ALBERT

Description: Introduction Crizotinib (Xalkori®) is an ALK inhibitor with proven efficacy in patients with ALK-rearranged advanced non-small cell lung cancer (NSCLC; Shaw AT et al, New Engl J Med 2013;368:2385–9). However, ALK rearrangement is implicated in other types of malignancy, including anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Here we assess the safety and anti-tumor activity of crizotinib in patients with advanced ALK-rearranged hematologic malignancies enrolled in an open-label phase 1b study (Pfizer; A8081013; NCT01121588). Methods ALK-positivity was confirmed by IHC for cases of ALCL; other malignancies required confirmation by FISH, PCR, or sequencing. Patients with brain metastases were eligible if neurologically stable for 2 weeks with no ongoing treatment requirement. Eligible patients received crizotinib 250 mg twice daily. Responses were assessed every 6 weeks using RECIST v1.1 or Revised Response Criteria for Malignant Lymphoma 2007 (Cheson criteria); best overall response was determined by RECIST or Cheson if only one assessment was available, and by Cheson criteria if both were available. Adverse events (AEs) were assessed using CTCAE v4.0. Results Fifteen patients with advanced ALK-positive hematologic malignancies were enrolled; 14 with ALK-positive ALCL and one with ALK-positive DLBCL. At the data cutoff date of July 15, 2013, treatment was ongoing in 10 patients, and there were five discontinuations (1 due to early death, 1 due to global deterioration of health and 3 due to disease progression). Nine patients (60%) were male, and the median age was 25 years (range 15–37 years). Most patients were white (60%), with the remainder Asian. Two patients (13%) received prior radiation therapy. All patients received prior systemic therapy (median 2 lines [range 1–6]). ECOG performance status (ECOG PS) at baseline was 0 for 3 patients (20%), 1 for 7 patients (47%), 2 for 4 patients (27%), and 3 for 1 patient (7%). Median duration of treatment was 33 weeks (range 0.1–117 weeks). There were 9 confirmed responses (5 complete response [CR] and 4 partial response [PR]), for an objective response rate (ORR) of 60%. Additionally, 1 patient experienced stable disease (SD) of 〉12 months. Overall, the clinical benefit rate (CBR; CR + PR + SD) was 67%. AEs (all causality) were reported for all 15 patients and were predominantly of grade 1 or 2. The most common AEs were diarrhea (47% of patients), vomiting (47%, including 1 grade 3 event), visual impairment (40%), asthenia (27%), cough (27%), and neutropenia (27%, including 2 grade 3 events). Four patients experienced grade 4 events (abdominal pain, increased creatinine phosphokinase, lymphopenia, and multi-organ failure), and one of these patients also experienced a grade 5 event (central nervous system hemorrhage). Conclusions Crizotinib showed anti-tumor activity in advanced ALK-rearranged hematologic tumors. The high ORR (60%) and CBR (67%) with crizotinib in this cohort is consistent with the high response rates seen with crizotinib in ALK-rearranged advanced NSCLC, and the safety profile of crizotinib was also similar to previous clinical experience with crizotinib. These data suggest that ALK inhibition can be effective in patients with ALK-positive hematologic malignancy and further investigation may be warranted in this setting. Disclosures: Gambacorti-Passerini: Pfizer: Research Funding. Off Label Use: Crizotinib is an ALK inhibitor which is indicated for use in ALK-positive advanced NSCLC. This study investigates the use of crizotinib in patients with ALK-positive malignancies other than NSCLC. Braiteh:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Pfizer: Research Funding. Taylor:1. Bayer HealthCare Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees; 1. Bayer HealthCare Pharmaceuticals, Inc.: Honoraria. Brega:Pfizer: Equity Ownership; Pfizer: Employment. Paolini:Pfizer: Equity Ownership; Pfizer: Employment. Selaru:Pfizer: Equity Ownership; Pfizer: Employment.

