Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With Dose-Escalated Rituximab

Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells, has become a standard of care in the treatment of B-cell malignancies, most often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has demonstrated improved activity in previously treated/poor prognosis CLL. We present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who received dose-escalated R as a single agent and achieved complete response (3 patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was minimal, with initial infusion reactions similar to those observed with standard dose infusions. There were no serious treatment-related adverse events or infections. Dose escalated R as a single agent may possibly be curative for some patients with B-cell malignancies, unlike the standard empiric dose of 375 mg/m2, and deserves further study.

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Immunomodulatory Drugs for the Treatment of B Cell Malignancies

International Journal of Molecular Sciences ◽

10.3390/ijms22168572 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8572

Author(s):

Nikolaos Ioannou ◽

Khushi Jain ◽

Alan G. Ramsay

Keyword(s):

Combination Therapy ◽

B Cell ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Immune Recognition ◽

Immunomodulatory Drugs ◽

B Cell Malignancies ◽

Cellular Compartments

Accumulating evidence suggests that the tumor microenvironment (TME) is involved in disease progression and drug resistance in B cell malignancies, by supporting tumor growth and facilitating the ability of malignant cells to avoid immune recognition. Immunomodulatory drugs (IMiDs) such as lenalidomide have some direct anti-tumor activity, but critically also target various cellular compartments of the TME including T cells, NK cells, and stromal cells, which interfere with pro-tumor signaling while activating anti-tumor immune responses. Lenalidomide has delivered favorable clinical outcomes as a single-agent, and in combination therapy leads to durable responses in chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphomas (NHLs) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Recently, avadomide, a next generation cereblon E3 ligase modulator (CELMoD), has shown potent anti-tumor and TME immunomodulatory effects, as well as promising clinical efficacy in DLBCL. This review describes how the pleiotropic effects of IMiDs and CELMoDs could make them excellent candidates for combination therapy in the immuno-oncology era—a concept supported by preclinical data, as well as the recent approval of lenalidomide in combination with rituximab for the treatment of relapsed/refractory (R/R) FL.

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Post Transplant Lymphoproliferative Disorders (PTLD): Prevalence, Clinical Features and Outcome.

Blood ◽

10.1182/blood.v110.11.5029.5029 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5029-5029

Author(s):

Cecilia Colorio ◽

Dolores Puente ◽

Andrea Rossi ◽

Gregorio Jaimovich ◽

Maria Tabares ◽

...

Keyword(s):

B Cell ◽

Disease Progression ◽

Cell Lymphoma ◽

Late Onset ◽

B Cell Lymphoma ◽

Large Cell ◽

Complete Response ◽

Solid Organ ◽

Allogeneic Bone ◽

Main Diagnosis

Abstract PTLD is a life threatening complication developing in 1–5% of transplant (Tx) recipients. Epstein Barr (EBV), Cytomegalovirus (CMV) and immunosuppression (IS) were identified as risk factors. Aggressive evolution and therapy related toxicity generate poor prognosis. We retrospectively analyzed data from 18 PTLD patients (pts) diagnosed at our hospital between March 1994- June 2007. All of them were at least one graft recipient and were under IS. RESULTS: Out of 1206 adult Tx recipients, 18 (1,5%) developed PTLD. Ninety-four percent were men, mean age 42,9 years (range: 18–72). Our study comprises 10 heart, 2 kidney, 2 lung, 1 heart-lung, 1 liver and 2 non related allogeneic bone marrow (BM) recipients. IS protocols included Cyclosporin A (16 pts), Azathioprine (8), Mycophenolate mofetil (7), Tacrolimus (4) and antitymocyte globulin (2). Pretx recipients serology for EBV and CMV were positive in 87 and 94% respectively. Sixty-six percent (12/18) disclosed late onset PTLD (median 49 months), all of them were solid organ (SO) recipients. BM recipients developed the disease within the first 6 months after Tx. Fifty percent presented extranodal involvement, 3/18 with BM infiltration and 3/18 showed lymphoma in the graft. Histologycal findings: 15/18 B cell lymphoma (8/15 large cell lymphoma), 1 peripheral T cell lymphoma, 1 early lesion infectious mononucleosis-like PTLD, 1 polymorphic hyperplasia PTLD. Immunophenotype: 89% were CD20+. Fifty percent of the group achieved response, 7/9 with complete response(CR). Three/9 pts obtained CR with reduction of IS alone.Treatment included Rituximab (63% pts), CHOP (56%) and radiotherapy (25%). Eleven/18 pts died, 4 due to disease progression, 6 by sepsis and 1 because of underlying hematological disease relapse. CONCLUSIONS: In our experience, PTLD was an uncommon complication. The late onset of the disease was the most frequent form of presentation among SO recipients. B cell lymphoma was the main diagnosis (83%). Fifty percent (9/18) achieved response and 78% of them showed CR. Disease progression and sepsis were the most important causes of death.

