Introduction

Oncology Letters

1792-1074 1792-1082

D.A. Spandidos

10.3892/ol.2023.13854

OL-25-6-13854

Articles

Effect of arsenic trioxide plus etoposide, solumedrol, high‑dose cytarabine and cisplatin chemotherapy on the treatment of relapsed or ref7ractory ALK+ anaplastic large cell lymphoma

Ding

* Lu

Huina

* Dong

Yan

Xiu

Bing

Liang

Aibin

Zhang

Wenjun

Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China

Correspondence to: Professor Aibin Liang or Professor Wenjun Zhang, Department of Hematology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, P.R. China, E-mail: lab7182@tongji.edu.cn zhangwenjun@tongji.edu.cn *

Contributed equally

06 2023

04 05 2023

25 6

268

05012023 13042023

2023

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

It has been reported that arsenic trioxide (ATO) regulates lymphoma cell cycle, apoptosis, autophagy and mitochondrial activity, while it synergizes with other cytotoxic agents. In addition, ATO targets anaplastic lymphoma kinase (ALK)-fusion oncoprotein to repress anaplastic large cell lymphoma (ALCL). The current study aimed to investigate the efficacy and safety of ATO plus etoposide, solumedrol, high-dose cytarabine and cisplatin (ESHAP) chemotherapy compared with ESHAP chemotherapy alone in patients with relapsed or refractory (R/R) ALK⁺ ALCL. A total of 24 patients with R/R ALK⁺ ALCL were enrolled in the present study. Among them, 11 patients were treated with ATO plus ESHAP, while the remaining 13 patients received ESHAP chemotherapy alone. Subsequently, treatment response, event-free survival (EFS), overall survival (OS) and adverse event (AEs) rates were recorded. Both complete response (72.7% vs. 53.8%; P=0.423) and objective response (81.8% vs. 69.2%; P=0.649) rates were higher in the ATO plus ESHAP group compared with the ESHAP group. However, statistical significance was not reached. In addition, EFS was significantly prolonged (P=0.047), while OS was not significantly increased (P=0.261) in the ATO plus ESHAP group compared with the ESHAP group. More specifically, the 3-year accumulating EFS and OS rates were 59.7 and 77.1% in the ATO plus ESHAP group, respectively, and 13.8 and 59.8% in the ESHAP group, respectively. The majority of AEs, such as thrombocytopenia (81.8% vs. 46.2%; P=0.105), fever (81.8% vs. 46.2%; P=0.105) and dyspnea (36.4% vs. 15.4%; P=0.182), were more prevalent in the ATO plus ESHAP group compared with the ESHAP group. However, no statistical significance was observed. In conclusion, the current study indicated that ATO plus ESHAP chemotherapy could exert a superior efficacy compared with ESHAP chemotherapy alone in patients with R/R ALK⁺ ALCL.

anaplastic large cell lymphoma relapsed or refractory anaplastic lymphoma kinase positive arsenic trioxide ESHAP chemotherapy

Shanghai Municipal Health Commission Project

201840100

This study was supported by Shanghai Municipal Health Commission Project (grant no. 201840100).

Introduction

Anaplastic large cell lymphoma (ALCL) is a rare type of peripheral/mature T-cell lymphoma with high heterogeneity, accounting for ~15% of T cell lymphoma cases and 1–3% of all non-Hodgkin's lymphomas cases (1,2). According to the recent World Health Organization (WHO) classification, ALCL is detailly categorized into anaplastic lymphoma kinase (ALK) positive ALCL (ALK⁺ ALCL), ALK-negative ALCL (ALK⁻ ALCL), primary cutaneous ALCL (pcALCL) and breast-implant associated ALCL (BIA-ALCL) (3). Among the above ALCL subtypes, ALK⁺ ALCL exhibits a relatively better prognosis compared with the other types, such as ALK⁻ ALCL, with a 5-year overall survival (OS) rate of >80% (4). However, 30–40% of patients with ALK⁺ ALCL will develop a relapsed or refractory (R/R) disease to cytotoxic drugs, thus leading to relatively poor outcomes. Currently, the salvage treatment options for R/R ALK⁺ ALCL are not sufficient (5,6).

