Unconfirmed Complete Response Research Articles

Comparing niraparib versus platinum-taxane doublet chemotherapy as neoadjuvant treatment in patients with newly diagnosed homologous recombination–deficient stage III/IV ovarian cancer: study protocol for cohort C of the open-label, phase 2, randomized controlled multicenter OPAL trial

BackgroundMaintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib’s efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination–deficient tumors.MethodsOPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator’s discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator’s discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination–deficient. The primary endpoint is the pre–interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1.DiscussionOPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination–deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery.Trial registrationClinicalTrials.gov NCT03574779. Registered on February 28, 2022.

Feasibility of implementation of the early tumor shrinkage as a potential predictive marker to daily clinical practice in patients with RAS wild type metastatic colorectal cancer, treated with cetuximab - a non-interventional observational study.

With the aim to show the feasibility of early tumor shrinkage (ETS) concept implementation into daily clinical practice in the Czech Republic, a non-interventional, multicentric, single arm, prospective study in real world set-up was performed. The study objectives were to explore the time interval from the treatment starting date to the date of the first radiographic control (TFRC) and evaluate the proportion of patients who achieved ≥ 20% tumor regression within the first 8 weeks of first-line therapy, in the real-world settings. The medians of TFRC in all individual participating centers were > 12 weeks (range 14.0-36.4 weeks). TFRC ≤ 8 weeks was reported for only 3% of patients in the cohort with first-line therapy, and there were only 3 patients (1%) who achieved tumor regression of ≥ 20% by day 60 (8.6 weeks). These findings indicate that the basic time parameter of ETS could not realistically be employed in routine oncology care of patients with metastatic colorectal cancer (mCRC) in the Czech Republic, unless there would be a strict request to perform TRFC by week 8 since the initiation of the therapy. In addition, the frequency of objective tumor response to first-line therapy with cetuximab + chemotherapy was evaluated. Based on the relative regression in the sum of diameters of measurable metastatic lesions, unconfirmed partial responses were achieved in 42.4 % and unconfirmed complete response in 8.6% of patients, altogether corresponding to the overall response rate of 51% with first-line therapy. The frequency of responses was higher among patients with left than right sided primary tumors. It seems that the regimen of cetuximab/FOLFOX might be more active in frontline therapy of right sided RAS wild type mCRC than cetuximab/FOLFIRI.

Zanubrutinib plus Cytarabine in Patients with Refractory/Relapsed Primary Central Nervous System Lymphoma

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive extranodal non-Hodgkin lymphoma. Currently, there is no standard of care for the treatment of refractory or relapsed PCNSL (r/r PCNSL). We conducted a prospective single-arm phase II study to evaluate zanubrutinib plus cytarabine for r/r PCNSL. Methods: Using Simon’s two-stage design, we analyzed 34 patients who received high-dose cytarabine (3.0 g/m2 once daily) for 2 days and zanubrutinib (160 mg twice daily) for 21 days each cycle for up to 6 cycles. The study was registered at www.chictr.org.cn as #ChiCTR2000039229. Results: The median follow-up was 19 months. The overall response rate was 64.7% (95% confidence interval [CI], 47.9–78.5%) with a complete remission or unconfirmed complete remission rate of 47.1% (16/34) and a partial remission rate of 17.6% (6/34). The median progression-free survival was 4.5 months (95% CI, 1.5–9.4), and the median OS was 18 months (95% CI, 9.5 to not estimable). The median duration of the response was 9 months (95% CI, 3.2 to not estimable). The most common treatment-emergent adverse events were thrombocytopenia (55.9%). No treatment-related death occurred. Conclusion: Zanubrutinib and cytarabine showed efficacy in r/r PCNSL with an acceptable safety profile.

Three-year follow-up analysis of phase 1/2 study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.

The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up. Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480mg, or 480mg under fasted conditions. Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment. The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.

Chidamide plus prednisone, cyclophosphamide, and thalidomide for relapsed or refractory peripheral T-cell lymphoma: A multicenter phase II trial.

Although the treatment of peripheral T-cell lymphoma (PTCL) has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory-particularly for relapsed or refractory (R/R) patients. This phase II trial was designed to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate the standard chemotherapy for a variety of reasons. We conducted a multicenter phase II clinical trial in which we combined chidamide (30 mg twice weekly) with prednisone (20 mg daily after breakfast), cyclophosphamide (50 mg daily after lunch), and thalidomide (100 mg daily at bedtime) (the CPCT regimen) for a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. Forty-five patients were ultimately enrolled from August 2016 to April 2021 with respect to Chinese patients at nine centers. Our primary objective was to assess the overall response rate (ORR) after the treatment with CPCT. Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% (32/45) and 28.9% (13/45), respectively, and after a median follow-up period of 56 months, the median progression-free survival (PFS) and overall survival (OS) were 8.5 months and 17.2 months, respectively. The five-year PFS and OS rates were 21.2% (95% confidence interval [CI], 7.9-34.5%) and 43.8% (95% CI, 28.3-59.3%), respectively. The most common adverse event was neutropenia (20/45, 44.4%), but we observed no treatment-related death. The all-oral CPCT regimen was an effective and safe regimen for R/R PTCL patients who could not tolerate standard chemotherapy for various reasons. ClinicalTrials.gov , NCT02879526.

10221-ML-11 A CASE OF PRIMARY CENTRAL NERVOUS SYSTEM ADULT T CELL LEUKEMIA

Abstract Adult T cell leukemia (ATL) manifesting only in the central nervous system (CNS) at presentation is rare. We present a case of primary CNS ATL. 54 year old male presenting with multiple enhanced lesions in the cerebrum went under biopsy and was diagnosed as T-cell lymphoma. While systemic workup was negative, human T-cell leukemia virus type 1 (HTLV-1) antibody was found to be seropositive. Southern blotting using peripheral blood DNA revealed positivity for clonal proliferation of HTLV-1 infected cells. He was therefore clinically diagnosed as primary CNS ATL. He received chemotherapy using methotrexate, procarbazine and vincristine (MPV), and gained a complete response unconfirmed (CRu) after completion of four cycles. However, relapse occurred after the fifth cycle of MPV. Salvage treatment using etoposide, cisplatin, cytarabine and prednisone (ESHAP), whole brain radiation therapy, and lenalidomide, were delivered as second, third, and fourth line therapies, but were ineffective and disease continued to progress. He was therefore treated by best supportive care. Primary CNS ATL should be considered in the differential diagnosis of brain tumors. Southern blotting using peripheral blood might be useful for clinical diagnosis in such cases.

