Vol. 139, No. 4 YAKUGAKU ZASSHI 139,629633 (2019) 629
―Regular Article― Comparison of Pegˆlgrastim and Filgrastim for the Primary Prophylactic EŠect for Preventing Febrile Neutropenia in Patients Undergoing Rituximab with Dose-adjusted EPOCH Chemotherapy
Tatsuo Kataoka,Hiroshi Sakurashita, Takanori Taogoshi, Ryo Nishigakiuchi, Tetsuya Murase, Satoru Izumitani, Yasuyuki Saeki, and Hiroaki Matsuo
Department of Pharmacy, Hiroshima University Hospital; 123 Kasumi, Minami-ku, Hiroshima 7348551, Japan.
(Received May 14, 2018; Accepted December 12, 2018)
The combination of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin with rituximab (DA-EPOCH-R) is used for non-Hodgkin lymphoma patients. Febrile neutropenia (FN) is a common com- plication of treatment with myelo-suppressive chemotherapy, so preventing FN is important for maintaining chemother- apy dosage. Recently, pegˆlgrastim has been used as the primary prophylaxis of FN in Japan, but there have been few cases reported using pegˆlgrastim for the primary prophylaxis in DA-EPOCH-R. In this study, we retrospectively com- pared the e‹cacy of pegˆlgrastim with that of ˆlgrastim in patients receiving DA-EPOCH-R in Hiroshima University Hospital. E‹cacy assessment was based on incidence of FN and serious neutropenia (neutrophil count ＜500/mL), hospitalization days and chemotherapy dosage level. Ten patients met the inclusion criteria: pegˆlgrastim (n＝5, 30 cy- cles) or ˆlgrastim (n＝5, 16 cycles). No diŠerence in e‹cacy existed between pegˆlgrastim and ˆlgrastim in the ˆrst cy- cle; however, 2 of 5 patients in ˆlgrastim group reduced dose level in the total cycles of chemotherapy, no patients in peg- ˆlgrastim group reduced. In conclusion, pegˆlgrastim seemed better than ˆlgrastim for the primary prophylaxis in DA- EPOCH-R.
Key words―pegˆlgrastim; ˆlgrastim; primary prophylaxis; dose-adjusted etoposide, prednisolone, vincristine, cy- clophosphamide and doxorubicin with rituximab chemotherapy
regimen has been used for NHL patients. In the DA- INTRODUCTION EPOCH-R regimen, granulocyte colony-stimulating Febrile neutropenia (FN) was deˆned as an axillary factor (G-CSF) is recommended to use for individual temperature above 37.5°C or oral temperature above patient dose adjustment.3) In Hiroshima University 38.0°C and an absolute neutrophil count (ANC) Hospital, patients receiving DA-EPOCH-R were ＜500/mLorANC＜1000/mL and expected to fall often given G-CSF for individual patient dose adjust- below 500/mL within 48 h, according to the deˆnition ment and the primary prophylaxis of FN. Recently, of FN in the Clinical Practice guideline for FN in pegˆlgrastim was approved in Japan for the primary Japan.1) When FN occurs, we decrease chemotherapy prophylaxis of FN. Pegˆlgrastim seems to better dose and/or delay chemotherapy treatment schedule; eŠect than ˆlgrastim in reducing FN in some these approaches lead to an eŠect on relative dose in- reports,46) however in these studies pegˆlgrastim tensity (RDI). This is the reason prevention of FN is mainly used higher dose than Japan (6mgvs.3.6 a very important matter. Pettengell et al.reported mg). In Japanese study showed non-inferiority of a about patients with non-Hodgkin lymphoma (NHL) single subcutaneous dose of pegˆlgrastim compared who received prednisone, vincristine, cyclophospha- with daily subcutaneous doses of ˆlgrastim,7) mide and doxorubicin (CHOP) chemotherapy. The however these eŠect was not clear in clinical practice. group receiving reduced chemotherapy (RDI 90％) Pegˆlgrastim was used instead of daily G-CSF in the had reduce overall survival compared with the RDI ＞ DA-EPOCH-R regimen; however, few cases have 90％ group.2) From this report, preventing FN or been reported about using pegˆlgrastim for the pri- neutropenia seems to have a potential impact for mary prophylaxis of FN and dose adjustment in DA- chemotherapy outcome. Recently, dose-adjusted EPOCH-R and its e‹cacy has been poorly under- etoposide, prednisone, vincristine, cyclophosphamide stood. In this study, we retrospectively compared the and doxorubicin with rituximab (DA-EPOCH-R) e‹cacy of pegˆlgrastim with ˆlgrastim used for this purpose in patients receiving DA-EPOCH-R. e-mail: ta-kataoka0208＠hiroshima-u.ac.jp
