Pediatric Hematology and Oncology
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Treatment of chemotherapy-Induced Neutropenia in Children with Subcutaneously Administered Recombinant Human Granulocyte ColonyStimulating Factor Jun Okamura, Masaru Yokoyama, Ichiro Tsukimoto, Atsushi Komiyama, Minoru Sakurai, Shinsaku Imashuku, Sumio Miyazaki, Kazuhiro Ueda, Yoshiyuki Hanawa & Fumimaro Takaku To cite this article: Jun Okamura, Masaru Yokoyama, Ichiro Tsukimoto, Atsushi Komiyama, Minoru Sakurai, Shinsaku Imashuku, Sumio Miyazaki, Kazuhiro Ueda, Yoshiyuki Hanawa & Fumimaro Takaku (1992) Treatment of chemotherapy-Induced Neutropenia in Children with Subcutaneously Administered Recombinant Human Granulocyte Colony-Stimulating Factor, Pediatric Hematology and Oncology, 9:3, 199-207, DOI: 10.3109/08880019209016587 To link to this article: http://dx.doi.org/10.3109/08880019209016587
Published online: 09 Jul 2009.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipho20 Download by: [137.189.171.235]
Date: 18 March 2016, At: 22:59
TREATMENT OF CHEMOTHERAPY-INDUCED NEUTROPENIA IN CHILDREN WITH SUBCUTANEOUSLY ADMINISTERED RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMUIATl NG FACTOR Jun Okamura, MD
Section of Pediatrics, National Kyushu Cancer Center, 3-1-1 0 Notame, Minami-ku, Fukuoka 815, Japan
Masaru Yokoyama, MD
0
Department of Pediatrics, Hirosaki University, Zaifucho 5,
Hirosaki, Japan
lchiro Tsukimoto, MD
Department of Pediatrics, Toho University, Ohmorinishi
0
5-21-16, Ohtaku, Tokyo, Japan
Downloaded by [] at 22:59 18 March 2016
Atsushi Komiyama, MD
0
Department of Pediatrics, Shinshu University, Asahi 3-1-1,
Matsumoto, Japan
Minoru Sakurai, MD
0
Department of Pediatrics, Mie University, Edobashi 2-174,
Tsu, Japan
Shinsaku Imashuku, MD
0 Department of Pediatrics, Kyoto Prefectural Medical College, Kajiicho 465, Kawaramachidori, Hirokoji-Agaru, Kamikyoku, Kyoto, Japan
Sumio Miyazaki, MD
Department of Pediatrics, Saga Medical College, Nabeshima
0
5-1-1, Saga, Japan
Kazuhiro Ueda, MD
Department of Pediatrics, Hiroshima University, Kasumi 1-2-3, Minamiku, Hiroshima, Japan 0
Yoshiyuki Hanawa, MD
0
Department of Pediatrics, Toho University, Ohmorinishi
5-21-16, Ohtaku, Tokyo, Japan
Fumimaro Takaku, MD
0
Department of Internal Medicine, Tokyo University, Hongo
7-3-1, Bunkyoku, Tokyo, Japan 0 Fijy-six children with various malignancies were treated subcutaneously with recombinant human granulocyte colony-stimulating fattor (rhC-CSE KRN 8601)for neutropenia induced by cancer chemotherapy. Patients received thefirst chemotherapy without rhC-CSF (control course). In the second course, rhG-CSF was given once abily, starting 3 days afin completion of identical chemotherapy (day 3) and continuing until day 12. A t day 12, the white blood counts and neutrophil counts were found to be 6.8 and 30 times hig-her in the rhC-CSF course than in the control course (P .0001).Nadirs of white blood counts and neutrophils were signijicantly elevated in the rhC-CSF course (P ,003and .0001, respectively). rhC-CSF administration shortened the neutropenic period in the majority of patients. Children tolerated the rhC-CSF administration well and we have hereby confirmed that rhC-CSF administration is use@ for proceeding with chemotherapy in children with cancer.
- -
KEY WORDS: drug-induced ncutropmia, rhC-CSI? subcutaneous administration. Pediatric Hematology and Oncoloa, 9.199-207, 1992 Copyrifht 0 1992 by Hemisphne Publishing Corporation
199
200
J.OKAMURAETA1
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INTRODUCTION Doses of chemotherapeutic agents used against cancer are usually limited due to the occurrence of myelosuppression, especially neutropenia. Despite great progress in the supportive care of children with malignant neoplasms, profound neutropenia followed by a life-threatening infection remains one of the main causes of treatment failure. It is a well-recognized fact that the incidence of developing bacterial and/or fungal infections significantly increases when the neutrophil count falls below 0.5 X 109/L.' Recently, recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been produced' in large quantities. Several clinical studies using rhG-CSF have indicated that it can reduce both the duration and degree of neutropenia induced by aggressive ~hemotherapy.~.'~ However, these studies were performed almost exclusively in adult patients and little is known about the effect of rhG-CSF in children. In order to explore the effect and safety of this newly produced factor, we undertook a multi-institutional study of rhG-CSF in children who were receiving cytotoxic chemotherapy to treat various malignant neoplasms.
PATIENTS AND METHODS Patients Fifty-six patients under 18 years old with histologically or cytologically proven malignancies entered this study between March 1989 and September 1989. Patients who had received prior chemotherapy, radiotherapy, or both were eligible. In each case, the study protocol was carefully explained to the parents (and in some cases to the patients) in detail and an informed consent was obtained. The study was done under the ethical guidelines of each individual institution.