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Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting CD19, in subjects with relapsed or refractory advanced B-cell malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8065 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8065-8065 ◽

Cited By ~ 1

Author(s):

Trishna Goswami ◽

Andres Forero ◽

Mehdi Hamadani ◽

Anne Sonet ◽

Gregor Verhoef ◽

...

Keyword(s):

Monoclonal Antibody ◽

Phase I ◽

B Cell ◽

Transmembrane Protein ◽

Single Agent ◽

Tumor Lysis Syndrome ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

B Cell Malignancies ◽

Antibody Targeting

8065 Background: Novel B-cell targeting agents, including monoclonal antibodies such as rituximab, are among recent advances in treatment of B-cell malignancies. New approaches are needed for patients progressing after rituximab-based therapies. MEDI-551 is an afucosylated monoclonal antibody targeting CD-19, a B-cell restricted transmembrane protein with enhanced affinity and antibody-dependent cellular cytotoxicity. Methods: Pts with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, or multiple myeloma received single agent MEDI-551 at dosages ranging from 0.5 mg/kg to 12 mg/kg via intravenous infusion over 28-day cycles; cohorts 1-6 received 0.5, 1, 2, 4, 8, and 12 mg/kg, respectively. Results: 25 pts were enrolled in the phase I portion Jun 2010–Aug 2011. No maximum tolerated dose (MTD) was achieved. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Six pts had grade 3 toxicities including tumor lysis syndrome, infusion reaction, thrombocytopenia, and neutropenia, or grade 4 neutropenia. No grade 5 AEs were seen. All pts recovered. Three partial responses (PR) and 2 complete responses (CR) were seen in DLBCL and FL pts at 0.5, 4, and 8 mg/kg. Activity included a CR lasting 9 mo. in a FL pt in cohort 1, who is currently being retreated with MEDI-551 on relapse. Conclusions: MEDI-551 demonstrated a safety profile warranting further study and showed no MTD reached at the highest dose studied. Anti-tumor activity is suggested by the responses achieved across dose levels. Phase II is currently enrolling subjects. This study is funded by MedImmune, LLC. [Table: see text]

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Doublet Versus Triplet PET: Is END of Therapy PET Needed IF Interim PET Is Negative in Hodgkin'S or Diffuse Large B CELL Lymphoma?

Blood ◽

10.1182/blood.v128.22.5354.5354 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5354-5354

Author(s):

Imran K Tailor ◽

Bilal Btoosh ◽

Shaimaa Hamdy ◽

Shanker Raja ◽

Mohammed O Alharbi ◽

...

Keyword(s):

B Cell ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Complete Response ◽

Interim Pet ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: Baseline (PETb) and end of therapy (PETe) FDG PET is standard of care in the management of hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). The role of interim PET (PETi) in HL is well established while its role in DLBCL is not well defined. We evaluated the utility of triPET (PETb, PETi and PETe ) in management of these two lymphomas. Methods: Retrospective review of PET archives revealed a total of 37 pts (HL=22, DLBCL=15). TriPET were acquired per accepted protocol. SUVmax and Deauville scores (DSc) were obtained from five target lesions, the average i.e. composite SUVmax & DSc were computed for each pt. Statistical analyses were performed with the composite maxSUV (cSUV) and Deauville scores (cDSc) (using EXCEL). Following statistics were performed (separately and combined in HL and DLBCL); mean+SD, PPV and NPV for complete response (CR) Vs. progressive disease (PD) on PETi using the following variables 1. cSUV and 2. cDSc and 3. delta change (DELT). Median progression free survival (PFS) was the clinical endpoint for response. Results: The mean PFS in our group was 17 and 15 months in HL and DLBCL respectively. Using cut off thresholds for intP to predict CR at cSUV<=2.0, , cDSC<=2.0 and DELT >=80%,. In HL: for cSUV- PPV 67%, NPV 95%; for DELT of cSUV PPV 100%, NPV 95%; for cDSC-PPV 30%, NPV 100%. In DLBCL: for cSUV- PPV 25%, NPV 100%; for DELT of cSUV PPV 33%, NPV 100%; for cDSC- PPV 50%, NPV 100%. Conclusion: The results from our series suggest that PETi has a role not only in HL but in DLBCL as well. Our modest cohort suggests that a negative PETi in DLBCL had a NPV of 100% across cSUV, cDSc and DELT, with regards to CR. Our data also suggests that PETe is not needed if PETi is -ve. While in HL subset, our results concur with results from other groups, this needs to be validated in a larger series. Disclosures No relevant conflicts of interest to declare.

