Palonosetron and Dexamethasone for The Prevention of Nausea and Vomiting In Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation
Su-Peng Yeha,b,c, Woei-Chung Loa,d, Ching-Yun Hsieha, Li-Yuan Baia,c, Ching-Chan Lina, Po-Han Lina, Chen-Yuan Lina, Yu-Min Liaoa, Chang-Fang Chiua,c
a Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, 2 Yuh Der Road; Taichung 404; Taiwan
b Stem Cell Research Lab., Department of Medical Research, China Medical University Hospital, 2 Yuh Der Road; Taichung 404; Taiwan
c China Medical University, 2 Yuh Der Road; Taichung 404; Taiwan
d Regency Specialist Hospital, No.1 Jalan Suria, Bandar Seri Alam, 81750 Masai, Johor,
Malaysia
Corresponding author: Su-Peng Yeh, MD.
Division of Hematology and Oncology, Department of Medicine,
China Medical University Hospital; 2 Yuh Der Road; Taichung 404; Taiwan Tel. No.: 886-4-22052121 ext. 1513; Fax No.: 886-4-22337675
E-mail: [email protected] Abstract
Purpose: The primary aim of this study was to evaluate the efficacy of Palonosetron 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
combined with Dexamethasone in the prevention of vomiting, and especially nausea, in patients receiving allogeneic stem cell transplantation.
Methods: Palonosetron 0.25mg was given to 27 patients receiving allogeneic transplantation on the first day of conditioning, and then every other day during the entire conditioning period. Dexamethasone was given daily also during conditioning. Vomiting and nausea were recorded daily according to CTCAE version 4.0 from the start of conditioning to Day 7 after transplantation. In addition, MASCC Anti-emetic Tool (MAT) was also used in parallel to evaluate the intensity of nausea.
Results: The treatment was well tolerated. 25.9% and 40.7% of the patients had grade 2/3 vomiting and nausea respectively during conditioning. The incidences of grade 2/3 vomiting and nausea were even higher in the first week after transplantation (40.7% and 51.8% respectively). The score of MAT correlated well with the grade of CTCAE. However, the difference in the mean intensity of nausea between period of conditioning and the first week after HSCT was significant only by using MAT (0.96±1.829 vs 3.81±3.386, p=0.001) but not CTCAE (1.26±0.903 vs 1.63±0.967, p=0.152).
Conclusion: Palonosetron combined with dexamethasone is effective in preventing vomiting during conditioning. However, more effort should be made to alleviate nausea during conditioning and both nausea and vomiting in the first week after transplantation. Furthermore, MAT has a higher discriminant power than CTCAE in assessing the 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
intensity of nausea in patients receiving allogeneic transplantation.
Key Words: Chemotherapy induced nausea and vomiting (CINV), Palonosetron, allogeneic transplantation
Introduction
Nausea and vomiting, although not the life threatening conditions by themselves, are the most severe side effects of chemotherapy perceived by patient [1-3]. The launch of 5-hydroxytryptamine receptor antagonists (5-HT3 RAs) is one of the major breakthroughs in 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61
combating chemotherapy-induced nausea and vomiting (CINV). However, the clinical benefit of using 5-HT3 RA was seen predominantly in the control of acute CINV. The control of delayed CINV remained unsatisfied clinically, especially in patients receiving multiple-day chemotherapy [4-7] or high dose chemotherapy [8-14]. Palonosetron is a second generation 5-HT3 RA with a stronger binding affinity and a much longer plasma-elimination half-life comparing to the first-generation 5-HT3 RAs [15-17]. The improved efficacy of Palonosetron in preventing acute CINV and chronic CINV of patients receiving moderately (MEC) or highly emetogenic (HEC) chemotherapy had been established in prior studies [18-21]. More recently, the efficacy of Palonosetron in preventing CINV of patients receiving multiple-day chemotherapy for hematological malignancies [22, 23], as well as of patients receiving high dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) were encouraging [24, 25].
