Int J Hematol (2014) 99:457–462 DOI 10.1007/s12185-014-1538-6
ORIGINAL ARTICLE
Efficacy of aprepitant in preventing nausea and vomiting due to high-dose melphalan-based conditioning for allogeneic hematopoietic stem cell transplantation Masatoshi Sakurai • Takehiko Mori • Jun Kato • Yuya Koda • Taku Kikuchi • Sumiko Kohashi • Masuho Saburi • Takaaki Toyama • Yoshinobu Aisa • Tomonori Nakazato Noriko Beppu • Soichiro Tsuda • Naoyuki Shigematsu • Shinichiro Okamoto
•
Received: 17 January 2014 / Revised: 10 February 2014 / Accepted: 12 February 2014 / Published online: 12 March 2014 Ó The Japanese Society of Hematology 2014
Abstract High-dose melphalan has been gaining recognition as a highly emetogenic agent used in hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to elucidate the efficacy of aprepitant in preventing high-dose melphalan-induced emesis. Sixty patients who received melphalan (70 mg/m2/day, 2 days) and fludarabine (125 mg/m2/day, 5 days) as conditioning for allogeneic HSCT for hematological malignancies, and who received ondansetron and methylprednisolone as an antiemetic prophylaxis, were eligible. Twenty of these 60 patients also received aprepitant for 5 days (aprepitant group); the remaining 40 patients served as a control. The rates of complete response (CR), defined as no emesis without rescue medications, and complete protection (CP), defined as no emesis with or without rescue medications, were assessed between the two groups. The observation period was 12 days from the first day of melphalan administration. The CR and CP rates were significantly M. Sakurai T. Mori (&) J. Kato Y. Koda T. Kikuchi S. Kohashi M. Saburi T. Toyama Y. Aisa T. Nakazato S. Okamoto Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: [email protected] Y. Aisa T. Nakazato Department of Hematology, Yokohama Municipal Citizen’s Hospital, Kanagawa, Japan N. Beppu S. Tsuda Department of Hospital Pharmacy, Keio University Hospital, Tokyo, Japan N. Shigematsu Department of Radiology, Keio University School of Medicine, Tokyo, Japan
higher in the aprepitant group than in the control group during the observation period (35 % versus 10 %, P \ 0.05; 85 % versus 33 %, P \ 0.001; respectively). These results suggest that aprepitant in combination with ondansetron and steroid effectively ameliorates nausea and vomiting caused by the high-dose melphalan-based conditioning for allogeneic HSCT. Keywords High-dose melphalan Aprepitant Allogeneic hematopoietic stem cell transplantation Nausea
Background High-dose melphalan has been widely used, alone or in combination with other anticancer agents, as a component of conditioning for hematopoietic stem cell transplantation (HSCT) [1, 2]. Although melphalan is categorized as an agent with a moderate emetic risk, its emetogenicity at high doses has not been fully assessed [3]. Although a recent guideline for pediatric cancer patients categorized melphalan ([50 mg/m2) as a moderate risk agent, the major current guidelines for chemotherapy-induced nausea and vomiting (CINV) do not even add melphalan in the list of emetogenic anticancer agents [4–6]. However, high-dose melphalan is known to have the potential to cause moderate to severe emesis in the early phase [1, 7]. Based on these findings, a combination regimen of 5-hydroxytryptamine-3 receptor antagonist (5-HTRA) with steroid is currently recommended for the prevention of high-dose melphalaninduced nausea/vomiting [5]. However, the efficacy of 5-HTRA-based regimens for this purpose is not satisfactory [8, 9]. In addition, the delayed emesis due to high-dose melphalan is being more
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recognized [1, 9]. Despite this, only limited attempts have been made to evaluate the efficacy of the addition of aprepitant to 5-HTRA-based regimens in preventing nausea and vomiting caused by conditioning for HSCT including high-dose melphalan [10–12]. Although the outcome seemed favorable, the major conditioning regimens evaluated in these studies were multi-agent combination regimens such as BEAM (BCNU, etoposide, cytarabine, and melphalan). The efficacy of adding aprepitant to the 5-HTRA-based regimens to prevent CINV due to highdose melphalan alone has been evaluated in only one noncomparative study [12]. Therefore, we have conducted a retrospective comparative study to evaluate the efficacy of adding aprepitant to prevent high-dose melphalaninduced nausea and vomiting.
