Refractory non-Hodgkin Lymphoma Research Articles

High-Dose Ara-C, Carboplatin, Etoposide, and Steroids (ACES) Is Effective in Relapse and Refractory Non-Hodgkin Lymphoma

BackgroundA standard chemotherapy regimen for relapse or refractory non-Hodgkin lymphoma (RR-NHL) is unexplained yet.Although platinum-based therapies, such as dexamethasone, high-dose cytarabine, and cisplatin and etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHAP), are the most commonly used second-line therapies for RR-NHL; nephrotoxicity is a potentially anxious side effect of platinum compounds. In addition, these regimens require a large volume of fluid replacement to prevent nephrotoxicity. ACES comprises carboplatin, 100 mg/m2 on days 1-4; etoposide, 80 mg/m2 on days 1-4; high-dose Ara-C, 2 g/m2 on day 5; and methylprednisolone, 500 mg/day for 5 days from the first day (Niitsu et. al. Eur J Haematol. 1996). However, ACES shows less renal toxicity and gastrointestinal symptoms by replacing cisplatin with carboplatin than that shown by ESHAP. The efficacy and safety of ACES are still unclear because clinical study on ACES regimen for lymphoma is limited. Therefore, we retrospectively evaluated the therapeutic effects and adverse events (AE) in RR-NHL patients who were treated with ACES regimens.Patients and methodsWe analyzed 116 refractory [patients who had not achieved complete response (CR) in the last chemotherapy (n = 78)] and relapse (n = 36) NHL patients who were treated with ACES regimen at our hospital from 2006 to 2016. ACES was performed at every 3 weeks. Among B-cell NHLs (n = 87), 80.4% of patients were treated with rituximab plus ACES. Patients 65 years of age or older were given two-thirds of the standard dose. The median age was 72 years (20-92 years) and median follow-up period was 386 days (29-3177 days). Histological analysis revealed diffuse large B-cell lymphoma (DLBCL) (n = 56), follicular lymphoma (FL) (n = 16), peripheral T-cell lymphoma (PTCL) (n = 19), and other NHLs (n = 25). The ACES regimen was administered as the second-line therapy in 71 (62.2%) patients, and more than third-line therapy in 36 (31%) patients. Sixteen patients underwent auto-PBSCT. We further analyzed the relationships between the clinical outcome [overall response rate (ORR), CR, disease-free survival, and overall survival (OS)], clinical data [sex, patient age (>65 years), performance status (>2), clinical stage (CS>III), IPI (>HI), FLIPI (>HI), number of prior therapies (>2), response to last chemotherapy, period from the last chemotherapy (<60 days), auto-PBSCT], and laboratory parameters [white blood cell count (>5000/µl), lymphocyte count (>1000/µl), platelet count (>15000/µl), LDH (elevated or normal), sIL-2R (elevated or normal), and CRP (elevated or normal)] before initiating ACES regimen. AE were graded according to CTCAE version 4.ResultsThe median number of cycles of ACES regimen was 2 (range: 1-11). Among all patients, ORR was 50% with CR 22.4%. ORR in DLBCL, FL, and PTCL were 50%, 68.8%, and 42.1%, and CR rates were 21.4%, 37.5%, and 16.6%, respectively.The overall median survival duration was 12.6 months; 3- and 5-year OS rates were 33.6% and 30.5%, respectively. Either of CS, elevated CRP, LDH, PS>2, number of previous therapies, response to last chemotherapy, sIL-2R, or period from the last chemotherapy was significantly associated with shorter OS (P= 0.026, P < 0.001, P= 0.003, P= 0.002, P= 0.03, P < 0001, P= 0.001, and P < 0.001, respectively). In multivariate analysis, LDH, period from the last treatment, and CRP were significantly associated with a decreased CR rate (P = 0.049, P = 0.034, and P = 0.004, respectively). The 3-year OS rate in DLBCL, FL, and PTCL were 35.2%, 62.1%, and 32%, respectively. OS was significantly longer in FL than in DLBCL and PTCL (P = 0.027).Hematological AE of grade 3 or higher included neutropenia in 90.5% and thrombocytopenia in 70.6% of patients; sepsis and pneumonia developed in two patients. Increased serum creatinine level of grade 3 or higher was observed only in 8.6% [grade 2 (n = 7), grade 3 (n = 3)].ConclusionIn this study, we analyzed a relatively large number of patients with NHL who were treated with ACES. Although this study included many patients with unfavorable factors such as older age, more than third-line therapy and refractory treatments before ACES, response rates, and OS were comparable with other salvage regimens including ESHAP. In ACES, carboplatin was administrated without continuous hydration, and renal toxicity was less than that in ESHAP. Therefore, we suggest that ACES is an option for treatment of RR-NHL. DisclosuresNo relevant conflicts of interest to declare.