Description: Purpose Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive lymphoma with poor prognosis. The response rate to L-asperagenase(L-ASP) based multi-agent regimens is highly effective. Several clinical trials demonstraed good response and less toxicity for pegaspargase (PEG-ASP) in comparison to L-ASP. This is the first prospective study to evaluate the efficacy and safety of PEG-ASP combined with gemcitabine and oxaliplatin (PEG-ASP + Gemox) for patients with treatment-naïve and refractory or relapsed ENKTL. Patients and methods 61 eligible patients treated by PEG-ASP + Gemox from March 2010 to March 2013 were analyzed. 36 newly -diagnosed patients and 25 refracrory/replased patients were enrolled, we also conducted extra matched-pair analysis between 20 stage IE/IIE cases selected from 36 newly -diagnosed patients in PEG-ASP + Gemox group and 18 stage IE/IIE patients in L-ASP + Gemox regimen group(unpublished data, Table 1,2). PEG-ASP + Gemox dosages were as follows: Gemcitabine 1000 mg/m2; day 1,8; oxaliplatin 130 mg/m2 day 1, PEG-ASP 2500 U/m2 im day1. The regimen was repeated every 3 weeks for a maximum of 6 cycles including 3 cycles induction chemotherapy for stage IE/IIE patients followed by involved-field radiotherapy. Furthermore autologous haematopoietic stem cell transplantation(AHSCT) was recommended to refractory/relapsed patients after achieved good response. Results 55 patients were evaluable for response after a median 4 (1¨C6 ) cycles. The overall response(OR) rate was 90.9% (50/55), with a complete remission (CR) rate of 60.0% (33/55). After a median follow-up of 16.2 (4.0-39.5)months, the 1-, 2-year OS rates were 88.2%, 83.2%, and the 1-, 2- year PFS rates were all 85.2%. The median follow-up time was 19.6 (4.0-39.5)months for treatmen-naive patients. their OR, CR, partial remission(PR) rates were 94.0% (31/33), 66.7% (22/33), 27.3% (9/33), respectively. Both 1-, 2-year OS rates were 94.0%, 1-, 2-year PFS rates were all 93.9%. The median follow-up time was 18.7(4.5-36.2) months for refractory/replased patients. The OR and CR rates were 86.4% (19/22), 50.0% (11/22). The 1-, 2-year OS rates were 80.4% ,70.4%, the 1-, 2-year PFS rates were all 72.7%. Patients who achieved CR had undergone a median of two cycles (2¨C6). All patients received 187 cycles of chemotherapy, the incidence of rates of grade 1 and 2 adverse events were as follows: neutropenia, 69.6%; vomit 39.5%, transaminase elevation, 37.9%. Grade 3 and 4 adverse reactions were rare. Conclusion Our clinical trisl have demonstrated high efficacy and quick achievement of CR for the first time for PEG-ASP+Gemox regimen in the management of treatment-naïve and refractory/relapsed ENKTL patients. It also provided good chance of AHSCT as consolidation for chemosensitive patients. Meanwhile, PEG-ASP+Gemox regimen was conveniant and less toxic. Further investigation for PEG-ASP + Gemox regimen is warranted. Disclosures: No relevant conflicts of interest to declare.