Patients and methods Study design This retrospective single-center analysis was designed to evaluate the efficacy of aprepitant for the prevention of CINV due to high-dose melphalan given as part of conditioning for allogeneic HSCT. Aprepitant was added to the clinical practice at Keio University Hospital (Tokyo, Japan) for the prevention of CINV due to high-dose melphalan in January 2010 (the aprepitant group). Patients treated from March 2003 until December 2009 served as historical control (the control group). Patients and treatments Patients who received conditioning with fludarabine (25 mg/m2/day; 5 days, days -6 to -2) and high-dose melphalan (70 mg/m2/day; 2 days, days -3 and -2) for allogeneic HSCT from March 2003 to October 2012 were enrolled in the analysis. Patients receiving low-dose total body irradiation (TBI; 2–4 Gy) to prevent graft rejection were also included, while those who received TBI [4 Gy were excluded to minimize the effects of TBI on nausea and vomiting. The data including patient characteristics, laboratory data, and records on nausea and vomiting were collected from the institutional database and medical records. Data on nausea and vomiting recorded daily by physicians and nurses were also collected from the medical records. The patients universally received an antiemetic regimen consisting of intravenous ondansetron at a dose of 4 mg every 12 h and intravenous methylprednisolone at a dose of 62.5 mg every 12 h during the 2 days of melphalan administration. In the aprepitant group, patients additionally received aprepitant orally starting 1 day after the second
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dose of melphalan for 5 days. The doses of aprepitant were 125 mg/day on the first day and 80 mg/day on the following 4 days. Rescue medications, such as metoclopramide and chlorpromazine, were given for the treatment of nausea and vomiting at the discretion of each physician. For the prophylaxis of graft-versus-host disease (GVHD), patients basically received short-term methotrexate (15 mg/m2 on day 1, and 10 mg/m2 on days 3, 6, and 11) and cyclosporine A (CsA) or tacrolimus. CsA (3 mg/kg/day) or tacrolimus (0.03 mg/kg/day) was given by continuous infusion starting on day -1. In cases of allogeneic HSCT from HLA-identical siblings and CB donors, the methotrexate on day 11 was omitted. Definitions The primary end point of this study was to compare the incidence of vomiting after conditioning between the control and aprepitant groups. A complete response (CR) was defined as no emesis and no use of rescue medications. Complete protection (CP) was defined as no emesis with or without the addition of rescue antiemetics [9]. The observation phases were defined as follows: overall, from the first day of melphalan administration through 10 days after the last dose of melphalan (12 days); early, from the first day of melphalan administration through 24 h after the last dose of melphalan (3 days); delayed, later than 24 h after the last dose of melphalan through 10 days after the last dose of melphalan (9 days). The number of ‘‘days without any food’’ was defined as the duration for which patients were unable to eat anything due to nausea/vomiting. Adverse events were assessed and graded according to Common Terminology Criteria for Adverse Events v4.0. Statistical analysis The differences between the two groups were compared using Fisher’s exact test or Mann–Whitney’s U test as appropriate. P values \0.05 were considered to be statistically significant.
Results Patients A total of 60 patients were included in the analysis. Forty patients served as the control group and 20 as the aprepitant group. Patient characteristics are shown in Table 1. No significant differences were observed in any of the variables between the two groups. The commonest diagnoses in both groups were malignant lymphoma and multiple myeloma.
Aprepitant for melphalan-induced emesis
459
Table 1 Patient characteristics Aprepitant group (n = 20)
Control group (n = 40)
52 (25–66)
47 (29–60)
10/10
21/19
8
12
Median age Years (range)
0.161
Gender Male/female
1.000
Diagnosis Multiple myeloma
0.173
Malignant lymphoma
8
25
Acute lymphoblastic leukemia
3
1
Myeloproliferative neoplasm
1
1
Myelodysplastic syndrome
0
1
Additional TBI (2–4 Gy) Yes
P values
1.000 5
9
Stem cell sources and types of donor
0.385
BM/PBSC from HLA-identical sibling
1/0
6/2
BM from HLA-matched unrelated donor
13
25
BM from HLA-mismatched unrelated donor
4
5
CB from HLA-mismatched unrelated donor
2
2
TBI was delivered in 5 of 20 patients in the aprepitant group and in 9 of 40 patients in the control group. To exclude the effect of TBI, the same analyses were performed in patients who did not receive TBI (15 in the aprepitant group and 31 in the control group). Similarly, the CR and CP rates were significantly higher in the aprepitant group than in the control during the overall phase (40 versus 10 %, P \ 0.05 and 87 versus 29 %, P \ 0.001, respectively) and the delayed phase (40 versus 10 %, P \ 0.05 and 87 versus 29 %, P \ 0.001, respectively), but not during the early phase (60 versus 52 %, P = 0.754; 93 versus 97 %, P = 1.000, respectively). In addition, the duration of the inability to take any food was also significantly shorter in the aprepitant group than in the control group during the overall phase (6.0 ± 4.9 versus 2.5 ± 4.3 days, P \ 0.01). Adverse events Adverse events, including oral mucositis, malaise, fever, insomnia, and liver or renal dysfunction, were evaluated during the overall observation period. There were no statistical differences in the incidences of grade 2 or greater adverse events between the two groups (Table 2).