Study Design (Figure 1) When the treatment protocol for each patient happened to include two identical courses of chemotherapy (ie, the same drugs of the same dosages in an identical schedule), the patient was then considered to be a candidate for the study. The patient was eligible for the study only when an absolute neutrophi1 count (ANC) became less than 0.5 X 109/L during the first course of chemotherapy (control course). The patient was then registered with the central office for the second course in which he or she received rhG-CSF (rhGCSF course).
rhG-CSF FOR DRUG-INDUCED NEUTROPENIA
Day 0 1 Chemotherapy
-
Day0 Day3 1 1 Chemotherapy
201
Day 12
1
rh G-CSF 50pg/m2, s.c., 10 Days 1
Control Course
rh G-CSF Course FIGURE 1. Study design.
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Administration of rhC-CSF
Bacterially synthesized rhG-CSF (KRN 8601) was supplied by Kirin Brewery (Tokyo, Japan) in collaboration with Amgen Biologicals (Thousand Oaks, California, USA). It was a clear, colorless, sterile, protein solution, free of particulates at a concentration of 250 pg/mL. rhG-CSF was given as a single subcutaneous injection at a dose of 50 pg/m2. The treatment consisted of a single daily administration for 10 days, starting 3 days after termination of chemotherapy. (For the purpose of comparing the hematological parameters between the control phase and the rhG-CSF phase, the last day of each chemotherapy course was designated as day 0. Therefore, rhG-CSF was administered on days 3-12.) During the study, all patients were monitored by daily physical examination, vital signs including temperature, determination of the complete blood cell count including differential and platelet count every other day, and measurement of biochemical profile including renal and liver function tests, Creactive protein, serum lactate dehydrogenase (LDH), routine urinalysis and coagulation profile including prothrombin and partial thromboplastin time once a week. Pharmacokinetics of rhC-CSF
The plasma concentration of rhG-CSF was measured in 5 patients by a radioimmunoassay (RIA) using polyclonal rabbit anti-G-CSF antibody, 125 Ilabeled rhG-CSF, and goat antiserum to rabbit IgG. The sensitivity of the assay used was 0.1 ng/mL. Statistical Analysis
Hematological parameters on days 3 and 12 of the two chemotherapy courses (control and rhG-CSF courses) for each patient were analyzed by the Wilcoxon matched-pairs signed-ranks test. Percentages of patients in the twc
202
J.OKAMURA ET A 1
courses who became febrile (temperature over 38 "C) during this period were compared by the U test. The number of infections occurring during the study was analyzed by the x2 test with Yates' continuity correction.
RESULTS
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The characteristics of the 56 children registered in this study are shown in Table 1. Thirty-six were boys and 20 were girls. Seventeen of 56 patients had hematological malignancies (malignant lymphoma and acute lymphoblastic leukemia). The rest had various types of solid tumors. Forty-two patients had had various types of combination chemotherapy using steroids, vinca alkaloids, alkylating agents, anthracyclines, and others, and 13 had undergone prior radiotherapy. Thirteen had received no previous treatment in the year preceding this study. Effect of rhG-CSF on Myelosuppression Induced by Chemotherapy Table 2 shows the changes in hematological parameters induced by chemotherapy in the control and rhG-CSF courses. O n day 12 of the course, the total WBC and neutrophil counts (median) were significantly higher in the rhG-CSF course than in the control course (8200/pL vs 1200/pL, and 5658/ pL vs 19O/pL, respectively) (P * .0001). As was expected, rhG-CSF induced TABLE 1 Patient Characteristics Category
No. of cases
Age (Yr)
0-5 6-1 1 12-18 Sex
M
32 12 12 36 20
F Diagnosis Neuroblastoma Malignant lymphoma Acute lymphoblastic leukemia Rhabdomyosarcoma Other Previous therapy within 1 year Chemotherapy Radiotherapy Both Nil Total
16 10
7 8 15 30 1 12 13 56
rhG-CSF FOR DRUG-INDUCED NEUTROPENIA
203
TABLE 2 Effect of rhG-CSF on Hematological Parameters Median counts at (n)
Day 3
WBC"
C G
41
1500(400-5100) NS 1500(200-6600)
1200(300-7300) 8200(700-43500)
ANC'
C G
41
969( 30-4820) NS 792( 0-6468)
190( 0-4657) 5658( 0-36323)
C
40
38( 0-175) NS 16( 0-266)
Monocyte'
G
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Day 12
Course
Parameter
(n)
425( 40-2900) 625( 40-2900)
56
26( 0-325) 81( 9-897)
198( 0-1554) 549( 14-3263)
56
26( 0-110) NS O( 0- 128)
56
192( 0-1755) NS 152( 0-2300)
NS
43
101( 14-415) NS 81 ( 10-292)
9.3(6.4-12.2) NS 9.3(6.6- 12.6)
36
8.3(5.2-10.5) NS 8.4(5.8- 12.0)
I
C G
40
365( 15-2397) NS 337( 20-2496)
519( 54-2790) *I 909( 144-2698)
Plateletb
C G
36
211( 25-530) NS 169( 31-423)
229( 41-864) 213( 33-689)
Hb"
C G
31
10.1(6.2-12.1) NS 9.6(6.6-14.1)
--
- -
-
*,
56
Lymphocyte"
"106/L; 109/L; 'g/dL. C control course, G rhG-CSF course. * P ,0001, **P ,0003, ***P< ,003, NS
Nadirs (range)
not significant.