Description: The prognostic value of dynamic monitoring C-reactive protein (CRP) serum levels in NK/T-cell lymphoma Background and Objective C-reactive protein (CRP) is a kind of acute phase protein against inflammatory reaction. CRP has been proved to be associated with prognosis in various malignancies. Yet, the prognostic value of CRP in natural killer/T-cell lymphoma (NK/TCL) remains to be discussed. In this study, we aimed to observe the dynamic change of CRP serum levels during anti-lymphoma treatment, and to evaluate the prognostic value of CRP as a simple and economical biomarker during the early stage of treatment in patients with NK/T-cell lymphoma. Patients and Methods Between January 2003 and December 2011, 161 patients with newly diagnosed NK/TCL at the Sun Yat-sen University Cancer Center (SYSUCC) were reviewed retrospectively. Clinical and laboratory information was collected and analyzed. The following CRP serum levels were evaluated: pretreatment CRP (CRP0), early-treatment CRP (CRP1, after one cycle of chemotherapy, or two or three weeks since beginning of radiation), and post-treatment CRP (CRP2, after first-line treatment, or failure of first-line treatment). Results Overall, 161 patients were reviewed and analyzed. The median age was 44 years (range, 11¨C74). The majority had localized disease (stage I/ II; 75.5%). The CRP serum levels (mean ± standard deviation) were as follows: CRP0, 17.2±23.1 mg/L; CRP1, 14.0±30.0 mg/L; CRP2, 14.1±27.0 mg/L. The pretreatment CRP serum levels correlated with others unfavorable factors, including serum lactate dehydrogenase (LDH) (P = 0.005), presence of bulky disease (P = 0.002), presence of B symptoms (P = 0.017), the International Prognostic Index (IPI) score (P = 0.001) and the Korean Prognostic Index (KPI) score (P = 0.001). By the time of the final follow up assessment (May 2013), the median follow-up time was 23.0 months (range, 1.0-106.0 months). The median overall survival (OS) and progression-free survival (PFS) were 45.0 months (range, 1.0-106.0 months) and 32.0 months (range, 1.0-74.0 months), respectively. The independent unfavorable prognostic factors for OS (P 〈 0.05) in multivariate analysis included: elevated CRP1 (P 〈 0.001), presence of bulky disease (P = 0.007), and elevated β2-microglobulin (β2-mg) serum levels (P = 0.004). The receiver operating characteristic analysis revealed a similar cut-off value of CRP (8.16 mg/L) to the default value of the biochemical analyzer (8.2 mg/L). In addition, the result suggested a satisfying capacity of CRP1 in predicting response to initial treatment (sensitivity 94%, specificity 74%) and 5-year OS (sensitivity 75%, specificity 90%), among different serum biomarkers, including EBV-DNA, LDH, β2-mg, CRP0, CRP1, and CRP2. In all groups of patients classified according to dynamic CRP values, the patients with CRP0 (+) /CRP1(-) presented the most favorable prognosis (5-year estimated OS: 72.5%). Conclusions Our study suggests that elevated early-treatment CRP is an independent unfavorable prognostic factor for patients with NK/TCL. Compared with the baseline CRP, the dynamic change of CRP levels may provide more important information for prognosis during treatment. Disclosures: No relevant conflicts of interest to declare.

Description: Background and Objective Natural killer/T-cell lymphoma (NK/TCL) is featured with inflammatory symptoms and poor prognosis. Currently, new treatment targets and modalities are urgently needed for patients with high risk NK/TCL. As one of the most important factors in the microenvironment of lymphomas, tumor-associated macrophages (TAM) may display either positive or negative effect on tumor proliferation and metastases, depending on the polarization of macrophages (M2 or M1 type). It is well established that the activation and differentiation of TAM are determined by different stimuli from the microenvironment. The characteristic cytokine spectrum of M1 type macrophages is high expression of IL-6 and IL-12, and low expression of IL-10. In contrast, the characteristic cytokine spectrum of M2 type macrophages is high expression of IL-10 and low expression of IL-12. Prior studies have revealed that IL-4, IL-10 and IL-13 are key cytokines which stimulate the differentiation from monocytes to M2 polarized TAM. Our study was designed to explore the cytokine spectrum secreted by NK/TCL and TAM in the microenvironment of NK/TCL. We aimed to prove that NK/TCL could induce the differentiation from monocytes to M2 polarized TAM, by secreting special cytokines. Material and Methods The cell lines involved in the study were as follows: the human NK/TCL cell lines (NK-YS, SNK-6 and SNT-8); the