Discussion
GVHD prophylaxis
0.471
Cyclosporine plus methotrexate
2
8
Tacrolimus plus methotrexate
18
32
TBI total body irradiation, BM bone marrow, PBSC peripheral blood stem cell, CB cord blood, HLA human leukocyte antigen
Comparison of antiemetic efficacy between the two groups The CR rate was significantly higher in the aprepitant group than in the control during the overall phase (35 versus 10 %, P \ 0.05; Fig. 1). The difference was more remarkable during the delayed phase (35 versus 10 %, P \ 0.05), but was not significant during the early phase (50 versus 45 %, P = 0.787; Fig. 1a). The CP rate was significantly higher in the aprepitant group than in the control during the overall phase (85 versus 33 %, P \ 0.001; Fig. 1b). Similar to the case with the CR rate, the difference was significant during the delayed phase (90 versus 33 %, P \ 0.001), but was not significant during the early phase (90 versus 95 %, P = 0.595; Fig. 1b). The duration of inability to take any food was significantly shorter in the aprepitant group than in the control group during the overall phase (6.0 ± 5.0 versus 2.9 ± 4.2 days, P \ 0.01, Fig. 2).
The results of the present study demonstrated that the addition of aprepitant to 5-HTRA and steroid significantly alleviated CINV caused by high-dose melphalan-based conditioning as compared to 5-HTRA and steroid; that is, aprepitant increased the CR and CP rates by 25 % and over 50 %, respectively. In particular, it was notable that the CP (no emesis with or without the addition of rescue antiemetics) rate was over 80 % in patients receiving aprepitant in addition to 5-HTRA and steroid, whereas it was only 30 % in the control group. Owing to this efficacy, the duration of the inability to take any food was significantly shortened by adding aprepitant, suggesting that an aprepitant-containing regimen could improve the quality of life of patients who receive high-dose melphalan [13]. Since identical basic regimen, consisting of the same dosage of 5-HTRA and steroid, was used in both groups, the efficacy could be inferred to reflect the net efficacy of aprepitant. CINV remains one of the most distressing side effects for patients undergoing chemotherapy. Especially in the setting of HSCT, the majority of the patients receive highdose chemotherapy as conditioning, which is considered highly emetogenic [14]. In contrast to cyclophosphamide, cytarabine, and busulfan, the emetic risk of high-dose melphalan has not been sufficiently studied and evaluated [1, 6, 7, 14–17]. The results of the previous studies and the
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Proportion of complete response
(%) 100 80 60
*
*
40 20 0 Overall phase
Early phase
(%) 100
*
**
**
80 60 40 20 0
Overall phase
Delayed phase
Fig. 1 Comparison of prophylactic efficacy for high-dose melphalaninduced emesis. All patients received ondansetron and methylprednisolone, and the patients in the aprepitant group received aprepitant orally for 5 days. The observation phases were defined as follows: overall, from the first day of melphalan administration through 10 days after the last dose of melphalan (12 days); early, from the first day of melphalan administration through 24 h after the last dose of melphalan (3 days); delayed, later than 24 h after the last dose of melphalan through 10 days after the last dose of melphalan (9 days).
(days)
Control group (n=20) Aprepitant group (n=40)
(b) Proportion of complete protection
Control group (n=40) Aprepitant group (n=20)
(a)
Early phase
Delayed phase
a The proportion of complete response (no emesis and no use of rescue medications) was significantly higher in the aprepitant group than in the control during the overall and delayed phases (*P \ 0.05), but not during the early phase. b The rate of complete protection (no emesis with or without the addition of rescue antiemetics) was significantly higher in the aprepitant group than in the control during the overall and delayed phases (**P \ 0.001), but not during the early phase
Table 2 Adverse events of grade 2 or greater Aprepitant group (n = 20)
12 10 8
17 (85 %)
30 (75 %)
0.513
Malaise
16 (80 %)
35 (88 %)
0.464
Insomnia
10 (50 %)
19 (48 %)
1.000
3 (15 %)
10 (25 %)
0.513
20 (100 %)
33 (83 %)
0.084
Diarrhea
4
P values
Oral mucositis
Abdominal pain 6
Control group (n = 40)
Hepatic dysfunction
1 (5 %)
3 (8 %)
1.000
Renal dysfunction
1 (5 %)
3 (8 %)
1.000
Graded according to Common Terminology Criteria for Adverse Events v4.0
2 0 Control group (n=40)
Aprepitant group (n=20)
Fig. 2 Comparison of number of days of inability to take any food. The duration of the inability to take any food was significantly shorter in the aprepitant group than in the control (*P \ 0.01)
notably low CR and CP rates (10 and 33 %, respectively) of the control group in the present study indicated the high emetogenic potential of high-dose melphalan even under prophylaxis with 5-HTRA and steroid [7–9]. Thus, such unsatisfactory outcomes of the antiemetic management for CINV due to high-dose melphalan with the standard prophylactic regimen consisting of 5-HTRA and steroid prompted us to search for a more effective prophylactic regimen using aprepitant. Only a few studies have evaluated the efficacy of aprepitant in preventing nausea and vomiting caused by