2019 The Pharmaceutical Society of Japan 630 YAKUGAKU ZASSHI Vol. 139, No. 4 (2019)
Table 1. Dose-adjusted Etoposide, Prednisolone, Vin- PATIENTS AND METHODS cristine, Cyclophosphamide, Doxorubicin, Rituximab Regi- meninHiroshimaUniversityHospital(Level 1 dose) Study Design and Patient Selection This study was approved by the Hiroshima University Institu- Drug Dose Route Treatment days tional Ethical Committee (approval No. E-401). Etoposide 50 mg/m2/d civ 1, 2, 3, 4 Consecutive patients with aggressive NHL who Doxorubicin 10 mg/m2/d civ 1, 2, 3, 4 2 received the DA-EPOCH-R regimen were screened Vincristine 0.4 mg/m /d civ 1, 2, 3, 4 Cyclophosphamide 750 mg/m2/ddiv 5 from April 2013 to February 2017. The patients en- Prednisolone 60 mg/m2/d div or po 1, 2, 3, 4, 5 ( ) rolled in this study fulˆlled the following criteria: 1 Rituximab 375 mg/m2/ddiv received ˆlgrastim or pegˆlgrastim for the primary G-CSF sc 6～ prophylaxis in the ˆrst cycle; (2) received DA- Next cycle Day 21
EPOCH-R regimen Level 1 dose in the ˆrst cycle; (3) G-CSF: granulocyte colony-stimulating factor. civ: continuous in- no ˆxed dosage with renal or hepatic function. We ex- travenous drip infusion. div: intravenous drip infusion. po: per os.sc:sub- cutaneously. cluded patients who received ˆlgrastim or pegˆl- grastim with ANC ＜1000/mL in the ˆrst cycle. Patients were divided into two group according to the cycle was administered similarly. drug received, daily subcutaneous injection of Gran Evaluation of E‹cacy and Adverse Event In or biosimilars of ˆlgrastim (ˆlgrastim)(FG group) theˆrstcycle,wecheckedthewhitebloodcell or single subcutaneous injection of G-Lasta(pegˆl- (WBC) count, ANC, incidence of FN, duration of grastim)(PEG group). ˆlgrastim use, hospital duration from start of Data Collection Data were collected and chemotherapy, and dose level at second cycle. managed using Data Warehouse database system. The duration of ˆlgrastim was deˆned as days ˆl- Age, sex, performance status, chemotherapy history, grastim used for preventing FN, so days ˆlgrastim bone marrow inˆltration, date of chemotherapy initi- used after incidence of FN were not included in the ation and completion, the number of chemotherapy duration. cycles, date of ˆlgrastim initiation and completion, In total cycles, we checked incidence of leukopenia complete blood counts (CBCs), date of FN onset and (Grade 4),neutropenia(Grade 4) and FN, duration hospital duration from start of chemotherapy were of ˆlgrastim use, hospital duration from start extracted from medical records. Hospital duration chemotherapy; average of hospital duration in each was decided by the physician considering patient con- cycle, and dose level change. We checked bone pain dition and myelosuppression; at ˆrst cycle, patient for adverse event. Each adverse event was graded ac- could leave hospital after recovery of myelosuppres- cording to the National Cancer Institute Common sion with physician's decision. Toxicity Criteria (version 4.0). We deˆned the CBCs measured within 7 d before Statistical Analysis Analysis of the patient's administration of the DA-EPOCH-R regimen as ini- background and other normal distributions was per- tial blood test value. formed using the Student's t-test; for non-normal dis- Chemotherapy and Dose Adjustment DA- tributions we used the Mann-Whitney U test. Analy- EPOCH regimen was administered as previously sis of incidence of FN, leukopenia or neutropenia and described3) with slight modiˆcation. Prednisone was dose level of chemotherapy was performed using the changed to prednisolone and vincristine capped at 2 Fisher's exact test. p＜0.05 was considered statistical- mg (Table 1 shows Level 1 dose DA-EPOCH-R regi- ly signiˆcant. men). Rituximab was administered at a ˆxed dose of RESULTS 375 mg/m2 per day of body surface area and adminis- tration date was decided by the physician in charge. Patient Characteristics Twenty patients with Cycles were administered at intervals of at least 21 d NHL received the DA-EPOCH-R regimen from April and the pharmacodynamics dose adjustment was 2013 to February 2017 and 10 of them were excluded based on CBCs at the nadir of each cycle. Filgrastim from analysis. Five of them were given G-CSF after 75 mg per day was administered at least 24 h after ANC fell to less than 1000/mL, 3 received ˆxed chemotherapy until post nadir or pegˆlgrastim 3.6 mg/ chemotherapy dosage with renal function, and the Vol. 139, No. 4 (2019) YAKUGAKU ZASSHI 631