human diffuse large B-cell lymphoma cell line (OCI-LY8); and the human acute monocytic leukemia cell line (THP-1). We analyzed the cytokine spectrums in the supernatant of the cell lines mentioned above by using a multiplex suspension array (Bio-Plex Pro Human Cytokine 27-Plex Panel, Bio-rad). Then, we examined the cytokine spectrums in the supernatant of THP-1 cell lines which were cultured in the following groups of medium: A. Roswell Park Memorial Institute (RPMI) 1640 medium; B. RPMI 1640 medium with phorbol-12-myristate- 13-acetate (PMA, PMA can stimulate the activation of M1 polarized macrophages from THP-1 cell line); C. RPMI 1640 medium mixed with supernatants from NK/TCL cell lines; D. RPMI 1640 medium mixed with supernatant from the OCI-LY8 cell line. To balance the existing cytokines secreted by lymphoma cells, a same sample of medium mixed with the corresponding supernatants from lymphoma cell lines were used for baseline concentration as controls, respectively, in group C and D. Results There were a variety of elevated cytokines detected in NK/TCL cell lines, including: IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-9, IL-13, IP-10, MCP-1 and IFN-¦Ã. There were no IL-4, IL-10 or IL-13 detected in the supernatant of OCI-LY8 cell line. The morphology and cytokine concentration of THP-1 cell lines in different groups were showed in Figure 1 and Table 1, respectively. In group B, the concentration of IL-1b was significantly higher than group A; In group C, the concentration of IL-1ra, IL-10 and IL-6 were significantly higher than group A, while the concentration of IL-12 was significantly lower, and the concentrations in group C gradually increased (IL-12 decreased) with time prolonged, which indicated a M2 polarization. There was no significant difference in terms of cytokine concentration between group A and group D (Table 1). Conclusions Our study suggests that the NK/TCL cell lines can secrete various cytokines. Some of these cytokines could induce the differentiation from monocytes to M2 polarized TAM, and the key cytokines might be IL-4, IL-10 and IL-13. The interactions between NK/TCL and TAM may provide novel targets for treatment of NK/TCL. Disclosures: No relevant conflicts of interest to declare.

Description: Backgroud and Purpose: Extranodal natural killer/T-cell lymphoma (ENKTL) is an uncommon, aggressive form of non-Hodgkin's lymphoma. Optimal therapeutic strategies have not been fully defined yet. We reported the outcome of P-Gemox for the treatment of chemotherapy-naïve, refractory ENKTL in 2013 ASH meeting at the first time. Although several clinical trials have demonstrated the efficacy and tolerability of P-Gemox, we collected and anlyzed the real-world data of P-Gemox in Chinese patients with ENKTL. Patients and methods All cases with ENKTL from 2008 to 2017 were analyzed retrospectively P-Gemox were as follows: gemcitabine 1000 mg/m2; day 1,8; oxaliplatin 130 mg/m2 day 1, pegaspargase 2000-2500 U/m2 im day1. The regimen was repeated every 3 weeks. For newly diagnosed stage I/II patients, P-Gemox regimen was administered as induction chemotherapy for 4-6cycles and followed by involved-field radiotherapy or with"sandwiched" radiotherapy/chemotherapy. Furthermore autologous haematopoietic stem cell transplantation (ASCT) was recommended to chemo-sensitive refractory/relapsed patients as consolidation. All patients come to hospital regularly. Results: 267 patients with ENKTL were treated at the 10 institutions, in the department of Oncology or hematology in China between 2008 and 2017. Patient characteristics are summarized in Table 1. All patients received P-Gemox regimen, 209 patients (78.2%) as first-line therapy and 46 patients (22.0%) as second-line therapy. The median number of treatment cycles was 4.6(1-8) in the first line, 3.3 (2-6) in the second line, 243 patients were evaluable for response. The overall response (OR) rate was 84.8% (206/243), with a complete remission (CR) rate of 59.3% (144/243) (Table2). After the median follow-up time was 43.5 months (range, 1.5-101 months). The median OS of whole group was not reached, the median PFS was 61.0 months. The OS and PFS of the newly diagnosed patients is superior to refractory and relapsed patients (Fig1 A, B, P10%) were thrombocytopenia, 29.2%, neutropenia, 27.7%(Table 3) . Conclusion: P-Gemox regimen followed by EIFRT yielded promising results for patients with stage I/II ENKTL. While for advanced or refractory/relapsed patients, P-Gemox was still unsatisfied . ASCT consolidation for good responders may improve the longterm outcom. Toxicity was moderate and tolerable. Disclosures No relevant conflicts of interest to declare.