Elucidating Exposure-Response (Safety and Efficacy) of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Containing Antibody Drug Conjugate, for Recommended Phase 2 Dose Determination in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

▪Introduction: ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate (ADC) composed of a humanized CD19-specific IgG1 antibody stochastically conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin via a cleavable maleimide linker. In this Phase 1 dose escalation trial of heavily pre-treated patients with B-cell non-Hodgkin lymphoma (NHL), loncastuximab tesirine (Lonca-T) 15 to 200 µg/kg was administered every 3 weeks (q3w) by intravenous infusion. The dose and pharmacokinetic (PK) exposure of Lonca-T were modeled as drivers of safety (treatment-emergent adverse events [TEAEs]) and efficacy (reduction in tumor size) for the determination of the Recommended Phase 2 Dose (RP2D).Methods:Concentrations of PBD-conjugated antibody (Ab) in serum were determined using a validated electrochemiluminescence immunoassay, then analyzed by population PK methodology using NONMEM (version 7.3, first-order conditional estimation). Associations between exposure (dose and Bayesian-estimated individual-patient exposure metrics) and the maximum severity of early (Cycle 1) and early or later (all cycles) TEAEs were evaluated for overall TEAEs, anemia, platelets, neutrophils, hemoglobin, fatigue, edema and pleural effusion. Associations of dose and PK with maximum change from baseline tumor size were also determined to identify potential relationships between exposure and activity (complete response plus partial response). For the PK population, drug concentrations were described using the log-transformed both sides approach with a 3-compartment open model and zero-order infusion. In the final population model, gender was retained as a covariate on central volume of distribution.Results: Data from 44 patients (28 males and 16 females) were included in the population PK model. Patients had a mean (range) age of 67 years (24-85) and weight of 87 kg (42-143). A positive relationship was apparent for maximum severity TEAEs, anemia, and thrombocytopenia both in Cycle 1 and in later cycles. A positive relationship was evident for neutropenia, edema and pleural effusion in later cycles only. For patients with and without Grade 3/4 TEAEs, median (5th, 95th percentile) PBD-conjugated Ab area under the curve (AUC) was 13.6 mg*Day/L (0.359, 40.8), and 6.33 mg*Day/L (0.308, 35.0), respectively. Increased exposure to Lonca-T in Cycle 1 was associated with decreased tumor size, with the model giving a dosage of 120 µg/kg q3w as a median minimum dose necessary for requisite efficacy. To achieve at least a 50% tumor size reduction from baseline, the median (min, max) PBD-conjugated Ab AUC was ~66 mg*Day/L (4.69, 294), which is close to the median AUC values of 63.9 and 66.9 mg*Day/L from patients in the 120 and 200 µg/kg cohorts, respectively.Conclusions: By quantitating the differences between exposure associated with grade of a given TEAE and the exposure necessary for efficacy, an optimal dose of Lonca-T associated with an acceptable set of toxicity thresholds was preliminarily identified. Since this trial is ongoing, supplemental pending data will be incorporated into the model, particularly for the 150 µg/kg dose, for an alternate dosage frequency (q6w), for individual patient CD19 status at baseline, and for NHL subtype, to provide the rationale for dosage and regimen selection and definition of the RP2D. DisclosuresO'Connor:ADC Therapeutics: Research Funding. Kahl:Seattle Genetics: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy. Hamadani:Takeda, Otsuka, MedImmune, Merck, ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene, Cellerant, Jansen, MedImmune: Consultancy. Caimi:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Reid:ADC Therapeutics, Millennium: Research Funding. Feingold:ADC Therapeutics: Employment, Other: Potential equity interest. Havenith:ADC Therapeutics: Employment, Other: Stock option interest. He:ADC Therapeutics: Employment, Other: Potential equity interest. Mould:Projections Research Inc, a consulting company for pharmaceutical industry: Consultancy. Freedman:Projections Research Inc, Gerson Lerhrman Group: Consultancy; Freedman patent: Patents & Royalties. Boni:ADC Therapeutics: Employment, Other: Potential equity interest.

Efficacy and Safety of Novel Targeted Drug' Apatinib in Relapse or Refractory Non-Hodgkin Lymphoma: An Open Label, Single-Armed, Exploratory Study

▪Background: Apatinib, a small molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, is a first-generation oral antiangiogenesis drug approved in the People's Republic of China for use as a subsequent line of treatment for advanced gastric cancer, also have shown remarkable efficacy in many solid cancers. But evidence of antitumor activity in patients with Lymphoma is still limited. We conducted an open-label, single-armed, exploratory study in relapse or refractory non-hodgkin lymphoma patients for the efficacy and safety of apatinib.Methods: Patients age between 18 and 70 years with histologically confirmed non-hodgkin lymphoma and had to have taken at least two lines of chemotherapy fail before participating in the study were eligible for enrollment. Additional enrollment criteria were as follows: at least one measurable lesion, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and acceptable organ function. All eligible patients took a treatment comprised of oral apatinib 500mg once daily with 21 days as a treatment cycle. Treatment interruption resulting from toxicities was allowed for no more than 7 days (either continuously or cumulatively) in each treatment cycle. Efficacy was evaluated every two cycles. The primary end point was response rate. Secondary end points included progression-free survival (PFS) and overall survival (OS).Results: Between February 2016 and December 2016, 21 patients were enrolled. Baseline clinical characteristics are listed in Table 1. The ORR (CR plus PR) was 47.6% (10 of 21 patients) included 9.5% CRs and 38.1% PRs. 23.8% patients achieved stable disease made the DCR 71.4% (15/21) (Table 2). Response rates by histology were: DLBCL, 6 of 11 patients; MCL, one of two; FL, one of one; ENKT, one of four; and PTCL, two of three. The median OS was 7.3 months (95% CI, 7.1 to 7.9) and the median PFS was 7.1 months (95% CI, 4.2 to 7.3). Adverse events (AEs) are listed in Table 3. Most patients suffered from grade 1 to grade 2 treatment-related adverse events. Dose modifications resulting from toxicity occurred on two patients for hand-foot syndrome and proteinuria, respectively. Death resulting from toxicity was not observed. The most common nonhematologic adverse events were proteinuria (47.6%), hypertension (42.9%) and hand-foot syndrome (33.3%).Conclusions: In our study, the results we presented showed the VEGFR-TKI apatinib might have a rapid, safe and high efficacy on relapsed or refractory non-Hodgkin lymphoma patients. And more clinic trials are expected to be taken to identification the efficacy of apatinib on lymphoma further. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Population Pharmacokinetic and Exposure-Response Modeling for the EZH1/2 Dual Inhibitor DS-3201b in Patients with Non-Hodgkin Lymphomas