Arsenic trioxide (ATO), a Chinese traditional medicine, has attracted increasing attention globally due to its excellent anti-cancer effects (7,8). Currently, ATO is commonly used to treat several types of cancer, such as hepatocellular carcinoma, cervical cancer and leukemias (9–11). Regarding the effect of ATO on lymphoma treatment, it has been reported that ATO exerts its anti-tumor activity via several ways. Therefore, previous studies showed that ATO could induce lymphoma cell apoptosis via inactivating the Wnt/β-catenin and nuclear factor-κB (NF-κB) pathways (12,13), arresting lymphoma cell cycle (14), inhibiting mitochondrial activity and angiogenesis (14), modulating autophagy (15) and cooperating with other cytotoxic agents (16). Interestingly, another study revealed that ATO could inactivate ALK-fusion oncoprotein to repress ALK⁺ diffuse large B-cell lymphoma cell viability (17). More particularly, ATO could target the nucleophosmin-ALK fusion protein to promote the apoptosis of ALK⁺ ALCL cells (18). The above findings could provide evidence for uncovering the potency of ATO in treating R/R ALK⁺ ALCL. However, relevant data are still missing.

Therefore, the current study aimed to compare the efficacy and safety of ATO plus etoposide, solumedrol, high-dose cytarabine (ara-C) and cisplatin (ESHAP) chemotherapy with ESHAP chemotherapy alone for the treatment of patients with R/R ALK⁺ ALCL.

Materials and methods <sec> <title>Patients

A total of 24 patients with R/R ALK⁺ ALCL were enrolled between January 2018 and June 2022 in this prospective, cohort study. The inclusion criteria were as follows: i) Patients histologically diagnosed as ALCL; ii) confirmed as ALK⁺ ALCL by Ventana immunohistochemistry assay; iii) diagnosed as R/R ALCL patients, where refractory ALCL was defined as progression during the first-line treatment, and relapsed ALCL was defined as initially reaching CR, then disease occurred again confirmed by biopsy examination; iv) aged >18 years old; and v) treated with ESHAP alone or ATO plus ESHAP. The exclusion criteria were the following: i) Newly diagnosed ALCL patients; ii) patients with a prior history of hematopoietic stem cell transplantation; iii) with other malignant diseases; iv) without available clinical data for study analysis; and v) pregnant or breastfeeding female patients. Notably, the enrolled patients do not fit the stem cell transplantation in this study, therefore, no related transplantation information is available. The following ALCL patients were considered as not suitable for stem cell transplantation: i) Elderly patients with poor physical condition. ii) Donor mismatch. iii) Patients with high allergic constitution or severe allergic history. iv) Complicated with heart, lung, liver, kidney, and other important organ dysfunction even after treatment. v) Coagulation dysfunction such as hemophilia. vi) Serological test positive such as AIDS, syphilis and so on. vii) Chromosome or gene defects, immune function defects. viii) Patients unwilling to receive stem cell transplantation. The study was approved by the Ethics Committee of Tongji Hospital with approval number Ethical Review-KYSB-2018-139, Tongji University School of Medicine; and informed consent was obtained from all patients before the start of this prospective study. The enrolled patients were not involved in other clinical trial.

Data collection and treatment

The clinical characteristics of patients with R/R ALK⁺ ALCL were recorded after inclusion. The present study did not intervene in the treatment of patients. Patients were treated with ESHAP alone or ATO plus ESHAP based on patients' disease condition, benefit expectation, and patients' willingness. Generally, patients with higher disease state and acceptable physical condition (ECOG PS) tended to choose the ATO plus ESHAP treatment, others tended to choose ESHAP treatment. Patients treated with ESHAP alone were included in the ESHAP group, while those treated with ATO plus ESHAP chemotherapy in the ATO plus ESHAP group. Each treatment cycle lasted four weeks. Patients treated with the ESHAP regimen received etoposide (40 mg/m²; 1st-4th day), methylprednisolone (500 mg; 1st-5th day), ara-C (2 g/m²; 5th day) and cisplatin (25 mg/m²; 1st-4th day), as previously described (19). ATO (10 mg; 5 days/week) was administrated by intravenous injection (20). ATO has been approved to treat R/R lymphoma in China, which includes R/R ALCL.