Description: Background ENKTL is a subtype of mature T cell and NK cell lymphoma, with a higher incidence in Asia than in Europe and North America. Pts with rr-ENKTL have a poor prognosis after failing an L-asparaginase-based regimen, and lack effective treatment. Epstein-Barr virus (EBV) infection is one of the mechanisms and characteristics of ENKTL, which induces immune tolerance of tumor by upgrading PD-L1 expression in tumor cells. Blocking the PD-1 pathway could, therefore, be an effective treatment for ENKTL. A Phase 2 trial is being conducted to evaluate CS1001, a first full-length, fully human immunoglobulin G4 (IgG4) mAb directed against PD-L1, in pts with rr-ENKTL. Method This is a multicenter, single-arm, Phase 2 clinical trial to evaluate CS1001 monotherapy in rr-ENKTL. Pts aged 18-75 years with rr-ENKTL after failing prior asparaginase-based chemotherapy or chemoradiotherapy were eligible if they had ECOG performance status (PS) ≤ 1, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. All the pts will receive CS1001 1200 mg intravenously every 3 weeks for up to 2 years, until disease progression, intolerance, etc. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included ORR by investigators, complete and partial response rate, time to response, duration of response (DoR) and progression-free survival, overall survival and safety. Adverse events (AEs) were summarized according to NCI CTCAE v4.03. Result As of June 17, 2019, 29 pts (male: 16, 55.2%; median age: 44 years, range 30-74) were enrolled. Twenty (20, 69.0%) pts entering the study had an ECOG PS of 1. Twenty-two (22, 75.9%) pts had Stage IV of disease at screening. Eight (8, 27.6%) pts received 2 lines of prior systemic therapy and 6 (20.7%) pts received ≥3 lines of prior systemic therapy. The median duration of follow-up was 5.55 (range, 0.69-12.19) months. Among the 22 efficacy-evaluable pts, the investigator-assessed ORR was 40.9%. A total of 7 (31.8%) pts achieved complete response (CR), and 2 (9.1%) pts had partial response (PR); 1 additional pt achieved PR after pseudo-progression. The DoR ranged from 0.03+ to 8.61+ months; median DoR was not achieved. All CR pts were still in remission. The IRRC assessments were not available at the time of data cut-off. The median duration of treatment was 11.7 (range, 2.9 to 53.0) weeks. Fifteen (15, 51.7%) pts remained on treatment and 14 (48.3%) had discontinued from study treatment (12 due to progressive disease, 2 due to AEs). The majority of pts (25, 86.2%) had treatment-emergent AEs (TEAEs), of whom 21 (72.4%) pts reported treatment-related AEs (TRAEs). The most frequently reported (≥10%) TRAEs were pyrexia (6, 20.7%), blood thyroid stimulating hormone increased (4, 13.8%), white blood cell count decreased (4, 13.8%), and rash (3, 10.3%). Three (3, 10.3%) pts reported Grade (G) ≥3 TRAEs. Two (2) G5 AEs (death and haemophagocytic lymphohistiocytosis) were reported in 2 pts; none was assessed as related to CS1001 by the investigators. Serious AEs were observed in 5 (17.2%) pts, and 1 of them (sinus node dysfunction) was assessed as related to CS1001 by the investigator. Immune-related AEs (irAEs) were reported in 5 pts, including a G3 rash and the remaining irAEs were G1. TEAEs that led to permanent treatment discontinuation occurred in 2 (6.9%) pts, which included haemophagocytic lymphohistiocytosis (G5) and facial nerve disorder (G2). No death or permanent discontinuation due to AEs were assessed as related to the study drug. After data cut-off date, 3 additional pts reached response assessment time point, of which 2 pts achieved CR, resulting in ORR of 44% (11/25) and a CR rate of 36% (9/25). The updated data will be reported at the ASH conference. Conclusion In this study, CS1001 was shown to be active with a high CR rate and durable response, and was generally well-tolerated in pts with rr-ENKTL. The preliminary safety and efficacy profile of CS1001 support further exploration and development of CS1001 in rr-ENKTL pts. Disclosures No relevant conflicts of interest to declare.