A Phase (Ph) 2 Study of TL-895, a Highly Selective, Novel Covalent BTK Inhibitor (BTKi), in Patients (pts) with Treatment-Naïve (TN) and Relapsed/Refractory (R/R) BTKi-Naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Background: Covalent BTKi have become the backbone of CLL/SLL therapy. Through improved target kinase selectivity, second generation BTKi offer improved safety with potentially better efficacy, yet compartmental clearance leading to complete remission (CR) remains elusive. TL-895 is a potent, second generation, irreversible, oral BTKi with best-in-class selectivity (Gulrajani 2023) over other second generation BTKi; which may lead to improved safety and clearance of leukemic disease to induce deeper and more durable responses. Methods: This multicenter Ph 2 study (NCT02825836) enrolled symptomatic, BTKi-naïve CLL/SLL pts ≥18 years with ECOG PS 0-2. The R/R and TN arms enrolled sequentially and pts were randomly assigned to receive TL-895 at 100 mg (Arm 1 [R/R] and Arm 4 [TN]) or 150 mg (Arm 2 [R/R] and Arm 3 [TN]) twice a day continuously until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR: partial remission [PR], nodular PR [nPR], or CR) per iwCLL 2018 criteria and key secondary were CR rate, safety and BTK occupancy. Results: As of 11 July 2023, 84 pts were enrolled at 12 sites throughout the US and Europe. In TN Arms 3 and 4 (n=21 each), 57% of pts were IGHVUNMUT, 14% had del17p/ TP53MUT and 29% bulky (≥5 cm) adenopathy. Median baseline ALC was 77x10 9/L (range 2-444) in Arm 3 and 46x10 9/L (range 3-215) in Arm 4. In R/R Arms 1 and 2 (n=21 each), pts received a median of 2 prior therapies (range 1-5), 69% of pts were IGHVUNMUT, 48% had del17p/ TP53MUT and 52% bulky adenopathy. Median baseline ALC was 21x10 9/L (range 1-235) in Arm 1 and 34x10 9/L (range 2-178) in Arm 2. In TN Arms 3 and 4, at a median follow-up of 8 months ([mo] range 1-10), the ORR was 86%. In the R/R Arms 1 and 2, at a median follow-up of 23 mo (range 1-26), the ORR was 86% and 81%, respectively. At the 100 mg dose, two unconfirmed CRs (uCR) pending bone marrow (BM) biopsy were reported in R/R Arm 1. At the 150 mg dose, one CR, one uCR pending BM biopsy and two nPRs were reported, two each in R/R Arm 2 and TN Arm 3. All CRs/uCRs and nPRs occurred by week 48. In TN Arm 3 150 mg dose, a faster time to response was observed compared to TN Arm 4 100 mg dose ( Figure 1), with a median ALC reduction of 50% by 3 mo compared to 6 mo, respectively (Figure 2). Additionally, at a median of only 5 mo (range 0.3-8.3), 62% (13/21) of pts in Arm 3 compared with 20% (4/21) of pts in Arm 4 had complete resolution of lymphocytosis in their blood (<4 x10 9/L). Full trough target occupancy (median ≥95%) was achieved in both TN and R/R pts, with low intrapatient variability and near complete inhibition of signaling proteins downstream of BTK by FACS analysis. In the TN arms, treatment-emergent adverse events (TEAEs) regardless of causality were reported in 88% of pts (36% grade [Gr] 3, 0% Gr 4). Most common TEAEs (>10%), were anemia (21%), neutropenia (14%), COVID-19 and upper respiratory tract infection (URTI; 12% each). Most common Gr 3/4 TEAEs (>10%) were anemia and neutropenia (12% each). In the R/R arms, TEAEs were reported in 98% of pts (31% Gr 3, 14% Gr 4). Most common TEAEs were neutropenia (31%) and COVID-19 (21%), thrombocytopenia (19%), diarrhea (17%), anemia, hypertension (HTN) and URTI (14% each), sinusitis and pneumonia (12% each). Most common Gr 3/4 TEAE was neutropenia (26%). In the TN arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (2%; 0%), HTN (5%; 2%), and headache (2%; 0%) with no events of atrial fibrillation (AFib) or major hemorrhage. In the R/R arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (5%; 0%), HTN (14%; 5%), headache (5%; 0%), AFib (5%; 5%) and major hemorrhage (2%, 2%). Gr 5 TEAEs occurred in six R/R pts (three in each arm) and one TN Arm 4 pt, including three COVID-related deaths; none were considered related to TL-895. Excluding COVID-related deaths, median progression free survival (PFS) was not reached with an estimated 8 mos PFS rate of 93% (95% CI, 79-95) in TN pts and 84% (95% CI, 69-93) at 22 mos in R/R pts. Treatment discontinuations included 2 Richter's transformations, one each in TN Arms 3 and 4. Conclusion: Treatment with TL-895 resulted in rapid clearance of leukemic compartments, particularly in TN pts, leading to earlier and deeper responses than expected with monotherapy BTKi. In R/R pts with a very high frequency of del17p/ TP53MUT, remissions have been durable. With a very low incidence of AEs typical of less selective BTKi (e.g., AFib, major hemorrhage, rash and headache), TL-895 has the potential to be a best-in-class backbone BTKi.