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high-dose melphalan [10–12]. Those studies all drew similar conclusions supporting the potential of aprepitant for preventing high-dose melphalan-induced nausea and vomiting. However, those studies had several limitations that should be taken into account. The most important limitation was that the majority of the conditioning regimens evaluated in those studies included BEAM chemotherapy consisting of emetogenic agents other than melphalan, which made it difficult to evaluate the net efficacy for high-dose melphalan-induced nausea and vomiting [10, 11]. In one study, a third of the patients received high-dose melphalan and the efficacy of adding aprepitant to 5-HTRA and steroid was evaluated, but not in a comparative manner [12]. In the present study, all patients received fludarabine in addition to high-dose melphalan; however, fludarabine is categorized as an agent
Aprepitant for melphalan-induced emesis
with minimal to low emetic risk, and indeed in the present study no patients experienced nausea or vomiting during the 3-day therapy with fludarabine alone before starting melphalan without any antiemetic prophylaxis (data not shown). Therefore, we believe fludarabine’s effect is negligible in the evaluation of CINV during conditioning consisting of fludarabine and high-dose melphalan. Therefore, to the best of our knowledge, the present study is the first to clearly demonstrate the net efficacy of aprepitant in preventing nausea and vomiting in patients receiving high-dose melphalan. Under prophylaxis with 5-HTRA and steroid in the present study, the CR and CP rates were over 45 and 90 %, respectively, in the early phase regardless of whether aprepitant was added. Therefore, the notable difference in CR and CP rates observed during the overall phase between the aprepitant and control groups reflected the difference in the delayed phase, but not that in the early phase. This finding demonstrated the potential of high-dose melphalan for inducing delayed emesis, which was consistent with the results of the previous studies [1, 9, 11]. Although delayed emesis was initially described in patients receiving cisplatin, its association with other agents has also been reported [18]. In patients receiving highly emetogenic cisplatin-based chemotherapy, the addition of aprepitant (a neurokinin-1 receptor antagonist) to 5-HTRA and steroid significantly alleviated both early and delayed emesis [19–22]. These findings suggest that aprepitant could be a promising drug with the potential to improve the control of delayed emesis caused by cisplatin [18]. To the best of our knowledge, the present study is the first to focus on the effects of aprepitant on the delayed emesis caused by high-dose melphalan. Although the dose was low (2–4 Gy), the use of TBI could have affected the outcome of CINV in the present study [23]. Therefore, a subpopulation analysis was performed by excluding patients who received TBI. The results were similar to those observed in all patients. This suggests that aprepitant could alleviate CINV due to high-dose melphalan regardless of the additional TBI, consistent with the previous report [24]. The lack of effects of TBI on CINV could be explained by the low dose applied in this study. In the present study, aprepitant was well tolerated and was not associated with any specific adverse events, consistent with the previous results [10–12, 19–22]. Although aprepitant has been reported to have a favorable safety profile, it was assessed mainly in standard-dose chemotherapy, but not fully evaluated in high-dose chemotherapy. Therefore, future studies should systematically evaluate its safety in the setting of high-dose chemotherapy. In addition, physicians should be aware of the potency of its interactions with various agents, such as steroids and chemotherapeutic agents [25–27]. Since one study demonstrated that
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aprepitant did not affect the pharmacokinetics of melphalan [28], aprepitant was initiated 1 day after the last dose of melphalan in the present study to avoid the possible interaction between melphalan and aprepitant. Although aprepitant was shown in the present study to be safely administered in patients receiving high-dose melphalan, the schedule of aprepitant administration should be carefully determined to avoid causing unexpected adverse events through drug interaction. The limitations of this study are the small number of subjects evaluated and its retrospective nature. However, the doses and schedules of both antiemetic agents and chemotherapy in the present study were completely identical between the study group and the control group except for aprepitant. Therefore, despite the retrospective nature of the study, the results obtained could have accounted for a clinically meaningful effect of aprepitant on CINV caused by high-dose melphalan. Large-scale studies should be performed in a randomized fashion to further evaluate the role of aprepitant in this setting. Acknowledgments The authors are indebted to Yuri Niizuma for her skillful data management of the patients and Satomi Yamanaka for her skillful patient care. Conflict of interest SO received research funding from GlaxoSmithKline Inc.