Description: Hui-qiang Huang and Won-Seog Kim contributed equally to this work. Introduction: NKTCLs are rare, Epstein-Barr virus-associated distinct subtypes of peripheral T-cell lymphoma. These are primarily extranodal and of the nasal type and are more common in Asia and Central/South America (Tse and Kwong. Blood 2013. 121:4997-5005). Outcomes for patients (pts) with R/R NKTCL are very poor, and with no standard therapy, there exists a highly unmet medical need for this pt population. Clinical data from NKTCL pts suggest CD38 as a new prognostic biomarker and novel target for therapy (Wang et al. Ann Hematol 2015. 94:1381-8). Daratumumab (DARA) is a human IgGk monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action that is approved for newly diagnosed and relapsed/refractory multiple myeloma (MM). Interim results from stage 1 of a phase 2 study (NCT02927925) of DARA monotherapy in pts with R/R NKTCL demonstrated high tolerability and pre-specified futility criteria were not met (Kim et al. Blood 2018. 132:1617). Here we present data from stage 2 of the study. Methods: This phase 2 study with Simon's 2-stage design evaluated DARA monotherapy in pts with histologically confirmed extranodal NKTCL nasal type per WHO classification that was refractory to or relapsed after ≥1 line of chemotherapy, and who were not candidates for other treatment modalities. Pts without available tumor samples for biomarker determination were not eligible. DARA 16 mg/kg was administered by IV infusion once weekly for 8 weeks, every other week for 16 weeks, and every 4 weeks thereafter until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) based on blinded independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Additional endpoints included progression-free survival (PFS) and duration of response based on BICR, overall survival (OS), and safety. Protocol-specified futility criterion for ORR (defined as at most 1 of 15 pts with complete response [CR]/partial response [PR]) was not met at interim analysis of 16 pts; stage 2 enrolled an additional 16 pts. Results: A total of 32 pts were treated with DARA monotherapy. Median age was 56 years, 91% had an ECOG score of 0 or 1, median time from initial NKTCL diagnosis was 24.0 months, median (range) plasma EBV-DNA at baseline was 900 (0-94,800) kIU/L, and 50% of pts had CD38 expression values ≥50%. At the clinical cut-off (June 4, 2019), 91% of pts discontinued treatment (disease progression [66%], pt withdrawal [13%], physician decision [9%], and adverse event [AE; 3%]). At a median follow-up of 16.7 months, ORR based on BICR was 25.0% (Table 1). Response rates were similar for pts who received 20%) all-grade treatment-emergent adverse events (TEAEs) are listed in Table 2. Eighteen (56%) pts had grade 3/4 TEAEs; thrombocytopenia (22%), and anemia, leukopenia, and neutropenia (16% each) were most common (≥15%). Two pts discontinued treatment due to TEAEs. Infusion-related reactions (IRRs) occurred in 63% of pts and were generally mild: only 2 (6%) pts had grade 3 IRRs (urticaria, hypertension, hypotension), and no grade 4 IRRs were reported. Response to DARA was not associated with CD38 expression: mean (standard deviation) percentage of tumor cells that expressed CD38 was 41.6% (31.92) in non-responders and 56.7% (39.33) in responders. Reductions in NK cells, complement protein C1q, and CD38+ Treg cells were observed in the majority of pts after 1 cycle of DARA. The percentage of pts with an EBV-DNA load reduction from baseline of greater than 25% was 50% in responders and 16.7% in non-responders (Figure 1). Conclusions: DARA 16 mg/kg was well tolerated with no new safety concerns, and only 2 patients discontinuing due to TEAEs. DARA monotherapy demonstrated an encouraging response rate (ORR: 25%) in pts with R/R NKTCL and warrants further study in this poor prognosis pt population. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding. Kim:Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy, Research Funding. Yoon:J&J: Research Funding. Lim:National Cancer Centre Singapore: Employment. Qing:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. OffLabel Disclosure: Daratumumab is under investigation for NKTCL; daratumumab is approved for use as monotherapy in multiple myeloma.