Improving the Utilization and Tolerability of Thiotepa-Based Autologous Stem Cell Transplantation in Primary CNS Lymphoma

Background: Thiotepa-based autologous stem cell transplantation (ASCT) improves survival in primary central nervous system lymphoma (PCNSL) but up to 30-60% of patients are unable to receive ASCT after MATRix induction, frequently due to treatment-related adverse events. Common conditioning regimens such as thiotepa/BCNU or thiotepa/busulfan/cyclophosphamide have also been associated with risks of pulmonary toxicity or increased transplant-related mortality. Novel strategies to improve the utilization and tolerability of ASCT are therefore needed to maximize the curative potential of this therapy in PCNSL. Methods: This retrospective population-based study included all patients diagnosed with large B-cell lymphoma-type PCNSL who were intended for ASCT in the province of Alberta, Canada between 2011 and 2022. Provincial treatment guidelines recommended an abbreviated, low-intensity induction protocol to reduce toxicity and increase transplantation rates (Figure 1B). Step 1 included 2 cycles of rituximab/high-dose methotrexate (HD-MTX). Step 2 involved 1 cycle of rituximab/high-dose cytarabine (HDAC) for peripheral blood stem cell mobilization. Step 3 consisted of 2 cycles of rituximab/HD-MTX/HDAC and was made optional in July 2018 so that patients with sufficient disease response and performance status following Step 2 could proceed immediately to ASCT. Conditioning consisted of thiotepa 300 mg/m 2 ×2 days and busulfan 3.2mg/kg ×3 days (TT/Bu). Dose reductions of TT/Bu by 10% for every 5 years over the age of 60 were recommended as of May 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and compared between groups using the log-rank test. Results: The intention-to-transplant (ITT) cohort included 71 patients with median age 58 years (range 26-72), representing 81% of patients aged 18-60 and 55% of those aged 61-72 who were diagnosed with PCNSL in Alberta during the study period. The proportion of patients aged 61-72 who were treated with ITT increased from 42% before 2018 to 70% afterwards. Fifty-six (79%) ITT patients proceeded to ASCT while 15 (21%) did not due to poor performance status (n=6), treatment-related adverse events (n=5), or disease progression (n=4). There was 1 (1%) death due to infection-related non-relapse mortality (NRM) during induction. The routine omission of Step 3 starting in 2018 resulted in high transplantation rates at 29/35 (83%) compared to 27/36 (75%) in the preceding era. With median follow-up time 3.9 years, the 4-year PFS was 69% (95% CI 56-79%) and OS was 80% (95% CI 67-88%) in the ITT cohort (Figure 1A). For the 56 patients who received ASCT, 4-year PFS was 75% (95% CI 57-86%) and OS was 85% (95% CI 68-93%) from the time of ASCT. There was no significant difference in PFS between patients in complete response (CR)/unconfirmed CR versus partial response (PR) before ASCT (p=0.86); however, 5 patients with progressive disease before ASCT had inferior PFS compared to those with CR/CRu/PR (4-year PFS 40% vs 82%, p=0.0002). Relapse occurred in 8 (14%) patients at median 373 days (range 54-1411) after ASCT, including 7 with CNS relapse and 1 with systemic relapse. No patient in remission after ASCT received whole brain radiation therapy and most recovered without clinically significant neurologic deficits. There were no deaths due to transplant-related mortality. NRM occurred in 2 (4%) patients due to an unrelated cancer and stroke 1.1 and 4.3 years after ASCT, respectively. Among 27 patients >60 years old treated with ITT, 17 (63%) proceeded to ASCT, including 6 who received dose reductions of TT/Bu. The transplantation rate in this age group increased from 45% to 75% following the routine omission of Step 3. All 17 transplanted patients remain alive and in remission with median follow-up 2.5 years. Conclusion:In this real-world study of 71 patients with PCNSL, an abbreviated, low-intensity induction protocol resulted in high transplantation rates (~80%) and favorable long-term outcomes with 4-year OS 80%. Notably, TT/Bu conditioning achieved a low incidence of relapse with no transplant-related mortality observed, including among patients >60 years old. These data demonstrate that de-escalated induction therapy can result in improved rates of successful ASCT, thereby optimizing the outcomes of PCNSL.

A Phase II Study of Chidamide Plus R-GDP Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Transplantation: Efficacy and Safety Analysis

Background: A significant subset of Diffuse large B-cell lymphoma (DLBCL) patients (30%-40%) face treatment failure, necessitating effective salvage chemotherapy. We conducted a phase II study evaluating the efficacy and safety of chidamide plus R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin) in relapsed/refractory (r/r) DLBCL patients. Methods: This open-label, single-arm study included 27 patients with r/r DLBCL who were ineligible for autologous stem cell transplantation. Prior to the induction monotherapy phase, chidamide was administered orally at a dose of 30 mg twice a week for one week. The combination therapy phase consisted of oral chidamide at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period, along with intravenous administration of rituximab, gemcitabine, dexamethasone, and cisplatin on a 21-day cycle. Results: A total of 27 patients received at least one dose of Chidamide plus R-GDP and were evaluated for safety. The median follow-up period was 17.0 months (range: 3.5 to 55 months). Radiological response assessment was available for 24 patients, who constituted the efficacy population. Fourteen patients completed six cycles of chidamide plus R-GDP (per-protocol population), while 10 patients discontinued treatment at the data cutoff. The baseline characteristics of enrolled patients included a median age of 67 years, predominantly older than 65 years. Approximately half of the patients exhibited elevated lactate dehydrogenase levels. All patients had received prior therapy with R-CHOP or equivalent chemoimmunotherapy. The majority of cases were classified as stage III/IV and non-germinal center B-cell-like (non-GCB) type by immunohistochemistry. Refractory or relapsed DLBCL within 1 year since the last treatment was observed in 74.0% of patients. Efficacy Outcomes: The investigator-assessed best objective response rate (ORR) was 79.2% (95% CI: 75.1% to 83.3%), with a complete response (CR) rate of 45.8% (95% CI: 41.6% to 49.9%) and a partial response (PR) rate of 33.3% (95% CI: 29.3% to 37.4%). The median time to response was 1.2 months, and the median time to CR or CRu (unconfirmed complete response) was 3.9 months. The best disease control rate was 87.5%. Among the patients who completed six cycles of chidamide plus R-GDP, the best ORR was 100%, with 71.4% achieving CR and 28.6% PR. Kaplan-Meier plots reveal that the median investigator-assessed progression-free survival (PFS) for the efficacy population was 5.9 (95% CI, 3.1 to 12.4) months. The median overall survival was 48.3 (95% CI, 13.1 to not reach (NR)) months. Safety Outcomes: A total of 13 patients (48.1%) required treatment interruption, primarily due to adverse events (22.2%) and disease progression (18.5%). Among patients who completed six cycles of chidamide plus R-GDP, 57.1% required a chidamide dose reduction. The most frequent treatment-emergent adverse event was anemia, occurring in all patients. Thrombocytopenia was the most common grade ≥3 adverse event leading to treatment interruption or dose reduction, affecting 48.1% of patients. Non-hematologic events included hypocalcemia (59.3%), hyponatremia (55.6%), and hypokalemia (44.4%). Three patients experienced grade 3 pneumonitis, and one patient had grade 3 skin rash. Conclusion: Chidamide plus R-GDP salvage chemotherapy demonstrated promising efficacy (ORR: 79.2%; CR rate: 45.8%) in r/r DLBCL patients. Adverse events were manageable but necessitated monitoring. Larger trials are needed to validate these findings and establish chidamide plus R-GDP as a potential treatment option for this challenging population. Keywords: relapsed/refractory DLBCL, salvage chemotherapy, chidamide, R-GDP, efficacy, safety

