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Efficacy of ESHAP Regimen in Transplant Ineligible Patients with Relapsed/Refractory T-Cell Lymphoma

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Efficacy of ESHAP Regimen in Transplant Ineligible Patients with Relapsed/Refractory T-Cell Lymphoma Original Article J Hematol. 2018;7(4):131-139 Efficacy of ESHAP Regimen in Transplant Ineligible Patients With Relapsed/Refractory T-Cell Lymphoma Lalita Norasetthadaa, b, Adisak Tantiworawita, Thanawat Rattanathammetheea, Chatree Chai-Adisaksophaa, Thanapat Chaipoha, Ekarat Rattarittamronga Abstract Introduction Background: Salvage chemotherapy is the mainstay for the treatment Peripheral T-cell lymphomas (PTCLs) are accounting for 10% of relapsed/refractory peripheral T-cell lymphomas (R/R PTCLs). ES- of non-Hodgkin lymphoma (NHL) in western countries [1] HAP regimen, consisting of etoposide, methylprednisolone, high-dose and in Thailand [2]. The outcome of patients with PTCL is in- Ara-C, and cisplatin is considered one of the well-accepted regimens ferior to those with aggressive B-cell lymphoma [3]. Depend- for R/R lymphoma. Though, the evidence of long-term efficacy of ES- ing on subtypes of T-cell lymphoma, the outcome of patients HAP on R/R PTCLs is limited. This study aims to determine the ef- with ALK-positive anaplastic large cell lymphoma (ALCL) is ficacy and safety of ESHAP as a first salvage regimen, not followed by more favorable than those with other subtypes for which long- autologous stem cell transplantation (ASCT), in R/R PTCLs. term survival is less than 30% [4]. Despite an initial response to CHOP or CHOP-like chemotherapy, the majority of patient Methods: Patients with PTCLs, who progressed after one prior ther- experiences disease progression thereafter [5]. Attempt to im- apy and received ESHAP as a salvage treatment without subsequent prove a durable response by upfront autologous stem trans- ASCT, were recruited from the prospective observational study in the plantation (ASCT) appears to provide a favorable outcome patients with lymphoma. [6]. When disease relapses, salvage chemotherapy followed by Results: From January 2005 to April 2015, 33 patients with R/R PT- ASCT is considered the standard of care [7]. In the absence of CLs received ESHAP as first salvage regimen at Chiang Mai Univer- ASCT, the survival of patients with relapsed or refractory (R/R) sity Hospital. The overall response rate was 46% (complete remission PTCLs is dismal with median overall survival of 5 months [8]. (CR) 39%). The median duration of response was 18 months. Median On the contrary to the success of novel therapies in the treat- second progression-free survival (PFS) and overall survival (OS) ment of B-cell counterpart [9, 10], the recently approved thera- were 8.0 and 11.0 months, respectively. Patients having late relapse pies for R/R PTCLs including pralatrexate [11], romidepsin had more favorable OS than those having early relapsed or refractory [12], and belinostat [13] provided a response rate of less than disease with a median OS of 21, 17 and 3 months, respectively (P = 30%. The optimal treatment of PTCLs remains challenging as 0.001). Patients achieving CR after ESHAP had significantly better the recommendation of treatment for R/R PTCLs derives from median OS (39, 7 and 5 months, P < 0.0001) and second PFS (33, 2 retrospective and phase II studies. Thus, combined chemother- and 2 months, P < 0.0001) than those achieving PR or having progres- apy regimens remain the established therapy for R/R PTCLs. sive disease. Grade 3-4 neutropenia (45.5%) and thrombocytopenia However, the salvage regimen of choice is still undefined (33.4%) were common but manageable. due to the lack of large randomized controlled trials. ESHAP regimen, consisting of etoposide, methylprednisolone, high- Conclusions: ESHAP offers a long-term survival in some transplant dose Ara-C, and cisplatin is considered one of the well-accept- ineligible patients with PTCLs who were chemosensitive with late ed regimens for R/R lymphoma [14], though the evidence of relapse after front-line therapy. These results require further investi- long-term efficacy of ESHAP on PTCLs is limited. The pur- gation in a prospective study. pose of this study was to determine the efficacy of ESHAP regimen, not followed by ASCT, as a first salvage therapy for Keywords: Peripheral T-cell lymphoma; ESHAP; Relapsed lympho- patients with R/R PTCLs. ma; Chemotherapy Patients and Methods Manuscript submitted August 21, 2018, accepted September 17, 2018 aDivision of Hematology, Department of Internal Medicine, Faculty of Medi- Study design and patient selection cine, Chiang Mai University, Chiang Mai, Thailand bCorresponding Author: Lalita Norasetthada, Division of Hematology, Depart- ment of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chi- According to our institute’s treatment guidelines to uniform ang Mai, 50200, Thailand. Email: [email protected] treatment for reducing error during chemotherapy prescrip- tion, handling and administration, ESHAP is recommended as doi: https://doi.org/10.14740/jh459w a first-line salvage regimen for patients with R/R PTCLs, ex- Articles © The authors | Journal compilation © J Hematol and Elmer Press Inc™ | www.thejh.org This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits 131 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited Efficacy of ESHAP Regimen in R/RPTCLs Patients J Hematol. 