Evaluation

Treatment response was evaluated after treatment based on the computed tomography scan results according to the Revised Response Criteria for Malignant Lymphoma (21). Additionally, the survival data of patients were also recorded. The last date of follow-up was November 30, 2022. Subsequently, event-free survival (EFS) and OS were calculated. Finally, the data on adverse events (AEs) were acquired and graded using the Common Terminology Criteria for Adverse Events v4.03.

Statistical analysis

All statistical analyses were performed using SPSS v22.0 software (IBM Corp.). GraphPad Prism v7.0 software (GraphPad Software, Inc.) was utilized for graph construction. The comparisons between the ESHAP and ATO plus ESHAP groups were performed using t-test, Wilcoxon rank sum test, χ² test and Fisher's exact test. The association between the treatment regimen and EFS and OS was evaluated using Kaplan-Meier curves and analyzed with a log-rank test. P<0.05 was considered to indicate a statistically significant difference.

Results <sec> <title>Patients' characteristics

Patients with R/R ALK⁺ ALCL in the ATO plus ESHAP group (n=11) exhibited an average age of 31.0±10.7 years, including 81.8% male and 18.2% female patients. Among all patients, 72.7% suffered from refractory disease, while 27.3% from relapsed disease. In terms of patients with R/R ALK⁺ ALCL in the ESHAP group (n=13), their average age was 32.8±12.8 years, including 69.2 and 30.8% male and female patients, respectively. The majority of the above patients (53.8%) were diagnosed with refractory disease, while the remaining 46.2% with relapsed disease. 10 (76.9%), 2 (15.4%), and 1 (7.7%) patient received first-line CHOP, EPOCH, and ESHAP in the ESHAP group, respectively; then 6 (54.5%), 4 (36.4%), and 1 (9.1%) patient received first-line CHOP, EPOCH, and ESHAP in the ATO plus ESHAP group, respectively; besides, no difference was observed regarding the first line treatment options between the two groups (P=0.470). No differences were observed in the patients' baseline characteristics between the ESHAP and ATO plus ESHAP groups (all P>0.05; Table I).

Treatment response

In detail, 72.7, 9.1, 0.0 and 18.2% of patients achieved complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), respectively, in the ATO plus ESHAP group. Additionally, in the ESHAP group, 53.8, 15.4, 0.0 and 30.8% of patients achieved CR, PR, SD and PD, respectively (Fig. 1A). Furthermore, CR rate (72.7% vs. 53.8%; P=0.423) and objective response rate (ORR; 81.8% vs. 69.2%; P=0.649) were higher in the ATO plus ESHAP group compared with the ESHAP group. However, no statistically significant difference was observed (Fig. 1B and C).

EFS and OS assessment

Encouragingly, EFS was prolonged in the ATO plus ESHAP group compared with the ESHAP group (P=0.047; Fig. 2A). More particularly, the 1-, 2- and 3-year accumulating EFS rates were 71.6, 59.7 and 59.7%, respectively, in the ATO plus ESHAP group. In the ESHAP group, the 1-, 2- and 3-year accumulating EFS rates were 46.2, 27.7 and 13.8%, respectively. Regarding OS rate, the results showed that it was higher in the ATO plus ESHAP group compared with the ESHAP group. However, there was not a statistically significant difference (P=0.261; Fig. 2B). Furthermore, the 1-, 2- and 3-year accumulating OS rates were 90.0, 77.1 and 77.1%, respectively, in the ATO plus ESHAP group, while the 1-, 2- and 3-year accumulating OS rates in the ESHAP group were 76.9, 59.8 and 59.8%, respectively.