Residual diffusion-weighted imaging hyperintense signal in primary central nervous system lymphoma can predict early recurrence.

The treatment response of primary central nervous system lymphomas (PCNSLs) is mainly evaluated using postcontrast T1-weighted imaging (T1WI). Because poorly enhanced lesions may contain residual tumors, the combination of evaluation methods will potentially improve the accuracy of determining treatment effectiveness. In this study, we evaluated the usefulness of diffusion-weighted imaging (DWI) in predicting recurrence among patients with PCNSL who achieved complete response (CR)/unconfirmed CR (CRu). Fifty-four patients newly diagnosed with PCNSL who were treated at our institution and achieved CR/CRu at the end of treatment were included in this study. The patients were divided into two groups according to the presence or absence of residual DWI hyperintense signal at the tumor site at the end of treatment. Kaplan-Meier analysis was performed to analyze the median overall survival (OS) and progression-free survival (PFS). The mean age of the 54 patients was 66.4 ± 13.3 years. The induction therapies were HD-MTX in 20 patients, R-MPV in 29 patients, and other chemotherapies in five patients. Radiotherapy was performed in 35 patients, high-dose cytarabine therapy in 14 patients, and autologous hematopoietic stem cell transplantation in one patient, and of the 54 patients, 10 had no consolidation therapy. The residual DWI hyperintense signal sign was observed in 18 patients. The R-MPV regimen was statistically associated with a lower rate of residual DWI hyperintense signal (p = 0.0453). The median PFS was statistically shorter in the residual DWI hyperintense signal group than in the non-residual DWI hyperintense signal group (14.0 months vs. 85.1 months) (p < 0.0001, log-rank test). A residual DWI hyperintense signal at the end of treatment was statistically associated with shorter PFS. Among patients who achieved CR/CRu evaluated based on postcontrast T1WI, DWI could be a valuable additional sequence to predict the early recurrence of PCNSL.

P11.67.B A RETROSPECTIVE STUDY OF 222 PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA - OUTCOMES INDICATIVE OF IMPROVED SURVIVAL OVER TIME

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. MATERIAL AND METHODS We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in 5 referral centers in Israel between 2001-2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation. RESULTS Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5gr/m2 (range 1.14-6 gr/m2) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median PFS and OS were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS:12.5 vs. 34.2 p=0.006 and OS:19.9 vs 77.3 p=0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and ECOG performance status. CONCLUSION The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX- based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the INTRODUCTION of HDC-ASCT.

A retrospective study of 222 patients with newly diagnosed primary central nervous system lymphoma-Outcomes indicative for improved survival overtime.

Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in five referral centers in Israel between 2001 and 2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation (HDC-ASCT). Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5g/m2 (range 1.14-6g/m2 ) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24months, the median progression-free survival (PFS) and overall survival (OS) were 21.9 and 43.5months respectively with a significant improvement since 2012 (PFS: 12.5 vs. 34.2 p=0.006 and OS: 19.9 vs. 77.3 p=0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and Eastern Cooperative Oncology Group performance status. The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX-based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the introduction of HDC-ASCT.

Targeting EZH2 to overcome the resistance to immunotherapy in microsatellite stable colorectal cancer: Results from the CAIRE study.

3599 Background: Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. Targeting EZH2 can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). The CAIRE study is first study investigating the impact of EZH2 inhibition in combination with immune checkpoint inhibitor in solid tumors. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of tazemetostat (800 mg BID) combined with durvalumab (1120 mg every 3 weeks) in patients with advanced microsatellite stable colorectal cancer. The primary endpoint was the disease control rate within 24 weeks after treatment onset defined as the proportion of patients with at least a tumor assessment showing connfirmed or unconfirmed complete response, confirmed or unconfirmed partial response or stable disease based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 47 pts were enrolled at Institut Bergonié (Bordeaux, Centre). Median age was 67.7 (range 39.6 – 84.0). Median number of previous treatment lines was 4: (range 1 – 6). The most common treatment related adverse events were grade 1/2 asthenia, nausea. No death was related to the treatment. Among the 34 pts for whom blinded central review of imaging was available for at least one imaging tumor assessment, best tumor response was confirmed partial response, stable disease and progressive disease in 1 (2.9%), 11 (32.3%) and 22 (64.7%) patients respectively. The disease control rate was 35.3% (95%CI 19.7 – 53.5). Conclusions: The CAIRE study met its first endpoint for disease control rate in patients with advanced colorectal cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT04705818 .