2018;7(4):131-139 cluding cutaneous T-cell lymphoma (CTCL) and subcutaneous rospectively revised from clinical and imaging records based panniculitis-like T-cell lymphoma (SPTL), who are ineligible on the Response Criteria for Malignant Lymphoma [16]. Tox- for ASCT. While patients who are eligible for ASCT receive icity was classified and graded according to the National Can- DICE regimen consisting of dexamethasone, ifosfamide, car- cer Institute Common Toxicity Criteria (CTC) Version 3.0. boplatin and etoposide, then responding patients will be trans- Responses to primary therapy were categorized as refractory ferred for ASCT at the transplant center. After the year of 2011, disease defined as response less than PR after frontline chem- the recommendation for R/R extranodal NK/T cell lymphoma otherapy, early relapsed disease (relapsed within 12 months (ENKTL) has been changed to L-asparaginase with methotrex- after the completion of frontline treatment) and late relapsed ate and dexamethasone (Asp-Met-Dex). From the prospective disease (relapsed 12 months after the completion of frontline registry of lymphoma patients, we recruited adult patients with treatment). R/R PTCLs after anthracycline-based chemotherapy who were ineligible for ASCT and received ESHAP as salvage therapy between January 2005 and April 2015 at Chiang Mai Universi- Statistical methods ty Hospital. All patients had given informed consent to receive treatment per institutional standards. Histological diagnoses Patients who received at least one cycle of ESHAP were ana- were made by hematopathologist according to WHO classifica- lyzed. The primary endpoint was overall response rate (ORR), tion. At relapse or progression, tissue biopsy of the tumor was defined as the sum of patients with CR, unconfirmed CR (CRu), routinely performed when sites of involvement were surgical and PR. Secondary endpoints were second progression-free accessible. Patients were restaged with computed tomography survival (PFS) and overall survival (OS). Duration of response (CT) and bone marrow (BM) biopsy. Time of relapse from di- (DOR) was measured for patients with CR, CRu and PR from agnosis, clinical characteristics, including International Prog- the first date of documentation of response until progression or nostic Index (IPI) [15] at diagnosis and secondary IPI at relapse date of the last assessment. Chi-squared and Fisher exact test were recorded. The study was approved by the Research Ethics were used to compare responses between groups according to Committee of the Faculty of Medicine, Chiang Mai University baseline characteristics at relapse and multivariable analysis and conducted in accordance with the Declaration of Helsinki. for factors predicting response were analyzed by the logistic regression model. OS was measured from date of relapse/pro- Treatment plan gression to date of last follow-up or death from any cause. Sec- ond PFS was calculated from date of first relapse/progression to date of last follow-up, second relapse/progression or death Each 21-day cycle consisted of etoposide at a dose of 40 mg/ from any cause. Probabilities of OS and second PFS were es- m2/day on days 1 - 4 (intravenous (IV) infusion over 1 h), meth- timated by using the Kaplan and Meier method and using log- ylprednisolone at 500 mg/day on days 1 - 5 (IV infusion in 15 rank test for survival comparison. Cox regression analysis was min), Ara-C at 2 g/m2 on day 5 (IV infusion in 2 h) and cisplatin used for multivariable analysis, including factors with P < 0.1 at 25 mg/m2 as a continuous infusion from day 1 to day 4. For in univariate analysis. All statistical analyses were performed patients older than 65 years of age, etoposide and Ara-C doses using SPSS 16.0 for Windows (SPSS, Chicago, IL). were reduced by 50% according to the institute’s guideline. Pa- tients were hospitalized and observed throughout each course of ESHAP. Filgrastim (G-CSF) at a dose of 300 µg/day subcutane- Results ous injection for 7 days was administered to every patient as pri- mary neutropenic prophylaxis. Patients who developed febrile Patients neutropenia had etoposide and Ara-C doses reduced by 20% and 50%, respectively, in subsequent cycles. A 25% and 50% reduction of the cisplatin dose was made for serum creatinine of Of 102 patients with PTCLs, excluding CTCL and SPTL, di- 1.5 - 2.0 mg/dL and 2.1 - 3.0 mg/dL, respectively. Cisplatin was agnosed between January 2005 and April 2015, 62 patients re- omitted if the serum creatinine was greater than 3 mg/dL. Co- lapsed. Thirty-four patients received ESHAP, only one of them trimoxazole and acyclovir were given to every patient according underwent ASCT.
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