▪Introduction: Epigenetic regulators are an emerging new target class for cancer therapy. Enhancer of zeste homolog 1 (EZH1) and EZH2 are alternative subunits of polycomb repressive complex 2 (PRC2), and catalyze tri-methylation of the 27th lysine residue of histone H3 (H3K27). The tri-methylation of H3K27 (H3K27me3) plays an important role in the repression of genes associated with tumor suppression and cell differentiation. DS-3201b is a dual inhibitor of EZH1/2 with activity against hematological cancer cell lines that include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia-lymphoma (ATL). The first-in-human (FIH) study (NCT02732275) is on-going to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and potential anti-tumor activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), including ATL. This preliminary analysis was aimed to develop a population PK model, to explore the exposure-response (E-R) relationships for key safety and PD endpoints, and to find the optimal dose and schedule for DS-3201b.Methods: As of August 2, 2017, clinical data that include plasma levels of DS-3201a (a free form of DS-3201b) and platelet counts were collected from 15 patients with NHL who were participated in the FIH study. They received DS-3201b oral once-daily dosing ranging from 150 mg to 300 mg in 28-day cycles. Population PK analysis for DS-3201a in plasma was carried out and the potential influence of patient characteristics on the PK of DS-3201a was investigated in a covariate analysis. The PK/PD model for platelet counts was developed using a semi-mechanistic model which consists of compartments that imitate platelet proliferation, maturation, circulation, and a feedback on proliferation. Preliminary E-R analyses were also performed for PD biomarker.Results: A 2-compartment PK model with first order elimination and absorption lag-time best characterized the plasma concentration-time profile of DS-3201a. Serum albumin was a significant covariate for total clearance. In the FIH study, platelet counts decreased to a nadir during the first treatment cycle and it returned to baseline without drug interruption in most patients who received 150 mg or 200 mg doses, whereas all patients who received 300 mg required dose interruption. The PK/PD model with drug effect on platelet proliferation and feedback compartments aptly described the time-course of platelet counts. Model-based simulations showed that up-titration schedule based on each patient's platelet count after cycle 1 treatment could allow administration of higher DS-3201b doses to a subset of patients with low risk of grade ≥3 thrombocytopenia. The results of E-R relationship for the inhibition of H3K27me3 in surrogate tissues will also be presented.Conclusion: We developed preliminary population PK and E-R models for DS-3201b in patients with relapsed or refractory NHL. Model-based simulations suggested that up-titration approach can be effective for DS-3201b to ensure continuity of treatment benefit while minimizing dose-dependent thrombocytopenia. DisclosuresAtsumi:Daiichi Sankyo Co., Ltd.: Employment. Yoshiba:DaiichiSankyo Co., Ltd: Employment. Maruyama:Dai-ichi Sankyo, Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, GSK, Eisai, Mundipharma, Takeda, AbbVie, MSD, Sanofi, Pfizer, Otsuka, Novartis, Solasia, Zenyaku: Research Funding; Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, Eisai, Mundipharma, Takeda: Honoraria. Tobinai:HUYA Bioscience: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Servier: Research Funding; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Ishida:Kyowa Hakko Kirin Co., Ltd. Celgene K.K. Bayer Pharma AG: Honoraria, Research Funding. Ishitsuka:Celgene Kyowa Hakko Kirin Bristol-Myers Squibb Chugai Pharmaceutical Takeda Pharmaceutical mundiharma Taiho Daiichi Sankyo Janssen Novartis Pfizer Astellas sanofi Genzyme Alexion Sumitomo Dainippon Eisai Mochida Shire Otsuka Ono Teijin: Honoraria, Research Funding. Tsukasaki:Kyowa-Kirin: Honoraria; Chugai/Roche: Honoraria; DaiichiSankyo: Consultancy; Celgene: Honoraria, Research Funding; Mundypharma: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; HUYA: Honoraria. Adachi:Daiichi Sankyo Co., Ltd.: Employment. Fujitani:DaiichiSankyo: Employment. Tachibana:Daiichi Sankyo Co., Ltd: Employment. Yoshihara:Daiichi Sankyo Co., Ltd: Employment. Ishizuka:Daiichi Sankyo Co., Ltd: Employment.

Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Risk Factors Predicting Graft-Versus-Host Disease and Relapse-Free Survival (GRFS) after Allogeneic Hematopoietic Stem Cell Transplantation in Relapse/Refractory Non-Hodgkin Lymphomas

Although the increasing of novel drugs has improved the survival outcomes with non-Hodgkin lymphoma (NHL), about 50% of them have failed to respond or relapse and small fraction only could be cured by autologous hematopoietic stem cell transplantation (autoHSCT). So, allogeneic hematopoietic stem cell transplantation (alloHSCT) considers as a definitive modality of cure for relapsed or refractory NHL. However, it still associated with problematic concerns including graft-versus-host disease (GVHD), relapse, and non-relapse death. The success of alloHSCT is based on the measurement of survival duration with clinically significant negative events such as a novel composite endpoint of GVHD and relapse-free survival (GRFS) where the events were acute GVHD grade 3-4, moderate to severe chronic GVHD, relapse or death. Based on these reasons, we assessed GRFS and attempt to identify the prognostic factors of GRFS in patients with relapse/refractory NHL.MethodsWe retrospectively analyzed a consecutive 82 adult patients with relapse/refractory NHL who received an alloHSCT as salvage purpose between January 2008 and March 2016.ResultsMedian age at alloHSCT and follow-up duration were 38 (19-65) years and 28 months (1-112 months), respectively. 73 patients (89%) in aggressive histologic subgroup, 37 patients (45.1%) of bone marrow involvement, and favorable disease status as CR/PR at alloHSCT was in 45 patients (54.9%). 32 patients (65%) were received autoHSCT prior to alloHSCT. Majority (n=78, 95%) received reduced intensity conditioning regiemens, and donor type was HLA matched related (n=27, 33%), matched unrelated (n=45, 55%) and haploidentical (n=10, 12%).The 3-year overall survival (OS), progression-free survival (PFS), the cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (CI of NRM) were 50.9%, 44.4%, 34.8%, and 20.0%, respectively. Also, the 1-year OS, PFS, CIR, and CI of NRM were 66.7%, 56.8%,19.7% and 17.3%, respectively, and the 1-year GRFS was 40.7% in the group of all relapse/refractory NHL. By the multivariate analysis, received more than the third-line chemotherapy before the transplant, high IPI scoring at diagnosis, and unfavorable disease status as stable disease/ progressive disease at alloHSCT were associated with a worse GRFS at 1-year post alloHSCT (HR 1.88, p=0.045; HR 1.92, p=0.025; HR 1.94, p=0.024).ConclusionGRFS is a useful endpoint that is worth investigating tool as a maker of favorable HCT in lymphoma. These data suggest that the early adaptation of alloHSCT in the group of chemosensitive relapse with low-risk IPI score provide the highest GRFS rates as successful HCT in relapse/refractory NHL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Phase I/II Trial of Lenalidomide and Ofatumumab for the Treatment of Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL)

Introduction:Outcomes for patients with NHL who are refractory to first line therapy as well as relapsed disease are poor. Lenalidomide, an immunomodulatory drug, stimulates T-cell proliferation, IL2, IL10 and IFN-gamma production. Ofatumumab, a monoclonal anti-CD20 antibody has shown to have activity as monotherapy in B-cell NHL. This phase I/II study evaluates the safety and clinical activity of the combination treatment of lenalidomide and ofatumumab for relapsed/refractory NHL.Methods:Patients with histologically confirmed diagnosis of CD20+ NHL, recurrent/ refractory to at least one prior therapy were eligible for the study. All the patients received 8 weekly infusions of ofatumumab 1000mg. Dose escalation of lenalidomide was done in three planned dose cohorts. Cohort 1 received 15mg per day, cohort 2 and 3 received 20mg and 25mg per day respectively on days 1-21 every 28 days. The study design involved a standard 3+3 approach. Dose reduction Cohort (-1) at 10mg/day was built into the protocol in the event of a dose limiting toxicity in cohort 1. Phase II evaluated lenalidomide at maximum tolerated dose (MTD) and ofatumumab in 36 patients. Flow analysis for total T-cells, sIL2r, IL12, VEGF, TNFa levels were checked at baseline, 6 months, 12 months on therapy and at the time of discontinuation of treatment.Results:The MTD for lenalidomide was 10mg. Six patients in phase 1 treated at the MTD and 34 patients enrolled on Phase II were eligible for evaluation. Data was analyzed for all patients treated at the MTD (n=40). Twelve (30%) patients had diffuse large B-cell lymphoma (DLBCL), 12 (30%) follicular lymphoma (FL), 6 (15%) mantle cell lymphoma (MCL), 6 (15%) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), 4(10%) other lymphomas. The median age was 64.5 years (35.5-80.7). Thirty one (78%) were male, 40 (100%) caucasians, 45% had stage IV disease. Number of lenalidomide cycles ranged from 1-63. In the phase I cohort, grade 3-4 adverse events included neutropenia (10%), thrombocytopenia (10%) and secondary malignancies (20%). Grade 3-4 adverse events on Phase II were neutropenia (42%), thrombocytopenia (8%), infusion reactions (8%) and secondary malignancies (17%). Overall response rate [stable disease (SD), partial response (PR) + complete response CR] was 67% (95% %CI:52%-80%) including 11 (92%) patients with FL, 5 (83%) MCL, 3 (25%) DLBCL and 4(66%) CLL/SLL. CR was noted in 3 patients which included DLBCL, FL and MCL. The durability of response in patients who achieved CR was 7.02 years (DLBCL), 2.89 years (FL) and 2.54 years (MCL). At 6 months, the mean change from baseline in sIL2r was 389.8 [SD=421 p=0.002], CD3+T = -0.43 [SD=0.77, p=0.04]. The median change in sIL2r and CD3+CD4+G was lower for patients with CR when compared to patients with PR or SD [sIL2r:-82.7 vs 543.5, p=0.02; CD3_CD4_G: -26.1 vs. -0.82, p=0.02]. Median progression free survival (PFS) was 6.8 months (2.3-12.1). Median overall survival (OS) was 19.8 months (7.4-42.8). Estimated 1 year PFS was 38% and 2 years was 20%. Estimated 1 year OS was 56%, 2-year survival was 49%.Conclusion:The combination of lenalidomide at 10 mg for 21/28 days and ofatumumab has manageable toxicities and produces some durable response in patients with relapsed/refractory indolent NHL including FL, MCL, and CLL/SLL. DisclosuresLunning:Celgene: Consultancy; BMS: Consultancy; Genentech: Consultancy; Onyx: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Juno: Consultancy; Epizyme: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Pharmacyclics: Consultancy. Armitage:Tesario bio Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Consultancy; Conatus- IDMC: Consultancy. Vose:Incyte: Research Funding; Acerta: Research Funding; Allos Therapeutics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Kite: Research Funding; Merck: Research Funding; Onyx: Research Funding; Seattle Genetics: Research Funding; US Biotest: Research Funding; Bristol-Myers Squibb: Research Funding.

