Refractory non-Hodgkin Lymphoma Research Articles

Evaluation of Different Treatment Regimens for Relapsed and Refractory NHL: Single Institute Experience

Background and Aim: The treatment of choice for relapsed or refractory Non-Hodgkin Lymphoma (NHL) mainly, is High dose chemotherapy with autologous stem cell transplantation. However, its use is mostly restricted to patients responding to salvage chemotherapy. In this study, our aim was to evaluate outcome and toxicity of different treatment modalities of relapsed and refractory NHL. Patient and Methods: This retrospective study included 217 patients were diagnosed as refractory or relapsed NHL. Those patients received different treatment modalities as GDP (Gemcitabine, dexamethasone, cisplatin), DHAP (Dexamethasone, Cytarabine, and Cisplatin), MINE (Mitoxantrone, ifosfamide, etoposide and mesna), CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone), and CVP (Cyclophosphamide, vincristine and prednisone). Results: The median age of patients in the study was 50 years. Patients who received DHAP showed ORR of 62%, which was the highest response. The most common adverse effects were hematological which were more noticed in patients, received CHOP. Sixty one patients (54.5%) had anemia, 54 patients (48.2%) had neutropenia and 55 patients (49.1%) had thrombocytopenia, but the difference between the different lines of treatment wasn’t significant p value of 0.95. The median time to relapse is 10 months and the median survival time is 40 months. The 3-year PFS rates of all patients were 49.3%, while the 3 year OS rates were 54.8%. Conclusion: The overall and PFS didn’t show any difference between different lines of treatment.

Outcome of Second Line Chemotherapy (Gemcitabine, Dexamethasone, and Cisplatin) in Relapsed and Refractory Non Hodgkin Lymphoma

AbstractBackground: The treatment of patients with relapsed or refractory non-Hodgkin lymphoma remains challenging. The strategy for management of relapsed or refractory disease is to deliver salvage chemotherapy, followed by autologous stem-cell transplantation in responding patient. Such salvage therapies typically consist of cytotoxic agents that have not been used in first line therapy.Aim of Study: In this study we are trying to study one of the salvage chemotherapy lines which is GDP regarding response rate, quality of life and toxicity.Patients and Methods: Seventy patients diagnosed as refractory or relapsed NHL were included in the study; all patients received GDP for 4 to 6 cycles. Primary end point was to evaluate overall response to treatment; secondary end point was to evaluate quality of life and toxicity. An informed written consent was obtained from all the patients and approval of Research Ethics Committee of Assiut, Faculty of Medicine was obtained prior to the study.Results: The overall response was 65% with complete response 25% and partial response 40%. Regarding quality of life it was noticed that 32.9% patients using GDP were improved, 40% were stable patients while significant deteri-oration occurred in 27.1%. Regarding toxicity profile, occur-rence of neutropenia was 50% with grade III-IV 15%, throm-bocytopenia 40% with grade IV-V 5%, anemia 60% with grade II-III 7%. Nausea 50% with grade III-IV 3%, vomiting 40% with grade III-IV 10%, diarrhea 34.3% with grade II-III 5%. Renal toxicity 31.4% with grade I-II 15%, neurological toxicity 40% grade I-II 10%. Hepatic toxicity 25.7% with grade I-II 20%.Conclusion: GDP is effective as second line chemotherapy with good response rate, quality of life and a manageable range of toxicity.

Efficacy and Adverse Reactions of Gemcitabine Combined with Cyclophosphamide, Vinblastine and Prednisone Hydrogenation Regiments in Relapse and/or Refractory Non-Hodgkin's Lymphoma