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Tumor-associated myeloid-derived suppressor cells as a potential biomarker for prognostication of response in treatment of diffuse large cell lymphoma.

Journal of Global Oncology ◽

10.1200/jgo.2019.5.suppl.30 ◽

2019 ◽

Vol 5 (suppl) ◽

pp. 30-30

Author(s):

Kalyan KUSUM Mukherjee ◽

Sukanya Dhar ◽

Rajib Bhattacharjee ◽

Subhadip Das ◽

Mohona Chakraborty ◽

...

Keyword(s):

B Cell ◽

Immune Cells ◽

Residual Disease ◽

Cell Lymphoma ◽

Suppressor Cells ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Large Cell ◽

Potential Biomarker ◽

Cellular Components

30 Background: NHL is a type of lymphoma either B or T cell origin. However, 85% is of B cell type, especially diffuse large B cell lymphoma (DLBCL) with CD20+ in nature. Standard of care of CD20+DLBCL is R-CHOP 6 to 8 cycles and 66% patients generally respond to this treatment. Remaining 34% is still unresponsive to R-CHOP. Thus, establishment of a biomarker is required to intensify the treatment.Out of different scope of biomarker development, alterations in immune cellular components within tumor microenvironment may be tried as a potential biomarker to assess the possibility of occurrence of residual disease and relapse within 2 years for the DLBCL patients with 6-8 cycles of R-CHOP. Methods: : Selected CD20+ DLBCL patients (n=51) were treated with 6-8 cycles of R-CHOP and included in the present study with their informed consent. A panel of immune cells, like, T (CD4+, CD8+)-cells, regulatory T (CD4+CD25+FoxP3)-cells, MDSCs (CD33+CD11b+CD14-/+), memory T (CD8+CD45RO+)-cells and multidrug resistance (MDR) phenotypes (P-gp, MRP1), were studied by flow-cytometry and RT-PCR at different phases of treatment. Results: Within 51 selected patients, 9 were disease free and 11 patients exhibited stable disease for 2 years following the completion of treatment. Rest of the patients (n=31) showed relapse in different time periods. Among several immune cells studied, CD33+CD11b+MDSCs were remarkably elevated in high-grade residual-and-relapsed DLBCL patients compared to non-relapsed patients and normal healthy individuals. CD33+CD14+ monocytic, but not CD33+CD14-granulocytic MDSCs were mostly increased in relapsed patients than control. Moreover, expression of MDR phenotypic markers was found to be elevated in these relapsed patients. Among relapsed patients CD8+CD45RO+ memory T cells were increased, however, these cells are mostly corrupted in nature. Conclusions: Observed correlation between increased monocytic MDSCs with the occurrence of residual disease and/or relapse suggests monocytic MDSCs might be a potential biomarker for prediction of residual-and-relapsed DLBCL patients.

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Statins Potentiate the Cytotoxic Effect of ABT-199 in Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.3969.3969 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3969-3969

Author(s):

David A. Fruman ◽

Jong-Hoon Scott Lee ◽

Thanh-Trang T Vo ◽

Shruti Bhatt ◽

Jonathan H. Schatz ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Lymphoma Cells ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract BCL-2 is a key pro-survival protein that is highly expressed in many leukemias and lymphomas. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2 that has demonstrated impressive responses in chronic lymphocytic leukemia (CLL) leading to FDA approval for second line treatment of patients with 17p deletion. However, other hematologic malignancies are less responsive to ABT-199 as a single agent, suggesting that combinations of targeted therapies may be required to elicit more promising responses. We have investigated the potential of combining ABT-199 with HMG-CoA reductase (HMGCR) inhibitors (statins), which have known anti-cancer potential in hematologic malignancies. Using multiple chemically distinct statin compounds, we observed profound synergistic induction of apoptosis when combined with ABT-199 in both human diffuse large B cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML) cell lines. This synergy was also seen in primary murine B lymphoma cells over-expressing MYC and BCL-2. Importantly, addition of exogenous mevalonate completely rescued cells from the combination, confirming on-target efficacy of HMGCR inhibition. Using BH3 profiling, we found that simvastatin significantly primed lymphoma cells for undergoing apoptosis (termed mitochondrial priming). Notably, the degree of priming correlated with its ability to synergize with ABT-199, suggesting that BH3 profiling may be used to predict patient responses. The combination did not synergize to kill normal human peripheral blood mononuclear cells from healthy donors, suggesting that statins may selectively prime cancer cells for apoptosis. Mechanistic studies support the hypothesis that statins synergize with ABT-199 by suppressing protein prenylation, particularly protein geranylgeranylation. In support, the addition of exogenous geranylgeranyl pyrophosphate (GGPP) completely rescued cells from the effects of simvastatin. Furthermore, selective inhibition of protein geranylgeranyl transferase (GGT) increased priming and was sufficient to recapitulate the effects of simvastatin in combination with ABT-199. Statins and GGT inhibitors increased the mitochondrial abundance of a subset of BH3-only pro-apoptotic proteins. Lastly, we have identified Rap1A de-prenylation as a marker of pharmacodynamic response to statins in vivo. Thus, this project highlights a novel combination for use in aggressive lymphomas, establishes its efficacy and tolerability using preclinical models, and provides proof-of-concept to warrant investigation of its clinical potential. Disclosures Letai: AbbVie: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

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Safety of acalabrutinib (Acala) monotherapy in hematologic malignancies: Pooled analysis from clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8064 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8064-8064

Author(s):

Richard R. Furman ◽

John C. Byrd ◽

Roger G. Owen ◽

Susan Mary O'Brien ◽

Jennifer R. Brown ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Tolerability Profile ◽

B Cell Malignancies ◽

Major Hemorrhage ◽

Prolymphocytic Leukemia ◽

Grade 3

8064 Background: Acala is a next-generation, highly selective, covalent Bruton tyrosine kinase inhibitor approved in the US for patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and previously treated mantle cell lymphoma (MCL). We evaluated the safety profile of acala monotherapy (monotx) in multiple B cell malignancies. Methods: Data from pts with activated B-cell diffuse large B-cell lymphoma, CLL, follicular lymphoma, MCL, multiple myeloma, prolymphocytic leukemia, Richter syndrome, SLL, or Waldenström macroglobulinemia treated with ≥1 dose of acala monotx in 9 studies were pooled. Acala was administered at 100 mg BID in most pts (100–400 mg total dose daily). Adverse events (AE) were assessed. Results: A total of 1040 pts were included (median age: 67 y [range: 32–90]; ECOG status ≤1: 93%; median exposure duration: 24.6 mo [range: 0–58.5]). A total of 360 (34%) pts discontinued acala, most commonly due to progressive disease (PD; 17%). AEs led to acala discontinuation in 97 (9%) pts; those in > 2 pts were pneumonia (n = 5) and thrombocytopenia (n = 4). Incidence of AEs, including the most common (any grade and grade ≥3), are shown in the Table. Events of clinical interest (ECIs) included atrial fibrillation (afib) of any grade in 46 (4%) pts and grade ≥3 in 13 (1%) pts; major hemorrhage (any grade) in 37 (4%) pts; grade ≥3 infection in 183 (18%) pts; hypertension (any grade) in 79 (8%) pts and grade ≥3 in 36 (4%) pts; and second primary malignancies (SPM) excluding non-melanoma skin cancer (NMSC; any grade) in 68 (7%) pts. Median (range) time to first onset in days for each ECI (any grade) was: afib, 522 (8–1280); major hemorrhage, 293 (4–1327); infections, 92 (1–1317); hypertension, 157 (2–1345); SPM excluding NMSC, 339 (7–1499). Death was reported in 139 (13%) pts, most commonly due to PD (6%) and AEs (5%). Conclusions: Acala monotx has a favorable tolerability profile with increased exposure across multiple mature B cell malignancies. Additional analyses will further explore the longitudinal characteristics of AEs. [Table: see text]

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Complete Response of Primary Refractory ALK-Positive Large B-Cell Lymphoma Treated With Single-Agent Nivolumab

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.08.015 ◽

2020 ◽

Vol 20 (3) ◽

pp. e113-e117

Author(s):

Jose D. Sandoval-Sus ◽

Amanda Brahim ◽

Alina Khan ◽

Yehuda Deutsch ◽

Barbara Raphael ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Complete Response ◽

Large B Cell Lymphoma ◽

Alk Positive ◽

Large B Cell

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Lymhoma of the Oral Cavity. A Rare Entity with Favorable Prognosis. Ten-Year Experience of a Single Hematology Unit.

Blood ◽

10.1182/blood.v104.11.4595.4595 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4595-4595

Author(s):

Marina P. Siakantaris ◽

Tatiana Tzenou ◽

Theodoros P. Vassilakopoulos ◽

Marie-Christine Kyrtsonis ◽

Maria K. Angelopoulou ◽

...