higher nadir levels of total WBC and neutrophils than that of the control course. Interestingly, monocytes and lymphocytes were also elevated on day 12 in the rhG-CSF course (P 5 .0003). O n the other hand, there were no differences in the platelet and hemoglobin levels on day 12 between the control and rhG-CSF courses. There were no differences in nadir levels of monocytes, lymphocytes, platelets, and hemoglobin between the two courses after chemotherapy. To compare the severity of neutropenia induced by chemotherapy in the two courses, the duration of time between day 0 (the last day of chemotherapy) and the day when the neutrophil count recovered to 0.5 X 109/L was counted in each patient. rhG-CSF shortened the neutropenic period by an average of 8 days in 53 of 56 patients (94%). There were no differences in the duration of the neutropenic period between the two courses in 3 patients.
Clinical Observations during rhG-CSF Administration The incidence of fever (above 38OC occurring during the 10-day period (day 3 to day 12) was compared by the U test. Although the number of patients who remained afebrile during this period was larger in the rhG-CSF course than in the control course (33 patients vs 27 patients), rhG-CSF administration did not significantly decrease the febrile days (P .092). Infectious complications during the study were documented both in the control
-
J.OKAMURA ET A 1
204
course (8 patients) and in the rhG-CSF course (8 patients), including one sepsis in each course. It was interesting, however, that the fever (above 38OC) of unknown etiology (FUO) occurred less frequently in the rhG-CSF course (11 patients) than in the control course (27 patients) (I' .003, by the x2 test). The children tolerated the rhG-CSF administration well and mild bone pain was observed in 3 patients (5.3%). The bone pain was experienced in the lower back, lower extremities, or both, and lasted for only 1 or 2 days, respectively. No analgesic treatment was required for any of the patients. Elevation of serum LDH levels during the rhG-CSF administration was documented in 2 patients.
-
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Pharmacokineticsof rhC-CSF
Figure 2 illustrates the pharmacokinetics of rhG-CSF administered subcutaneously at a dose of 50 pg/m2 in 5 patients. Before administration, rhG-CSF
T
2
4
6
8
24 Time (hr.)
-
FIGURE 2. Plasma levels of rhG-CSF receiving 50 p g h 2 subcutaneously as a bolus injection (mean f SE,
R
5).
rhG-CSF FOR DRUG-INDUCED NEUTROPENIA
205
was not detected in any of the patients by the assay system, indicating that the plasma concentration of rhG-CSF was less than 0.1 ng/mL. The plasma concentration of rhG-CSF reached a peak level (5.37 ng/mL) at 4 hours after administration and dropped to 10% of the peak level after 24 hours. The plasma half-life (TI,*)and area under the curve (AUC) of rhG-CSF were calculated as 8.4 f 0.6 hours and 66 f 15 pg-h/L, respectiveIy.
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DISCUSSION To our knowledge, this was the first clinical study of subcutaneously administered rhG-CSF performed in children on a large scale. The results showed that myelosuppression induced by cytotoxic chemotherapy was greatly reduced by rhG-CSF in the majority of children with various cancers. When it was administered subcutaneously, the first administration starting 3 days after completion of the treatment, rhG-CSF induced a prompt recovery in the postchemotherapy fall in neutrophil counts. The neutropenic period (neutrophil count below 0.5 X 109/L) was significantly shorter (with a median of 8 days) in the course with rhG-CSF than that without. Neutrophil counts on day 12 and neutrophil nadirs were also 30 and 3.1 times higher, respectively, in the rhG-CSF course than in the control course (P .OOOl). Although an equal number of patients in the control and rhG-CSF courses developed documented infectious complications during the neutropenic period, rhG-CSF administration significantly decreased the incidence of FUO, which might be the sign of possible unproven infections. While rhG-CSF induced major increases in the circulating neutrophils, both monocytes and lymphocytes (which were reported to have no G-CSF receptors) were also significantly elevated on day 12 of the rhG-CSF course (Table 2). Although results have up to now have been controversial, similar unexpected observations, ie, rhG-CSF-induced increase in the number of monocytes and lymphocytes, have been previously reported both in humans6 and animal^.'^'" rhG-CSF did not, however, induce any changes in platelet counts when compared to that of the control course on day 12 in this study. This has been previously reported in studies of adults. Lindemann et al,I5 however, observed a depression of platelet counts with a nadir occurring on about day 10 of rhG-CSF administration. A spontaneous recovery was observed despite continuation of rhG-CSF administration. Observations in children plus other reports suggest one of two things: (1) rhG-CSF interacts with some other regulator or (2) rhG-CSF initiates production of other hematopoietic regulators by accessory cells or some compensatory homeostatic mechanism. Previous Japanese phase I and I1 studies of rhG-CSF (KRN 8601) in normal volunteers'* and adult patients with malignant lymphomaIg suggested subcutaneous administrations at 75 and 125 pg/body were equally safe and
-
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206
J. OKAMURA ET A 1
effective. We therefore gave the children entered into the study rhG-CSF subcutaneously at relatively small doses, 50 &m2. Subcutaneous administration has several advantages: First, even at this low dosage, sufficient serum level of rhG-CSF needed to increase the neutrophil count can be achieved and lasts at least 8 hours (Figure 2). In contrast, pharmacokinetic study of rhGCSF in adults indicated a rapid decrease in the plasma level when it was given as a single intravenous infusion." Second, since rhG-CSF is supplied at concentrations of 250 pg/mL, only a minimum volume (usually 0.1-0.3 mL) needs to be given for the majority of children. This lessens the degree of local pain at the injected site. Third, and most important, as it is much easier to inject subcutaneously than intravenously, especially when children are young, it can be given on an outpatient basis. Results of the clinical and pharmacokinetic data observed in the present study in children support the experiences in adults. Children in the study tolerated the course well and no serious toxicity necessitating the discontinuation of rhG-CSF administration was observed. Mild bone pain was the only complaint in 3 patients (5.3%) but was not severe enough to require treatment. In contrast to the recombinant human granulocyte/macrophage colony-stimulating factor administration in children with acute lymphoblastic leukemia" and aplastic anemia," no febrile episode, skin rash, or gastrointestinal symptom was recorded among the 56 patients studied. As has been reported in adult patients, elevation of LDH level was recorded in 2 patients (3.5%), this probably being due to the reflection of rapid increase in peripheral ne~trophils.~ Hyperuricemia, which was reported in adult patients by several investigator^,^""^ was not, however, observed in any of the children studied. In conclusion, rhG-CSF appears to be well tolerated by children. It significantly reduces the severity of neutropenia induced by cytotoxic chemotherapy. The ability to administer cycles of dose-intensive therapy safely and without delay may contribute to the further improvement in the survival of children with cancer.