Objective: To explore the clinical efficacy and adverse reactions of gemcitabine combined with cyclophosphamide, vinblastine and prednisolone (GCVP regiments) in the treatment of relapse and/or refractory non-hodgkin's lymphoma (NHL) in adults patients. Methods: 27 relapse and/or refractory non-hodgkin's lymphoma adult patients (Median:58 years old; range:47-72 years old) were diagnosed and previously treated with regimens such as R-CHOP(E), CHOP(E), MAED (Mitoxantrone, Cytarabine, Etoposide, Dexamethasone), FCM (Fludarabine, Cyclophosphamide, Mitoxantrone) based chemotherapy. There were 19 cases of diffuse large B cell lymphoma, 6 cases of follicular lymphoma, 1 case of NK/T cell type and 1 case of T cell NHL respectively. The GCVP chemotherapy (1000mg/m2 of gemcitabine, 750mg/m2 of cyclophosphamide, 25mg/m2 of vinblastine, intravenous drip on day 1 and day 8, prednisolone 50mg by intravenous drip on day 1 to day 5) were applied to these patients, safety and efficacy analyses were evaluated after two cycles. All patients provided written informed consent. Results: Among all the 27 patients who received GCVP chemotherapy, 3 patients achieved complete remission (CR) (11.11%), 15 patients achieved partial remission (PR) (55.56%), 9 patients with stable disease (SD) (33.33%), the overall response rate (ORR, CR+PR) was 66.67%. Patient's follow-up was continued after treatment, and the median duration of progression-free survival was 60 days. The main adverse events were bone marrow suppression, others were mild to moderate gastrointestinal reactions, a few had mild liver function damage, and it was reversible through hepatoprotection therapy. The most common grade ≥3 adverse events were leukopenia (33.33%, 9/27 cases), thrombocytopenia (40.74%, 11/27 cases), while anemia and gastrointestinal reaction were 11.11% (3/27 cases) and 3.70% (1/27 cases) respectively, no treatment-related death occurred. Discussion and conclusion: The overall outcomes for patients with lymphoma was improved, but there still part of NHL patients suffered form relapse or primary drug resistance, and the prognosis of these patients was poor. Gemcitabine combined with cyclophosphamide, vinblastine and hydrogenated prednisone has a good short-term efficacy in the treatment of relapse and/or refractory NHL. The main adverse reactions were hematologic toxicity and gastrointestinal reaction, mild liver function damage, and no treatment-related death was observed. DisclosuresNo relevant conflicts of interest to declare.

Thalidomide Combined with Interferons for the Treatment of Recurrent or Refractory Non-Hodgkin's Lymphoma

This study examined the clinical efficacy and safety of thalidomide combined with interferons for the treatment of recurrent/refractory non-Hodgkin's lymphoma. We retrospectively analysed the clinical data of 42 patients with recurrent or refractory non-Hodgkin's lymphoma (NHL) who were treated with a regimen of thalidomide combined and interferon α-1b (IFNα-1b) at Henan Tumour Hospital from July 2007 to January 2017. Specifically, the patients initially received 100 mg thalidomide in tablet form once daily at bedtime. If the patient tolerated the drug, the dose was increased to 200 mg. Recombinant human interferon α-1b was subcutaneously injected at a dosage of 60 μg every other day over a period of four weeks. The efficacy was monitored throughout each treatment cycle, adverse reactions were evaluated, and the progress of the disease was assessed during follow-up visits. Relevant indicators, such as the overall response rate (ORR), the overall survival (OS), the progression-free survival (PFS) for all patients, and the safety of the regimen, were analysed. Forty-two patients were treated with a regimen of thalidomide combined with interferons for at least 1 period. The efficacy of the treatment was evaluated for each patient. The objective response rate (CR + PR) was 73.8%. The median overall survival time was 28 months and the median progression-free survival (PFS) time was 21 months. According to the standards of lymphoid malignancies classified by the WHO in 2001, 36 patients were diagnosed with B-cell lymphoma, 24 of whom suffered from recurrent or refractory mantle cell lymphoma (MCL). The combination of thalidomide and interferons improved the conditions of 16 MCL patients, 8 of whom experienced CR and 8 of whom experienced PR. The median OS was 28 months, and the median PFS was 19 months for the patients with MCL. The primary adverse effects of the regimen were drug-induced fever and joint pain caused by the IFN and neurotoxicity and constipation caused by the thalidomide. The adverse reactions ranged in severity from degree I~II and could be alleviated by symptomatic treatment. Serious adverse reactions, such as anaphylactic shock, deep vein thrombosis and bradycardia, did not occur. DisclosuresNo relevant conflicts of interest to declare.