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ORIGINAL ARTICLE
Efficacy of aprepitant in preventing nausea and vomiting due to high-dose melphalan-based conditioning for allogeneic hematopoietic stem cell transplantation Masatoshi Sakurai • Takehiko Mori • Jun Kato • Yuya Koda • Taku Kikuchi • Sumiko Kohashi • Masuho Saburi • Takaaki Toyama • Yoshinobu Aisa • Tomonori Nakazato Noriko Beppu • Soichiro Tsuda • Naoyuki Shigematsu • Shinichiro Okamoto
•
Received: 17 January 2014 / Revised: 10 February 2014 / Accepted: 12 February 2014 / Published online: 12 March 2014 Ó The Japanese Society of Hematology 2014
Abstract High-dose melphalan has been gaining recognition as a highly emetogenic agent used in hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to elucidate the efficacy of aprepitant in preventing high-dose melphalan-induced emesis. Sixty patients who received melphalan (70 mg/m2/day, 2 days) and fludarabine (125 mg/m2/day, 5 days) as conditioning for allogeneic HSCT for hematological malignancies, and who received ondansetron and methylprednisolone as an antiemetic prophylaxis, were eligible. Twenty of these 60 patients also received aprepitant for 5 days (aprepitant group); the remaining 40 patients served as a control. The rates of complete response (CR), defined as no emesis without rescue medications, and complete protection (CP), defined as no emesis with or without rescue medications, were assessed between the two groups. The observation period was 12 days from the first day of melphalan administration. The CR and CP rates were significantly M. Sakurai T. Mori (&) J. Kato Y. Koda T. Kikuchi S. Kohashi M. Saburi T. Toyama Y. Aisa T. Nakazato S. Okamoto Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: [email protected] Y. Aisa T. Nakazato Department of Hematology, Yokohama Municipal Citizen’s Hospital, Kanagawa, Japan N. Beppu S. Tsuda Department of Hospital Pharmacy, Keio University Hospital, Tokyo, Japan N. Shigematsu Department of Radiology, Keio University School of Medicine, Tokyo, Japan
higher in the aprepitant group than in the control group during the observation period (35 % versus 10 %, P \ 0.05; 85 % versus 33 %, P \ 0.001; respectively). These results suggest that aprepitant in combination with ondansetron and steroid effectively ameliorates nausea and vomiting caused by the high-dose melphalan-based conditioning for allogeneic HSCT. Keywords High-dose melphalan Aprepitant Allogeneic hematopoietic stem cell transplantation Nausea
Background High-dose melphalan has been widely used, alone or in combination with other anticancer agents, as a component of conditioning for hematopoietic stem cell transplantation (HSCT) [1, 2]. Although melphalan is categorized as an agent with a moderate emetic risk, its emetogenicity at high doses has not been fully assessed [3]. Although a recent guideline for pediatric cancer patients categorized melphalan ([50 mg/m2) as a moderate risk agent, the major current guidelines for chemotherapy-induced nausea and vomiting (CINV) do not even add melphalan in the list of emetogenic anticancer agents [4–6]. However, high-dose melphalan is known to have the potential to cause moderate to severe emesis in the early phase [1, 7]. Based on these findings, a combination regimen of 5-hydroxytryptamine-3 receptor antagonist (5-HTRA) with steroid is currently recommended for the prevention of high-dose melphalaninduced nausea/vomiting [5]. However, the efficacy of 5-HTRA-based regimens for this purpose is not satisfactory [8, 9]. In addition, the delayed emesis due to high-dose melphalan is being more
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recognized [1, 9]. Despite this, only limited attempts have been made to evaluate the efficacy of the addition of aprepitant to 5-HTRA-based regimens in preventing nausea and vomiting caused by conditioning for HSCT including high-dose melphalan [10–12]. Although the outcome seemed favorable, the major conditioning regimens evaluated in these studies were multi-agent combination regimens such as BEAM (BCNU, etoposide, cytarabine, and melphalan). The efficacy of adding aprepitant to the 5-HTRA-based regimens to prevent CINV due to highdose melphalan alone has been evaluated in only one noncomparative study [12]. Therefore, we have conducted a retrospective comparative study to evaluate the efficacy of adding aprepitant to prevent high-dose melphalaninduced nausea and vomiting.
