Yeh et al
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Palonosetron and Dexamethasone for The Prevention of Nausea and Vomiting In
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Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation
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Su-Peng Yeha,b,c, Woei-Chung Loa,d, Ching-Yun Hsieha, Li-Yuan Baia,c, Ching-Chan Lina,
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Po-Han Lina, Chen-Yuan Lina, Yu-Min Liaoa, Chang-Fang Chiua,c
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a
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Division of Hematology and Oncology, Department of Internal Medicine, China Medical
University Hospital, 2 Yuh Der Road; Taichung 404; Taiwan
b Stem
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Cell Research Lab., Department of Medical Research, China Medical University
Hospital, 2 Yuh Der Road; Taichung 404; Taiwan
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c
China Medical University, 2 Yuh Der Road; Taichung 404; Taiwan
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d
Regency Specialist Hospital, No.1 Jalan Suria, Bandar Seri Alam, 81750 Masai, Johor,
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Malaysia
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Corresponding author: Su-Peng Yeh, MD.
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Division of Hematology and Oncology, Department of Medicine,
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China Medical University Hospital; 2 Yuh Der Road; Taichung 404; Taiwan
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Tel. No.: 886-4-22052121 ext. 1513; Fax No.: 886-4-22337675
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E-mail: supengyeh@gmail.com
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Abstract
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Purpose: The primary aim of this study was to evaluate the efficacy of Palonosetron
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combined with Dexamethasone in the prevention of vomiting, and especially nausea, in
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patients receiving allogeneic stem cell transplantation.
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Methods: Palonosetron 0.25mg was given to 27 patients receiving allogeneic
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transplantation on the first day of conditioning, and then every other day during the entire
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conditioning period. Dexamethasone was given daily also during conditioning. Vomiting
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and nausea were recorded daily according to CTCAE version 4.0 from the start of
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conditioning to Day 7 after transplantation. In addition, MASCC Anti-emetic Tool (MAT)
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was also used in parallel to evaluate the intensity of nausea.
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Results: The treatment was well tolerated. 25.9% and 40.7% of the patients had grade 2/3
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vomiting and nausea respectively during conditioning. The incidences of grade 2/3
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vomiting and nausea were even higher in the first week after transplantation (40.7% and
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51.8% respectively). The score of MAT correlated well with the grade of CTCAE.
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However, the difference in the mean intensity of nausea between period of conditioning
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and the first week after HSCT was significant only by using MAT (0.96±1.829 vs
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3.81±3.386, p=0.001) but not CTCAE (1.26±0.903 vs 1.63±0.967, p=0.152).
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Conclusion: Palonosetron combined with dexamethasone is effective in preventing
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vomiting during conditioning. However, more effort should be made to alleviate nausea
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during conditioning and both nausea and vomiting in the first week after transplantation.
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Furthermore, MAT has a higher discriminant power than CTCAE in assessing the intensity
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of nausea in patients receiving allogeneic transplantation.
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Key Words: Chemotherapy induced nausea and vomiting (CINV), Palonosetron,
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allogeneic transplantation
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Introduction
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Nausea and vomiting, although not the life threatening conditions by themselves, are
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the most severe side effects of chemotherapy perceived by patient [1-3]. The launch of
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5-hydroxytryptamine receptor antagonists (5-HT3 RAs) is one of the major breakthroughs
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in combating chemotherapy-induced nausea and vomiting (CINV). However, the clinical
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benefit of using 5-HT3 RA was seen predominantly in the control of acute CINV. The
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control of delayed CINV remained unsatisfied clinically, especially in patients receiving
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multiple-day chemotherapy [4-7] or high dose chemotherapy [8-14]. Palonosetron is a
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second generation 5-HT3 RA with a stronger binding affinity and a much longer
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plasma-elimination half-life comparing to the first-generation 5-HT3 RAs [15-17]. The
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improved efficacy of Palonosetron in preventing acute CINV and chronic CINV of
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patients receiving moderately (MEC) or highly emetogenic (HEC) chemotherapy had been
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established in prior studies [18-21]. More recently, the efficacy of Palonosetron in
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preventing CINV of patients receiving multiple-day chemotherapy for hematological
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malignancies [22, 23], as well as of patients receiving high dose chemotherapy with
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autologous hematopoietic stem cell transplantation (HSCT) were encouraging [24, 25].
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Allogeneic HSCT is much more complex than simply multiple-day chemotherapy
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with or without autologous HSCT. Many drugs, such as prophylactic antibiotic,
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prophylactic antifungal agent, and immunosuppressives are given to patients
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simultaneously with the conditioning chemoradiotherapy and might potentially contribute
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to nausea and vomiting. The efficacy of Palonosetron in the prevention of conditioning
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chemoradiotherapy-related nausea and vomiting remains unknown. Nausea is especially
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of our greater concern because it is less effectively prevented by 5-HT3 RA [26-28], is a
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subjective and unobservable phenomenon [29], and has a greater impact on quality of life
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than vomiting [30]. Furthermore, it is unknown whether the use of higher affinity and
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longer acting 5-HT3 RA will have any positive or negative impact on the
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transplant-related outcomes that were specifically concerned in the allogeneic
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transplantation, such as transplant-related mortality (TRM) and graft-versus-host disease
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(GVHD). We therefore conduct this prospective study to evaluate the efficacy of
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Palonosetron in the prevention of vomiting and nausea during the whole period of
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conditioning and the first week after allogeneic HSCT. For more carefully assessing the
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severity of nausea, both CTCAE grading system and Multinational Association of
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Supportive Care in Cancer antiemesis tool (MAT) scoring system were used
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simultaneously and it is our great interest to know how difference are CTCAE and MAT
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compared to each other. In addition, we also carefully look at the development and
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outcome of transplant-related morbidities and mortalities in these patients.
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Design and Methods
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Patients and Treatments
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Twenty-seven adults receiving allogeneic HSCT between May 2011 and Dec. 2012
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at China Medical University Hospital were enrolled in this study that had been approved
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by local institutional review board (IRB). They are 20 acute leukemia, 2 chronic myeloid
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leukemia, 1 myelodysplastic syndrome, 3 severe aplastic anemia, and 1 non-Hodgkin’s
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lymphoma. The median age of them is 39 (ranged from 21 to 60). All the 27 patients
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received peripheral blood stem cell transplantation from HLA-matched siblings (12),
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HLA-matched unrelated donors (9), and HLA-mismatched donors (6). GVHD prophylaxis
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consisted of standard cyclosporine-A started from Day -1 and short-course methotrexate
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given on Day 1, 3, 6, and 11. Anti-thymocyte globulin (ATG, Gemzyme) was also given to
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patients receiving stem cell from unrelated, or HLA mismatched donors. 17 patients
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received myeloablative conditioning (MAC, Fludarabine and myeloablative Busulfan
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(FluBu4) in 16 and total body irradiation (TBI) 12Gy plus Cyclophosphamide in 1, while
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10 patients received reduced-intensity condition (RIC, Fludarabine and non-myeloablative
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Busulfan (FluBu2) in 5, Fludarabine and Cyclophosphamide (FluCy) in 2, FluBu2Cy in 3.
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The mean age of patients receiving RIC is significantly higher than patients receiving
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MAC (52.3 years vs 34.1 years, p < 0.001, Mann Whitney test). The characteristics of
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these patients are summarized in table 1.
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All the patients received Palonosetron 0.25mg i.v. infusion 30 minutes before the
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start of conditioning chemoradiotherapy. Palonosetron 0.25mg was given subsequently
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every other day to cover the whole period of conditioning. Dexamethasone 10-15mg i.v.
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infusion was also given daily during conditioning. All the other anti-emetic drugs were
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prohibited at first. However, metaclopropamide and/or additional dexamethasone were
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allowed as rescue treatment for patients who had breakthrough vomiting or nausea.
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Efficacy and Safety Assessment
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The efficacy of Palonosetron combined with dexamethasone in the prevention of
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conditioning chemoradiotherapy-related vomiting and nausea was evaluated on a daily
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basis from the start of conditioning to Day 7 after HSCT. The severity of vomiting and
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nausea were determined based on the grading system of CTCAE version 4.0. In addition
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to this, we also used a 100-mm visual analog scale (VAS) from Chinese translation of
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MAT to evaluate the intensity of nausea, with 0 mm being labeled as no nausea and 100
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mm being nausea as bad as it can be.
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Adverse effects potentially associated with Palonosetron use, including constipation,
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diarrhea, headache, insomnia, and flatulence were recorded on a daily basis from the start
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of conditioning to Day 7 after HSCT. The severity of these symptoms was determined
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based on CTCAE version 4.0. In addition, the transplant-related outcome, including the
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timing of engraftment, the development of veno-occlusive disease, GVHD, relapse, and
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survival status, as well as cause of death were also collected in each patient.
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Statistics
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The differences in the grade of vomiting and nausea assessed by CTCAE version 4.0
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and the score of nausea assessed by MAT between period of conditioning and the first
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week after HSCT were evaluated by Mann-Whitney U-test. The correlation between the
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score of nausea assessed by MAT and grade of nausea assessed by CTCAE was
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determined by Spearman rank correlation test. Univariate analyses were performed to
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identify differences of following variables between patients with or without grade 2/3
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vomiting and nausea: age, gender (male / female), status at HSCT (complete remission /
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not in remission), lines of prior treatments (1 line / 2 or more lines), conditioning regimen
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(MAC / RIC), and the use of ATG (Yes / No). Odds ratio and 95% confidence intervals
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were calculated for each variable. To examine the independent association between grade
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2/3 vomiting and nausea and these variables, binary logistic regression was used for
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multivariate analysis. Two-tailed probability (p-value) less than 0.05 was considered
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significant and all of the statistical analysis was performed using SPSS software (SPSS
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Inc., Chicago, IL, USA).
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Result
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Efficacy on the prevention of vomiting and nausea
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During the period of conditioning to Day -1, 37% of the patients did not have
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vomiting (complete protection) and only 25.9% of the patients had grade 2/3 vomiting.
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Nausea is less effectively prevented. Only 22.2% of the patients did not have nausea and
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40.7% of the patients had grade 2/3 nausea. During the first week after HSCT (from Day 0
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to Day 7), 37% of the patients did not have vomiting. However, as much as 41.7% of the
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patients had grade 2/3 vomiting. Nausea is also more prominent in the first week after
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HSCT comparing to that during conditioning. Only 11.1% of the patients did not have
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nausea and 51.9% of the patients had grade 2/3 nausea (Figure 1). When we look at
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vomiting and nausea between Day 0 and Day 7 specifically, the incidence of grade 2/3
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vomiting decreased gradually to less than 20% after Day 3, by contrary, the incidence of
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grade 2/3 nausea remained higher than 30% through Day 0 to Day 6 (Figure 2).
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Comparing the severity of vomiting between period of conditioning and the first week
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after HSCT, we found there was no significant difference in the mean CTCAE grade of
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vomiting (1.259±0.447 vs 1.407±0.501 respectively, p=0.257). In assessing the severity of
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nausea, the grade of CTCAE correlates well with the score of MAT (ρ=0.609, p < 0.001,
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Spearman rank correlation test, Figure 3A). Nevertheless, the significant higher intensity
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of nausea in the first week after HSCT comparing to that in the period of conditioning was
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demonstrated only by using MAT scoring system (3.81±3.386 vs 0.96±1.829, p=0.001)
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but not CTCAE grading system (1.63±0.967 vs 1.26±0.903, p=0.177; Figure 3B).
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Risk factors for grade 2/3 vomiting and nausea
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Univariate analyses of factors (age, gender, status at HSCT, prior treatments,
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conditioning regimen, and the use of ATG) associating with grade 2/3 vomiting during
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conditioning chemoradiotherapy is shown in table 2. Of these, age is the only factor
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associated with grade 2/3 vomiting (odds ratio 0.656, 95% confidence interval
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0.441-0.978, p=0.038). In multivariate analysis, age remains an independent factor
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associated with grade 2/3 vomiting during period of conditioning (odds ratio 0.653, 95%
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confidence interval 0.426-1.000, p=0.050). On the other hand, MAC conditioning protocol
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is the only independent factor associated with grade 2/3 vomiting in the first week after
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HSCT (p=0.043). Independent factor associated with grade 2/3 nausea could not be
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identified in this study, although age associated with a trend of grade 2/3 nausea during
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period of conditioning (odds ratio 0.757, 95% confidence interval 0.567-1.011, p=0.059)
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Safety and Transplant-related Outcome
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The treatment of Palonosetron was well tolerated and based on our experience in
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allogeneic HSCT, we did not observe any significant difference in the side effect or other
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safety issues when comparing to the treatment using other 5HT3 RA such as Granisetron
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or Tropisetron. The most common adverse effects potentially associated with Palonosetron
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treatment was insomnia (75.1%). The incidence of other potential adverse effects,
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including constipation, diarrhea, headache, and flatulence, were between 14.8% and 37%.
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In addition to insomnia and constipation, there was no grade 2 or higher adverse effects
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(Figure 4).
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The median days to neutrophil and platelet engraftment are 14.889±4.552 days and
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20.642±5.582 days respectively. No patient had veno-occlusive disease (sinusoidal
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obstruction syndrome). The incidences of any and grade 3/4 acute GVHD are 50% and
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19.2% respectively. The incidences of any and extensive chronic GVHD are 57.7% and
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23.1% respectively. The TRM (Day 100 mortality rate) of this cohort is 7.4%. With
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median follow up time of 16.5 months, 19 patients (70.4%) remain alive and 5 had relapse
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(22.7% of patients with leukemia). 8 patients died, including 3 patients died of relapse, 2
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patients died of complication of GVHD, and the other 3 patients died of infection,
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intracranial hemorrhage, and post-transplant lymphoproliferative disorder respectively.
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Discussion
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CINV remains a significant medical problem in patients receiving stem cell
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transplantation even in the era of 5-HT3 RA [31]. However, our study showed that with
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the use of second generation 5-HT3 RA Palonosetron in combination with Dexamethasone,
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severe (grade 2 or 3) vomiting during period of conditioning chemoradiotherapy can
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largely be prevented and 74.1% of the patients had either no vomiting or grade 1 vomiting.
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Consistent with many prior studies, younger patients are at a higher risk of grade 2/3
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vomiting during conditioning. Using 33 years old as a cutting point based on ROC curve,
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patients younger than 33 years had 75% of grade 2/3 vomiting comparing to 5.3% of
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patients older than 33 years. We also compare the efficacy of Palonosetron retrospectively
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to 24 historical control patients who were matched for age, gender, conditioning regimen,
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donor type, disease type, and disease status before HSCT and received first generation
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5-HT3 RA (21 Tropisetron, 3 Granisetron) plus dexamethasone during conditioning
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treatment (Supplement table 1). The use of first generation 5-HT3 RA is associated with
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significant higher incidence of any vomiting (grade 1-3) both during conditioning (91.7%
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vs 63.0%, p=0.017, Mann-Whitney U-test) and the first week after transplantation (91.7%
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vs 66.7%, p=0.032; Mann-Whitney U-test, supplement figure 1). Nevertheless,
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prospective randomized study is needed to confirm the superiority of Palonosetron in the
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prevention of vomiting in allogeneic HSCT.
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Nausea was less effectively prevented comparing to vomiting. As much as 40.7% of
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the patients had grade 2 or 3 nausea during period of conditioning. An even more serious
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problem, as was shown in Figure 1, 2, and 3, is the higher incidence of grade 2 or 3
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vomiting and nausea in the first week after transplantation (between Day 0 to Day 7), a
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finding that has never been addressed in the literature. The reason why patients had more
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vomiting and nausea in the first week after HSCT comparing to those during period of
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conditioning cannot be answered in this study. The use of Cyclosporine-A (started from
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Day -1) and short course Methotrexate (given on Day 1, 3 and 6), as well as other
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concomitant medication may potentially worsen the condition of vomiting and nausea in
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these patients. However, delayed nausea and vomiting from chemotherapy given in the
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last few days of conditioning and the lack of coverage of antiemetics after Day 0 might
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probably be the major contributor. A study to examine whether additional Palonosetron
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given after alloHSCT can ameliorate nausea and vomiting will be started shortly in our
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institute. Also, though the grade of nausea assessed by CTCAE correlates well with the
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score of MAT, the difference in the intensity of nausea between period of conditioning and
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the first week after HSCT was significant only by using MAT scoring system (0.96±1.829
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vs 3.81±3.386, p=0.001) but not CTCAE grading system (1.26±0.903 vs 1.63±0.967,
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p=0.152), suggesting MAT scoring system has a higher discriminant power than CTCAE
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grading system in patients received alloHSCT and should be the preferred tool in
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assessing the severity of nausea in future studies.
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The use of Palonosetron in the setting of allogeneic transplantation is well tolerated
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and we do not observe any unexpected adverse effect. Although 75.1% of the patients had
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insomnia, it is easily manageable; besides, the high incidence of insomnia might also be
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due to the concomitant daily use of Dexamethasone. The potential impact of Palonosetron
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on GVHD has never been reported so far. It had been shown that 5-HT plays an important
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role in gut inflammation through activation of dendritic cell and subsequent activation of
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T cells [32] and 5HT-3 RA Tropisetron and Granisetron were shown to reduce
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inflammatory response and lipid peroxidation in the gut [33, 34] and other rheumatic
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diseases [35-38]. Palonosetron binds to the 5HT-3 receptor much more potent and exerts
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the inhibitory effect much longer than Tropisetron and Granisetron; however, we did not
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observe a lower incidence of GVHD or higher relapse rate by using Palonosetron. More
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studies are needed to explore the anti-inflammation and immune modulation effect of
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Palonosetron in the allogeneic transplantation.
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There are some limitations in the interpretation the result of this study. Firstly, almost
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all the patient received Fludarabine-based conditioning chemotherapy and only 1 patient
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received traditional TBI (12Gy) plus Cyclophosphamide. The efficacy of Palonosetron in
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the prevention of nausea and vomiting after TBI-based conditioning may need further
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study. Secondly, while Palonosetron has an extended elimination half-life of around 40
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hours and Palonosetron 0.25mg every 3 days was used in prior studies [23, 24], there were
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studies showing that Palonosetron 0.25mg daily for multiple days could be more effective
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in patients receiving high dose Cytarabine [22] or high dose Melphalan [25]. The most
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cost-effective dosing schedule of Palonosetron might be in between and so we used
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0.25mg every other day in this study. Nevertheless, the best dosing schedule of
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Palonosetron for multi-day conditioning chemotherapy remains to be investigated. Finally,
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only Metaclopropamide or additional dose of Dexamethasone were allowed for salvage
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treatment. Aprepitant was not allowed in this study because it is a moderate inhibitor of
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CYP3A4 and may alter the metabolism of CYP3A4 substrate such as Cyclosporine [39,
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40]. It is not known whether using Aprepitant during conditioning or using Palonosetron
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as salvage treatment will further improve the control rate.
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Conclusion
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Our study demonstrates Palonosetron combined with Dexamethasone is an effective and
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safe treatment for the prevention of vomiting caused by conditioning chemoradiotherapy.
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The transplant-related outcomes that were specifically concerned in the allogeneic setting
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such as TRM and GVHD were not negatively affected by Palonosetron. However, nausea
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is less effectively controlled. Furthermore, both vomiting and nausea in the first week after
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HSCT remain a significant medical problem and more effort should be made to address
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and improve this unmet need in future study.
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Acknowledgement: The authors would like to thank all the nursing staff of BMT unit
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(5H ward) and Yu-Ting Ho (research coordinator of this study) for their great help in this
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study. This study was supported in part by the research grant from Department of Health
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of Taiwan (DOH102-TD-C-111-005) and China Medical University Hospital (DMR
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98-008).
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Authorship and Disclosures:
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CC Lin, PH Lin, CY Lin, YM Liao contributed to clinical data collection, CF Chiu
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supervised the process of this study and reviewed the manuscript. All the authors have no
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relationships or conflict of interest to declare.
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SP Yeh, WC Lo, CY Hsieh designed the study, LY Bai,
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Figure Legends
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Figure 1: Incidence of grade 2/3 vomiting and nausea during period of conditioning
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(Early) and the first week after HSCT (Late). More patients had grade 2/3
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vomiting and nausea in the first week after HSCT comparing to those during
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period of conditioning. Also, nausea was less effectively prevented comparing
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to vomiting.
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Figure 2: Incidence of grade 2/3 vomiting and nausea in the first week after HSCT.
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The incidence of grade 2/3 vomiting decreased gradually to less than 20% after
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Day 3. However, the incidence of grade 2/3 nausea remained higher than 30%
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through Day 0 to Day 6.
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Figure 3: Severity of nausea assessed by CTCAE version 4.0 and MAT.
Figure 3A
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(Left figure): the grade of nausea assessed by CTCAE correlates well with the
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score of nausea assessed by MAT. Figure 3B (Right figure): the difference in
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the intensity of nausea between period of conditioning (early) and the first
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week after HSCT (late) was significant only by using MAT scoring system but
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not CTCAE grading system, suggesting MAT scoring system has a higher
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discriminant power than CTCAE grading system
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Figure 4: Incidence of potential adverse effects of Palonosetron. Insomnia is the most
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common adverse effect during period of conditioning, the incidences of other
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adverse effects were low and there was no grade 3/4 adverse effect observed in
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this study.
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Supplementary Figure Legends
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Incidence of any vomiting during conditioning and the first week after HSCT. The
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use of first generation 5-HT3 RA is associated with significant higher
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incidence of any vomiting (grade 1-3) both during conditioning (91.7% vs
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63.0%, p=0.017) and the first week after transplantation (91.7% vs 66.7%,
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p=0.032).
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