Discovery of Candidate Predictors of Response to Tazemetostat in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma Using NGS Technology on ctDNA Samples Collected Pre-Treatment

Discovery of Candidate Predictors of Response to Tazemetostat in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma Using NGS Technology on ctDNA Samples Collected Pre-Treatment

Response to the EZH2 Inhibitor Tazemetostat Is Independent of Cell of Origin Determined Via Hans Imunohistochemistry or Nanostring Lymphoma Subtyping Test in EZH2 Wild-Type DLBCL Patients

Response to the EZH2 Inhibitor Tazemetostat Is Independent of Cell of Origin Determined Via Hans Imunohistochemistry or Nanostring Lymphoma Subtyping Test in EZH2 Wild-Type DLBCL Patients

Improved Outcome of Newly Diagnosed Childhood Mature B-Cell Lymphoma/Leukemia with High Tumor Burden Treated with BFM95-Based Protocol Combining Rituximab: A Report from Shanghai, China

The Berlin-Frankfurt-Münster (BFM) based protocols have been wildly used in children with non-Hodgkin lymphoma (NHL) and leukemia for more than ten years in China. At the same time, rituximab has become a standard medicine in the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) and relapsed or refractory B-cell NHL. In this study, we explored the efficacy of rituximab in childhood CD20 positive B-NHL and B-cell acute leukemia (B-AL).To explore the effect of rituximab in mature B-cell lymphoma (B-NHL)/mature B-cell leukemia ((B-AL) in children, this study included children and adolescents aged younger than 18 years with newly diagnosed CD20 positive, stage III/IV B-NHL/B-AL for treatment combining NHL-BFM95-based protocol with rituximab. A total of 4 injections with 375 mg/m2 rituximab each were administered intravenously after prephase V course at one day before the following 4 course of chemotherapy. Retrospective cases diagnosed with stage III/IV B-NHL/B-AL in our center were used as historical control. All of these patients were treated under NHL-BFM90 based protocol. Patient characteristics, event free survival (EFS), recurrence and mortality were analyzed.From April 2009 to December 2015, 46 patients were recruited and treated with rituximab combining BFM95-based protocol (R+BFM95 protocol). 23 cases diagnosed with stage III/IV B-NHL/B-AL from January 2005 to March 2009 treated with BFM90-based protocol. All patients followed till December 31, 2016. This study recruited 35 males and 11 females with an average age of 6.9 years who were treated with R+BFM95 protocol. Among the historical control of 23 patients treated with BFM90-based chemotherapy, 18 were males and 5 were females and the average age of our historical control was 7.2 years. Among patients treated with R+BMF95 protocol, the average duration of continuous complete remission (CR) was 3.6 years. Compared with patients treated with BFM90-based protocol, the 5-year event free survival (EFS) of patients under R+BMF95 was higher (83.7±5.7% vs 69.6%±9.6% in R+BMF95 and BFM90 respectively), however the difference was not statistically significant (P=0.1062). Among subgroups of our patients between patients treated with R+BMF95 and BFM90, the 5-year EFS of patients with stage III disease was 87.3±6.1% vs 77.8±9.8% (P=0.2998), stage IV subgroup was 72.7%±13.4% vs 40.0±21.9% (P=0.0878), respectively. Among patients whose LDH level were below 500 U/L at diagnosis, R+BFM95 protocol achieved 100% EFS during our follow-up, nevertheless the 5-year EFS of patients in this group was not statistically different from that of patients treated with BFM90 (92.3±7.4%, P=0.2994). Among patients had LDH >500 U/L at diagnosis, the 5-year EFS in R+BFM95 group was 77.2±7.7% and significantly higher than that of BFM90 group (40.0±15.5%, P=0.0048). In the patient group treated with R+BFM95, there were 2 (2/46, 4.3%) did not achieve CR. During the follow-up, recurrence occurred in 5 patients (5/46, 10.9%) including 2 partial remission (PR). Early death occurred in 1 patient (1/46, 2.2%) in the first course due to tumor lysis syndrome. Two cases with recurrence were treated with R-ICE regimen however remission did not occur. All patients with recurrent disease died. In the control patients treated with BFM90-based protocol, there were 3 (3/23, 13.0%) did not achieve CR. One patient did not respond to chemotherapy therefore received second-look operation however the pathology was positive and he died of disease progression. The other 2 patients give up treatment after 2 courses of chemotherapy. One patient (1/23, 4.3%) died in the first course because of sepsis. One patient with relapsed disease received R-ICE treatment however not achieved remission again. All patients with recurrent disease also died in BFM90 group.To summarize, our study demonstrated the feasibility of rituximab for Chinese children with B-NHL/B-AL. Rituximab improved the prognosis of Chinese B-NHL/B-AL children, especially among patients with LDH >500U/L. However, the limited number of patients and retrospective study design suggested further randomized trial with larger number of patients to confirm the efficacy, as well as cost-effectiveness of rituximab in childhood B-NHL/B-AL in China. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A PHASE 2B STUDY TO EVALUATE THE EFFICACY AND SAFETY OF TUCIDINOSTAT (HBI‐8000) IN JAPANESE PATIENTS WITH RELAPSED OR REFRACTORY ADULT T‐CELL LEUKEMIA‐LYMPHOMA (ATL)