Patients and methods Study design This retrospective single-center analysis was designed to evaluate the efficacy of aprepitant for the prevention of CINV due to high-dose melphalan given as part of conditioning for allogeneic HSCT. Aprepitant was added to the clinical practice at Keio University Hospital (Tokyo, Japan) for the prevention of CINV due to high-dose melphalan in January 2010 (the aprepitant group). Patients treated from March 2003 until December 2009 served as historical control (the control group). Patients and treatments Patients who received conditioning with fludarabine (25 mg/m2/day; 5 days, days -6 to -2) and high-dose melphalan (70 mg/m2/day; 2 days, days -3 and -2) for allogeneic HSCT from March 2003 to October 2012 were enrolled in the analysis. Patients receiving low-dose total body irradiation (TBI; 2–4 Gy) to prevent graft rejection were also included, while those who received TBI [4 Gy were excluded to minimize the effects of TBI on nausea and vomiting. The data including patient characteristics, laboratory data, and records on nausea and vomiting were collected from the institutional database and medical records. Data on nausea and vomiting recorded daily by physicians and nurses were also collected from the medical records. The patients universally received an antiemetic regimen consisting of intravenous ondansetron at a dose of 4 mg every 12 h and intravenous methylprednisolone at a dose of 62.5 mg every 12 h during the 2 days of melphalan administration. In the aprepitant group, patients additionally received aprepitant orally starting 1 day after the second
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dose of melphalan for 5 days. The doses of aprepitant were 125 mg/day on the first day and 80 mg/day on the following 4 days. Rescue medications, such as metoclopramide and chlorpromazine, were given for the treatment of nausea and vomiting at the discretion of each physician. For the prophylaxis of graft-versus-host disease (GVHD), patients basically received short-term methotrexate (15 mg/m2 on day 1, and 10 mg/m2 on days 3, 6, and 11) and cyclosporine A (CsA) or tacrolimus. CsA (3 mg/kg/day) or tacrolimus (0.03 mg/kg/day) was given by continuous infusion starting on day -1. In cases of allogeneic HSCT from HLA-identical siblings and CB donors, the methotrexate on day 11 was omitted. Definitions The primary end point of this study was to compare the incidence of vomiting after conditioning between the control and aprepitant groups. A complete response (CR) was defined as no emesis and no use of rescue medications. Complete protection (CP) was defined as no emesis with or without the addition of rescue antiemetics [9]. The observation phases were defined as follows: overall, from the first day of melphalan administration through 10 days after the last dose of melphalan (12 days); early, from the first day of melphalan administration through 24 h after the last dose of melphalan (3 days); delayed, later than 24 h after the last dose of melphalan through 10 days after the last dose of melphalan (9 days). The number of ‘‘days without any food’’ was defined as the duration for which patients were unable to eat anything due to nausea/vomiting. Adverse events were assessed and graded according to Common Terminology Criteria for Adverse Events v4.0. Statistical analysis The differences between the two groups were compared using Fisher’s exact test or Mann–Whitney’s U test as appropriate. P values \0.05 were considered to be statistically significant.
Results Patients A total of 60 patients were included in the analysis. Forty patients served as the control group and 20 as the aprepitant group. Patient characteristics are shown in Table 1. No significant differences were observed in any of the variables between the two groups. The commonest diagnoses in both groups were malignant lymphoma and multiple myeloma.
Aprepitant for melphalan-induced emesis
459
Table 1 Patient characteristics Aprepitant group (n = 20)
Control group (n = 40)
52 (25–66)
47 (29–60)
10/10
21/19
8
12
Median age Years (range)
0.161
Gender Male/female
1.000
Diagnosis Multiple myeloma
0.173
Malignant lymphoma
8
25
Acute lymphoblastic leukemia
3
1
Myeloproliferative neoplasm
1
1
Myelodysplastic syndrome
0
1
Additional TBI (2–4 Gy) Yes
P values
1.000 5
9
Stem cell sources and types of donor
0.385
BM/PBSC from HLA-identical sibling
1/0
6/2
BM from HLA-matched unrelated donor
13
25
BM from HLA-mismatched unrelated donor
4
5
CB from HLA-mismatched unrelated donor
2
2
TBI was delivered in 5 of 20 patients in the aprepitant group and in 9 of 40 patients in the control group. To exclude the effect of TBI, the same analyses were performed in patients who did not receive TBI (15 in the aprepitant group and 31 in the control group). Similarly, the CR and CP rates were significantly higher in the aprepitant group than in the control during the overall phase (40 versus 10 %, P \ 0.05 and 87 versus 29 %, P \ 0.001, respectively) and the delayed phase (40 versus 10 %, P \ 0.05 and 87 versus 29 %, P \ 0.001, respectively), but not during the early phase (60 versus 52 %, P = 0.754; 93 versus 97 %, P = 1.000, respectively). In addition, the duration of the inability to take any food was also significantly shorter in the aprepitant group than in the control group during the overall phase (6.0 ± 4.9 versus 2.5 ± 4.3 days, P \ 0.01). Adverse events Adverse events, including oral mucositis, malaise, fever, insomnia, and liver or renal dysfunction, were evaluated during the overall observation period. There were no statistical differences in the incidences of grade 2 or greater adverse events between the two groups (Table 2).