Subgroup analyses

In patients with relapsed ALK⁺ ALCL, CR rate was higher in the ATO plus ESHAP group compared with the ESHAP group. However, there was not a statistically significant difference (100.0% vs. 66.7%; P=0.500; Fig. 3A). In addition, no difference was observed in ORR rate between both groups (100.0% vs. 100.0%; P=1.000; Fig. 3B). Consistently, no differences were obtained in the EFS (P=0.249) and OS (P=0.480) rates between the ATO plus ESHAP group and the ESHAP group (Fig. 3C and D). In patients with refractory ALK⁺ ALCL, CR (62.5% vs. 42.9%; P=0.619), ORR (75.0% vs. 42.9%; P=0.315), EFS (P=0.145) and OS (P=0.131) rates were more favorable in the ATO plus ESHAP group compared with the ESHAP group. However, this trend did not reach statistical significance (Fig. 3E-H).

Safety

Generally, the majority of AEs, including thrombocytopenia (81.8% vs. 46.2%; P=0.105), neutropenia (81.8% vs. 53.8%; P=0.211), fever (81.8% vs. 46.2%; P=0.105), anorexia (72.7% vs. 46.2%; P=0.240), nausea and vomiting (63.6% vs. 38.5%; P=0.219) and dyspnea (36.4% vs. 15.4%; P=0.182), were more prevalent in the ATO plus ESHAP group compared with the ESHAP group. However, no statistically significant differences were obtained (Table II). In terms of grade 3–4 AEs, thrombocytopenia (36.4% vs. 7.7%; P=0.142) and neutropenia (45.5% vs. 15.4%; P=0.182) were more commonly observed in the ATO plus ESHAP group compared with the ESHAP group.

Discussion

It has been also reported that ATO may serve as maintenance therapy in patients with adult T-cell leukemia/lymphoma after induction therapy (22–25). However, the treatment response of ATO in patients with R/R ALK⁺ ALCL remains unclear. Herein, ATO plus ESHAP chemotherapy numerically improved both CR and ORR compared with ESHAP. However, these data did not reach statistical significance, partially due to the limited sample size. The higher numerical CR and ORR rates in patients treated with ATO plus ESHAP could be due the followings: Firstly, a previous study showed that ATO could inhibit the growth of ALK⁺ ALCL cells via degrading the ALK fusion oncoprotein (18). Secondly, ATO could directly induce cytotoxicity in ALK⁺ ALCL cells via regulating several signaling pathways, such as the NF-κB, p38/mitogen-activated protein kinase and wnt/β-catenin pathways (13,26). Finally, ATO and ESHAP could exert a synergistic effect on inhibiting ALK⁺ ALCL cells. However, further validation experiments are needed. Overall, the above findings indicated that ATO plus ESHAP exerted a better treatment efficacy in patients with R/R ALK⁺ ALCL compared with ESHAP. It could be explained that since ATO is considered to be appropriately applied in R/R ALCL patients ineligible to stem cell transplantation; then in order to match with this group, the control group also set this criteria (not ineligible to stem cell transplantation). Therefore, patients not receiving stem cell transplantation were recruited in the study.

Although the overall prognosis of patients with ALK⁺ ALCL is relatively good, with a 5-year OS rate of ~80%, the survival rate of patients with R/R ALK⁺ ALCL is not satisfactory (27). A previous study showed that in patients with R/R ALK⁺ ALCL, the median (95% confidence interval) progression-free survival (PFS) and OS were 3.8 (range, 0.7-14.8 months) and 13.6 (range, 0.7–89 months) months, respectively (6). Another study also demonstrated that the 2-year PFS and OS rate in patients with R/R ALK⁺ ALCL treated with chemotherapy was 45.0 and 78.9%, respectively (28). Therefore, the development of effective treatment approaches for patients with R/R ALK⁺ ALCL is of great importance. The results of the current study revealed that treatment of patients with R/R ALK⁺ ALCL with ATO plus ESHAP chemotherapy promoted EFS and increased OS compared with the ESHAP group. However, the difference in OS between the two groups did not reach statistical significance. The above findings could be due to the fact that ATO plus ESHAP could inhibit the survival of ALK⁺ ALCL cells via multiple ways, including degradation of AKL fusion protein and synergizing cytotoxicity, thus improving OS. Secondly, the sample size of the current study could not be large enough to reveal a statistically significant difference in OS between the above groups.