A PHASE 2B STUDY TO EVALUATE THE EFFICACY AND SAFETY OF TUCIDINOSTAT (HBI‐8000) IN JAPANESE PATIENTS WITH RELAPSED OR REFRACTORY ADULT T‐CELL LEUKEMIA‐LYMPHOMA (ATL)

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions.

Aims:To review recent data and relevant of the role of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell non-Hodgkin lymphoma (NHL).Methods:Review and compilation of the most recent and relevant data published in full text and abstract forms of anti-CD19 CAR T-cell therapy for B-cell NHL.Results:Different anti-CD19 CAR T-cell therapy products have been tested and shown significant clinical activity across B-cell NHL patients. The objective responses in relapsed DLBCL, FL and MCL were 50–83%, 83–93% and 93%, respectively.Conclusions:Anti-CD19 CAR T-cell therapy is a viable option for poor risk refractory B-cell NHLs.

Current and Future Role of Medical Imaging in Guiding the Management of Patients With Relapsed and Refractory Non-Hodgkin Lymphoma Treated With CAR T-Cell Therapy.

Chimeric antigen receptor (CAR) T-cells are a novel immunotherapy available for patients with refractory/relapsed non-Hodgkin lymphoma. In this indication, clinical trials have demonstrated that CAR T-cells achieve high rates of response, complete response, and long-term response (up to 80%, 60%, and 40%, respectively). Nonetheless, the majority of patients ultimately relapsed. This review provides an overview about the current and future role of medical imaging in guiding the management of non-Hodgkin lymphoma patients treated with CAR T-cells. It discusses the value of predictive and prognostic biomarkers to better stratify the risk of relapse, and provide a patient-tailored therapeutic strategy. At baseline, high tumor volume (assessed on CT-scan or on [18F]-FDG PET/CT) is a prognostic factor associated with treatment failure. Response assessment has not been studied extensively yet. Available data suggests that current response assessment developed on CT-scan or on [18F]-FDG PET/CT for cytotoxic systemic therapies remains relevant to estimate lymphoma response to CAR T-cell therapy. Nonetheless, atypical patterns of response and progression have been observed and should be further analyzed. The potential advantages as well as limitations of artificial intelligence and radiomics as tools providing high throughput quantitative imaging features is described.

High-dose polychemotherapy with autologous hematopoietic stem cell transplantation in children with non-Hodgkin lymphomas

High-dose polychemotherapy with autologous hematopoietic stem cell transplantation in children with non-Hodgkin lymphomas

Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL).

2507 Background: C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 can eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. The tissue cross reactivity and whole genome membrane proteome array studies further confirmed the specificity of C-CAR039. Methods: GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system. Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen. Results: As of 1/31/2021, 28 patients were infused and 25 (DLBCL, n = 22; PMBCL, n = 1; tFL, n = 1; FL, n = 1) were evaluable for safety and efficacy at dose ranges of 1.0 x 106 to 5.0x106 CAR-T cells/kg. The median age was 54 (range, 28-71) years, median number of prior lines of therapy was 3 (range, 1–5), 76% (19/25) of patients were in Ann Arbor Stage III/IV, and 80% (20/25) were refractory to their last treatment. 5 patients (20%) received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Of the 25 patients, 24 (96%) experienced CRS, 23 (92%) were grade 1 or 2, 1 patient was grade 3. Median time to onset of CRS was 3 days (range, 0-10), with median duration of 4 days (range, 1-25). 2 patients had a grade 1 ICANS. Grade≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 88%, 40%, 16% and 0% of patients, respectively. The best overall response rate was 92%, complete response (CR) rate was 84% and median time to response was 1.0 month (range, 0.9-1.2). With a median follow-up of 5.3 months, 76% remained in CR. Kaplan Meyer estimation of PFS at 6 months was 87.3% (95% CI, 71.2 to 100.0). Median duration of response has not been reached. Furthermore, C-CAR039 showed an encouraging cellular kinetic profile. In 25 evaluable patients, the median Tmax was 11 day, the median Cmax was 139,497 copies/mg gDNA, and the median AUC0̃28DAY of 1,673,844 day*copies/μg gDNA. Conclusions: C-CAR039 demonstrated a favorable safety profile and promising efficacy in this early clinical trial in patients with r/r B-NHL that might allow it to differentiate from existing therapies. The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR-T and peer therapies. These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response. Clinical trial information: NCT04317885 , NCT04655677 , NCT04696432 , NCT04693676 .