REFERENCES 1. Body GP, Buckley M , Sathe YS, et al. Quantitative relationships between circulating leukocytes and
infection in patients with acute leukemia. Ann Z n t m Med. 1966;64:328-340. 2 . Souza LM, Boone TC, Gabrilove J , et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986;232:61-65. 3. Kitagawa S, Yuo A, Souza LM, et al. Recombinant human granulocyte colony-stimulating factor enhances superoxide release in human granulocytes stimulated by the chemotactic peptide. Biochm Biophys Res Commun. 1987;144:1143-1146. 4. Ohsaka A, Kitagawa S, Sakamoto S, et al. In vivo activation of human neutrophil functions by administration of recombinant human granulocyte colony-stimulating factor in patients with malignant lymphoma. Blood. 1989;74:2743-2748. 5. Bronchud MH, Scarffe JH, Thatcher N, et al. Phase 1/11 study of recombinant human granulocyte
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207
colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer. Br J Cancn. 1987;56:809-8 13. 6. Montyn G, Campbell L, Souza LM, et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet. 1988;i:667-672. 7. Gabrilove JL, Jakubowski A, Scher H, et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbility due to chemotherapy for transitional-cell carcinoma of the urothelium. N En81 JMed. 1988;318:1414-1422. 8. Gabrilove JL, Jakubowski A, Fain K, et al. Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium. J Clin Invesf. 1988;82:1454-1461. 9. Layton JE, Hockman H, Sheridan WP, et al. Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor. Blood. 1989;74:1303-1307. 10. Duhrsen U, Villeval J-L, Boyd J, et al. Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood. 1988;72:2074-2081. 11. Sheridan WP, Morstyn G, Wolf M, et al. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lanccf. 1989;ii:891895. 12. Morstyn G, Lieschke GJ, Sheridan W, et al. Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor. Sem H d o l . 1989;26:9- 13. 13. Morstyn G, Campbell L, Lieschke G, et al. Treatment of chemotherapy-induced neutropenia by subcutaneously administered granulocyte colony-stimulating factor with optimization of dose and duration of therapy. J Clin Oncol. 1989;7:1554-1562. 14. Neidhart J, Maugalik A, Kohler W, et al. Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving dose-intensive chemotherapy without bone marrow transplantation. J Clin Oncol. 1989;7:1685-1692. 15. Lindemann A, Herrmann F, Oster W, et al. Hematologic effects of recombinant human granulocyte colony-stimulating factor in patients with malignancy. Blood. 1989;74:2644-2651. 16. Lothrop CD, Waren DJ, Souza LM, et al. Correction of canine cyclic hematopoiesis with recombinant human granulocyte colony-stimulating factor. Blood. 1988;72:1324-1328. 17. Shuening FG, Storb R, Goehle S, et al. Effects of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation. Blood. 1989;74:1308-1 3 13. 18. Azuma J, Tsuji S, Park SE, et al. Phase I study of KRN 8601 (rhG-CSF) in normal healthy volunteers: safety and pharmacokinetics in consecutive subcutaneous administration. Clin Pharmncol. 1989;5:2253-2269 (in Japanese). 19. Ogawa M, Masaoka T, Takaku F. Phase I1 study of KRN 8601 in patients with neutropenia induced by chemotherapy for malignant lymphoma. Cfin Pharmacol. 1990;6:23-40 (in Japanese). 20. Azuma J, Hamaguchi T, Seung-Eun P, et al. Phase I study of KRN 8601 (rhG-CSF) in normal healthy volunteers: safety and pharmacokinetics in single intravenous infusion. Clin Phannacol. 1989;5:15791603 (in Japanese). 21. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/ macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood. 1989;73:849-857. 22. Guinan EC, Sieff CA, Oette DH, et al. A phase 1\11 trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia. Blood. 1990;76:1077-1082. Received June 26, 1991 Accepted November 6, 1991 Addsess correspondence 60 Jun Okamura.