PRELIMINARY RESULTS OF A PHASE 2 STUDY OF CHIDAMIDE, GEMCITABINE, VINORELBINE, AND MITOXANTRONE LIPOSOME (CHI‐GVM) IN RELAPSED/REFRATORY PERIPHERAL T‐CELL LYMPHOMA

Introduction: Patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) have a poor prognosis. There is no effective treatment for these patients. Mitoxantrone hydrochloride liposome showed high antitumor activity and low toxicity in lymphoma. In a phase II clinical study of mitoxantrone hydrochloride liposome monotherapy for R/R T-cell lymphoma, the overall response rate (ORR) and complete remission rate (CRR) of PTCL, not otherwise specified (PTCL, NOS) reached 34.4% and 18.8%. Our study aimed to explore whether the combination chemotherapy regimen containing mitoxantrone liposomes can improve the efficacy and survival of R/R PTCL. Methods: A Phase II, multicenter, single-arm, open-label study is planned at our center. All patients enrolled are R/R PTCL and will receive induction therapy with chidamide (20 mg, twice a week), gemcitabine (1 g/m2, d1), vinorelbine (20 mg/m2, d1), and mitoxantrone hydrochloride liposome (20 mg/m2, d1) (Chi-GVM) for 2–4 cycles. Patients aged 60 years or younger with complete remission (CR) / unconfirmed complete remission (CRu) / partial remission (PR) after 2–4 cycles of induction therapy received autologous stem cell transplantation (ASCT) prior to maintenance therapy. Patients after ASCT or patients over 60 years old with CR/CRu/PR receive maintenance therapy of chidamide (20 mg twice a week) until intolerance or disease progression (PD). Efficacy was assessed by contrast-enhanced CT or PET-CT every 2 cycles during treatment. The primary endpoint of the study was ORR and secondary endpoint was duration of remission (DOR) and1-year progression-free survival (1y-PFS). Results: A total of 7 patients were treated with Chi-GVM between September 2022 and February 2023, including 3 patients with PTCL, NOS; two patients with ALK negative anaplastic large cell lymphoma (ALCL, ALK-); and 2 patients with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Five male and two female were included, with a mean age of 57 years, and one patient was post-ASCT. Two patients were re-staged of stage I–II and five of stage III–IV prior to treatment, extranodal lesions including stomach, skin and intestinal. Four patients were evaluable for efficacy, 1 patient was lost to follow-up, and 2 patients did not reach the assessment time. Of the evaluable patients, 2 patients had a best response of CR and 2 patients experienced PD, one patient achieved CR and received consolidation therapy with ASCT. Grade 2 or 3 adverse events occurred in 5 patients, including 3 cases of leukopenia, 4 cases of neutropenia, 2 case of thrombocytopenia, and 1 case of hepatic insufficiency. One patient had myocardial damage before treatment, and kept stable after mitoxantrone hydrochloride liposome used. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Late Effects in Lymphoma Survivors No conflicts of interests pertinent to the abstract.

Abstract CT009: S1512: High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma

Abstract Background: Desmoplastic melanoma (DM) is a subtype of melanoma with high tumor mutation burden (TMB) due to ultraviolet light damage. A previously published retrospective review of patients with PD-1 blockade treated DM suggested this cancer may be highly responsive to PD-1 blockade (Eroglu et al. Nature 2018). S1512 is the first prospective study investigating PD-1 blockade with pembrolizumab in patients with DM. 1512 Cohort A results were presented and demonstrated a 59% complete pathologic response rate with neoadjuvant pembrolizumab in patients with resectable DM (Kendra et al. ASCO 2022). Herein, we present results from S1512 Cohort B in patients with metastatic DM. Experimental procedures: Patients aged ≥18 with metastatic DM received pembrolizumab 200 mg q3 weeks. Eligibility criteria included: Zubrod PS 0-2, no central nervous system metastases, autoimmune disease, or steroid ≥10 mg of prednisone. The primary endpoint was complete response rate (CR) assessed per RECIST 1.1, with the assumption that CR of 20% or higher indicates that the treatment is of interest. A single stage design with 21 eligible patients would have an alpha of 8.5% (when the true CR is 5%) and a power of 82%. Tumor assessments were performed every 9 weeks. Secondary endpoints included progression free survival (PFS), overall survival (OS), and toxicity assessment. Biopsies were analyzed by whole exome sequencing (WES) for mutational load and oncogenic driver mutations. Summary of data: 27 eligible patients were enrolled in Cohort B. 93% were male, 70% had Zubrod PS 0, median age 75 (range 59-90). Median number of cycles received: 15 (range 1-34). At the time of data cutoff, 3 patients remain on protocol treatment with pembrolizumab. Treatment was discontinued due to: 2 years of therapy (4), adverse event (AE) (8), physician and patient choice (6), progressive disease (4), and under review (2). Objective response rate (including both confirmed and unconfirmed partial and complete responses) was 85% (95% CI: 66%-96%), with 7/27 CR (26%) and 16/27 PR (59%). Grade 3 or higher adverse events were reported in 10 patients. WES analysis was available for 16 patients. Both baseline (N=10) and on-treatment biopsies (N=12) were evaluated for canonical genetic drivers of melanoma; 7 patients had tumors with loss of function (LOF) mutations in NF1, and all had mutations in TP53, with no case having activating mutations in BRAF or NRAS, consistent with the known genetic alterations in DM. The median TMB in baseline biopsies was 79.4 Mut/Mb (range 34.3-159). Conclusion: Patients with metastatic DM are exceptional responders to single agent PD-1 blockade with pembrolizumab. Based on this data, the pathologic subtype of melanoma can be used as a predictive biomarker of response to single agent pembrolizumab. Funding: U10CA180888 and U10CA180819; and in part by Merck Sharp &amp; Dohme LLC., a subsidiary of Merck &amp; Co., Inc., Rahway, NJ, USA Citation Format: Kari Kendra, Shay Bellasea, Zeynep Eroglu, Siwen Hu-Lieskovan, Katie M. Campbell, William Carson, David Wada, Jose A. Plaza, Jeffrey Sosman, Gino K. IN, Alexandra Ikeguchi, John Hyngstrom, Andres Brohl, Nikhil I. Khushalani, Joseph Markowitz, George Negrea, Samer Kasbari, Gary C. Doolittle, Umang Swami, Toni Roberts, Sapna P. Patel, Elad Sharon, James Moon, Michael C. Wu, Antoni Ribas. S1512: High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT009.