The Efficacy and Safety of Busulfan-Etoposide-Melphalan Regimen in Autologous Stem Cell Transplantation in Relapsed/ Refractory Hodgkin and Non-Hodgkin Lymphoma Patients: “A Single-Center Experience”

The Efficacy and Safety of Busulfan-Etoposide-Melphalan Regimen in Autologous Stem Cell Transplantation in Relapsed/ Refractory Hodgkin and Non-Hodgkin Lymphoma Patients: “A Single-Center Experience”

MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.

As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.

Results of a Phase 1 Trial of Gda-201, Nicotinamide-Expanded Allogeneic Natural Killer (NK) Cells in Patients with Refractory Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma

Background: The innate capacity of natural killer (NK) cells to kill tumor targets has been translated into cancer immunotherapy. GDA-201 is a novel allogeneic NK cell product derived from NK cells from healthy donors, expanded ex-vivo with nicotinamide (NAM) and IL-15. We previously reported improved killing function, in vivo proliferation, organ trafficking, and augmented resistance against exhaustion in pre-clinical models. We conducted a phase 1 study of GDA-201 in combination with monoclonal antibodies to enhance NK cell targeting through antibody-dependent cellular cytotoxicity (ADCC). We now report safety data in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), and report efficacy outcomes in pts with NHL. Methods: Following donor apheresis, CD3-depleted mononuclear cells were cultured for 14-16 days with NAM (5mM) and IL-15 (20ng/ml), resulting in a 40-fold increase in NK cells and increased expression of CD62L from 2.9% to 21%. GDA-201 contained ~98% NK cells, and CD3 content was maintained at &amp;lt;0.5% (&amp;lt;5x105/kg/dose). Pts with R/R B-cell NHL or MM received lymphodepleting (LD) therapy with cyclophosphamide (400mg/m2 IV x 3d) and fludarabine (30 mg/m2 /d IV x 3d), followed by GDA-201 (days 0 and 2) and low-dose IL-2 (6 million units sc x 3 doses). Pts with NHL or MM received rituximab (375 mg/m2) or elotuzumab (10 mg/kg), respectively, x 3 weekly infusions. Results: 30 pts were enrolled:15 with NHL and 15 with MM, in 3 cohorts of escalating GDA-201 dose; 15 pts received the maximum target dose (median dose 12.4 [range 2.0-26.0] x 107 cells/kg). There were no dose limiting toxicities. The most common grade 3/4 adverse events were thrombocytopenia (n=9), hypertension (n=5), neutropenia (n=4), febrile neutropenia (n=4), and anemia (n=3). There were no neurotoxic events, confirmed cytokine release syndrome, graft versus host disease, or marrow aplasia. One patient died of E-coli sepsis. In pts with NHL, histologies included diffuse large B cell lymphoma (DLBCL) (de novo n=5, transformed n=3), follicular lymphoma (FL) (n=6), and mantle cell lymphoma (n=1). Median age was 64 (range 48-83 years). Pts had a median of 3 lines of prior therapy (range 1-8); most were multiply relapsed or refractory (n=2), and 87% had advanced stage. Median follow-up was 10.8 months (range 4.3-27.5 months). Ten pts had complete response (CR): 6/6 pts with FL and 4/8 with DLBCL; 1 pt had partial response (PR), and overall response rate in pts with NHL was 73.3%. Median duration of response was 8.7 months (range 4.3-25 months). Flow cytometry confirmed the persistence of GDA-201 in peripheral blood for 7-10 days (range 2-92% donor NK cells on day 7), as well as enhanced in vivo proliferation (median Ki 67 99%). Flow cytometry of biopsied tissues at day 4 demonstrated trafficking to bone marrow and lymph nodes. Four pts underwent re-treatment with GDA-201 without LD chemotherapy; GDA-201 cells were detectable in blood after the re-treatment and likely contributed to deepening of response in 2 patients. Post-GDA-201 therapy included allogeneic (n=2) and autologous (n=1) hematopoietic stem cell transplantation. One-year estimates of progression-free survival and overall survival were 66% (95% CI 36-84%) and 82% (95% CI 42-95%), respectively. Conclusions: Cellular therapy using GDA-201 with monoclonal antibodies to enhance ADCC was well-tolerated, and demonstrated significant clinical activity in heavily pretreated pts with advanced NHL. Data support the future testing of multiple infusions to potentially enhance anti-tumor effect. The omission of lymphodepleting chemotherapy is feasible and contributes to safety of this approach. Phase II studies in aggressive and indolent NHL cohorts are planned. Disclosures Bachanova: Incyte: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. McKenna:Gamida: Other: Cell Manufacturing; Fate Therapeutics: Other: Cell Manufacturing; Intima: Other: Cell Manufacturing; Magenta: Other: Cell Manufacturing. Janakiram:Takeda, Fate, Nektar: Research Funding. Simantov:Gamida Cell: Current Employment. Lodie:Gamida Cell: Current Employment. Miller:Vycellix: Consultancy; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onkimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Consultancy, Patents &amp; Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents &amp; Royalties, Research Funding.