Description: Background: Peripheral T cell lymphoma (PTCL) and Extranodal NK/T cell lymphoma (ENKTCL) are rare types of non-Hodgkin's lymphoma (NHL), with a higher incidence in Asian countries. Outcomes for patients (pts) with relapsed or refractory(R/R) PTCL and ENKTCL are very poor, there is still lack of effective treatment for this patients population. Mitoxantrone is a syntheticc anthracenedione anticancer drug, which is effective on lymphoma, leukemia and other solid tumors. Tissue distribution or accumulation in tumor tissue of hydrochloride liposome (PLM60) was increased in our preclinical investigation. The pharmacokinetic parameters especially half-life of PLM60 was prolonged significantly in phase 1 trial. Phase Ib clinical studies showed good results of PLM60 in relapsed NHL. Therefore, we conduct this phase II clinical studies to evaluate the efficacy and safety of PLM60 in patients with R/R PTCL and ENKTCL. At present time, this is the first clinical study to evaluate PLM60 in treating R/R PTCL and ENKTCL worldwide. Methods : This is a single-arm, open-label, multi-center, phase II clinical study. The major inclusion criteria include age≥18 years old, pts with histologically confirmed PTCL (mainly including peripheral T cell lymphoma, NOS,PTCL-U; angioimmunoblastic T-cell lymphoma,AITL; anaplastic large cell lymphoma,ALCL; and other invasive NHL derived from T cells) and ENKTCL that was treated at least 1st line of chemotherapy, ECOG performance status 0 or 1. The main exclusion criteria included cumulative dose of doxorubicin 〉360mg/m2 and patients has clinically significant cardiac malfunction and uncontrollable underlying cardiovascular diseases. PLM60 20mg/m2 was administered intravenously , every 4 weeks for up to 6 cycles or until disease progression, intolerable toxicity, death or withdrawal due to the investigator's decision. The primary endpoint was objective response rate (ORR) based on investigator and independent central review (ICR) per Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma 2007. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Adverse events will be rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.03. This trial is registered at ClinicalTrials.gov, number NCT03776279. Results: 62 eligible patients were treated in 18 institutions in China between April 2018 and July 2019. Patient characteristics are summarized in Table 1. Median number of previous chemotherapy regimens was 2(1-7). At the cut-off day of July 20, 2019, 9 pts remained on treatment and 3 pts withdrew due to protocol violation and lost follow-up. 50 patients were evaluable for response, the investigator-assessed ORR was 54.0%(27/50)with CR rate 20.0%(10/50) (CR). The subtype CR rate were 17.6%(3/17), 17.6%(3/17), 18.2%(2/11), 13.3%(2/15)for PTCL-U, AITL, ALCL and ENKTCL respectively. The ORR were 42.1%(8/17), 42.1%(8/17), 45.5(5/11), 40.0(6/15), respectively (Figure 1). The median time to response was 8 weeks (ranged from 4 to 24 weeks) . Median follow-up was 3.8 (ranged from 0.2 to 14.4 m) months. Median PFS was 8.0months (95% CI, 6.1-9.9m), with a 6-month PFS rate of 73.1±9.4%. Median OS was not reached, with a 6-month OS rate of 77.3±6.9%(Figure 2a,b). All-grade treatment-emergent adverse events (TEAEs) are listed in Table 2. The most common toxicity of PLM60 was myelosuppression. The most common grade 3/4 toxicity(〉10% TEAEs) was neutropenia(25.8%) and lymphocytopenia(11.3%). There were no treatment-related deaths. Conclusion: PLM60 monotherapy yielded promising results for patients with R/R PTCL and ENKTCL with moderate toxicities. Further investigation is urgently needed. Disclosures No relevant conflicts of interest to declare.

