, 3, 6, 9, and 12 post-treatment. Disease response was assessed at the same time points, except Weeks 0 and 2, using International Myeloma Working Group and modified European Group for Blood and Bone Marrow Transplant criteria. Results: Overall, 22 patients with high-risk SMM were enrolled (age range 39 to 82 years), of whom 12 received PVX-410 monotherapy (3 low-dose; 9 target dose) and 10 received PVX-410 (target dose) + len. All 22 patients have either completed the study through post-treatment Month 12 (N=15) or discontinued before that time (N=7). PVX-410 was well-tolerated, with a treatment-emergent adverse event (TEAE) profile consistent with that expected, based on previous clinical studies with peptide vaccines. All (100%) 22 patients experienced at least 1 TEAE. Among monotherapy patients, the most common TEAEs were injection site pain (50%); fatigue (33%); and injection site erythema, pyrexia, and rash (each 25%). The TEAE profile of PVX-410+len was generally similar to that see with PVX-410 alone, although the incidence of commonly reported TEAEs was higher with the combination than with PVX-410 alone. The majority of TEAEs were Grade 1 in intensity and occurred within 2 days after study vaccine injection. No deaths or study drug-related serious adverse events were reported. PVX-410 was immunogenic as monotherapy (10/11 patients) and in combination with len (9/9), as demonstrated by an increase in the percentage of tetramer+ cells (≥1.5-fold increase over baseline) and interferon-gamma+ (IFN-γ) cells (≥2.0-fold increase over baseline) in the CD3+CD8+ cell population. This increase was statistically higher for IFN-γ+ cells after 2 vaccinations in the combination group. The CD8+ T-lymphocyte response was also characterized by increases from baseline in interleukin-2-, tumor necrosis factor-alpha-, and CD137-positive cells in both treatment groups. Furthermore, decreases in the naïve memory cell population and increases in the effector memory cell population were seen post-vaccination; this response was enhanced by the addition of len. Among the 12 monotherapy patients, 5 (2 low-dose; 3 target-dose) experienced progression to active disease within 9 months post-treatment, and 7 had stable disease (SD) at follow-up Month 12. Among the 9 evaluable PVX-410+len patients, 5 achieved at least a minimal response, with 1 patient achieving a partial response; 1 of these 5 patients then progressed to MM by Month 5 post-treatment. Four patients had SD at follow-up Month 12. Conclusions: Six doses of PVX-410 were well tolerated in 22 patients with high-risk SMM, with an expected AE profile both as monotherapy and in combination with len. An immune response to PVX-410 was seen with PVX-410 alone, which was enhanced by the addition of len. Based on these promising findings to date, investigation of PVX-410 in combination with immunogenic agents is continuing. Disclosures Nooka: Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Wang:Acerta: Consultancy, Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; BeiGene: Research Funding; Juno Therapeutics: Research Funding; Kite Pharma: Research Funding; Dava Oncology: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding. Kaufman:Incyte: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Peterkin:OncoPep: Employment. Lonial:Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; BMS: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Millenium: Consultancy. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Raje:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding.

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Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study

Blood ◽

10.1182/blood.v128.22.3326.3326 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3326-3326 ◽

Cited By ~ 4

Author(s):

Andrew Spencer ◽

Simon Harrison ◽

Jacob P. Laubach ◽

Jeffrey Zonder ◽

Ashraf Z Badros ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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A Phase III Study of Enoxaparin Vs Aspirin as Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated with Lenalidomide-Based Regimen.

Blood ◽

10.1182/blood.v116.21.1092.1092 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1092-1092 ◽

Cited By ~ 6

Author(s):

Federica Cavallo ◽

Francesco Di Raimondo ◽

Izhar Harda ◽

Barbara Lupo ◽

Alessandra Romano ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Cardiovascular Events ◽

