Japanese Journal of Clinical Oncology 31:43-45 (2001)
© 2001 Foundation for Promotion of Cancer Research
Delayed Recovery of Neutrophil Counts After Peripheral Stem Cell Transplantation Which Improved with Administration of a Minimal Dose of G-CSF: A Case Report
Hematopoietic Stem Cell Transplantation/Immunotherapy Unit, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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G-CSF administration may not affect the rate of engraftment unless sufficient numbers of stem cells are transplanted. However, there might be some cases in which neutrophil recovery is delayed after stem cell transplantation despite a relatively fast recovery of platelet counts and total white blood cell counts. This delayed engraftment might be observed in either autologous or allogeneic stem cell transplantation. Here we report four cases with delayed neutrophil engraftment which subsequently improved with administration of a minimal dose of G-CSF. As the response occurred on the day following G-CSF administration, a mobilization defect is suspected to be the mechanism of this delayed engraftment.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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High-dose chemotherapy with peripheral blood stem cell (PBSC) transplantation is commonly performed as part of standard treatment options for various malignancies. There is, however, significant controversy regarding the use of hematopoietic growth factors after transplantation. Some reports demonstrated that the recovery of blood counts was faster if growth factors were given after transplantation (1,2). In contrast, other data suggested that the number of transplanted CD34+ cells was more important (3). One report claims that post-transplant growth factors had only a minimal effect on engraftment if stem cells were mobilized with chemotherapy and a growth factor (4). There is some suggestion that the individualized use of granulocyte-colony stimulating factor (G-CSF) is most appropriate (5). Recently, we experienced several cases of patients who had very slow neutrophil recovery despite the fact that relatively large numbers of CD34+ cells were infused and fast recovery of total white blood cell (WBC) count and/or platelet counts was observed. In these cases a single injection of G-CSF significantly increased neutrophil counts by the following day.
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CASE REPORTS |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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Case 1
The patient was a 53-year-old male, diagnosed as multiple myeloma in May 1997. He was treated with VAD (vincristine, adriamycin, dexamethasone) combination chemotherapy for three cycles and then received high-dose cyclophosphamide followed by subcutaneous G-CSF injections for stem cell mobilization and autologous PBSC collection. He then proceeded to autologous PBSC transplantation in May 1998. After receiving conditioning therapy consisting of melphalan (140 mg/m2) and total body irradiation (TBI) at 12 Gy in eight fractions, he received 4.05 x 108/kg of mononuclear cells (MNC) containing 26.3 x 106/kg of CD34+ cells. He had an uneventful post-transplant course except for a delayed recovery of neutrophils, although his total WBC and platelet counts recovered relatively quickly. On day 11, his WBC count was 1200/µl, but his absolute neutrophil count (ANC) was only 48/µl and his platelet count was 115 000/µl. He was given one dose of G-CSF at a dose of 480 µg by subcutaneous injection on day 11. The next day his WBC was up to 4000/µl and his ANC was 1400/µl. He did not receive any additional G-CSF injections, but his ANC subsequently stayed above 1000/µl. His antibiotics were discontinued one by one starting on day 12 post-transplant. He was discharged to home on day 17.
Case 2
The patient was a 40-year-old female, diagnosed as stage II breast cancer in May 1994. She was free of disease after surgery (modified radical mastectomy). She had a local recurrence in 1996 and metastatic disease in 1997. She received CAF (cyclophosphamide, adriamycin, 5-fluorouracil) treatment and showed partial remission. She then had PBSC mobilization and collection following high-dose cyclophosphamide and subcutaneous G-CSF injections. After conditioning with cyclophosphamide, thiotepa and carboplatin, she received autologous PBSC transplantation consisting of 7.45 x 108/kg of MNC containing 21.7 x 106/kg of CD34+ cells in June 1998. Her post-transplant course was uneventful. Some neutrophils were seen in her peripheral blood as early as day 9. By day 13 she had a total WBC count of 2200/µl and her platelet count was 86 000/µl, but her ANC was only 370/µl. On day 13, G-CSF was given at 5 µg/kg by subcutaneous injection, then her WBC count increased to 5400/µl by the next day with ANC of 4000/µl. Her WBC and ANC remained above 3000 and 1000/µl, respectively, without any further G-CSF injections.