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Treatment of chemotherapy-Induced Neutropenia in Children with Subcutaneously Administered Recombinant Human Granulocyte ColonyStimulating Factor Jun Okamura, Masaru Yokoyama, Ichiro Tsukimoto, Atsushi Komiyama, Minoru Sakurai, Shinsaku Imashuku, Sumio Miyazaki, Kazuhiro Ueda, Yoshiyuki Hanawa & Fumimaro Takaku To cite this article: Jun Okamura, Masaru Yokoyama, Ichiro Tsukimoto, Atsushi Komiyama, Minoru Sakurai, Shinsaku Imashuku, Sumio Miyazaki, Kazuhiro Ueda, Yoshiyuki Hanawa & Fumimaro Takaku (1992) Treatment of chemotherapy-Induced Neutropenia in Children with Subcutaneously Administered Recombinant Human Granulocyte Colony-Stimulating Factor, Pediatric Hematology and Oncology, 9:3, 199-207, DOI: 10.3109/08880019209016587 To link to this article: http://dx.doi.org/10.3109/08880019209016587
Published online: 09 Jul 2009.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipho20 Download by: [137.189.171.235]
Date: 18 March 2016, At: 22:59
TREATMENT OF CHEMOTHERAPY-INDUCED NEUTROPENIA IN CHILDREN WITH SUBCUTANEOUSLY ADMINISTERED RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMUIATl NG FACTOR Jun Okamura, MD
Section of Pediatrics, National Kyushu Cancer Center, 3-1-1 0 Notame, Minami-ku, Fukuoka 815, Japan
Masaru Yokoyama, MD
0
Department of Pediatrics, Hirosaki University, Zaifucho 5,
Hirosaki, Japan
lchiro Tsukimoto, MD
Department of Pediatrics, Toho University, Ohmorinishi
0
5-21-16, Ohtaku, Tokyo, Japan
Downloaded by [] at 22:59 18 March 2016
Atsushi Komiyama, MD
0
Department of Pediatrics, Shinshu University, Asahi 3-1-1,
Matsumoto, Japan
Minoru Sakurai, MD
0
Department of Pediatrics, Mie University, Edobashi 2-174,
Tsu, Japan
Shinsaku Imashuku, MD
0 Department of Pediatrics, Kyoto Prefectural Medical College, Kajiicho 465, Kawaramachidori, Hirokoji-Agaru, Kamikyoku, Kyoto, Japan
Sumio Miyazaki, MD
Department of Pediatrics, Saga Medical College, Nabeshima
0
5-1-1, Saga, Japan
Kazuhiro Ueda, MD
Department of Pediatrics, Hiroshima University, Kasumi 1-2-3, Minamiku, Hiroshima, Japan 0
Yoshiyuki Hanawa, MD
0
Department of Pediatrics, Toho University, Ohmorinishi
5-21-16, Ohtaku, Tokyo, Japan
Fumimaro Takaku, MD
0
Department of Internal Medicine, Tokyo University, Hongo
7-3-1, Bunkyoku, Tokyo, Japan 0 Fijy-six children with various malignancies were treated subcutaneously with recombinant human granulocyte colony-stimulating fattor (rhC-CSE KRN 8601)for neutropenia induced by cancer chemotherapy. Patients received thefirst chemotherapy without rhC-CSF (control course). In the second course, rhG-CSF was given once abily, starting 3 days afin completion of identical chemotherapy (day 3) and continuing until day 12. A t day 12, the white blood counts and neutrophil counts were found to be 6.8 and 30 times hig-her in the rhC-CSF course than in the control course (P .0001).Nadirs of white blood counts and neutrophils were signijicantly elevated in the rhC-CSF course (P ,003and .0001, respectively). rhC-CSF administration shortened the neutropenic period in the majority of patients. Children tolerated the rhC-CSF administration well and we have hereby confirmed that rhC-CSF administration is use@ for proceeding with chemotherapy in children with cancer.
- -
KEY WORDS: drug-induced ncutropmia, rhC-CSI? subcutaneous administration. Pediatric Hematology and Oncoloa, 9.199-207, 1992 Copyrifht 0 1992 by Hemisphne Publishing Corporation
199
200
J.OKAMURAETA1
Downloaded by [] at 22:59 18 March 2016
INTRODUCTION Doses of chemotherapeutic agents used against cancer are usually limited due to the occurrence of myelosuppression, especially neutropenia. Despite great progress in the supportive care of children with malignant neoplasms, profound neutropenia followed by a life-threatening infection remains one of the main causes of treatment failure. It is a well-recognized fact that the incidence of developing bacterial and/or fungal infections significantly increases when the neutrophil count falls below 0.5 X 109/L.' Recently, recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been produced' in large quantities. Several clinical studies using rhG-CSF have indicated that it can reduce both the duration and degree of neutropenia induced by aggressive ~hemotherapy.~.'~ However, these studies were performed almost exclusively in adult patients and little is known about the effect of rhG-CSF in children. In order to explore the effect and safety of this newly produced factor, we undertook a multi-institutional study of rhG-CSF in children who were receiving cytotoxic chemotherapy to treat various malignant neoplasms.
PATIENTS AND METHODS Patients Fifty-six patients under 18 years old with histologically or cytologically proven malignancies entered this study between March 1989 and September 1989. Patients who had received prior chemotherapy, radiotherapy, or both were eligible. In each case, the study protocol was carefully explained to the parents (and in some cases to the patients) in detail and an informed consent was obtained. The study was done under the ethical guidelines of each individual institution.