Research Funding ◽

Low Dose ◽

Phase Iii ◽

Minor Bleeding ◽

Newly Diagnosed ◽

Advisory Committees ◽

To Receive

Abstract Abstract 1092 Background: Newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens have a high risk of thromboembolic events. Preliminary studies on MM patients receiving a combination of lenalidomide (R) and dexamethasone have shown an increased incidence of thrombosis as well, with a calculated odds ratio of about 3.5 of developing thrombosis. Aims: In a prospective, multicenter phase III trial (RV-MM-PI-209) newly diagnosed patients were treated with lenalidomide and low-dose dexamethasone (Rd) induction and subsequently randomized to receive consolidation with lenalidomide + melphalan + prednisone (MPR) or high dose melphalan (MEL200). In this sub-study we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) as anticoagulant prophylaxis during Rd induction and MPR consolidation. End-points were incidence of venous thromboembolism (VTE), acute cardiovascular events, sudden death, major and minor bleeding. Methods: 402 newly diagnosed MM patients were enrolled in the randomized trial RV-MM-PI-209. Treatment schedule included four 28 day cycles of lenalidomide (25 mg days 1–21) and low-dose dexamethasone (40 mg days 1,8,15,22) (Rd) as induction. As consolidation, patients were randomized to receive six 28-day cycles of melphalan (0.18 mg/kg days 1–4), prednisone (2 mg/kg days 1–4) and lenalidomide (10 mg days 1–21) (MPR, N=202) or tandem melphalan 200 mg/m2 with stem-cell support (MEL200, N=200). All eligible patients were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=166) or ASA (Aspirin 100 mg/d, N=176) for the duration of the induction therapy and for consolidation therapy in the MPR group; 60 patients were excluded from this sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Results: Patient characteristics and distribution of major risk factors were similar in the two groups. At the time of the present analysis 381 and 130 patients are evaluable during Rd induction and consolidation respectively. During the induction phase, the overall incidence of any grade 3–4 thrombotic events was 1% in the LMWH group, 2,4% in the ASA group (p=.45). VTE, mostly of the lower limbs were equally distributed in the two groups (1%; p not significant), while pulmonary embolism was observed only in the ASA group (2%; p not significant). Median time to onset of thrombotic events for patients who received LMWH or ASA were 2.1 and 1 months, respectively. No acute cardiovascular events were observed and only minor bleeding was detected in the LMWH group (1%). During consolidation no thrombotic events were observed in the MPR group, only one central venous catheter thrombosis was observed in the MEL200 group. Conclusion: The overall incidence of thrombotic events was less than 5% in all groups and confirmed the safety of low dose dexamethasone in association with Lenalidomide. No significant benefit was seen with LMWH over ASA in this patient population. LMWH and ASA are likely to be effective thromboprophylactic regimens in lenalidomide treated patients with newly diagnosed multiple myeloma. The analysis will be updated for the meeting. Disclosures: Cavallo: CELGENE: Honoraria. Guglielmelli:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN-CILAG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN-CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Distinct Gene Expression Patterns of Minimal Residual Disease (MRD) Cells in High-Risk AML Patients Identified By RNA-Sequencing

Blood ◽

10.1182/blood-2018-99-120260 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2757-2757

Author(s):

Christopher B. Benton ◽

Ahmed Al Rawi ◽

Feng Wang ◽

Jianhua Zhang ◽

Jeffrey L. Jorgensen ◽

...

Keyword(s):