A Phase I Study of Molibresib (GSK525762), a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of a Phase I/II Open Label Single Agent Study in Subjects with Non-Hodgkin's Lymphoma (NHL)

A Phase I Study of Molibresib (GSK525762), a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of a Phase I/II Open Label Single Agent Study in Subjects with Non-Hodgkin's Lymphoma (NHL)

Evaluation of the Effectiveness and Safety of Pixantrone for the Treatment of Multiply Relapsed or Refractory Aggressive Non Hodgkin B-Cell Lymphoma (aNHL) an Observational Multicentre Retrospective Study in a Real World Population

BACKGROUND: The objective of this study was to evaluate the effectiveness and safety of pixantrone as a rescue treatment for NHL patients in a real world population in Spain and Italy as data on the use of this drug in everyday clinical practice is still scarce.METHODS: The study included patients aged ≥18 years with histologically proven relapsed or refractory B-cell aNHL who were treated according to pixantrone's product information. Primary endpoint was progression-free survival (PFS). Secondary endpoints included the proportion of patients with complete response (CR), partial response (PR), overall response rate (ORR), overall survival (OS), as well as safety.RESULTS: 79 patients were included in 52 centers. At diagnosis, mean age was 65 years (95% CI 62-68) and 83% had ECOG 0-1. At pixantrone treatment initiation, 82% of patients presented Ann Arbor stage III-IV, and 64% an International Prognostic Index (IPI) Score ≥3; 85% were refractory and 15% relapsed. Median number of previous therapies was 3 (range 1-5). Patients received a median of two cycles of pixantrone (range 1-6). ORR was 29% with 13.2% CR and 15.8% PR. Median PFS and OS were 2.8 months (95% CI 2.1-3.6) and 4 months (95% CI 3.6-4.4), respectively. There was a trend towards better PFS in relapsed vs refractory patients (12.5 vs 2.6 months, respectively, p=0.059). Patients who received two or more cycles of pixantrone had 38% ORR (CR 17.5%; PR 19.3%). Adverse reactions to pixantrone were reported in 63% of patients. The most frequent toxicities were hematological (67.1%) and gastrointestinal (12%). No febrile neutropenia or clinical cardiotoxicity was reported.CONCLUSIONS: Although a high percentage of patients with very poor prognostic factors was included in this study (82% Ann Harbor III-IV, 63% IPI ≥3, and 85% refractory), treatment with pixantrone appears to be effective. There was a trend to better efficacy in terms of PFS in relapsed vs refractory patients. In those patients who received ≥2 cycles, pixantrone was more effective compared to those who received less than two cycles, with ORR similar to the pivotal study. Pixantrone treatment resulted active and well tolerated in real world clinical practice.Keywords: Refractory non-Hodgkin lymphoma; Relapsed non-Hodgkin lymphoma; Salvage therapy; pixantrone. DisclosuresSancho:Roche: Speakers Bureau; Janssen: Speakers Bureau; Kern Pharma: Speakers Bureau; Roche: Honoraria; Gilead: Honoraria; Celgene: Speakers Bureau; Mundipharma: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Bristol-Myers: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees. Grasso Cicala:Servier: Employment. Spione:Servier: Employment. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau.

Early Response Data for Pediatric Patients with Non-Hodgkin Lymphoma Treated with CD19 Chimeric Antigen Receptor (CAR) T-Cells