In terms of safety, it has been reported that the most common AEs of ATO are generally associated with hematological toxicities (20,23–25). Consistently, in the current study the data revealed that the main AEs of the two treatment approaches were also associated with hematological toxicity, such as anemia, leukopenia, thrombocytopenia and neutropenia. In addition, the incidence rate of total and grade 3–4 AEs were numerically higher in patients treated with ATO plus ESHAP compared with those treated with ESHAP. However, no statistical significance was observed. The above findings could be due to the cytotoxic activity of ATO to induce myelosuppression, thus enhancing the incidence of anemia, leukopenia, thrombocytopenia and neutropenia (29). Although ATO plus ESHAP could achieve a better treatment efficacy and survival in patients with R/R ALK⁺ ALCL, its administration should be carefully considered due to the high incidence of AEs, particularly those of grade 3–4. Therefore, clinicians should balance the survival gain and potential toxicity of ATO plus ESHAP when treating patients with R/R ALK⁺ ALCL.

However, the present study has some limitations that should be clarified. First, since R/R ALK⁺ ALCL is a relatively rare disease, the sample size of the current study is small. Therefore, the statistical power could be restricted. Secondly, the administration of ATO combined with other treatment options is not explored. Finally, the treatment efficacy of ATO plus ESHAP in patients with other types of ALCL, such as pcALCL and BIA-ALCL, is not investigated. Therefore, further studies are needed.

In conclusion, the current study demonstrated that treatment of patients with R/R ALK⁺ ALCL with ATO plus ESHAP chemotherapy exerted a superior treatment efficacy compared with ESHAP chemotherapy alone. However, further multicenter studies with larger sample sizes are needed to verify the above results. Furthermore, the potential toxicity of ATO plus ESHAP chemotherapy against the survival benefit should be balanced in clinical practice.

Acknowledgements

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

AL and WZ were responsible for the conception of the present study. YDi acquired the clinical data. HL and YDo analyzed and interpreted the data. BX was responsible for statistical analysis. All authors drafted the work and revised it critically for important intellectual content. AL, WZ and YDi confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Tongji Hospital, Tongji University School of Medicine (approval no. Ethical Review-KYSB-2018-139) and written informed consent was obtained from all patients before the start of this prospective study.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References 1

Zhang

Chien

Nam

Heo

Anaplastic large cell lymphoma: Molecular pathogenesis and treatment

Cancers (Basel)1416502022

10.3390/cancers14071650

35406421

Leventaki

Bhattacharyya

Lim

Pathology and genetics of anaplastic large cell lymphoma

Semin Diagn Pathol3757712020

10.1053/j.semdp.2019.12.002

31882178

Kaseb

Mukkamalla

SKR

Rajasurya

Anaplastic large cell lymphoma

StatPearlsTreasure Island (FL)2022

Savage

Harris

Vose

Ullrich

Jaffe

Connors

Rimsza

Pileri

Chhanabhai

Gascoyne

ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the international peripheral T-cell lymphoma project

Blood111549655042008

10.1182/blood-2008-01-134270

18385450

Sibon

Nguyen

Schmitz

Suzuki

Feldman

Gressin

Lamant

Weisenburger

Rosenwald

Nakamura

ALK-positive anaplastic large-cell lymphoma in adults: An individual patient data pooled analysis of 263 patients

Haematologica104e562e5652019

10.3324/haematol.2018.213512

31004022

Morel

Brière

Lamant

Loschi

Haioun

Delarue

Tournilhac

Bachy

Sonet

Amorim

Long-term outcomes of adults with first-relapsed/refractory systemic anaplastic large-cell lymphoma in the pre-brentuximab vedotin era: A LYSA/SFGM-TC study

Eur J Cancer831461532017

10.1016/j.ejca.2017.06.026

28735072

Wang

Jiang

Naranmandura

Therapeutic strategy of arsenic trioxide in the fight against cancers and other diseases

Metallomics123263362020

10.1039/c9mt00308h

32163072

Wahiduzzaman

Ota

Hosokawa

Novel mechanistic insights into the anti-cancer mode of arsenic trioxide

Curr Cancer Drug Targets201151292020

10.2174/1568009619666191021122006

31736446

Chen

Zhang

Jiao

Han

Efficacy and safety of the arsenic trioxide/lipiodol emulsion in the transcatheter arterial chemoembolization combined with apatinib in the treatment of advanced hepatocellular carcinoma

Can J Gastroenterol Hepatol202155657932021

10.1155/2021/5565793

34458205

Zhang

Pan

Yang

Huang

Effects of arsenic trioxide combined with platinum drugs in treatment of cervical cancer: A protocol for systematic review and meta-analysis of randomized controlled trials

Medicine (Baltimore)99e229502020

10.1097/MD.0000000000022950

33157935

Kutny

Alonzo

Abla

Rajpurkar

Gerbing

Wang

Hirsch

Raimondi

Kahwash

Hardy

Assessment of arsenic trioxide and all-trans retinoic acid for the treatment of pediatric acute promyelocytic leukemia: A report from the children's oncology group AAML1331 trial

JAMA Oncol879872022

10.1001/jamaoncol.2021.5206

34762093

Zhong

Chen

Arsenic trioxide induces the apoptosis and decreases NF-κB expression in lymphoma cell lines

Oncol Lett16626762742018

30333888

Zhang

Liu

Feng

Wang

The antitumor effects of arsenic trioxide in mantle cell lymphoma via targeting Wnt/β-catenin pathway and DNA methyltransferase-1

Oncol Rep38311431202017

10.3892/or.2017.5945

28901456

Long

Qing

Zhang

Chen

Zhang

Liang

Arsenic trioxide induces apoptosis of Burkitt lymphoma cell lines through multiple apoptotic pathways and triggers antiangiogenesis

Oncol Res191491632011

10.3727/096504011X12935427587885

21473291

Wei

Chen

Wang

Xie

Fan

Arsenic trioxide induces autophagy and antitumor effects in Burkitt's lymphoma Raji cells

Oncol Rep32155715632014

10.3892/or.2014.3369

25110043

Kouhpaikar

Sadeghian

Rafatpanah

Kazemi

Iranshahi

Delbari

Khodadadi

Ayatollahi

Rassouli

Synergy between parthenolide and arsenic trioxide in adult T-cell leukemia/lymphoma cells in vitro

Iran J Basic Med Sci236166222020

32742599

Yue

Chau

Kwong

Tse

Arsenic trioxide inhibits anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma through targeting ALK-fusion oncoprotein

Br J Haematol194108510902021

10.1111/bjh.17581

34121173

Piao

Chau

Yue

Kwong

Tse

Arsenic trioxide degrades NPM-ALK fusion protein and inhibits growth of ALK-positive anaplastic large cell lymphoma

Leukemia315225262017

10.1038/leu.2016.311

27795556

Park

Kim

Koo

Lee

Jeong

Huh

Kim

Lee

Suh

ESHAP salvage therapy for refractory and relapsed non-Hodgkin's lymphoma: A single center experience

Korean J Intern Med211591642006

10.3904/kjim.2006.21.3.159

17017664

Kchour

Tarhini

Kooshyar

El Hajj

Wattel

Mahmoudi

Hatoum

Rahimi

Maleki

Rafatpanah

Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL)

Blood113652865322009

10.1182/blood-2009-03-211821

19411628

Cheson

Pfistner

Juweid

Gascoyne

Specht

Horning

Coiffier

Fisher

Hagenbeek

Zucca

Revised response criteria for malignant lymphoma

J Clin Oncol255795862007

10.1200/JCO.2006.09.2403

17242396

Zhu

Lo-Coco

Jin

The simpler, the better: Oral arsenic for acute promyelocytic leukemia

Blood1345976052019

10.1182/blood.2019000760

31113776

Zhao

Sun

Kong

Zhang

Shi

Zhao

Hong

Qiao

A phase II study of arsenic trioxide in patients with relapsed or refractory malignant lymphoma

Med Oncol32792015

10.1007/s12032-015-0526-x

25698531

Hermine

Dombret

Poupon

Arnulf

Lefrère

Rousselot

Damaj

Delarue

Fermand

Brouet

Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma

Hematol J51301342004

10.1038/sj.thj.6200374

15048063

Marçais

Cook

Witkover

Asnafi

Avettand-Fenoel

Delarue

Cheminant

Sibon

Frenzel

de Thé

Arsenic trioxide (As₂O₃) as a maintenance therapy for adult T cell leukemia/lymphoma

Retrovirology1752020

10.1186/s12977-020-0513-y

32199462

Tang

Yao

Liu

Yuan

Hosoi

Huang

Wei

Chen

Arsenic trioxide induces expression of BCL-2 expression via NF-κB and p38 MAPK signaling pathways in BEAS-2B cells during apoptosis

Ecotoxicol Environ Saf2221125312021

10.1016/j.ecoenv.2021.112531

34303041

Daugrois

Bessiere

Dejean

Anton-Leberre

Commes

Pyronnet

Brousset

Espinos

Brugiere

Meggetto

Lamant

Gene expression signature associated with clinical outcome in ALK-positive anaplastic large cell lymphoma

Cancers (Basel)1355232021

10.3390/cancers13215523

34771686

Chen

Huang

Wang

Fang

Yao

Ren

Chen

Lin

Combination of crizotinib and chemotherapy in patients with relapsed or refractory anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL)

Leuk Lymphoma625715802021

10.1080/10428194.2020.1839658

33155495

Peng

Xiong

Feng

Liu

Weng

Encouraging early outcomes of treatment with arsenic trioxide combined with chemotherapy for alveolar rhabdomyosarcoma in children: 4 Case reports

Front Oncol117516232021

10.3389/fonc.2021.751623

34778066

Figure 1.

Comparison of treatment response between groups. Comparison of (A) treatment response rate by Wilcoxon rank sum test, (B) CR rate and (C) OR rate by χ² test between patients in the ESHAP group and those in the arsenic trioxide plus ESHAP group. ESHAP, etoposide, solumedrol, high-dose cytarabine and cisplatin; CR, complete response; OR, objective response; ATO, arsenic trioxide; PR, partial response; SD, stable disease; PD, progressive disease.

Figure 2.

Comparison of survival between groups. Comparison of (A) accumulating EFS rate and (B) accumulating OS rate between patients in the ESHAP group and those in the arsenic trioxide plus ESHAP group by log-rank test. *P<0.05. ESHAP, etoposide, solumedrol, high-dose cytarabine and cisplatin; EFS, event-free survival; ATO, arsenic trioxide; OS, overall survival.

Figure 3.

Subgroup analysis of treatment response and survival. Comparison of (A) CR rate, (B) OR rate, (C) accumulating EFS rate and (D) accumulating OS rate between groups of patients with relapsed ALK⁺ ALCL. Comparison of (E) CR, (F) OR rate, (G) accumulating EFS and (H) accumulating OS rates between groups of patients with refractory ALK⁺ ALCL. CR and ORR were compared using χ² test, accumulating EFS and OS rates were compared using log-rank test. CR, complete response; OR, objective response; EFS, event-free survival; OS, overall survival; ALK⁺ ALCL, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma; ATO, arsenic trioxide.

Table I.

Clinical characteristics of patients with R/R ALK⁺ ALCL.

Items	ESHAP group (n=13)	ATO plus ESHAP group (n=11)	P-value
Age (years), mean ± SD	32.8±12.8	31.0±10.7	0.709
Sex, no. (%)			0.649
Female	4 (30.8)	2 (18.2)
Male	9 (69.2)	9 (81.8)
Ann Arbor stage, no. (%)			0.755
I–II	3 (23.1)	3 (27.3)
III	7 (53.8)	4 (36.4)
IV	3 (23.1)	4 (36.4)
Disease status, no. (%)			0.423
Relapsed	6 (46.2)	3 (27.3)
Refractory	7 (53.8)	8 (72.7)
ECOG performance status, no. (%)			0.188
0	3 (23.1)	4 (36.4)
1	7 (53.8)	7 (63.6)
2	3 (23.1)	0 (0.0)
B symptoms, no. (%)			1.000
No	4 (30.8)	4 (36.4)
Yes	9 (69.2)	7 (63.6)
Previous chemotherapy, no. (%)			1.000
No	0 (0.0)	0 (0.0)
Yes	13 (100.0)	11 (100.0)
First-line chemotherapy regimen, no. (%)			0.470
CHOP	10 (76.9)	6 (54.5)
EPOCH	2 (15.4)	4 (36.4)
ESHAP	1 (7.7)	1 (9.1)
Previous radiation, no. (%)			0.199
No	13 (100.0)	9 (81.8)
Yes	0 (0.0)	2 (18.2)
Previous HSCT, no. (%)			1.000
No	13 (100.0)	11 (100.0)
Yes	0 (0.0)	0 (0.0)

The comparisons were performed using t-test, Wilcoxon rank sum test, χ² test or Fisher's exact test, as appropriate. R/R ALK⁺ ALCL, relapsed or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma; ESHAP, etoposide, solumedrol, high-dose ara-C and cisplatin; ATO, arsenic trioxide; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; EPOCH, etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin; HSCT, hematopoietic stem cell transplantation.

Table II.

Adverse events of patients with R/R ALK⁺ ALCL.

	ESHAP group (n=13)			ATO plus ESHAP group (n=11)

Items	Total	Grade 1–2	Grade 3–4	Total	Grade 1–2	Grade 3–4	P₁ value	P₂ value
Anemia, no. (%)	11 (84.6)	9 (69.2)	2 (15.4)	10 (90.9)	6 (54.5)	4 (36.4)	1.000	0.357
Leukopenia, no. (%)	9 (69.2)	7 (53.8)	2 (15.4)	10 (90.9)	6 (54.5)	4 (36.4)	0.327	0.357
Thrombocytopenia, no. (%)	6 (46.2)	5 (38.5)	1 (7.7)	9 (81.8)	5 (45.5)	4 (36.4)	0.105	0.142
Neutropenia, no. (%)	7 (53.8)	5 (38.5)	2 (15.4)	9 (81.8)	4 (36.4)	5 (45.5)	0.211	0.182
Fever, no. (%)	6 (46.2)	5 (38.5)	1 (7.7)	9 (81.8)	7 (63.6)	2 (18.2)	0.105	0.576
Fatigue, no. (%)	7 (53.8)	5 (38.5)	2 (15.4)	8 (72.7)	5 (45.5)	3 (27.3)	0.423	0.630
Anorexia, no. (%)	6 (46.2)	5 (38.5)	1 (7.7)	8 (72.7)	7 (63.6)	1 (9.1)	0.240	1.000
Nausea and vomiting, no. (%)	5 (38.5)	4 (30.8)	1 (7.7)	7 (63.6)	5 (45.5)	2 (18.2)	0.219	0.576
Stomatitis, no. (%)	6 (46.2)	5 (38.5)	1 (7.7)	6 (54.5)	5 (45.5)	1 (9.1)	0.682	1.000
Diarrhea, no. (%)	4 (30.8)	4 (30.8)	0 (0.0)	5 (45.5)	4 (36.4)	1 (9.1)	0.675	0.458
Elevated transaminase, no. (%)	4 (30.8)	4 (30.8)	0 (0.0)	5 (45.5)	4 (36.4)	1 (9.1)	0.675	0.458
Dyspnea, no. (%)	2 (15.4)	2 (15.4)	0 (0.0)	5 (45.5)	4 (36.4)	1 (9.1)	0.182	0.458
Elevated creatinine, no. (%)	3 (23.1)	2 (15.4)	1 (7.7)	4 (36.4)	4 (36.4)	0 (0.0)	0.659	1.000
Dizziness, no. (%)	1 (7.7)	1 (7.7)	0 (0.0)	2 (18.2)	2 (18.2)	0 (0.0)	0.576	1.000

The comparisons were performed using χ² test or Fisher's exact test, as appropriate. R/R ALK⁺ ALCL, relapsed or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma; ESHAP, etoposide, solumedrol, high-dose ara-C and cisplatin; ATO, arsenic trioxide. P₁, comparison of each adverse event's occurrence rate between groups; P₂, comparison of Grade 3–4 adverse event's occurrence rate between groups.