Real-World Evidence for the Safety and Effectiveness of Tirabrutinib in 140 Japanese Patients with Recurrent or Refractory Primary Central Nervous System Lymphoma: Interim Report of Postmarketing Surveillance

Background: Primary central nervous system lymphoma (PCNSL) is a brain tumor with a very poor prognosis. Tirabrutinib is a second-generation inhibitor of Bruton's tyrosine kinase with higher kinase selectivity than ibrutinib (Banerji et al., 2020), suggesting potentially fewer off-target adverse events-including infections, bleeding, and cardiovascular adverse events-that have been reported with ibrutinib. On the basis of results of a phase I/II study (ONO-4059-02; trial registration number: JapicCTI-173646), tirabrutinib was approved in Japan in March 2020 for recurrent or refractory PCNSL at a dose of 480 mg under fasted conditions. We conducted a prospective, noninterventional, multicenter, observational study (trial registration number: jRCT2011210002) to evaluate adverse drug reactions (ADRs) and the overall response rate (ORR) of tirabrutinib against recurrent or refractory PCNSL in Japan. This postmarketing all-case surveillance study started on May 20, 2020. We report the interim safety and effectiveness data for patients who started tirabrutinib administration from the start date through October 31, 2020. Methods: All patients were monitored up to 52 weeks. Collected data included baseline characteristics, laboratory test results, ADRs, and the ORR. ADRs were coded according to MedDRA, version 24.1. The ORR was evaluated according to the criteria of the International PCNSL Collaborative Group (IPCG). The timing and method of imaging study was at discretion of physician. Results: Data from 140 patients who received tirabrutinib treatment were analyzed for safety, and data from 127 of those patients were analyzed for effectiveness. A total of 13 patients were excluded from the effectiveness analysis because 9 patients had a history of prior treatment with tirabrutinib and 4 patients received tirabrutinib as off-label use for the treatment of newly diagnosed disease. Of the 140 patients, 72 (51.4%) were male. Their median age was 70 years (range, 30-88 years), and 98 patients (70.0%) were 65 years of age or older. The Karnofsky Performance Status scores were 80-100 for 49 patients (35.0%), 50-70 for 60 patients (42.9%), and ≤40 for 31 patients (22.1%). Fifteen patients (10.7%) had intraocular lymphoma. The median number of previous lines of treatment was 1 (range, 0-6) and for 67 patients (47.9%), tirabrutinib was second-line therapy. The median duration of tirabrutinib treatment was 147.0 days (range, 3-365 days); 28 patients (20.0%) continued taking tirabrutinib until the end of the observation period (365 days) and thereafter. Of the 95 patients who discontinued tirabrutinib treatment, 60 (63.2%) did so because of disease progression, 15 (15.8%) because of adverse events, 13 (13.7%) because they transferred to another hospital, 4 (4.2%) because they responded to treatment, and 13 (13.7%) for other reasons. The most common systemic ADRs were skin and subcutaneous tissue disorders, including rash, pruritus, erythema multiforme, and rash maculo-papular; these affected 43 (30.7%) of all 140 patients, of whom 12 (8.6%) had grade 3 or worse ADRs (Table 1). Seven patients (5.0%) discontinued tirabrutinib treatment due to grade 3 or worse (n = 6) or grade 2 (n = 1) skin-related ADRs. Infections and infestations were observed in 5 patients (3.6%), of whom 2 (1.4%) had grade 3 or worse infections or infestations. Grade 1 or 2 bleeding was observed in 2 patients (1.4%). No patients in this cohort had cardiovascular ADRs or grade 5 ADRs. At the end of the 52 weeks, 73 patients (52.1%) were still alive, 46 (32.9%) had died, and the status of 21 (15.0%) was unknown. With regard to effectiveness (n = 127), the ORR was 63.0% (n = 80) and the rate of confirmed or unconfirmed complete response was 37.0% (n = 47; Table 2). Conclusion: In this interim period of the postmarketing all-case surveillance study, the most common ADRs were skin and subcutaneous tissue disorders, and no new safety concerns were identified in addition to those in the clinical trial. The ORR and the rate of complete or unconfirmed complete response were comparable to those at the approved dose in the phase I/II study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary Results of Penpulimab Combined with RMA (rituximab, methotrexate, and cytarabine) for Newly Diagnosed Primary Central Nervous System Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) has been classified as large B-cell lymphomas (LBCL) of immune-privileged sites according to the 5th edition of the World Health Organization (WHO) Classification. The efficacy of high-dose methotrexate as a first-line treatment was suboptimal with a short effective remission time and low response rate. The recent discovery of the frequent copy number alterations in 9p24.1/PD-L1/PD-L2 and increased expression of PD-L1 in PCNSL provide the rationale to evaluate the efficacy of PD-1antibody in PCNSL. Methods: NCT05347641 is an ongoing Phase II, single-center, single-arm, open-label study, aimed to enrolled an estimated 23 newly diagnosed PCNSL patients. Enrolled patients first received the Pen-RMA induction treatment, including rituximab 375 mg/m2, d0; methotrexate 3.5g/m2, d1; cytarabine 1‒2g/m2, q12h, d2-3; penpulimab (an anti-PD1 antibody of IgG1 isotype) 200 mg, d5; 21d/cycle, for six cycles. Patients aged 60 years or younger, with complete response (CR)/unconfirmed complete response (CRu)/partial response (PR) after six cycles of induction treatment then underwent autologous stem cell transplantation (ASCT) before maintenance treatment. The maintenance regimen was administered based on patient response to ASCT, or to induction therapy for patients aged 60 years or older. Patients who achieved CR after ASCT or induction therapy then received 8 cycles of penpulimab as maintenance therapy, and those with PR after ASCT or induction therapy received whole brain radiotherapy (WBRT) combined with 8 cycles of penpulimab as maintenance. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every three cycles of the induction treatment. The primary endpoint of this study was two-year progression-free survival rate. Baseline tissue samples and sequential CSF or plasma samples were collected for targeted next-generation sequencing (NGS) at Nanjing Geneseeq Technology Inc. Results: Between April, 2022 and July, 2022, eleven newly diagnosed PCNSL patients has been enrolled. Treatment response was evaluable in eight patients. At the interim assessment point (after 3 cycles), six patients have achieved CR, with an overall response rate of 75.0%. Of these, three have completed 6 cycles of treatment and all achieved CR at the final assessment (Figure A). Adverse events of grade 3 or 4 occurred in five patients, including three neutropenia (27.3%), one thrombocytopenia (9.1%), and one renal dysfunction (9.1%). In the baseline samples, PIM1, MYD88L265P, and CD79B were the most common mutations, with a more comprehensive genomic landscape revealed by CSF than by blood (Figure B). All nine NGS-tested patients were classifier into the non-GCB subtype by the COO classification and the MCD subtype by the LymphGen classifier. CSF-based ctDNA monitoring was performed in two patients after 6 cycles of treatment. P01 had confirmed CR with ctDNA clearance in CSF. P07, was assessed as CR after 6 cycles, but the CSF ctDNA remained positive. This patient is currently receiving maintenance treatment and is being closely monitored for potential disease relapse. Interestingly, P02 and P04, who were PD and SD at interim evaluation, respectively, had markedly more mutations detected in their baseline plasma samples, indicating a poor prognosis (Figure A). Conclusion: The induction treatment of Pen-RMA has shown excellent responses in newly diagnosed PCNSL patients with mild hematologic toxicity. Our preliminary results also suggested that CSF-based ctDNA could facilitate diagnosis when tissue was inaccessible and show higher sensitivity than imageology in assessing the depth of remission. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Disparities in Somatic Mutations and Outcomes in Primary Central Nervous System Lymphoma Comparing Patients of Hispanic and Non-Hispanic Ethnicity