Allogeneic HSCT is much more complex than simply multiple-day chemotherapy with or without autologous HSCT. Many drugs, such as prophylactic antibiotic, prophylactic antifungal agent, and immunosuppressives are given to patients simultaneously with the conditioning chemoradiotherapy and might potentially contribute to nausea and vomiting. The efficacy of Palonosetron in the prevention of conditioning chemoradiotherapy-related nausea and vomiting remains unknown. Nausea is especially of our greater concern because it is less effectively prevented by 5-HT3 RA [26-28], is a 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
subjective and unobservable phenomenon [29], and has a greater impact on quality of life than vomiting [30]. Furthermore, it is unknown whether the use of higher affinity and longer acting 5-HT3 RA will have any positive or negative impact on the transplant-related outcomes that were specifically concerned in the allogeneic transplantation, such as transplant-related mortality (TRM) and graft-versus-host disease (GVHD). We therefore conduct this prospective study to evaluate the efficacy of Palonosetron in the prevention of vomiting and nausea during the whole period of conditioning and the first week after allogeneic HSCT. For more carefully assessing the severity of nausea, both CTCAE grading system and Multinational Association of Supportive Care in Cancer antiemesis tool (MAT) scoring system were used simultaneously and it is our great interest to know how difference are CTCAE and MAT compared to each other. In addition, we also carefully look at the development and outcome of transplant-related morbidities and mortalities in these patients.
Design and Methods Patients and Treatments
Twenty-seven adults receiving allogeneic HSCT between May 2011 and Dec. 2012 at China Medical University Hospital were enrolled in this study that had been approved by local institutional review board (IRB). They are 20 acute leukemia, 2 chronic myeloid 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100
leukemia, 1 myelodysplastic syndrome, 3 severe aplastic anemia, and 1 non-Hodgkin’s lymphoma. The median age of them is 39 (ranged from 21 to 60). All the 27 patients received peripheral blood stem cell transplantation from HLA-matched siblings (12), HLA-matched unrelated donors (9), and HLA-mismatched donors (6). GVHD prophylaxis consisted of standard cyclosporine-A started from Day -1 and short-course methotrexate given on Day 1, 3, 6, and 11. Anti-thymocyte globulin (ATG, Gemzyme) was also given to patients receiving stem cell from unrelated, or HLA mismatched donors. 17 patients received myeloablative conditioning (MAC, Fludarabine and myeloablative Busulfan (FluBu4) in 16 and total body irradiation (TBI) 12Gy plus Cyclophosphamide in 1, while 10 patients received reduced-intensity condition (RIC, Fludarabine and non-myeloablative Busulfan (FluBu2) in 5, Fludarabine and Cyclophosphamide (FluCy) in 2, FluBu2Cy in 3. The mean age of patients receiving RIC is significantly higher than patients receiving MAC (52.3 years vs 34.1 years, p < 0.001, Mann Whitney test). The characteristics of these patients are summarized in table 1.
All the patients received Palonosetron 0.25mg i.v. infusion 30 minutes before the start of conditioning chemoradiotherapy. Palonosetron 0.25mg was given subsequently every other day to cover the whole period of conditioning. Dexamethasone 10-15mg i.v. infusion was also given daily during conditioning. All the other anti-emetic drugs were prohibited at first. However, metaclopropamide and/or additional dexamethasone were 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119
allowed as rescue treatment for patients who had breakthrough vomiting or nausea. Efficacy and Safety Assessment
The efficacy of Palonosetron combined with dexamethasone in the prevention of conditioning chemoradiotherapy-related vomiting and nausea was evaluated on a daily basis from the start of conditioning to Day 7 after HSCT. The severity of vomiting and nausea were determined based on the grading system of CTCAE version 4.0. In addition to this, we also used a 100-mm visual analog scale (VAS) from Chinese translation of MAT to evaluate the intensity of nausea, with 0 mm being labeled as no nausea and 100 mm being nausea as bad as it can be.
Adverse effects potentially associated with Palonosetron use, including constipation, diarrhea, headache, insomnia, and flatulence were recorded on a daily basis from the start of conditioning to Day 7 after HSCT. The severity of these symptoms was determined based on CTCAE version 4.0. In addition, the transplant-related outcome, including the timing of engraftment, the development of veno-occlusive disease, GVHD, relapse, and survival status, as well as cause of death were also collected in each patient.