Study Design (Figure 1) When the treatment protocol for each patient happened to include two identical courses of chemotherapy (ie, the same drugs of the same dosages in an identical schedule), the patient was then considered to be a candidate for the study. The patient was eligible for the study only when an absolute neutrophi1 count (ANC) became less than 0.5 X 109/L during the first course of chemotherapy (control course). The patient was then registered with the central office for the second course in which he or she received rhG-CSF (rhGCSF course).
rhG-CSF FOR DRUG-INDUCED NEUTROPENIA
Day 0 1 Chemotherapy
-
Day0 Day3 1 1 Chemotherapy
201
Day 12
1
rh G-CSF 50pg/m2, s.c., 10 Days 1
Control Course
rh G-CSF Course FIGURE 1. Study design.
Downloaded by [] at 22:59 18 March 2016
Administration of rhC-CSF
Bacterially synthesized rhG-CSF (KRN 8601) was supplied by Kirin Brewery (Tokyo, Japan) in collaboration with Amgen Biologicals (Thousand Oaks, California, USA). It was a clear, colorless, sterile, protein solution, free of particulates at a concentration of 250 pg/mL. rhG-CSF was given as a single subcutaneous injection at a dose of 50 pg/m2. The treatment consisted of a single daily administration for 10 days, starting 3 days after termination of chemotherapy. (For the purpose of comparing the hematological parameters between the control phase and the rhG-CSF phase, the last day of each chemotherapy course was designated as day 0. Therefore, rhG-CSF was administered on days 3-12.) During the study, all patients were monitored by daily physical examination, vital signs including temperature, determination of the complete blood cell count including differential and platelet count every other day, and measurement of biochemical profile including renal and liver function tests, Creactive protein, serum lactate dehydrogenase (LDH), routine urinalysis and coagulation profile including prothrombin and partial thromboplastin time once a week. Pharmacokinetics of rhC-CSF
The plasma concentration of rhG-CSF was measured in 5 patients by a radioimmunoassay (RIA) using polyclonal rabbit anti-G-CSF antibody, 125 Ilabeled rhG-CSF, and goat antiserum to rabbit IgG. The sensitivity of the assay used was 0.1 ng/mL. Statistical Analysis
Hematological parameters on days 3 and 12 of the two chemotherapy courses (control and rhG-CSF courses) for each patient were analyzed by the Wilcoxon matched-pairs signed-ranks test. Percentages of patients in the twc
202
J.OKAMURA ET A 1
courses who became febrile (temperature over 38 "C) during this period were compared by the U test. The number of infections occurring during the study was analyzed by the x2 test with Yates' continuity correction.
RESULTS
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The characteristics of the 56 children registered in this study are shown in Table 1. Thirty-six were boys and 20 were girls. Seventeen of 56 patients had hematological malignancies (malignant lymphoma and acute lymphoblastic leukemia). The rest had various types of solid tumors. Forty-two patients had had various types of combination chemotherapy using steroids, vinca alkaloids, alkylating agents, anthracyclines, and others, and 13 had undergone prior radiotherapy. Thirteen had received no previous treatment in the year preceding this study. Effect of rhG-CSF on Myelosuppression Induced by Chemotherapy Table 2 shows the changes in hematological parameters induced by chemotherapy in the control and rhG-CSF courses. O n day 12 of the course, the total WBC and neutrophil counts (median) were significantly higher in the rhG-CSF course than in the control course (8200/pL vs 1200/pL, and 5658/ pL vs 19O/pL, respectively) (P * .0001). As was expected, rhG-CSF induced TABLE 1 Patient Characteristics Category
No. of cases
Age (Yr)
0-5 6-1 1 12-18 Sex
M
32 12 12 36 20
F Diagnosis Neuroblastoma Malignant lymphoma Acute lymphoblastic leukemia Rhabdomyosarcoma Other Previous therapy within 1 year Chemotherapy Radiotherapy Both Nil Total
16 10
7 8 15 30 1 12 13 56
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TABLE 2 Effect of rhG-CSF on Hematological Parameters Median counts at (n)
Day 3
WBC"
C G
41
1500(400-5100) NS 1500(200-6600)
1200(300-7300) 8200(700-43500)
ANC'
C G
41
969( 30-4820) NS 792( 0-6468)
190( 0-4657) 5658( 0-36323)
C
40
38( 0-175) NS 16( 0-266)
Monocyte'
G
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Day 12
Course
Parameter
(n)
425( 40-2900) 625( 40-2900)
56
26( 0-325) 81( 9-897)
198( 0-1554) 549( 14-3263)
56
26( 0-110) NS O( 0- 128)
56
192( 0-1755) NS 152( 0-2300)
NS
43
101( 14-415) NS 81 ( 10-292)
9.3(6.4-12.2) NS 9.3(6.6- 12.6)
36
8.3(5.2-10.5) NS 8.4(5.8- 12.0)
I
C G
40
365( 15-2397) NS 337( 20-2496)
519( 54-2790) *I 909( 144-2698)
Plateletb
C G
36
211( 25-530) NS 169( 31-423)
229( 41-864) 213( 33-689)
Hb"
C G
31
10.1(6.2-12.1) NS 9.6(6.6-14.1)
--
- -
-
*,
56
Lymphocyte"
"106/L; 109/L; 'g/dL. C control course, G rhG-CSF course. * P ,0001, **P ,0003, ***P< ,003, NS
Nadirs (range)
not significant.