Table 2. Summary of Patient Characteristics Table 3. Summary of Results in First Cycle
Patient FG (n＝5) PEG (n＝5) p-value FG PEG p-value (n＝5) (n＝5) AEFJ Sex (male/female) 4/14/11.0 Leukopenia (Grade 4), n (％) 3(60.0) 0(0.0) 0.17 Age (year) 59.4(3578) 47.6(3370) 0.29 Neutropenia (Grade 4), n (％) 3(60.0) 1(20.0) 0.52 Febrile neutropenia, n (％) 1(20.0) 1(20.0) 1.00 2 1.70 1.69 Body surface area (m ) (1.511.83) (1.531.84) 0.89 6.4 Filgrastim use duration (d) (410) Bone marrow inˆltration 1/40/51.0 (Yes/No) ＜10 d 4 Previous chemotherapy 10 d 1 2/31/41.0 treatment (Yes/No) Hospital duration from start of 19.0 16.2 0.55 Performance status chemotherapy (d) (1423) (1033) 4/1/03/2/0 (0/1/2) Reduced dose level to ＜11(20.0) 0(0.0) 1.00 Age and body surface area are shown mean (minmax). Performance Leukopenia (Grade 4): white blood cell count ＜ 1000/mL. Filgrastim status was corrected by physician records. FG: ˆlgrastim group, PEG: peg- use duration and hospital duration from start of chemotherapy, days are ˆlgrastim group. shown mean (minmax). other 2 received a higher dose of ˆlgrastim than used in this study (300 mg/body). Clinical characteristics patients in the FG group. Moreover, hospital dura- of 10 patients are shown in Table 2. Five patients were tion from start of chemotherapy in the PEG group in the FG group (patient A to E) and others were in was signiˆcantly shorter than that in the FG group (p the PEG group (patient F to J). Patient factors as- ＜0.01)(Table 4). There were no dose adjustment sociatedwithahighFNriskaccordingtoASCOand by thrombocytopenia. NCCN guidelines―patient age (＞65), poor perfor- In the PEG group, 3 patients experienced bone mance status (＞2) and chemotherapy history―were pain, on the other hand, FG group none. No patient not signiˆcantly diŠerent in the two groups (Table 2 stopped pegˆlgrastim by adverse event. and Supplementary Table S1). DISCUSSION Evaluation of E‹cacy and Adverse Event In 3 of 5 patients in the FG group, the G-CSF received was In this retrospective study, pegˆlgrastim seemed to changed to pegˆlgrastim from ˆlgrastim at a certain have better e‹cacy than ˆlgrastim for use to prevent cycle, and these cycles were excluded from analysis. FN in patients given the DA-EPOCH-R regimen. In the PEG group, no patients received ˆlgrastim. In the DA-EPOCH-R regimen, we can modify the A summary of data at the ˆrst cycle is shown in Ta- chemotherapy dosage based on patient tolerability ble 3. The number of incidence of FN was the same aŠected by clearance of chemotherapy drugs.3) For between the two groups; the FG group tended to have this reason, DA-EPOCH had a better outcome than lower WBC and ANC count in the nadir than the CHOP in NHL lymphoma patients.8) We adjusted PEG group. Hospital duration from start of dose level in each cycle according to the depth of the chemotherapy was not signiˆcantly diŠerent in the hematologic nadir, and neurotoxicity. ANC reduc- two groups (p＝0.55). Patient G in the PEG group tion (＜500/mL) was one of these dose-limiting received 2 cycles of chemotherapy without being dis- factors;3) primary administration of G-CSF for charged from the hospital;itmusthavein‰uenced preventing reduction of ANC and RDI is very im- hospital duration analysis (Supplementary Table portant in treatment of DA-EPOCH. S2). TheincidentrateofFNinpatients who received the Sixteen cycles from 5 patients in the FG group and DA-EPOCH-R regimen in our study was 10.8％(ˆve 30 cycles from 5 patients in the PEG group were ana- of 46 cycles). This was similar to previous reports.8,9) lyzed. Data at the total cycles is shown in Table 4. In Though patient characteristics were not diŠerent be- the FG group, patient B and C received a lower dose tween the two groups, the PEG group tended to have of chemotherapy, however no patient received a low- higher WBC and ANC count in the nadir in the ˆrst er dose in the PEG group (Table 4).Patientsinthe cycle, and reduced incidence of severe neutropenia PEG group had lower incidence of leukopenia and FN in total cycles. Previous reports showed that (Grade 4),neutropenia(Grade 4) and FN than pegˆlgrastim prophylaxis reduced hospitalization of 632 YAKUGAKU ZASSHI Vol. 139, No. 4 (2019)