Background: Primary central nervous system lymphoma (PCNSL) is characterized by frequent MYD88 L265P activating mutations, biallelic CDKN2A loss, and mutations in CD79B, PIM1, and CARD11. However, the extent to which mutations vary by ethnicity is unknown. The purpose of this study is to describe differences in genetic mutations and survival between PCNSL patients of different ethnicities. Methods: We retrospectively analyzed patients ≥ 18 years with PCNSL diagnosed between January 2011- December 2020 and treated at UCSF-Fresno and University of Oklahoma. Next generation sequencing was performed on Formalin Fixed Paraffin Embedded tissue. We examined mutations in 434 genes by DNA analysis and 1408 genes by RNA analysis. Sequencing was performed using an Illumina NextSeq 550 system platform. The clinical data including age, sex, ethnicity, race, ECOG performance status, number and location of lesions, HIV status, LDH, protein in the CSF, and treatment regimens were reviewed. Treatment response was assessed by MRI using the international consensus group response criteria. Comparison of patient characteristics and rate of genetic alterations between Hispanic and Non-Hispanic patients was done using the Fisher exact test or Chi-square test. Time-to-event analyses were conducted using the Kaplan-Meier method and were compared by a log-rank test. Univariate analyses were performed via the Cox proportional hazards model. Analysis was performed with STATA version 16.0. Results: Among the 51 patients analyzed, the median age was 61. 54% were males and 43% were Hispanic. 13% had HIV, 27% had deep brain involvement, and 58% had non-germinal center (non-GC) type per Hans Criteria. 81% of Hispanic patients had non-GC vs 41% non-Hispanic (P=0.006). There was no statistically significant difference in age, performance status, HIV status, deep brain involvement, or CSF involvement between Hispanic non-Hispanic patients. 90% of patients received systemic chemotherapy for initial treatment, with 41% receiving high dose Methotrexate, Rituximab and Temozolomide. No patients received autologous stem cell transplant in first remission. 90% Hispanic Vs 89% Non-Hispanic received systemic chemotherapy (P=0.447). 29 patients (56%) achieved complete response (CR)/unconfirmed complete response (CRu). 2-year progression-free survival (PFS) was 67.4%, and 2-year overall survival (OS) was 55% for all patients. 177 genetic alterations were detected with the most common being MYD88, CD79B, TET2, PIM1, ETV6 and TP53 (table). Hispanic patients, compared with non-Hispanic patients, had a lower rate of MYD88 mutation (40.9% vs 72.4%, P=0.024) and TP53 mutation (0.0% vs 24.1%, P=0.001). 2-year PFS in Hispanics was 40% vs 30% in non-Hispanics (P=0.526) and 2-year OS in Hispanics was 0.63% vs 0.33% in non-Hispanics (P=0.05). In univariate analysis, age and genetic alterations (MYD88, CD79B, TET2, PIM1 and ETV6) were not associated with significant differences in 2-year PFS or OS. Performance status (ECOG ≤ 2), negative CSF cytology, and treatment with multi-agent chemotherapy rather than high dose Methotrexate alone were associated with better 2-yr OS. Conclusions: We identified highly recurrent genetic alterations in PCNSL. Our data suggest that some heterogeneity in the most frequent mutations in PCNSL may be related to ethnicity. Hispanic patients in our study have better 2-year OS; however, the data is limited by the retrospective analysis and the small patient number. Further studies on a larger patient population are warranted to evaluate genetic heterogeneity in different ethnic groups and effect of ethnicity and socio- economic status on outcomes in patients with PCNSL Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Disease Characteristics and Treatment Outcomes with HLX01: A Real-World Study in Patients with B-Cell Non-Hodgkin Lymphoma in China