Keyword(s):

T Cell ◽

Oral Cavity ◽

B Cell ◽

Cell Lymphoma ◽

Early Stage ◽

Clinical Stage ◽

B Cell Lymphoma ◽

Large Cell ◽

Complete Response ◽

Clinicopathologic Characteristics

Abstract Lymphomas of the oral cavity consist <5% of the malignancies of the region. B-cell lymphoma of the diffuse large cell histology is the predominant type (B-DLCL). The purpose of our study was to describe the clinicopathologic characteristics of a group of patients with oral cavity lymphomas and their treatment outcome. We reviewed the records of 46 patients (21 males and 25 females) with oral lymphomas who were diagnosed and treated in our Service, between 1993 and 2003. The mean age was 57 years and the most prevalent site of involvement was the tonsil (41.3%) followed by the tongue (15.2%), while 8.7% had >1 involved sites. Thirty six patients (pts) (78.3%) had clinical stage I or II and 10 (21.7%) advanced stage disease. A monoclonal lymphocytic population was detected in the blood of 7 pts (15.2%) by PCR (IgH or TCR rearrangement), 4 of them with early stage lymphoma. 56.5% of the lesions were diagnosed as B-DLCL and only 10.8% as peripheral T-cell lymphomas. Nineteen pts with B-DLCL received CHOP or equivalent chemotherapy regimens and 11 CHOP combined with anti-CD20. Chlorambucil was administered in 4 pts with MALT lymphoma and local radiotherapy as the sole treatment in 1. The pts with T-cell lymphoma received CHOP (3) or interferon alfa-2b (2). Thirty eight pts are in complete remission. There were 3 deaths due to the disease (1 MALT, 1 predominantly small cleaved cell and 1 B-DLCL). Three additional pts relapsed and achieved complete response with a second chemotherapy course and 2 pts developed a lymphoma of different histology. In conclusion, oral lymphoma is a rare disease mainly of a diffuse large B-cell histology and a prolonged survival, when treated with chemotherapy (10-year Event Free Survival 82.5%).

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Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8016 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8016-8016

Author(s):

Andrew David Zelenetz ◽

Nishitha Reddy ◽

Deepa Jagadeesh ◽

Anastasios Stathis ◽

Huda S. Salman ◽

...

Keyword(s):

B Cell ◽

Single Agent ◽

Objective Response ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Combination Group ◽

Intermittent Schedule ◽

B Cell Malignancies ◽

Days Of Therapy ◽

Grade 3

8016 Background: ME-401, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study, and previously demonstrated a high objective response rate (ORR) in FL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) when given on a continuous (CS) or an intermittent schedule (IS). IS appeared to significantly reduce the incidence of immune-mediated adverse events of special interest (AESI) associated with PI3kδ inhibitors (diarrhea, rash, transaminase elevation, pneumonitis). We report maturing data from patients treated on the IS in this study. Methods: Eligible patients (pts) had FL, CLL/SLL, marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL), at least 1 prior therapy, adequate bone marrow and organs function, ECOG status ≤2, and no prior PI3K therapy. IS dosing: ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m2 for 8 doses in Cycles 1-6. Results: Total of 57 pts treated with IS: 35 FL, 10 CLL/SLL, 4 MZL, and 8 DLBCL with 38 (67%) currently still ongoing. Median age: 66 years (range 38-94) and median prior therapies: 2 (range 1-8). As of January 2020, median follow-up = 9.7 mo (range 0.6-25.4+). Grade 3 AESI reported in 7 pts: 2 diarrhea (3.5%), 2 colitis (3.5%), 1 rash (2%), 1 ALT increased (2%), and 1 pneumonitis (2%). No Grade 3 AESI reported beyond Cycle 3. Discontinuation for AE in 3 pts (5%). There were no discernable safety differences between the monotherapy and rituximab combination groups. ORR was 83% in FL (76% in monotherapy group, 88% in combination group) and 89 % in CLL/SLL (100%, 83%), with median duration of response not reached. Median PFS was not reached in all patients with FL and CLL (combined analysis of both single agent and with rituximab). ORR was 100% (4/4) in MZL and 25 % (2/8) in DLBCL (in combination group only). Conclusions: ME-401 administered on an IS was well-tolerated, with a low-rate of Grade 3 class-related AESI and achieved a high-rate of durable objective responses in R/R indolent B-cell malignancies. These results may differentiate ME-401 and support further evaluation as a single-agent and in combination regimens. An ongoing global trial is evaluating ME-401 by IS in pts with FL after failure of ≥2 prior therapies (NCT03768505). Clinical trial information: NCT02914938 .

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