A Phase 1 Study of HMPL-689, a Small Molecule, Highly Selective, and Potent Inhibitor of Phosphoinositide 3 Kinase-Delta, in Patients with Relapsed or Refractory Lymphoma

Background: The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there is an unmet medical need for more effective and well-tolerated therapeutic agents for patients with advanced relapsed, refractory, or resistant NHL. HMPL-689 is a novel, orally available, highly selective, and potent small molecule inhibitor of phosphosinositide 3 kinase-delta (PI3Kδ), a crucial signaling transduction molecule in the BCR signaling pathway. A global clinical study of HMPL-689 is currently ongoing in the USA and the EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of this study are expected soon. Herein is the description of an ongoing phase 1, open-label, multi-center, single-arm study of HMPL-689 in patients with advanced relapsed, refractory, or resistant (R/R) NHL (NCT03786926). Study Population: Target patient population is adult patients with histologically confirmed advanced relapsed, refractory, or resistant NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Patients are ineligible for the study if they have primary central nervous system lymphoma. Objectives and Endpoints: The primary objective is to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) of HMPL-689. The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities The secondary objective is to evaluate the pharmacokinetic (PK) parameters and preliminary efficacy. The secondary endpoints include concentration-time profiles, PK parameters, and efficacy parameters, including objective response rate, time to response, duration of response, and progression-free survival. Study Design: Study consists of a dose escalation and dose expansion stages. The dose-escalation stage utilizes a mTPI-2 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses for escalation cohorts are 10, 15, 20, 25, 30, 35, 40, 45, and 50 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death. The expansion stage will be dosed at the MTD. Approximately 10 patients will be enrolled in each of the following cohorts: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),Mantle cell lymphoma (MCL),Follicular lymphoma (FL)Marginal zone lymphoma (MZL)Peripheral T-cell lymphoma (PTCL)Cutaneous B-cell lymphomaWaldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM) Statistical Methods: The maximum sample size in the dose-escalation stage will be determined based on the accumulated safety data and the mTPI-2 design. The maximum sample size under the mTPI-2 method is k × (d + 1), where k denotes the cohort size and d denotes the number of doses. The minimum cohort size in this study is 3 patients per cohort. To ensure that the highest dose (if needed) is reached, it is estimated that approximately 33-39 patients will be needed in this study. For dose expansion, approximately 70 patients (10 in each cohort) will provide robust safety data in the patient populations studied. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%. Data will be summarized by dose level, subtype of malignancy, and overall as appropriate. Continuous assessments will be summarized by number of patients (n), mean, standard deviation, median, minimum and maximum. Significance: This study is the first global clinical study of HMPL-689, a novel inhibitor of the BCR signaling pathway, which is currently enrolling patients with advanced relapsed, refractory, or resistant NHL who have exhausted all approved therapeutics options available. Disclosures Lawrence: Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Hahka-Kemppinen:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo:Consultancy;Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics:Research Funding.Kania:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.

A Phase 1 Study of HMPL-523, Highly Selective and Potent a Small Molecule Inhibitor of Spleen Tyrosine Kinase in Patients with Relapsed or Refractory Lymphoma

Background: The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there continue to be unmet medical need for more effective and less toxic therapeutic agents for patients with advanced relapsed, refractory or resistant lymphoma. HMPL-523 is a novel, orally available, highly selective, and potent small molecule inhibitor of spleen tyrosine kinase (SYK), a crucial component of BCR signaling pathway. A clinical study is currently ongoing in the USA and in EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of these trials are expected soon. Herein is the description of an ongoing phase 1 open-label, multi-center, single-arm study of HMPL-523 in patients with advanced relapsed, refractory or resistant (R/R) NHL (NCT03779113). Study Population: Targeted patient population is adult patients with histologically confirmed advanced relapsed, R/R NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Objectives and Endpoints: The primary objective is to assess safety and tolerability of HMPL-523 and to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities The secondary objectives are to characterize the pharmacokinetic (PK) parameters and to evaluate the safety and preliminary efficacy of HMPL-523. The secondary endpoints are the incidence of treatment-emergent adverse events (TEAE), PK parameters, and efficacy parameters, including objective response rate, duration of response, time to response, and progression-free survival. Study Design: Study consists of a dose escalation stage and an expansion stage. The dose-escalation utilizes a modified 3+3 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses of escalation cohorts are 100, 200, 400, 600 and 800 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death. The expansion stage will be dosed at the MTD to further evaluate safety, tolerability, PK, drug exposure, target engagement, PD and their correlation with clinical benefit of HMPL-523. Approximately 10 patients will be enrolled in each of the following cohorts: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),Mantle cell lymphoma (MCL),Follicular lymphoma (FL)Marginal zone lymphoma (MZL)Peripheral T-cell lymphoma (PTCL)Cutaneous B-cell lymphomaWaldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM) Statistical Methods: For the escalation stage, the sample size is based on the dose-escalation rules of the 3+3 design. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in a given cohort of 6 patients is 46.9%, 26.5%, and 5.8%, respectively. For the dose expansion stage, a total of 70 patients (10 patients per expansion cohort) will provide robust safety data in the study patient populations. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%. Safety parameters, including DLTs, recorded TEAEs, clinical laboratory parameters, vital signs, 12-lead ECG parameters and physical examination findings, will be summarized by dose level across both dose escalation and dose expansion stages. Efficacy endpoints will be summarized by dose level for each type of malignancy. Significance: This study is the first global clinical study of HMPL-523, a novel inhibitor of the BCR signaling pathway currently enrolling patients with advanced relapsed, refractory or resistant NHL who have exhausted all approved therapeutics options available. Disclosures Lawrence: Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Hahka-Kemppinen:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Kania:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.