Background:Pediatric patients with relapsed or refractory CD19+non-Hodgkin lymphoma (NHL) have poor outcomes despite use of chemotherapy and hematopoietic stem cell transplant (HSCT). Clinical trials of CD19 CAR T-cells have demonstrated efficacy in salvaging adult patients with relapsed and refractory NHL.Objectives:The objectives of this analysis is to assess the safety, toxicity, feasibility and efficacy of SCRI-CAR19v1 for pediatric patients with relapsed or refractory NHL.Design/Methods:The ongoing phase 2 trial (NCT02028455) has enrolled and treated 8 pediatric subjects with CD19+NHL. Subjects underwent apheresis, with their CD4 and CD8 T cell subsets prepared immunomagnetically. T cells were stimulated with anti-CD3xCD28 bead stimulation, and then transduced with a SIN lentiviral vector to direct co-expression of the FMC63scFv:IgG4hinge:CD28tm:4-1BB:ζ CAR and the selection/tracking/suicide construct EGFRt. The transduced cells were propagated using recombinant human cytokines to numbers suitable for clinical use. Subjects received lymphodepletion of fludarabine and cyclophosphamide followed by 1x106CD19 CAR T-cells/kg as a 1:1 ratio of CD4 and CD8 cells. Response was assessed at 3 and 9 weeks. Adverse events were graded according to CTCAEv4 except cytokine release syndrome (CRS) was graded according to Lee et al.Results: Treated subjects had relapsed or refractory diffuse large B cell lymphoma (DLBCL) (4/8), Burkitt's lymphoma (2/8), gray zone B cell lymphoma (1/8), primary mediastinal B cell lymphoma (PMBCL) (1/8), and ranged from 4-18 years old. Two subjects received prior hematopoietic stem cell transplant (HSCT); the subject with PMBCL received auto- and allogeneic HSCT and a subject with Burkitt's received autologous HSCT. Five subjects received prior immunotherapy with brentuximab, nivolumab, rituximab, and/or obinutuzumab. One subject had received ibrutinib. No subject had received prior CAR T-cells. CD4 and CD8 products were successfully manufactured and infused for all subjects. All subjects had expansion of CAR T-cells in the peripheral blood, bone marrow and CSF, with ongoing persistence at last check (range 14 days - 9 months). Toxicity information through day 30 revealed the occurrence of mild CRS in 4 subjects (grade 1 n=3, grade 2 n=1), and one case of severe CRS (grade 3). Mild neurotoxicity was observed in 2 subjects (grade 1 n=1, grade 2 n=1) with no occurrence of severe neurotoxicity. Response assessment at 3 weeks (n=6) revealed anti-tumor responses in 5 subjects, including complete response (CR) by week 9 (n=2, both DLBCL). CR was not sustained in either subject despite ongoing CAR T cell persistence. One of these subjects had a PET avid lesion proven by biopsy to be necrotic tissue but subsequently developed CD19+recurrence at that site. The other subject developed a new CD19+site of disease at six months; however, achieved a 2nd CR 3 weeks after receiving a second infusion of the originally manufactured CAR T-cells. One partial response (PR) subject experienced clearance of marrow disease with stable lymphoma but developed CD19 negative progression at 9 weeks. Updated enrollment, toxicity and response assessments will be presented.Conclusion:SCRI-CAR19v1 therapy demonstrates efficacy in pediatric patients with relapsed and refractory NHL and appears to be well tolerated with less severe toxicities than observed for pediatric patients with CD19+leukemia. Persistence of the CAR T-cells is excellent with no early loss of CAR T-cell engraftment reported to date. Although early responses were observed, these were not durable perhaps reflecting biologic/immunologic differences between B cell lymphomas in children in comparison to NHL in adults. DisclosuresPulsipher:Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria; CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Park:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Updated Report on Identification of Molecular Predictors of Tazemetostat Response in an Ongoing NHL Phase 2 Study

Updated Report on Identification of Molecular Predictors of Tazemetostat Response in an Ongoing NHL Phase 2 Study

Avadomide (CC-122), a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Avadomide (CC-122), a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Final Results of a CTEP Sponsored Phase I Study of Alistertib in Combination with Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma

Background: Over-expression of Aurora A has been shown in many subtypes of non-Hodgkin lymphoma (NHL) and is a negative prognostic factor in mantle cell lymphoma (MCL), where expression correlates with tumor proliferative signature (Ki67), and may contribute to cell cycle dysregulation. Aurora A regulates chromosomal stability through effects on mitosis and cell cycle regulation. Bortezomib increases both pro-apoptotic proteins and cell cycle dependent kinase inhibitors. Thus, there is a strong scientific rationale to combine Aurora A kinase and proteasome inhibition. We evaluated the combination of alistertib, an oral Aurora A kinase inhibitor, with bortezomib and rituximab in a CTEP sponsored phase 1 study of patients with relapsed /refractory (RR) low grade NHL or MCL.Methods: Patients with RR low grade NHL or MCL, who had received at least one line of immuno-chemotherapy were treated according to a 3 + 3 design with 3 dose escalation cohorts (DL1, DL2, and DL3) to identify the recommended phase 2 dose (RP2D) with an expansion cohort at the RPTD. Patients received alisertib 30mg BID (DL1 and DL2) or 40mg BID (DL3) on days 1-7, bortezomib subcutaneous 1mg/m2 (DL1) or 1.3 mg/m2 (DL2 and DL3) on days 1, 8, and 15, and rituximab 375mg/m2 on day 1 for the first 8 cycles, and subsequently q 3 months. An expansion cohort was treated at DL3. Treatment cycles were 28 days. Dose Limiting Toxicity (DLT) was defined within the first cycle of therapy.Results: A total of 24 patients at 3 sites were enrolled between 06/2013 and 02/2018, including DL1: 3, DL2: 7; DL3: 14. Median age was 64 (range 46-87). Twelve patients (50%) were male. Nineteen patients had low grade NHL, and 5 patients had MCL. Performance status was 0-1 in 22 (92%) patients, and 2 in 2 (8%) patients.Dose Escalation and Safety: The recommended phase II dose (RP2D) was DL3, with the only DLT in DL3 (prolonged grade 4 neutropenia). The most common grade 3-4 AEs at all dose levels were neutropenia (34%), thrombocytopenia (13%), anemia (8%), and fatigue (8%); grade 2 alopecia occurred in 37% (Table 1). Other grade 4 AEs included hypertension & hypotension, respiratory failure, hyperkalemia and hyperuricemia (n=1 (4%) each); one patient died of GI hemorrhage deemed unrelated to study treatment (NSAID overdose). Grade 3 neutropenia and leukopenia was seen in 4 patients and thrombocytopenia in 1. There was one grade 3 AE each of: hypertension, pulmonary hypertension, pneumonitis, fatigue, diarrhea, infusion reaction, lung infection, and febrile neutropenia.Efficacy: A total of 18 patients were evaluable for response. Five patients were not evaluable for response for the following reasons: withdrawal of consent (3, 1 each DL1, 2, 3), non-compliance (1 DL2), and death unrelated to study drug (1, DL2). For patients who were treated with at least 3 cycles of therapy, and had a restaging CT scan, the median duration of therapy was 142 days, (range 29-590). Response was seen in 7/18 evaluable patients for an overall response rate (ORR) of 38%; 4 of 18 patients (22%) had a complete response (CR), and 4 of 18 patients (22%) had a partial response (PR). An additional 8/18 patients (44%) had stable disease for a clinical benefit rate of 88%. With a median follow-up of 30.9 months, the median PFS was 6.9 months (95%CI 4.1-28.0) and median OS not reached. OS at 3 years was 64.9% (95% CI 44.1-95.3%; Fig. 1). Median duration of response was 14.1 mo (95% CI 2.63-NR).Conclusion: Alisertib in combination with bortezomib and rituximab is a well-tolerated regimen with significant and durable activity in heavily pretreated low grade NHL and MCL. The RP2D is DL3 (R + bortezomib 1.3mg/m2 and 1.8 alisertib 40mg bid). A correlation of Aurora Kinase tumor expression with clinical outcome is planned. [Display omitted] DisclosuresBarta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Diefenbach:Merck: Consultancy, Research Funding; Genentech: Consultancy; Incyte: Research Funding; Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Denovo: Research Funding.

Clinical Response and Tolerability of Selinexor in Acute Myeloid Leukemia and Other Hematologic Malignancies - a Systematic Review

IntroductionSelinexor, a SINE (selective inhibitor of nuclear export) compound, inhibits exportin 1 (XPO1) involved in transport of tumor suppressor proteins leading to apoptosis of tumor cells. XPO1 is overexpressed in variety of cancer including ovarian cancer, pancreatic cancer, glioma, osteosarcoma, leukemia, lymphoma, and multiple myeloma. The aim of this study is to summarize clinical response and adverse events of selinexor in hematological neoplasms.MethodsA comprehensive literature search on PubMed, Embase, AdisInsight and Clinicaltrials.gov was completed on July 12, 2018. Studies focusing on efficacy and/or adverse events of selinexor in patients with hematological neoplasms were included for the review.ResultsOut of 321 studies found on initial search, we finalized 15 studies (8 phase I and 7 phase I/II) after screening by two reviewers. AMLSelinexor in combination with high-dose cytarabine and mitoxantrone has shown overall response rate (ORR) of 70% among 20 patients with acute myeloid leukemia (AML), Wang et al., 2018. Out of 12 newly diagnosed AML (ND AML) patients, 11 (92%) patients showed response with complete response (CR) in 7, CR with incomplete recovery (CRi) in 3 and partial response (PR) in 1 patient. Among 8 relapsed/refractory AML (R/R AML) patients, only 3 patients showed CR while 5 had treatment failure (TF), ORR in this subset was 38%. In 81 evaluable R/R AML patients receiving selinexor as monotherapy only 14% of the patients showed response while 31% patients had disease progression (PD) along with grade ≥3 hematological adverse events (AEs) of thrombocytopenia, anemia and neutropenia in 19%, 15% and 13% patients, respectively (Garzon et al., 2017). MMRelapsed refractory multiple myeloma patients receiving selinexor combined with pomalidomide and dexamethasone have achieved ORR of 60% with CR in 1 and PR in 5 patients (Chen et al., 2016 n=10) with grade ≥3 neutropenia in 8 patients. In another regimen with doxorubicin and dexamethasone the clinical benefit rate (CBR) was 26% with 15% overall response (Rachid et al., 2017 n=27). Grade ≥3 neutropenia, thrombocytopenia and hyponatremia occurred in 33%, 33% and 30% of patients, respectively. NHLKuruvilla et al. observed ORR in 31% patients with relapsed refractory non-Hodgkin lymphoma with single-agent selinexor. Grade ≥3 thrombocytopenia, neutropenia and anemia occurred in 47%, 32% and 27% patients, respectively. The efficacy of selinexor in phase I and I/II clinical trials is given in table 1 while toxicity is mentioned in table 2. With selinexor, the most common hematological and nonhematological AEs noted were thrombocytopenia and hyponatremia, respectively. ConclusionSelinexor based combination regimens have shown better clinical response against AML as compared to monotherapy. The efficacy results in multiple myeloma and other hematological malignancies are also encouraging. The adverse events like cytopenias were common as in other chemotherapy regimens. DisclosuresNo relevant conflicts of interest to declare.

The Role of High Molecular Weight Kininogen in Lymphoma Microvascular Density and Growth

Background: Non-Hodgkin lymphoma (NHL) is a common malignancy in childhood and adolescence. The prognosis of relapsed and refractory NHL remains poor, and new approaches to therapy are needed. High molecular weight kininogen (HK) is a central component of the kallikrein-kinin system. Previous work has demonstrated that in vitro, the kallikrein-cleaved form of HK induces apoptosis of proliferating endothelial cells. Prior studies performed in our laboratory have demonstrated the increased angiogenesis and tumor growth in the absence of HK in B16F10 melanoma and Lewis lung carcinoma models. However, the role of endogenous kininogen in modulating the growth and of hematologic malignancy is unknown. To elaborate the role of HK in in the development and progression of a murine lymphomas, we assessed growth and vascularization of T-cell lymphoma xenografts in wild type (WT) and kininogen deficient (mKNG1-/-) mice.Methods: Murine T-cell lymphoma (EL-4) cells (1 x 10^6) were implanted into wild-type and mKNG1-/- mice. Tumor size was measured using calipers and tumor volume was calculated using the formula V = length x width^2 x 0.52. Fifteen days after cell implantation, tumors were harvested, processed and analyzed by immunofluorescent staining with anti-CD31 antibodies to determine microvascular density (MVD).Results: EL-4 lymphomas grew more rapidly and to larger sizes in mKNG1-/- mice compared to wild-type mice, with significant differences apparent by day 11 after tumor implantation (p<0.001). By Day 15, the volume of tumors in mKNG1-/- mice was approximately ~2-fold greater than in wild-type mice (Figure 1A). Weights of EL-4 Lymphomas were determined after 15 days of implantation and found significantly different between two groups (Figure 1B). To assess whether the difference in growth rates of lymphomas in wild-type and mKNG1-/- correlated with differences in angiogenesis, the microvascular density within tumors from these animals was compared by counting vessels stained with anti-CD31 antibodies (Figure 1D). Compared to wild-type mice, lymphomas in kininogen deficient mice demonstrated significantly greater microvascular density when either random fields were assessed (Figure 1C and 1D, P < 0.001).Conclusion: These findings suggest that HK is an important endogenous regulator of angiogenesis and tumor growth in this T- cell Lymphoma model. Although the role of kininogen has been described in solid tumor models, this study is the first to demonstrate that kininogen specifically angiogenesis in a hematopoietic tumor. Further work is needed to understand the mechanisms underlying these findings and inform anti-angiogenic therapies to increase the options for patients with hematopoietic malignancies such as NHL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Tandem Induction Radiation and Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Tandem Induction Radiation and Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Outcomes of Patients with Recurrent and Refractory Lymphoma Undergoing Allogeneic Hematopoietic Cell Transplantation with BEAM Conditioning and Sirolimus- and Tacrolimus-Based GVHD Prophylaxis

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

InVivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin's Lymphomas.

Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19-specific CAR-transduced Tcell products (CD19.CARTs), 2G (with CD28 only) and 3G (CD28 and 4-1BB), were infused simultaneously in 16 patients with relapsed or refractory non-Hodgkin's lymphoma. 3G CD19.CARTs had superior expansion and longer persistence than 2G CD19.CARTs. This difference was most striking inthe five patients with low disease burden and few circulating normal B cells, in whom 2G CD19.CARTs had limitedexpansion and persistence and correspondingly reduced areaunder the curve. Of the 11 patients with measurable disease, three achieved complete responses and three had partial responses. Cytokine release syndrome occurred in six patients but was mild, and no patient required anti-IL-6 therapy. Hence, 3G CD19.CARTs combining 4-1BB with CD28 produce superior CART expansion and may be of particular value when treating low disease burden in patients whose normal B cells are depleted by prior therapy.

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study

BackgroundVenetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine–rituximab (BR) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). Patients and methodsBR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. ResultsSixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n=4) or respiratory failure (n=1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3months [95% confidence interval (CI) 10.4–NR], not yet reached, and 10.7months (95% CI 4.3–21.0), respectively. ConclusionsThis study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registeredClinicaltrials.gov, NCT01594229.

Comparison of Efficacy of Pembrolizumab between Epstein-Barr Virus‒Positive and ‒Negative Relapsed or Refractory Non-Hodgkin Lymphomas.

PurposePembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and programmed cell death ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), real-world data about the efficacy of pembrolizumab in NHL patients are limited.Materials and methodsWe analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)‒positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression.ResultsSeven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV-negative subtypes did not respond such as diffuse large B-cell lymphoma and T-lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%).ConclusionPembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL.

CLINICAL CHARACTERISTICS AND TREATMENT RESULTS OF PEDIATRIC RELAPSED/REFRACTORY NON-HODGKIN’S LYMPHOMAS

Despite the development and active use of modern high-effective therapeutic protocols for pediatric non-Hodgkin’s lymphomas (NHL), treatment results of relapses and refractory disease are unsatisfactory. In the current issue international practices and own experience in relapsed/refractory pediatric NHL are presented: lymphoblastic lymphomas, anaplastic large cell lymphoma, and heterogeneous group of mature B-cell lymphomas. Chemotherapy protocols, results of nelarabine, rituximab, crizotinib, brentuximab vedotin, stem cell transplantation use for relapsed/refractory pediatric NHL treatment are presented. In 27 relapsed NHL patients treated inN.N.BlokhinNationalMedicalResearchCenterof Oncology, overall survival was 29.1 ± 7.9% (median follow-up 56.3 ± 14.4 months). Primary refractory NHL cases were fatal. Own and literature data make it necessary further study of new therapeutic approaches aimed at improvement of results in relapsed/refractory NHL.

Abstract SY42-01: Targeting T cell malignancies with gene edited CAR-T

Abstract T-cell malignancies represent a class of devastating hematologic cancers with high rates of relapse and mortality in both children and adults for which there are currently no effective or targeted therapies. Despite intensive multiagent chemotherapy regimens, fewer than 50% of adults and 75% of children with T-ALL survive beyond five years. For those who relapse after initial therapy, salvage chemotherapy regimens induce remissions in 20-30% of cases. Allogeneic stem cell transplant, with its associated risks and toxicities, is the only curative therapy. Targeted therapy against T-cell malignancies represents a significant unmet medical need. Such targeted therapies have shown great potential for inducing both remissions and even long-term relapse-free survival in patients with B-cell leukemia and lymphoma. Engineered T cells that express a chimeric antigen receptor (CAR) directed against T-cell malignancies are limited by several significant obstacles, but are a promising cancer immunotherapy. First, the shared expression of target antigens between T effector cells and T-cell malignancies results in fratricide, or self-killing, of CAR-T cells. Second, harvesting adequate numbers of autologous T cells without contamination by malignant cells is, at best, technically challenging and prohibitively expensive. Third, the use of genetically modified CAR-T cells from allogeneic donors may result in life-threatening graft-vs.-host disease (GvHD) when infused into immune-compromised HLA-matched or mismatched recipients. We hypothesized that deletion of CD7 and the T-cell receptor alpha chain (TRAC) using CRISPR/Cas9 in CAR-T targeting CD7 (UCART7) would result in the efficient targeting and killing of malignant T cells without significant effector T-cell fratricide or induction of GvHD. We chose to target CD7 on malignant T cells because it is overexpressed on the vast majority of T-cell and NK-cell malignancies. Second, germline biallelic deletion of CD7 resulted in mice with normal T-cell numbers, T-cell subsets, and T-cell function. We generated a CD7 CAR using a anti-CD7 single chain variable fragment (scFv) created using commercial gene synthesis and cloned into the backbone of a 3rd-generation CAR with CD28 and 4-1BB internal signaling domains. The construct was modified to express CD34 via a P2A peptide to enable detection of CAR following viral transduction. Human primary T cells were activated using anti-CD3/CD28 beads for 48 hours prior to bead removal and electroporation with CD7 gRNA, TRAC gRNA, and Cas9 mRNA. On day three, T cells were transduced with lentivirus particles encoding either CD7 CAR or CAR CD19 control and allowed to expand for a further 6 days. Transduction efficiency and ablation of CD7 and TRAC was confirmed by flow cytometry. Multiplex CRISPR/Cas9 gene-editing resulted in the simultaneous deletion of both CD7 and TRAC in 72.8%±1.92 of cells, as determined by FACS analysis. To prevent alloreactivity, CD3+ CAR-T were removed from the product by magnetic depletion. UCART7 effectively killed T-ALL cell lines (CCRF-CEM, MOLT3, and HSB2) and human primary T-ALL blasts in vitro. Next, we tested the capacity of UCART7 to kill primary T-ALL in vivo without xenogeneic GvHD. Considerable expansion of alloreactive T cells, severe GvHD (mean clinical GvHD score = 5.66), and a robust graft vs. leukemia effect were observed in recipients of WT T cells. In contrast, GvHD was completely absent, T cells were undetectable, and considerable tumor burden was observed in mice receiving TRACΔ T cells. Mice receiving UCART7 had no GvHD and unlike UCART19 controls, effectively cleared T-ALL blasts. Fratricide-resistant and allo-tolerant "off-the-shelf" UCART7 signifies a novel strategy for treatment of relapsed and refractory T-ALL and non-Hodgkin's T-cell lymphoma. Citation Format: John F. Dipersio, Matthew Cooper. Targeting T cell malignancies with gene edited CAR-T [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY42-01.

Abstract 301: Targeting the anti-apoptotic BCL-2 family protein provides an effective and precise therapeutic strategy for NHL

Abstract Background: Despite advances in the treatment of non-Hodgkin's lymphoma (NHL), refractory NHL remains a major clinical challenge. The B-cell lymphoma protein-2 (BCL-2) family is frequently overexpressed in NHL, which is associated with poor prognosis by promoting cell growth and resistance to antitumorigenic agents. In this study, by using different BCL-2 family protein inhibitors, we aim to further classify the survival dependency of NHL for anti-apoptotic BCL-2 family members and explore novel approaches to rationally develop combination therapies by completely blocking the activity of the Bcl-2 family proteins. Methods: Cell viability was determined by CCK-8 assay. Apoptotic activity was confirmed by Annexin V-propidium iodide (PI) apoptosis detection, Western blot analysis and mitochondrial membrane potentials detection analysis. In vivo, NHL xenograft models were established to analyze the antitumor effect of the BCL-2 family protein inhibitors. Results: We evaluated the inhibitory effect of of Bcl-2 targeted inhibitors and synergy in combination with other molecular targeted agents in NHL. While those NHL cell lines with only high levels of BCL-2 protein are sensitive to Bcl-2 selective inhibitor, the dual Bcl-2/Bcl-xL inhibitor APG-1252 and its active metabolite APG-1252-M1 potently induced mitochondria-dependent apoptosis in NHL cell lines that possess high expression of both BCL-2 and BCL-XL proteins. After the treatment of APG-1252-M1, apoptosis including caspase-3 activation, PARP cleavage, and mitochondrial membrane potentials change was observed rapidly within four hours. We further demonstrated that APG-1252-M1 showed synergistic effects with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in those sensitive cell lines by modulating STAT3 signaling pathways. However, cell lines harboring high expression of anti-apoptotic protein MCL-1 were resistant to APG-1252-M1. Furthermore, we observed that APG-1252-M1 exhibited strong synergistic effect with dual PI3K/mTOR inhibitors NVP-BEZ235 in those resistant cell lines with high levels of Mcl-2 protein. Conclusions: Taken together, our data provide an effective and precise therapeutic strategy for NHL through determining NHL addiction to anti-apoptotic BCL-2 family proteins, and then target-guided application of BCL-2 family inhibitors as a monotherapy or in combination with other molecular targeted agents to completely block the Bcl-2 family proteins, thus to restore the apoptotic cell death. Citation Format: Qiu-Yun Luo, Han-Jie Yi, Xiang-Lei Yan, Miaozhen Qiu, Bao-Xia Li, Lin Zhang, Wen-Tao Pan, Lu-Ping Yuan, Zhen-Yi Liu, Douglas D. Fang, Yifan Zhai, Jian Sun, Da-Jun Yang. Targeting the anti-apoptotic BCL-2 family protein provides an effective and precise therapeutic strategy for NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 301.