Description: Background Chemosensitive disease before stem cell transplantation (SCT) has been considered as one of the most important prognostic factors in predicting favorable outcomes following SCT. However, chemotherapy resistance develops rapidly in relapsed and/or refractory aggressive B-cell non-Hodgkin’s lymphomas (NHL). Development of novel target drugs and regimens may help address these clinical issues. Our phase I/II clinical trial confirms that lenalidomide plus rituximab (LR) is well tolerated and effective for patients with relapsed and/or refractory B-cell NHL. Patients and Methods We retrospectively analyzed the data from our clinical trials of LR in aggressive NHL patients [Mantle Cell Lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular grade 3 lymphoma (FLG3) and transformed large cell lymphoma (TL)](Wang et al., Lancet Oncol 13:716-23, 2012; Wang et al., Leukemia 2013 Apr 2) and provided further details and longer follow-up on the efficacy and safety of novel combination of LR followed by SCT. Patients enrolled in our clinical trials received oral lenalidomide 20 mg once daily on days 1-21 of each 28-day cycle and 375mg/m2 of intravenous rituximab once a week for four weeks only during cycle one, beginning on day 1. Patients were treated with LR until disease progression, SCT, or withdrawal due to toxicity. Overall survival (OS) was defined as time from study entry to the date of death or until the last survival date if still alive. Progression-free survival (PFS) was defined as time from study entry to the date of disease progression or death. Results From March 31, 2006 to December 15, 2010, twenty-two patients were enrolled in our study and underwent SCT after receiving LR combination. Patients received either allogeneic (n=16) or autologous (n=6) SCT following the study treatment. The median age of the patients was 59.5 years (range, 46-74), and 18 of them were male. The median time from diagnosis to initiation of LR therapy was 25.5 months (range, 3-99.4). The median number of previous treatment regimens was two (range, 1-4). Five (23%) patients received SCT before enrolling in our study. All patients had received previous rituximab-containing treatments. Histologies were: MCL (n=12), DLBCL (n=5), FLG3 (n=1) and TL (n=4). Of the sixteen patients who proceeded to allogeneic SCT, two were given myeloablative conditioning regimens, the remaining fourteen were given the reduced intensity conditioning (RIC) regimens. The preparative regimens were FCR(fludarabine + cyclophosphamide + rituximab) in 2 patients, FCR plus alemtuzumab in 2, or plus alemtuzumab and low dose TBI(total body irradiation) in 3, or plus Ibritumomab Tiuxetan(zevalin) in 3, fludarabine+bendamustine/ rituximab in 2, fludarabine+ busulfan in 1 and others in 3. All of the six patients who proceeded to auto-SCT were given R-BEAM( rituximab, BCNU, etoposide, cytarabine, melphalan) regimen. Eleven patients underwent SCT from a matched unrelated donor and five from a matched sibling donor. The median time from best response date of LR regimen to SCT date was 4 months (range 1-14). The ORRs were 77% (n=17, with 10 CR + 7 PR) before undergoing SCT and 100% (n=22, all of patients got CR) following SCT. Hematological toxicity of LR combination was common. Grade 3-4 hematological toxicities included neutropenia (87%), lymphopenia (46%) and thrombocytopenia (41%). Eight (36%) patients required dose reductions and neutropenia was the most frequent cause. Incidence of acute graft versus host disease (GVHD) (grade II-IV) and chronic GVHD following SCT were: 31% (5/16) and 56% (9/16), respectively. After a median follow-up of 22 months (range 6-59), nine (41%) patients were alive [MCL(n=2), DLBCL(n=3), TL(n=3), FLG3(n=1)]. Two (9%) patients who received auto-SCT died due to progression of disease (one with MCL and another with DLBCL ), ten (45%) due to complications following a subsequent allogeneic transplant (GVHD, pneumonia and sepsis), and one (4.5%) due to liver failure following auto-SCT. The median PFS was 21 months. Estimated 1-year, 3-year and 5-year PFS rates were 77.3%, 30.3% and 30.3%, respectively. Median OS times were 30 months. Estimated 1-year, 3-year and 5-year OS rates were 95.5%, 38.6% and 38.6%, respectively. Conclusions The results suggest that the novel combination of LR is an effective and safe regimen, and may offer a bridge to SCT in patients with relapsed and/or refractory aggressive B-cell NHL. Disclosures: No relevant conflicts of interest to declare.