Discussion
GVHD prophylaxis
0.471
Cyclosporine plus methotrexate
2
8
Tacrolimus plus methotrexate
18
32
TBI total body irradiation, BM bone marrow, PBSC peripheral blood stem cell, CB cord blood, HLA human leukocyte antigen
Comparison of antiemetic efficacy between the two groups The CR rate was significantly higher in the aprepitant group than in the control during the overall phase (35 versus 10 %, P \ 0.05; Fig. 1). The difference was more remarkable during the delayed phase (35 versus 10 %, P \ 0.05), but was not significant during the early phase (50 versus 45 %, P = 0.787; Fig. 1a). The CP rate was significantly higher in the aprepitant group than in the control during the overall phase (85 versus 33 %, P \ 0.001; Fig. 1b). Similar to the case with the CR rate, the difference was significant during the delayed phase (90 versus 33 %, P \ 0.001), but was not significant during the early phase (90 versus 95 %, P = 0.595; Fig. 1b). The duration of inability to take any food was significantly shorter in the aprepitant group than in the control group during the overall phase (6.0 ± 5.0 versus 2.9 ± 4.2 days, P \ 0.01, Fig. 2).
The results of the present study demonstrated that the addition of aprepitant to 5-HTRA and steroid significantly alleviated CINV caused by high-dose melphalan-based conditioning as compared to 5-HTRA and steroid; that is, aprepitant increased the CR and CP rates by 25 % and over 50 %, respectively. In particular, it was notable that the CP (no emesis with or without the addition of rescue antiemetics) rate was over 80 % in patients receiving aprepitant in addition to 5-HTRA and steroid, whereas it was only 30 % in the control group. Owing to this efficacy, the duration of the inability to take any food was significantly shortened by adding aprepitant, suggesting that an aprepitant-containing regimen could improve the quality of life of patients who receive high-dose melphalan [13]. Since identical basic regimen, consisting of the same dosage of 5-HTRA and steroid, was used in both groups, the efficacy could be inferred to reflect the net efficacy of aprepitant. CINV remains one of the most distressing side effects for patients undergoing chemotherapy. Especially in the setting of HSCT, the majority of the patients receive highdose chemotherapy as conditioning, which is considered highly emetogenic [14]. In contrast to cyclophosphamide, cytarabine, and busulfan, the emetic risk of high-dose melphalan has not been sufficiently studied and evaluated [1, 6, 7, 14–17]. The results of the previous studies and the
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Proportion of complete response
(%) 100 80 60
*
*
40 20 0 Overall phase
Early phase
(%) 100
*
**
**
80 60 40 20 0
Overall phase
Delayed phase
Fig. 1 Comparison of prophylactic efficacy for high-dose melphalaninduced emesis. All patients received ondansetron and methylprednisolone, and the patients in the aprepitant group received aprepitant orally for 5 days. The observation phases were defined as follows: overall, from the first day of melphalan administration through 10 days after the last dose of melphalan (12 days); early, from the first day of melphalan administration through 24 h after the last dose of melphalan (3 days); delayed, later than 24 h after the last dose of melphalan through 10 days after the last dose of melphalan (9 days).
(days)
Control group (n=20) Aprepitant group (n=40)
(b) Proportion of complete protection
Control group (n=40) Aprepitant group (n=20)
(a)
Early phase
Delayed phase
a The proportion of complete response (no emesis and no use of rescue medications) was significantly higher in the aprepitant group than in the control during the overall and delayed phases (*P \ 0.05), but not during the early phase. b The rate of complete protection (no emesis with or without the addition of rescue antiemetics) was significantly higher in the aprepitant group than in the control during the overall and delayed phases (**P \ 0.001), but not during the early phase
Table 2 Adverse events of grade 2 or greater Aprepitant group (n = 20)
12 10 8
17 (85 %)
30 (75 %)
0.513
Malaise
16 (80 %)
35 (88 %)
0.464
Insomnia
10 (50 %)
19 (48 %)
1.000
3 (15 %)
10 (25 %)
0.513
20 (100 %)
33 (83 %)
0.084
Diarrhea
4
P values
Oral mucositis
Abdominal pain 6
Control group (n = 40)
Hepatic dysfunction
1 (5 %)
3 (8 %)
1.000
Renal dysfunction
1 (5 %)
3 (8 %)
1.000
Graded according to Common Terminology Criteria for Adverse Events v4.0
2 0 Control group (n=40)
Aprepitant group (n=20)
Fig. 2 Comparison of number of days of inability to take any food. The duration of the inability to take any food was significantly shorter in the aprepitant group than in the control (*P \ 0.01)
notably low CR and CP rates (10 and 33 %, respectively) of the control group in the present study indicated the high emetogenic potential of high-dose melphalan even under prophylaxis with 5-HTRA and steroid [7–9]. Thus, such unsatisfactory outcomes of the antiemetic management for CINV due to high-dose melphalan with the standard prophylactic regimen consisting of 5-HTRA and steroid prompted us to search for a more effective prophylactic regimen using aprepitant. Only a few studies have evaluated the efficacy of aprepitant in preventing nausea and vomiting caused by