higher nadir levels of total WBC and neutrophils than that of the control course. Interestingly, monocytes and lymphocytes were also elevated on day 12 in the rhG-CSF course (P 5 .0003). O n the other hand, there were no differences in the platelet and hemoglobin levels on day 12 between the control and rhG-CSF courses. There were no differences in nadir levels of monocytes, lymphocytes, platelets, and hemoglobin between the two courses after chemotherapy. To compare the severity of neutropenia induced by chemotherapy in the two courses, the duration of time between day 0 (the last day of chemotherapy) and the day when the neutrophil count recovered to 0.5 X 109/L was counted in each patient. rhG-CSF shortened the neutropenic period by an average of 8 days in 53 of 56 patients (94%). There were no differences in the duration of the neutropenic period between the two courses in 3 patients.
Clinical Observations during rhG-CSF Administration The incidence of fever (above 38OC occurring during the 10-day period (day 3 to day 12) was compared by the U test. Although the number of patients who remained afebrile during this period was larger in the rhG-CSF course than in the control course (33 patients vs 27 patients), rhG-CSF administration did not significantly decrease the febrile days (P .092). Infectious complications during the study were documented both in the control
-
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204
course (8 patients) and in the rhG-CSF course (8 patients), including one sepsis in each course. It was interesting, however, that the fever (above 38OC) of unknown etiology (FUO) occurred less frequently in the rhG-CSF course (11 patients) than in the control course (27 patients) (I' .003, by the x2 test). The children tolerated the rhG-CSF administration well and mild bone pain was observed in 3 patients (5.3%). The bone pain was experienced in the lower back, lower extremities, or both, and lasted for only 1 or 2 days, respectively. No analgesic treatment was required for any of the patients. Elevation of serum LDH levels during the rhG-CSF administration was documented in 2 patients.
-
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Pharmacokineticsof rhC-CSF
Figure 2 illustrates the pharmacokinetics of rhG-CSF administered subcutaneously at a dose of 50 pg/m2 in 5 patients. Before administration, rhG-CSF
T
2
4
6
8
24 Time (hr.)
-
FIGURE 2. Plasma levels of rhG-CSF receiving 50 p g h 2 subcutaneously as a bolus injection (mean f SE,
R
5).
rhG-CSF FOR DRUG-INDUCED NEUTROPENIA
205
was not detected in any of the patients by the assay system, indicating that the plasma concentration of rhG-CSF was less than 0.1 ng/mL. The plasma concentration of rhG-CSF reached a peak level (5.37 ng/mL) at 4 hours after administration and dropped to 10% of the peak level after 24 hours. The plasma half-life (TI,*)and area under the curve (AUC) of rhG-CSF were calculated as 8.4 f 0.6 hours and 66 f 15 pg-h/L, respectiveIy.
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DISCUSSION To our knowledge, this was the first clinical study of subcutaneously administered rhG-CSF performed in children on a large scale. The results showed that myelosuppression induced by cytotoxic chemotherapy was greatly reduced by rhG-CSF in the majority of children with various cancers. When it was administered subcutaneously, the first administration starting 3 days after completion of the treatment, rhG-CSF induced a prompt recovery in the postchemotherapy fall in neutrophil counts. The neutropenic period (neutrophil count below 0.5 X 109/L) was significantly shorter (with a median of 8 days) in the course with rhG-CSF than that without. Neutrophil counts on day 12 and neutrophil nadirs were also 30 and 3.1 times higher, respectively, in the rhG-CSF course than in the control course (P .OOOl). Although an equal number of patients in the control and rhG-CSF courses developed documented infectious complications during the neutropenic period, rhG-CSF administration significantly decreased the incidence of FUO, which might be the sign of possible unproven infections. While rhG-CSF induced major increases in the circulating neutrophils, both monocytes and lymphocytes (which were reported to have no G-CSF receptors) were also significantly elevated on day 12 of the rhG-CSF course (Table 2). Although results have up to now have been controversial, similar unexpected observations, ie, rhG-CSF-induced increase in the number of monocytes and lymphocytes, have been previously reported both in humans6 and animal^.'^'" rhG-CSF did not, however, induce any changes in platelet counts when compared to that of the control course on day 12 in this study. This has been previously reported in studies of adults. Lindemann et al,I5 however, observed a depression of platelet counts with a nadir occurring on about day 10 of rhG-CSF administration. A spontaneous recovery was observed despite continuation of rhG-CSF administration. Observations in children plus other reports suggest one of two things: (1) rhG-CSF interacts with some other regulator or (2) rhG-CSF initiates production of other hematopoietic regulators by accessory cells or some compensatory homeostatic mechanism. Previous Japanese phase I and I1 studies of rhG-CSF (KRN 8601) in normal volunteers'* and adult patients with malignant lymphomaIg suggested subcutaneous administrations at 75 and 125 pg/body were equally safe and
-
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J. OKAMURA ET A 1
effective. We therefore gave the children entered into the study rhG-CSF subcutaneously at relatively small doses, 50 &m2. Subcutaneous administration has several advantages: First, even at this low dosage, sufficient serum level of rhG-CSF needed to increase the neutrophil count can be achieved and lasts at least 8 hours (Figure 2). In contrast, pharmacokinetic study of rhGCSF in adults indicated a rapid decrease in the plasma level when it was given as a single intravenous infusion." Second, since rhG-CSF is supplied at concentrations of 250 pg/mL, only a minimum volume (usually 0.1-0.3 mL) needs to be given for the majority of children. This lessens the degree of local pain at the injected site. Third, and most important, as it is much easier to inject subcutaneously than intravenously, especially when children are young, it can be given on an outpatient basis. Results of the clinical and pharmacokinetic data observed in the present study in children support the experiences in adults. Children in the study tolerated the course well and no serious toxicity necessitating the discontinuation of rhG-CSF administration was observed. Mild bone pain was the only complaint in 3 patients (5.3%) but was not severe enough to require treatment. In contrast to the recombinant human granulocyte/macrophage colony-stimulating factor administration in children with acute lymphoblastic leukemia" and aplastic anemia," no febrile episode, skin rash, or gastrointestinal symptom was recorded among the 56 patients studied. As has been reported in adult patients, elevation of LDH level was recorded in 2 patients (3.5%), this probably being due to the reflection of rapid increase in peripheral ne~trophils.~ Hyperuricemia, which was reported in adult patients by several investigator^,^""^ was not, however, observed in any of the children studied. In conclusion, rhG-CSF appears to be well tolerated by children. It significantly reduces the severity of neutropenia induced by cytotoxic chemotherapy. The ability to administer cycles of dose-intensive therapy safely and without delay may contribute to the further improvement in the survival of children with cancer.