Statistics
The differences in the grade of vomiting and nausea assessed by CTCAE version 4.0 and the score of nausea assessed by MAT between period of conditioning and the first week after HSCT were evaluated by Mann-Whitney U-test. The correlation between the score of nausea assessed by MAT and grade of nausea assessed by CTCAE was 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139
determined by Spearman rank correlation test. Univariate analyses were performed to identify differences of following variables between patients with or without grade 2/3 vomiting and nausea: age, gender (male / female), status at HSCT (complete remission / not in remission), lines of prior treatments (1 line / 2 or more lines), conditioning regimen (MAC / RIC), and the use of ATG (Yes / No). Odds ratio and 95% confidence intervals were calculated for each variable. To examine the independent association between grade 2/3 vomiting and nausea and these variables, binary logistic regression was used for multivariate analysis. Two-tailed probability (p-value) less than 0.05 was considered significant and all of the statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL, USA).
Result
Efficacy on the prevention of vomiting and nausea
During the period of conditioning to Day -1, 37% of the patients did not have vomiting (complete protection) and only 25.9% of the patients had grade 2/3 vomiting. Nausea is less effectively prevented. Only 22.2% of the patients did not have nausea and 40.7% of the patients had grade 2/3 nausea. During the first week after HSCT (from Day 0 to Day 7), 37% of the patients did not have vomiting. However, as much as 41.7% of the 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159
patients had grade 2/3 vomiting. Nausea is also more prominent in the first week after HSCT comparing to that during conditioning. Only 11.1% of the patients did not have nausea and 51.9% of the patients had grade 2/3 nausea (Figure 1). When we look at vomiting and nausea between Day 0 and Day 7 specifically, the incidence of grade 2/3 vomiting decreased gradually to less than 20% after Day 3, by contrary, the incidence of grade 2/3 nausea remained higher than 30% through Day 0 to Day 6 (Figure 2). Comparing the severity of vomiting between period of conditioning and the first week after HSCT, we found there was no significant difference in the mean CTCAE grade of vomiting (1.259±0.447 vs 1.407±0.501 respectively, p=0.257). In assessing the severity of nausea, the grade of CTCAE correlates well with the score of MAT (ρ=0.609, p < 0.001, Spearman rank correlation test, Figure 3A). Nevertheless, the significant higher intensity of nausea in the first week after HSCT comparing to that in the period of conditioning was demonstrated only by using MAT scoring system (3.81±3.386 vs 0.96±1.829, p=0.001) but not CTCAE grading system (1.63±0.967 vs 1.26±0.903, p=0.177; Figure 3B).
Risk factors for grade 2/3 vomiting and nausea
Univariate analyses of factors (age, gender, status at HSCT, prior treatments, conditioning regimen, and the use of ATG) associating with grade 2/3 vomiting during conditioning chemoradiotherapy is shown in table 2. Of these, age is the only factor associated with grade 2/3 vomiting (odds ratio 0.656, 95% confidence interval 0.441-160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178
0.978, p=0.038). In multivariate analysis, age remains an independent factor associated with grade 2/3 vomiting during period of conditioning (odds ratio 0.653, 95% confidence interval 0.426-1.000, p=0.050). On the other hand, MAC conditioning protocol is the only independent factor associated with grade 2/3 vomiting in the first week after HSCT (p=0.043). Independent factor associated with grade 2/3 nausea could not be identified in this study, although age associated with a trend of grade 2/3 nausea during period of conditioning (odds ratio 0.757, 95% confidence interval 0.567-1.011, p=0.059)
Safety and Transplant-related Outcome
The treatment of Palonosetron was well tolerated and based on our experience in allogeneic HSCT, we did not observe any significant difference in the side effect or other safety issues when comparing to the treatment using other 5HT3 RA such as Granisetron or Tropisetron. The most common adverse effects potentially associated with Palonosetron treatment was insomnia (75.1%). The incidence of other potential adverse effects, including constipation, diarrhea, headache, and flatulence, were between 14.8% and 37%. In addition to insomnia and constipation, there was no grade 2 or higher adverse effects (Figure 4).
The median days to neutrophil and platelet engraftment are 14.889±4.552 days and 20.642±5.582 days respectively. No patient had veno-occlusive disease (sinusoidal obstruction syndrome). The incidences of any and grade 3/4 acute GVHD are 50% and 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197
19.2% respectively. The incidences of any and extensive chronic GVHD are 57.7% and 23.1% respectively. The TRM (Day 100 mortality rate) of this cohort is 7.4%. With median follow up time of 16.5 months, 19 patients (70.4%) remain alive and 5 had relapse (22.7% of patients with leukemia). 8 patients died, including 3 patients died of relapse, 2 patients died of complication of GVHD, and the other 3 patients died of infection, intracranial hemorrhage, and post-transplant lymphoproliferative disorder respectively.
Discussion
CINV remains a significant medical problem in patients receiving stem cell transplantation even in the era of 5-HT3 RA [31]. However, our study showed that with the use of second generation 5-HT3 RA Palonosetron in combination with Dexamethasone, severe (grade 2 or 3) vomiting during period of conditioning chemoradiotherapy can largely be prevented and 74.1% of the patients had either no vomiting or grade 1 vomiting. Consistent with many prior studies, younger patients are at a higher risk of grade 2/3 vomiting during conditioning. Using 33 years old as a cutting 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217
point based on ROC curve, patients younger than 33 years had 75% of grade 2/3 vomiting comparing to 5.3% of patients older than 33 years. We also compare the efficacy of Palonosetron retrospectively to 24 historical control patients who were matched for age, gender, conditioning regimen, donor type, disease type, and disease status before HSCT and received first generation 5-HT3 RA (21 Tropisetron, 3 Granisetron) plus dexamethasone during conditioning treatment (Supplement table 1). The use of first generation 5-HT3 RA is associated with significant higher incidence of any vomiting (grade 1-3) both during conditioning (91.7% vs 63.0%, p=0.017, Mann-Whitney U-test) and the first week after transplantation (91.7% vs 66.7%, p=0.032; Mann-Whitney U-test, supplement figure 1). Nevertheless, prospective randomized study is needed to confirm the superiority of Palonosetron in the prevention of vomiting in allogeneic HSCT.
Nausea was less effectively prevented comparing to vomiting. As much as 40.7% of the patients had grade 2 or 3 nausea during period of conditioning. An even more serious problem, as was shown in Figure 1, 2, and 3, is the higher incidence of grade 2 or 3 vomiting and nausea in the first week after transplantation (between Day 0 to Day 7), a finding that has never been addressed in the literature. The reason why patients had more vomiting and nausea in the first week after HSCT comparing to those during period of conditioning cannot be answered in this study. The use of Cyclosporine-A (started from Day -1) and short course Methotrexate (given on Day 1, 3 and 6), as well as other 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236
concomitant medication may potentially worsen the condition of vomiting and nausea in these patients. However, delayed nausea and vomiting from chemotherapy given in the last few days of conditioning and the lack of coverage of antiemetics after Day 0 might probably be the major contributor. A study to examine whether additional Palonosetron given after alloHSCT can ameliorate nausea and vomiting will be started shortly in our institute. Also, though the grade of nausea assessed by CTCAE correlates well with the score of MAT, the difference in the intensity of nausea between period of conditioning and the first week after HSCT was significant only by using MAT scoring system (0.96±1.829 vs 3.81±3.386, p=0.001) but not CTCAE grading system (1.26±0.903 vs 1.63±0.967, p=0.152), suggesting MAT scoring system has a higher discriminant power than CTCAE grading system in patients received alloHSCT and should be the preferred tool in assessing the severity of nausea in future studies.
The use of Palonosetron in the setting of allogeneic transplantation is well tolerated and we do not observe any unexpected adverse effect. Although 75.1% of the patients had insomnia, it is easily manageable; besides, the high incidence of insomnia might also be due to the concomitant daily use of Dexamethasone. The potential impact of Palonosetron on GVHD has never been reported so far. It had been shown that 5-HT plays an important role in gut inflammation through activation of dendritic cell and subsequent activation of T cells [32] and 5HT-3 RA Tropisetron and Granisetron were shown to reduce 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255
inflammatory response and lipid peroxidation in the gut [33, 34] and other rheumatic diseases [35-38]. Palonosetron binds to the 5HT-3 receptor much more potent and exerts the inhibitory effect much longer than Tropisetron and Granisetron; however, we did not observe a lower incidence of GVHD or higher relapse rate by using Palonosetron. More studies are needed to explore the anti-inflammation and immune modulation effect of Palonosetron in the allogeneic transplantation.
There are some limitations in the interpretation the result of this study. Firstly, almost all the patient received Fludarabine-based conditioning chemotherapy and only 1 patient received traditional TBI (12Gy) plus Cyclophosphamide. The efficacy of Palonosetron in the prevention of nausea and vomiting after TBI-based conditioning may need further study. Secondly, while Palonosetron has an extended elimination half-life of around 40 hours and Palonosetron 0.25mg every 3 days was used in prior studies [23, 24], there were studies showing that Palonosetron 0.25mg daily for multiple days could be more effective in patients receiving high dose Cytarabine [22] or high dose Melphalan [25]. The most cost-effective dosing schedule of Palonosetron might be in between and so we used 0.25mg every other day in this study. Nevertheless, the best dosing schedule of Palonosetron for multi-day conditioning chemotherapy remains to be investigated. Finally, only Metaclopropamide or additional dose of Dexamethasone were allowed for salvage treatment. Aprepitant was not allowed in this study because it is a moderate inhibitor of 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274
CYP3A4 and may alter the metabolism of CYP3A4 substrate such as Cyclosporine [39, 40]. It is not known whether using Aprepitant during conditioning or using Palonosetron as salvage treatment will further improve the control rate.
Conclusion
Our study demonstrates Palonosetron combined with Dexamethasone is an effective and safe treatment for the prevention of vomiting caused by conditioning chemoradiotherapy. The transplant-related outcomes that were specifically concerned in the allogeneic setting such as TRM and GVHD were not negatively affected by Palonosetron. However, nausea is less effectively controlled. Furthermore, both vomiting and nausea in the first week after HSCT remain a significant medical problem and more effort should be made to address and improve this unmet need in future study.
Acknowledgement: The authors would like to thank all the nursing staff of BMT unit (5H ward) and Yu-Ting Ho (research coordinator of this study) for their great help in this study. This study was supported in part by the research grant from Department of Health of Taiwan (DOH102-TD-C-111-005) and China Medical University Hospital (DMR 98-008).
Authorship and Disclosures: SP Yeh, WC Lo, CY Hsieh designed the study, LY Bai, CC Lin, PH Lin, CY Lin, YM Liao contributed to clinical data collection, CF Chiu 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294
supervised the process of this study and reviewed the manuscript. All the authors have no relationships or conflict of interest to declare.
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Figure Legends
Figure 1: Incidence of grade 2/3 vomiting and nausea during period of conditioning (Early) and the first week after HSCT (Late). More patients had grade 2/3 vomiting and nausea in the first week after HSCT comparing to those during period of conditioning. Also, nausea was less effectively prevented comparing to vomiting.
Figure 2: Incidence of grade 2/3 vomiting and nausea in the first week after HSCT. The incidence of grade 2/3 vomiting decreased gradually to less than 20% after Day 3. However, the incidence of grade 2/3 nausea remained higher than 30% through Day 0 to Day 6.
Figure 3: Severity of nausea assessed by CTCAE version 4.0 and MAT. Figure 3A (Left figure): the grade of nausea assessed by CTCAE correlates well with the 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466
score of nausea assessed by MAT. Figure 3B (Right figure): the difference in the intensity of nausea between period of conditioning (early) and the first week after HSCT (late) was significant only by using MAT scoring system but not CTCAE grading system, suggesting MAT scoring system has a higher discriminant power than CTCAE grading system
Figure 4: Incidence of potential adverse effects of Palonosetron. Insomnia is the most common adverse effect during period of conditioning, the incidences of other adverse effects were low and there was no grade 3/4 adverse effect observed in this study. 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487
Supplementary Figure Legends
Incidence of any vomiting during conditioning and the first week after HSCT. The use of first generation 5-HT3 RA is associated with significant higher incidence of any vomiting (grade 1-3) both during conditioning (91.7% vs 63.0%, p=0.017) and the first week after transplantation (91.7% vs 66.7%, p=0.032). 488 489 490 491 492 493 494 495 496 497 498 499