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high-dose melphalan [10–12]. Those studies all drew similar conclusions supporting the potential of aprepitant for preventing high-dose melphalan-induced nausea and vomiting. However, those studies had several limitations that should be taken into account. The most important limitation was that the majority of the conditioning regimens evaluated in those studies included BEAM chemotherapy consisting of emetogenic agents other than melphalan, which made it difficult to evaluate the net efficacy for high-dose melphalan-induced nausea and vomiting [10, 11]. In one study, a third of the patients received high-dose melphalan and the efficacy of adding aprepitant to 5-HTRA and steroid was evaluated, but not in a comparative manner [12]. In the present study, all patients received fludarabine in addition to high-dose melphalan; however, fludarabine is categorized as an agent
Aprepitant for melphalan-induced emesis
with minimal to low emetic risk, and indeed in the present study no patients experienced nausea or vomiting during the 3-day therapy with fludarabine alone before starting melphalan without any antiemetic prophylaxis (data not shown). Therefore, we believe fludarabine’s effect is negligible in the evaluation of CINV during conditioning consisting of fludarabine and high-dose melphalan. Therefore, to the best of our knowledge, the present study is the first to clearly demonstrate the net efficacy of aprepitant in preventing nausea and vomiting in patients receiving high-dose melphalan. Under prophylaxis with 5-HTRA and steroid in the present study, the CR and CP rates were over 45 and 90 %, respectively, in the early phase regardless of whether aprepitant was added. Therefore, the notable difference in CR and CP rates observed during the overall phase between the aprepitant and control groups reflected the difference in the delayed phase, but not that in the early phase. This finding demonstrated the potential of high-dose melphalan for inducing delayed emesis, which was consistent with the results of the previous studies [1, 9, 11]. Although delayed emesis was initially described in patients receiving cisplatin, its association with other agents has also been reported [18]. In patients receiving highly emetogenic cisplatin-based chemotherapy, the addition of aprepitant (a neurokinin-1 receptor antagonist) to 5-HTRA and steroid significantly alleviated both early and delayed emesis [19–22]. These findings suggest that aprepitant could be a promising drug with the potential to improve the control of delayed emesis caused by cisplatin [18]. To the best of our knowledge, the present study is the first to focus on the effects of aprepitant on the delayed emesis caused by high-dose melphalan. Although the dose was low (2–4 Gy), the use of TBI could have affected the outcome of CINV in the present study [23]. Therefore, a subpopulation analysis was performed by excluding patients who received TBI. The results were similar to those observed in all patients. This suggests that aprepitant could alleviate CINV due to high-dose melphalan regardless of the additional TBI, consistent with the previous report [24]. The lack of effects of TBI on CINV could be explained by the low dose applied in this study. In the present study, aprepitant was well tolerated and was not associated with any specific adverse events, consistent with the previous results [10–12, 19–22]. Although aprepitant has been reported to have a favorable safety profile, it was assessed mainly in standard-dose chemotherapy, but not fully evaluated in high-dose chemotherapy. Therefore, future studies should systematically evaluate its safety in the setting of high-dose chemotherapy. In addition, physicians should be aware of the potency of its interactions with various agents, such as steroids and chemotherapeutic agents [25–27]. Since one study demonstrated that
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aprepitant did not affect the pharmacokinetics of melphalan [28], aprepitant was initiated 1 day after the last dose of melphalan in the present study to avoid the possible interaction between melphalan and aprepitant. Although aprepitant was shown in the present study to be safely administered in patients receiving high-dose melphalan, the schedule of aprepitant administration should be carefully determined to avoid causing unexpected adverse events through drug interaction. The limitations of this study are the small number of subjects evaluated and its retrospective nature. However, the doses and schedules of both antiemetic agents and chemotherapy in the present study were completely identical between the study group and the control group except for aprepitant. Therefore, despite the retrospective nature of the study, the results obtained could have accounted for a clinically meaningful effect of aprepitant on CINV caused by high-dose melphalan. Large-scale studies should be performed in a randomized fashion to further evaluate the role of aprepitant in this setting. Acknowledgments The authors are indebted to Yuri Niizuma for her skillful data management of the patients and Satomi Yamanaka for her skillful patient care. Conflict of interest SO received research funding from GlaxoSmithKline Inc.
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