REFERENCES 1. Body GP, Buckley M , Sathe YS, et al. Quantitative relationships between circulating leukocytes and
infection in patients with acute leukemia. Ann Z n t m Med. 1966;64:328-340. 2 . Souza LM, Boone TC, Gabrilove J , et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986;232:61-65. 3. Kitagawa S, Yuo A, Souza LM, et al. Recombinant human granulocyte colony-stimulating factor enhances superoxide release in human granulocytes stimulated by the chemotactic peptide. Biochm Biophys Res Commun. 1987;144:1143-1146. 4. Ohsaka A, Kitagawa S, Sakamoto S, et al. In vivo activation of human neutrophil functions by administration of recombinant human granulocyte colony-stimulating factor in patients with malignant lymphoma. Blood. 1989;74:2743-2748. 5. Bronchud MH, Scarffe JH, Thatcher N, et al. Phase 1/11 study of recombinant human granulocyte
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colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer. Br J Cancn. 1987;56:809-8 13. 6. Montyn G, Campbell L, Souza LM, et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet. 1988;i:667-672. 7. Gabrilove JL, Jakubowski A, Scher H, et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbility due to chemotherapy for transitional-cell carcinoma of the urothelium. N En81 JMed. 1988;318:1414-1422. 8. Gabrilove JL, Jakubowski A, Fain K, et al. Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium. J Clin Invesf. 1988;82:1454-1461. 9. Layton JE, Hockman H, Sheridan WP, et al. Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor. Blood. 1989;74:1303-1307. 10. Duhrsen U, Villeval J-L, Boyd J, et al. Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood. 1988;72:2074-2081. 11. Sheridan WP, Morstyn G, Wolf M, et al. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lanccf. 1989;ii:891895. 12. Morstyn G, Lieschke GJ, Sheridan W, et al. Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor. Sem H d o l . 1989;26:9- 13. 13. Morstyn G, Campbell L, Lieschke G, et al. Treatment of chemotherapy-induced neutropenia by subcutaneously administered granulocyte colony-stimulating factor with optimization of dose and duration of therapy. J Clin Oncol. 1989;7:1554-1562. 14. Neidhart J, Maugalik A, Kohler W, et al. Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving dose-intensive chemotherapy without bone marrow transplantation. J Clin Oncol. 1989;7:1685-1692. 15. Lindemann A, Herrmann F, Oster W, et al. Hematologic effects of recombinant human granulocyte colony-stimulating factor in patients with malignancy. Blood. 1989;74:2644-2651. 16. Lothrop CD, Waren DJ, Souza LM, et al. Correction of canine cyclic hematopoiesis with recombinant human granulocyte colony-stimulating factor. Blood. 1988;72:1324-1328. 17. Shuening FG, Storb R, Goehle S, et al. Effects of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation. Blood. 1989;74:1308-1 3 13. 18. Azuma J, Tsuji S, Park SE, et al. Phase I study of KRN 8601 (rhG-CSF) in normal healthy volunteers: safety and pharmacokinetics in consecutive subcutaneous administration. Clin Pharmncol. 1989;5:2253-2269 (in Japanese). 19. Ogawa M, Masaoka T, Takaku F. Phase I1 study of KRN 8601 in patients with neutropenia induced by chemotherapy for malignant lymphoma. Cfin Pharmacol. 1990;6:23-40 (in Japanese). 20. Azuma J, Hamaguchi T, Seung-Eun P, et al. Phase I study of KRN 8601 (rhG-CSF) in normal healthy volunteers: safety and pharmacokinetics in single intravenous infusion. Clin Phannacol. 1989;5:15791603 (in Japanese). 21. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/ macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood. 1989;73:849-857. 22. Guinan EC, Sieff CA, Oette DH, et al. A phase 1\11 trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia. Blood. 1990;76:1077-1082. Received June 26, 1991 Accepted November 6, 1991 Addsess correspondence 60 Jun Okamura.