Gene Expression ◽

High Risk ◽

Board Of Directors ◽

Rna Sequencing ◽

Research Funding ◽

Mononuclear Cells ◽

Post Treatment ◽

Advisory Committees ◽

Diagnostic Samples ◽

Equity Ownership

Abstract INTRODUCTION Evolving techniques have made possible the direct detection, physical isolation, and study of AML minimal residual disease (MRD) after treatment. This could allow for better identification of therapeutic vulnerabilities in AML. Prior studies have focused on cells that initiate leukemia in mouse models, known as leukemia-initiating cells (LIC), generally with a foundational CD34+CD38- immunophenotype. LIC are typically derived from diagnostic samples of untreated patients. Such stem-like cells do not necessarily represent the residual fraction of AML after treatment. Relapse may originate from non-LIC, and the presence of phenotypically and molecularly defined MRD is now firmly established as a critical prognostic factor for patients. High-risk AML is characterized by relapse, despite morphologic complete remission with initial therapy in most cases. RNA-sequencing was performed on pre- and post-treatment AML subpopulations, including MRD, from high-risk patients, to determine differences in gene expression. METHODS Matched primary AML samples were collected from marrow and peripheral blood of patients with high-risk AML (including patients with unfavorable karyotype and/or TP53 mutation) at diagnosis and after treatment. Mononuclear cells were flow-sorted for bulk (CD45dim) and LIC (Lin-CD34+CD38-CD123+) from diagnostic samples. Post-treatment samples were sorted for bulk mononuclear cells (MNC) and MRD, based on difference-from-normal/MRD immunophenotype specific for each patient as determined from established 20-marker clinical flow cytometry analysis. RNA was isolated using low-input methodology, and RNA-sequencing was performed using Illumina HiSeq 2000. Gene expression was assessed using GO-Elite, and differences between patients and subpopulations were assessed using rank product method. RESULTS Gene expression in MRD was analyzed by RNA-sequencing in comparison to diagnostic samples in eight patients with high-risk AML. Four patients had unfavorable karyotype, including two with TP53 mutations. Patients had additional high-risk features, such as FLT3-ITD or RUNX1 mutations, or secondary/therapy-related AML. Treatment consisted of chemotherapy (6/8) or hypomethylating agents (2/8), with or without other targeted drugs. Residual leukemia was detected in post-treatment samples in all study patients. Significant differences in gene expression were detected between MRD and other sorted populations, including diagnostic bulk AML and LIC. Relevant MRD pathways included those with strong interactions with the microenvironment. Anti-apoptotic mechanisms, cytoskeletal, and cell adhesion related genes, WNT/beta-catenin signaling, and TGFbeta signaling ranked among the most relevant processes in AML MRD subpopulations (Figure 1A, GO-Elite interactome of highly expressed genes in AML MRD). To identify potentially critical and unique MRD-specific genes, rank product method was applied using 1) the most highly expressed genes in AML MRD, 2) the most differential expressed genes between MRD and bulk AML at diagnosis, and 3) the most differentially expressed genes between MRD and bulk MNC after treatment. Among the top 50 scoring genes using this approach (Figure 1B), 16 genes were among the top 5% of genes expressed in MRD among all patients and 20 genes have cell surface gene-products (shown in yellow). Several potential leukemia- and cancer-related genes of interest were identified (shown in bold). CONCLUSIONS Key differences exist between the gene expression profiles of post-treatment MRD from high-risk AML patients, in comparison to other populations and subpopulations of sorted cells before and after treatment. The highlighted differences suggest that MRD relies on specific intrinsic gene expression changes and microenvironmental interactions, and therefore may be targetable after elimination of bulk AML with initial therapy. Accessible surfacesome targets are among top hits. Disclosures Konopleva: cellectis: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; Stemline Therapeutics: Research Funding. Andreeff:Astra Zeneca: Research Funding; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy; Celgene: Consultancy; Reata: Equity Ownership; SentiBio: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Unrelated Donor Transplants for Older AML Patients Using a Low Dose TBI Containing Regimen Are As Efficacious As Related Donor Transplants, and Exhibit Favorable Outcomes for Intermediate Risk Disease.

Blood ◽

10.1182/blood.v120.21.3119.3119 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3119-3119

Author(s):

Gregory A. Yanik ◽

John M. Magenau ◽

Shin Mineishi ◽

Attaphol Pawarode ◽

Keith Alangaden ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Low Dose ◽

Acute Gvhd ◽

Unrelated Donor ◽

Intermediate Risk ◽

Advisory Committees ◽

Related Donor

Abstract Abstract 3119 Hematopoietic stem cell transplants (HCT) for older patients with acute myelogenous leukemia (AML) have increased significantly over the past decade, associated with the use of reduced intensity conditioning (RIC) regimen. In the unrelated donor (URD) setting, anti-thymocyte globulin (ATG) has routinely been used to improve engraftment and decrease the incidence and severity of graft versus host disease (GVHD). We hypothesized that replacing ATG with low dose total body irradiation (TBI) during conditioning would provide sufficient immunosuppression to permit engraftment in older patients undergoing unrelated donor transplants for AML. Outcome data, including engraftment and GVHD rates were then compared to similar patients undergoing matched related donor (MRD) HCT for AML. Methods: Between 2007–2012, 50 patients (55–70 years, median 61 years) with AML in CR1 (n=41) or >CR1 (n=9) were prospectively enrolled on an IRB-approved clinical trial using a RIC regimen. Donors were either MRD (n=23), or URD (n=27) if a suitable MRD was not available. HLA matched donors were available in 39 of the 50 patients, with single antigen mismatched donors used in 11 (41%) URD cases. All patients were conditioned with fludarabine (160 mg/m2) + busulfan (6.4 mg/m2) [FluBu2]; URD recipients additionally received 200cGy TBI on day -1 pre-transplant. GVHD prophylaxis was tacrolimus and mycophenolate. Patients exhibited high risk (n=21) or intermediate risk (n=29) disease at initial diagnosis, as defined by cytogenetic and molecular criteria. High risk (HR) patients included those with either a FLT3 mutation, monosomy 5 or 7, 5q-, 7q-, t(6:9) or complex cytogenetics (> 3 abnormalities). Patients with t(8:21), t(16:16) or inv 16 were excluded from analysis. Stem cell sources included peripheral stem cells (n=49) or marrow (n=1). Results: For the entire cohort, the 1y and 3y relapse free survival (RFS) was 56% (95% CI: 43–69) and 43% (95% CI: 28–58) respectively, with 1y and 3y overall survival (OS) rates 58% (95% CI:46–74) and 44% (95% CI: 27–62%). There was no significant difference in 1y RFS between URD and MRD recipients [62±9.5% vs 48±11%] or 3y RFS [44±11% vs 40±12%], p = 0.42 (Figure). There was no difference in outcome by age, with 3y RFS 42.5±11% for patients 55–59 yrs (n=20) and 40±12% for patients 60–70 yrs (n=30), p =0.54. The median donor age was 37 yrs (range 19–50) for URD and 58 yrs (range 42–70) for MRD recipients. The median CD34 cell dose infused was 5.0 × 10(6)/kg in both cohorts [range URD: 1.2 –8.3 × 10(6), MRD: 1.9 –9.8 × 10(6)]. There was no difference in time to neutrophil engraftment, with both cohorts engrafting a median 12 days post-transplant. Primary graft failure occurred in 1 (3.4%) URD recipient, who received an HLA mismatched graft. No cases of secondary graft failure occurred in either cohort. Day 100 CD33 chimerism was all donor in all URD cases, and in 75% of MRD recipients. Grade 2–4 acute GVHD developed in 44% URD and 30% MRD respectively, with grade 3–4 acute GVHD in 7% URD and 10% MRD. Patients with intermediate risk disease experienced 1y and 3y RFS of 74±8.5% and 3-year RFS 62±10.5%, respectively. By comparison, transplant outcomes were poor for patients with high risk disease, with 1y and 3y RFS only 31±10% and 13±10% (Figure). Conclusion: Replacing ATG with low dose TBI in older AML patients undergoing RIC URD does not appear to compromise engraftment or increase GVHD rates. Survival is similar to that experienced by MRD recipients who are transplanted without either ATG or TBI. RFS for patients with high risk AML was poor, but patients with intermediate risk AML may benefit from this strategy when compared to historical results with non-transplant approaches for this patient population. Disclosures: Talpaz: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; B.M.S.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Couriel:Therakos: Speakers Bureau; Merck: Speakers Bureau.

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A Phase 2 Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Llmphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with High-Risk Genomic Features

Blood ◽

10.1182/blood.v128.22.4388.4388 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4388-4388 ◽

Cited By ~ 1

Author(s):

Jeffrey A. Jones ◽

Amy J. Johnson ◽

Farrukh T. Awan ◽

Quihong Zhao ◽

Natarajan Muthusamy ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Early Stage ◽

Phase 2 ◽

Advisory Committees ◽

Immune Synapse ◽

Phase 2 Study ◽

Treatment Naïve

Abstract BACKGROUND: Patients (pts) with CLL/SLL are at high risk for infections, and pts with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated activity in treatment-naïve CLL/SLL, can potentially restore immune system dysfunction associated with CLL/SLL. We present results from an NCI/CTEP-sponsored, randomized phase 2 study (NCI 8834) of low-dose lenalidomide designed to assess the ability of lenalidomide to restore immune synapse response and humoral immunity, as well as delay progression of asymptomatic, genetically high-risk, early-stage CLL/SLL. METHODS: Pts with genetically high-risk CLL/SLL (unmutated IGHV, deletion(17p)/(11q), and/or complex abnormal karyotype) were eligible if they were treatment-naïve, did not meet IWCLL 2008 criteria for initiating therapy, age ≥ 18 but < 80 years, ECOG ≤ 2, no history of autoimmune cytopenia, no venous thromboembolic event ≤6 months prior, and adequate end-organ function. Pts were randomized to receive lenalidomide either concurrent with (Arm A) or sequential to (Arm B) 2 doses of 13-valent protein-conjugated pneumococcal vaccine (Prevnar-13) administered 2 months apart (see figure). Lenalidomide was dosed at 2.5 mg/day during the first 28-day cycle to reduce risk for tumor flare and increased to 5 mg/day for the second and subsequent cycles as tolerated. Treatment continued for at least 24 cycles in the absence of disease progression or irreversible Grade ≥ 3 adverse event (AE). Anti-pneumococcal antibody titers, the primary endpoint of the study, were measured in each arm at 1 and 2 months after the second dose of vaccine and every 6 months thereafter. Secondary endpoints included clinical response, IWCLL 2008 response after 24 cycles, and progression-free survival (PFS). RESULTS: 49 pts were randomized. Median age at enrollment was 59 (range 40-70) years, median time from diagnosis 1.26 (range 0.15-9) years, and ECOG = 0 in 96%. Baseline clinical and genetic risk factors were similar between the 2 arms (see table). In general, AE were mild and manageable. Gr ≥3 AE were uncommon and included (in ≥10% pts): neutropenia in 10 (20%) and hypophosphatemia in 6 (12%). The most common treatment-emergent Gr 1/2 AEs included neutropenia in 27 pts (55%), diarrhea in 26 (53%), rash in 25 (51%), and thrombocytopenia in 23 (47%). Gr 1/2 infections were reported in 17 (35%), but only 1 Gr 3 infection (pneumonia) was observed. Gr 1/2 tumor flare was observed in 2 pts (4%). There were no thromboembolic events. Seroprotection against 7 pneumococcal serotypes (1, 3, 4, 5, 14, 19F, and 23F) was measured 4 weeks after the second dose of vaccine. All but 4 pts (3 in Arm A, 1 in Arm B) achieved seroprotection against ≥1 serotype, and the median number against which seroprotection was achieved was 3 (range: 0-7) in both arms. Mean IgG/IgM/IgA levels at baseline were 722/109/49, and improved to 820/136/51 and 947/197/59 after 12 and 24 cycles of treatment, respectively. Disposition of study patients and treatment responses are summarized in the table; after median 31 cycles received, 59% of patients remain on treatment. 75% of patients achieved a clinically assessed disease response, and of the 34 patients that completed IWCLL response assessment after 24 cycles of therapy (including CT scans and bone marrow biopsy), 9 achieved a PR, 23 SD, and 2 PD. Median PFS has not yet been reached; 1 year PFS was 88% (95%CI 74-94), 2 year PFS was 78% (63-88), and estimated 3 year is PFS 72% (95%CI 56-83). CONCLUSIONS: Low-dose lenalidomide can be administered to asymptomatic, genetically high-risk, early-stage CLL patients with modest toxicity and high rates of durable clinical response. Some anti-pneumococcal vaccine response was achieved by nearly all treated patients on both schedules. Lenalidomide effectively prevented and/or reversed the expected progression of hypogammaglublinemia, which may explain the low incidence of infection, and near absence of severe infection, observed here. Figure Figure. Disclosures Jones: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Novartis Oncology: Consultancy; Innate Pharma: Research Funding; Pharmacyclics: Consultancy. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

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Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-127049 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 266-266

Author(s):

Sagar Patel ◽

Saulius K. Girnius ◽

Binod Dhakal ◽

Lohith Gowda ◽

Raphael Fraser ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Disease Status ◽

Cell Leukemia ◽

Advisory Committees ◽

Primary Plasma Cell Leukemia ◽

Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score >90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling: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; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽

10.1182/blood-2021-148139 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2455-2455

Author(s):

Carlos Bachier ◽

Henning Schade ◽

Behyar Zoghi ◽

Aravind Ramakrishnan ◽

Nirav N. Shah

Keyword(s):

Stem Cell ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽

10.1182/blood-2019-124350 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4116-4116

Author(s):

Anna Dodero ◽

Anna Guidetti ◽

Fabrizio Marino ◽

Cristiana Carniti ◽

Stefania Banfi ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Tp53 Mutation ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

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