Introduction B-cell non-Hodgkin lymphoma (NHL) is the most common hematological malignancy encompassing heterogenous subtypes (Dotan et al., PT 2010). Rituximab (R) has changed the treatment landscape of NHL; approvals of rituximab biosimilars have improved access to and the affordability of this treatment (Mohammed et al., J Blood Med 2019). HLX01 is the first rituximab biosimilar approved for the treatment of NHL and chronic lymphocytic leukemia in China. In a Phase 3 trial enrolling patients with diffuse large B-cell lymphoma (DLBCL), HLX01 demonstrated bioequivalence to reference rituximab in terms of efficacy and safety (Shi et al., J Hematol Oncol 2020). The current study is an ongoing, observational study with the objectives of characterizing the distribution of B-cell NHL subtypes in patients receiving HLX01 and assessing the effectiveness and safety of HLX01 in patients with B-cell NHL subtypes in a real-world setting in China. Methods This multicenter, real-world study enrolled adult patients with pathologically confirmed B-cell NHL subtypes at 40 hospitals in China. HLX01 (either as monotherapy or combination therapy) was recommended, but the selection of treatment regimen was at the investigator's discretion. The primary endpoint was the distribution of B-cell NHL subtypes in patients receiving HLX01. Secondary endpoints were objective response rate (ORR) and complete response (CR) rate in patients with B-cell NHL and progression-free survival (PFS) and overall survival (OS) rates at 1, 3, and 5 years in subgroups categorized by disease characteristics. Response was evaluated every 6 weeks until disease progression or end of treatment, using the Lugano 2014 criteria. After treatment, disease and survival status were followed up every 2 months. Safety was monitored until 1 month after treatment completion. Here, we report results from baseline to 1-year follow-up. Results Between April 2020 and June 2021, 2053 patients were enrolled; of these patients, 1898 had evaluable efficacy data (full analysis set [FAS]) and 1878 had completed ≥ 5 treatment cycles (per-protocol set [PPS]). Overall, the most common subtype was DLBCL (1231/2053, 60.0%), followed by follicular lymphoma (293/2053, 14.3% [Table 1]). Among patients in the FAS, R-CHOP was the most commonly used regimen (1006/1898, 53.0%). Other regimens included BR (175/1898, 9.2%), R monotherapy (150/1898, 7.9%), R2 (63/1898, 3.3%), R-EPOCH (56/1898, 2.95%), DA-R-EPOCH (48/1898, 2.5%), R-DA-EDOCH (18/1898, 0.95%), R-EDOCH (11/1898, 0.58%), and others (371/1898, 19.5%). In the FAS, 868 (45.7%) patients had CR/CRu (CR + unconfirmed CR) and 883 (46.5%) had partial response, contributing to an ORR of 92.3%; in the PPS, the ORR was 93.2%. In 215 patients with evaluable OS and PFS data, median OS and PFS were not reached, and 1-year OS and PFS rates were 90.7% and 74.4%, respectively. In patients with DLBCL in the FAS, 519 (45.5%) had CR/CRu and the ORR was 91.8%. In 139 evaluable patients with DLBCL, 1-year OS and PFS rates were 91.3% and 75.6%, respectively. The ORRs in most subtypes exceeded 90% (Table 2). Among all patients, 423 (20.6%) experienced adverse events (AEs), most of which were grade 1 or 2 in severity. The most common AEs were decreased white blood cell count (3.9%), decreased neutrophil count (3.5%), and nausea/vomiting (3.3%). Conclusions DLBCL is the most common subtype in HLX01-treated patients with B-cell NHL in China. HLX01 showed clinical benefits with favorable safety profiles in patients with B-cell NHL subtypes in a real-world setting. Clinical trial identification: ChiCTR2000032263. Research funding: None. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chidamide Plus Prednisone, Cyclophosphamide, and Thalidomide (CPCT) for Relapsed or Refractory Peripheral T-Cell Lymphoma: A Multicenter Phase II Trial

Purpose: Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of aggressive lymphomas that portends an unfavorable outcome. Although the treatment of PTCL has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory-particularly for relapsed or refractory (R/R) patients. We herein conducted a prospective, single-arm phase II clinical trial to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate standard chemotherapy for a variety of reasons. Methods: This was an open-label, single-arm, multicenter pivotal phase II study in which patients were enrolled at 9 centers. The flow chart of the CPCT regimen: a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. The CPCT regimen was administered orally until disease progression or unacceptable toxicity as follows: chidamide at 30 mg twice weekly, prednisone at 20 mg daily after breakfast, cyclophosphamide at 50 mg daily after lunch, and thalidomide at 100 mg daily at bedtime. Our primary objective was to assess overall response rate (ORR) after treatment with CPCT, with secondary objectives to evaluate the duration of response, one-year overall survival (OS), and one-year progression-free survival (PFS). Results: Forty-five patients were ultimately enrolled in the present study for response and safety assessments from August 2016 to April 2021 with respect to Chinese patients (the characteristics of the 45 patients with at least one treatment response assessment are listed in Figure 1A). Twenty-three patients (51.1%) were heavily pretreated before enrollment. Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% and 28.9%, respectively, and after a median follow-up period of 56 months, the median PFS and OS were 8.5 and 17.2 months, respectively (Figure 1B). The median median duration of response (DOR) was six months with a range of 0.7-71.5 months, and most responders (41 patients, 91.1%) had a DOR more than three months. Twenty-eight patients (62.2%) exhibited a DOR over six months and 17 patients (37.8%) had a DOR over 12 months. The one-year PFS and OS rates were 42.2% (95% CI, 27.7%‒56.7%) and 57.8% (95% CI, 43.3%‒72.3%), respectively, and the five-year PFS and OS rates were 21.2% (95% CI, 7.9%‒34.5%) and 43.8% (95% CI, 28.3%‒59.3%), respectively. Although subgroup survival analysis indicated no significant differences among different histopathologies (Figure 1C and D), the median PFS (p<0.001) and OS (p<0.001) were not attained for patients who achieved CR/CRu (N=13) (Figure 1E and F). The most common grade 3/4 adverse event was neutropenia (24.5%), but we observed no treatment-related mortality. Conclusions: In conclusion, the all-oral CPCT regimen was a well-tolerated and effective treatment for R/R PTCL patients who could not tolerate standard chemotherapy for a variety of reasons. However, further studies that entail a larger sample size in different subtypes of PTCL are still required. This trial was registered in ClinicalTrials.gov (NCT02879526). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal