Huangming Hong

A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis

BACKGROUND The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. METHODS We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. FINDINGS We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. INTERPRETATION PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. FUNDING Samsung Biomedical Research Institute.

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease

Background Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. Patients and methods We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. Results After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. Conclusions Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.

Recombinant human thrombopoietin (rh-TPO) for the prevention of severe thrombocytopenia induced by high-dose cytarabine: a prospective, randomized, self-controlled study

Abstract The aim of this randomized phase II study was to investigate the optimal timing of the administration of thrombopoietin to prevent cytarabine-induced thrombocytopenia. Fifty-two patients who were scheduled for high-dose cytarabine treatment were randomly assigned to receive either the standard prophylactic mode (starting thrombopoietin, 15,000 units/day on days 2–11) or the pre-chemo mode (starting thrombopoietin, 15,000 units/day on days -4, -2, and 2–9) during the first cycle of chemotherapy with a switch to the other mode in the second cycle. The thrombocytopenia rate in the standard mode and the pre-chemo mode were PLT < 50 × 109/L, 67.3% versus 46.2% (p = .001); and PLT < 25 × 109/L, 48.1% versus 26.9% (p = .001). The platelet transfusion rate was reduced in pre-chemo mode, with 7 patients requiring 10 units of platelets, whereas 13 patients required 24 units in standard mode (p = .038). Grade III/IV thrombopoietin-related toxicity was not observed. The prophylactic use of thrombopoietin was effective and safe. Trial registration: ChiCTR-OPB-15007591.

Surgical resection followed by chemotherapy may be an effective treatment strategy for primary gastrointestinal natural killer/T-cell lymphoma: A single center experience

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare and severe malignancy. ENKTL is primarily located in the upper aerodigestive tract; the nasal/nasopharyngeal localization represents 75% of cases, and other sites involved include the skin, gastrointestinal (GI) tract, testis, bone marrow and spleen [1]. Patients with NK/T-cell lymphoma outside the upper aerodigestive tract tend to present with more aggressive clinical features and have a more unfavorable prognosis. To date, little information regarding primary GI NK/T-cell lymphomas (GINKTLs) is available. Previous studies have reported that the incidence of GINKTL is less than 0.1 cases per 100 000 persons per year [2,3]. Treatment strategies for nodal non-Hodgkin lymphoma (NHL) are well established; however, much debate and controversy remain regarding the optimal approach in GINKTL. Due to the rarity of primary GINKTL, empirical standards in the treatment of GINKTL, consisting of surgical resection of the primary tumor mass followed by chemotherapy or radiotherapy (or both), have not been evaluated prospectively. Hence we initiated a retrospective study to investigate the clinical features of GINKTL, analyze the impact of surgical resection on outcome and delineate its major prognostic factors.

Recurrent PD-L1 Structural Rearrangements in Natural Killer/T Cell Lymphoma Patients with Complete Response to PD-1 Blockade Therapy

This study aims to identify recurrent genetic alterations in relapsed or refractory (RR) natural-killer/T-cell lymphoma (NKTL) patients who have achieved complete response (CR) with programmed cell death 1 (PD-1) blockade therapy. Seven of the eleven patients treated with pembrolizumab achieved CR while the remaining four had progressive disease (PD). Using whole genome sequencing (WGS), we found recurrent clonal structural rearrangements (SR) of the PD-L1 gene in four of the seven (57%) CR patients’ pretreated tumors. These PD-L1 SRs consist of inter-chromosomal translocations, tandem duplication and micro-inversion that disrupted the suppressive function of PD-L1 3’UTR. Interestingly, recurrent JAK3-activating (p.A573V) mutations were also validated in two CR patients’ tumors that did not harbor the PD-L1 SR. Importantly, these mutations were absent in the four PD cases. With immunohistochemistry (IHC), PD-L1 positivity could not discriminate patients who archived CR (range: 6%-100%) from patients who had PD (range: 35%-90%). PD-1 blockade with pembrolizumab is a potent strategy for RR NKTL patients and genomic screening could potentially accompany PD-L1 IHC positivity to better select patients for anti-PD-1 therapy.Abstract Natural killer/ T-cell lymphoma (NKTL) patients failing L-asparaginase regimens have extremely poor treatment outcomes. Previous case series showed promising activity when relapsed or refractory NKTL patients were treated with anti-programmed death 1 (PD1) inhibitors. Here, we continue to unravel the molecular profiles with whole-genome sequencing (WGS) on an extended cohort of 11 pembrolizumab-treated patients (median age at diagnosis, 42 years; range, 27-66 years) with a median follow-up of 11 months (range, 2 - 25 months) since starting anti-PD1 therapy. Seven patients achieved complete response (CR) and four patients had progressive disease (PD). Using WGS, we found structural rearrangements of the PD-L1 gene, JAK3-activating mutations and ARID1B homozygous insertion in four, two and one of the CR patients’ tumors, respectively. Interesting, these alterations, especially PD-L1 rearrangements, were absent in the four PD cases. Expression of PD1 ligand (PD-L1) was strong in nine patients (5 CR and 4 PD cases) and weak in two patients (both CR). PD1 blockade with pembrolizumab was a potent strategy for NKTL patients and genomic screening could potentially accompany PD-L1 immunohistochemical screening to better select patients for anti-PD1 therapy.

Angioimmunoblastic T-cell lymphoma: a prognostic model from a retrospective study

Abstract Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma with unique clinical and pathological features. This study aim to design a prognostic model specifically for AITL, providing risk stratification in affected patients. A total of 115 newly diagnosed AITL patients were retrospectively analyzed. The estimated five-year overall survival (OS) rate for all patients was 45.4%. Multivariate analysis found prognostic factors for survival were bone marrow involvement, number of extranodal sites >1, and performance status >1. We categorized three risk groups: group 1, no adverse factor; group 2, one factor; and group 3, two or three factors. Five-year OS was 86.9% for Group 1, 46.3% for Group 2, and 16.2% for Group 3 (p < .0001). The novel prognostic model balanced the distribution of patients into different risk groups with better predictive discrimination as compared to the International Prognostic Index and Prognostic Index for PTCL, unless otherwise specified.

Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

Purpose Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone administered every 3 weeks (R-CHOP-21) is the standard care for diffuse large B-cell lymphoma (DLBCL). It is unknown whether the dose-dense R-CHOP (R-CHOP-14) could improve the outcome of the disease in Asian population. Materials and Methods Newly diagnosed DLBCL patients were centrally, randomly assigned (1:1) to receive R-CHOP- 14 or R-CHOP-21. R-CHOP-14 was administered every 2 weeks, and R-CHOP-21 was administered every 3 weeks. Primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), progression-free survival (PFS), response rate and toxicities. Results Seven hundred and two patients were randomly assigned to receive R-CHOP-14 (n=349) or R-CHOP-21 (n=353). With a median follow-up of 45.6 months, the two groups did not differ significantly in 3-year DFS (79.6% for R-CHOP-14 vs. 83.2% for R-CHOP-21, p=0.311), 3-year OS (77.5% for R-CHOP-14 vs. 77.6% for R-CHOP-21, p=0.903), or 3-year PFS (63.2% for R-CHOP-14 vs. 66.1% for R-CHOP-21, p=0.447). Patients with an International Prognostic Index (IPI) score ≥ 2 had a poorer prognosis compared to those with an IPI score < 2. Grade 3/4 hematologic and non-hematologic toxicities were manageable and similar between R-CHOP-14 and R-CHOP-21. Conclusion R-CHOP-14 did not improve the outcome of DLBCL compared to R-CHOP-21 in Asian population. With manageable and similar toxicities, both of the two regimens were suitable for Asian DLBCL patients. For high-risk patients with IPI ≥ 2, new combination regimens based on R-CHOP deserve further investigation to improve efficacy.

Outcomes of patients with peripheral t-cell lymphoma in first complete remission: Data from three tertiary asian cancer centers

Peripheral T-cell lymphomas (PTCL) represent a heterogenous group of aggressive non-Hodgkin’s lymphoma, with poorer treatment outcomes compared to that of their B-cell counterparts, using conventional chemotherapy. Despite the lack of randomized data, upfront high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) has been associated with better treatment outcomes 3 and various guidelines now recommend that patients with chemosensitive PTCL should undergo upfront HDC/ASCT. Consistently, both retrospective and prospective studies suggest that such a strategy appears to benefit patients with responding disease, especially those in first complete remission (CR1). However, it is conceivable that PTCL patients who do achieve CR1 may have more favorable survival outcomes, regardless of the treatment they received. Thus, we performed a retrospective analysis of PTCL patients who attained CR1 following first-line induction therapy to determine the factors that would impact their survival outcomes, including the role of upfront HDC/ASCT. Prospectively maintained T-cell lymphoma databases from the National Cancer Centre Singapore (NCCS)/ Singapore General Hospital (SGH), Samsung Medical Centre, South Korea, and Sun Yat Sen University Cancer Centre, China, were retrospectively reviewed after approval from the institutional review boards of the individual institutions. We included patients with the following histological subtypes: PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)negative anaplastic large cell lymphoma (ALCL), and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) , previously known as type II enteropathic T-cell lymphoma, treated with curative intent. To standardize the effect of treatment on outcome, we excluded patients with ALK-positive ALCL because their first-line treatment would not include considerations for upfront HDC/ASCT and patients with natural-killer/ T-cell lymphoma whose treatment may have included upfront allogeneic stem cell transplantation. Upfront HDC/ASCT was not standard practice in any of the participating institutions and left to the discretion of the primary physician or tumor board decisions. We also excluded patients with composite lymphomas, cutaneous T-cell lymphomas and patients who were not treated with curative intent. We then reviewed the clinical characteristics, treatment and survival outcomes of patients who achieved CR1. Patients who had partial response, stable disease and progression of disease were excluded from the analysis. Treating physicians determined the end of treatment response assessments. The exact modality was as per institutional standards, which was either computed tomography or positron-emission tomography scans. Progression-free survival (PFS) was defined as the interval from diagnosis to progression, relapse or death. Overall survival (OS) was defined as the interval from diagnosis to death from any cause. Survival estimates were calculated using the Kaplan−Meier method. Survival curves were compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to assess the association between several prognostic factors such as age, stage, international prognostic index (IPI), prognostic index for

A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native Chinese patients with refractory solid tumors and lymphoma.

Purpose This study was conducted to assess the pharmacokinetics and safety of enzastaurin in native Chinese patients with refractory solid tumors and lymphoma. Methods Eligible patients received 500 mg of enzastaurin orally once daily. The pharmacokinetics of enzastaurin and its metabolites were assessed on days 14 to 18. Patients were allowed to continue receiving the agent in a safety extension phase until disease progression or presentation with unacceptable toxicity. Results Twenty-five patients received at least 1 dose of enzastaurin, and twenty-one patients completed the pharmacokinetic phase. Fifteen patients entered the safety extension phase. Except for transient, asymptomatic grade 3 QT interval prolongation in one patient who had baseline grade 2 QT prolongation, other adverse events were of grade 1 to 2. The t1/2, Cav, ss, and AUCτ, ss for enzastaurin and its primary active metabolite LSN326020 were 14 and 42 h, 1,210 and 907 nmol/L, and 29,100 and 21,800 nmol•h/L, respectively. One patient with relapsed diffuse large B-cell lymphoma achieved a partial response that lasted for 8.1 months. Conclusions The pharmacokinetics of enzastaurin in Chinese cancer patients were consistent with those observed in previous studies abroad. Enzastaurin 500 mg daily was well tolerated by Chinese patients. We recommend 500 mg daily as the phase II dose in this population. Its efficacy in lymphoma deserves further investigation. Trial Registration ClinicalTrials.gov: NCT01432951