Table 4. Results Data in Total Cycles
Patient Number of Neutropenia Febrile Filgrastim Hospital duration from Dose level inclusion cycles (Grade 4) neutropenia use duration start chemotherapy FG A4 3 07.3(68) 19.5(1523) 1, 1, 1, 1 B4 3 19.0(810) 19.8(1822) 1, 1, －1, －1 C1 1 1 4 201 D6 3 23.7(26) 12.6(1018) 1, 2, 2, 3, 2, 2 E1 0 0 4 141 PEG F6 0 0 ― 8.2(710) 1, 1, 1, 1, 1, 1 G6 1 1 ― 12.2(733) 1, 1, 2, 3, 3, 3 H6 2 0 ― 7.3(614) 1, 2, 3, 4, 5, 5 I6 0 0 ― 9.3(712) 1, 1, 1, 1, 1, 1 J6 0 0 ― 8.0(712) 1, 1, 1, 1, 1, 1
Filgrastim use duration and hospital duration from start of chemotherapy, days are shown average (minmax). Neutropenia (Grade 4): an absolute neutrophil count (ANC)＜500/mL. cancer patients10) or febrile neutropenia46) more than ˆlgrastim for maintaining RDI. ˆlgrastim prophylaxis. We also had similar results to Our study has shown that pegˆlgrastim more sig- these reports instead of lower pegˆlgrastim dose. niˆcantly reduced hospitalization duration than ˆl- Weycker et al. suggested that shorter courses of ˆl- grastim in total cycle analysis. Looking at the ˆrst cy- grastim prophylaxis are associated with increased risk cle, pegˆlgrastim also signiˆcantly reduced hospitali- of hospitalization.11) In our study, the shortest dura- zation duration compared with ˆlgrastim (PEG tion of ˆlgrastim was two days (Table 4),andin group without patient G vs. FG group, 12.0 d vs. 19.0 d, many cycles, duration of ˆlgrastim was shorter than p＜0.01). In our hospital, ˆlgrastim is administered duration designed in clinical trial: 1011 d.7,12) The daily during the hospital stay in the DA-EPOCH-R cause for high incident rate of FN in the FG group regimen. Conversely, pegˆlgrastim is used only one was considered to be short duration of ˆlgrastim; time in each chemotherapy cycle. When we use pegˆl- however, daily G-CSF such as ˆlgrastim has frequent- grastim, we can reduce hospitalization duration and ly been used in a short duration in clinical contribute to improving the patient's quality of life. practice.4,11) Pegˆlgrastim is more favorable in this The reduction of hospital duration seemed to point. decrease medical cost. However, there has been no Use of G-CSF for prophylaxis helps to reduce inci- study about cost-beneˆt performance for using ˆl- dence of severe neutropenia and FN and enable grastim versus pegˆlgrastim for primary prophylaxis higher dosage treatment in the DA-EPOCH-R regi- of FN in Japan. Thus, further study focused on the men. Khaled et al.reportedthattheEPOCHregimen medical cost of FN treatment is required to discuss without dose adjustment had worse overall survival this important point. than the CHOP regimen for NHL patients.13) Adjust- Our study had several limitations; 1) we retrospec- ments of chemotherapy dosage that depend on in- tively evaluated NHL patients at a single medical cen- dividual tolerability is also thought to aŠect clinical ter, so it seems our study population might not be outcome.3) There are few reports that show the corre- representative of the general NHL patient popula- lation between dose level and overall survival (OS) in tion; 2) dose adjustment after the second cycle was the DA-EPOCH-R regimen. In contrast, several decided by the physician, and in some cases the physi- reports showed no correlation between OS and dose cian did not increase the dosage to upper limit. level.3,14) Lamar et al. reported that the number of CONCLUSION completed cycles of DA-EPOCH-R was associated with NHL patients' death, disease progression, or Our retrospective study showed that pegˆlgrastim relapse at 2 years in NHL patients.14) Our study may be better than daily ˆlgrastim for dose adjust- showed that pegˆlgrastim is thought to be better than ment and as the primary prophylaxis of FN in the Vol. 139, No. 4 (2019) YAKUGAKU ZASSHI 633633
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