Case 3
A 62-year-old female with stage IIIB ovarian cancer, diagnosed in September 1995, underwent surgical debulking followed by four courses of taxol and cisplatin and two courses of taxol and carboplatin. She was in complete remission for more than 1 year but relapsed in November 1997. Laparoscopy showed multiple small nodules in her pelvic wall, all <5 mm in diameter. She received a course of carboplatin to evaluate chemotherapy responsiveness, to which she responded well. Then high-dose cyclophosphamide and subcutaneous G-CSF injections were given to mobilize PBSC. PBSC collection was done by apheresis. After conditioning with cyclophosphamide 40 mg/kg/day x 3, mitoxantrone 25 mg/m2/day x 3 and carboplatin 3400 mg as a 5-day continuous intravenous infusion, the patient underwent stem cell transplantation, receiving 2.41 x 108/kg of MNC containing 20.6 x 106/kg of CD34+ cells in June 1998. Her ANC was 380/µl by day 12. However, her ANC did not subsequently increase. On day 16, her WBC was 900/µl and her ANC was 360/µl, although her platelet count was already 238 000/µl. She was given a dose of G-CSF injection subcutaneously on that day and by the next day her WBC was 5000/µl, ANC 4200/µl and platelet count 237 000/µl. She did not require any additional G-CSF injections.
Case 4
The patient was a 46-year-old woman who was diagnosed as chronic myelogenous leukemia in the first chronic phase. The donor, her HLA-matched brother, was given G-CSF 5 µg/kg subcutaneously twice a day and PBSC harvesting was performed. The total number of harvested PBSC was 4.07 x 106 CD34+ cells/kg. She underwent allogeneic PBSC transplantation following the conditioning therapy with busulfan and cyclophosphamide in October 1999. The patient had delayed engraftment after transplantation, although she had an uneventful post-transplant course. Her neutrophil count did not exceed 300/µl by day 19 after transplantation, although her platelet count was already 112 000/µl and her oral mucositis was already improving by that time. She was given one subcutaneous injection of G-CSF 5 µg/kg and the next day her WBC count was 17 900/µl with ANC of 15 400/µl.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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G-CSF has been used to stimulate granulocyte recovery after stem cell transplantation. However, recent evidence shows that G-CSF may not have much effect on the neutrophil recovery rate if the number of CD34+ cells transplanted is adequate (6). In our institution, we did not see a significant difference in engraftment of neutrophils between groups receiving or not receiving G-CSF post-transplant (data not shown). There are some patients, however, in whom neutrophil recovery is delayed despite good MNC and/or CD34+ cell numbers transplanted, while total WBC counts and platelet counts have recovered quickly. In these patients, one or a few doses of G-CSF injections may accelerate neutrophil recovery significantly.
There could be many possible causes of the delayed neutrophil recovery after stem cell transplantation, e.g. delayed maturation of neutrophils. Decreased homing efficiency of stem cells and also abnormal neutrophil distribution may also play a role. However, in the cases presented here, the neutrophil count recovered to >500/µl after only one injection of G-CSF. As it may take more than a few days to stimulate the maturation of neutrophils from progenitors, delayed maturation is not likely to be the mechanism of delayed neutrophil recovery in these cases. Similarly, if the homing defect of the stem cells is the cause, only one injection of G-CSF would not solve the problem. Hence the mechanism of this phenomenon is most likely related to the abnormal distribution of mature neutrophils, i.e. neutrophils do not migrate into the peripheral blood for some reason. These neutrophils may be mobilized into peripheral blood after only one or a few injections of G-CSF.
This report suggests that, although it may be true that G-CSF does not accelerate the engraftment of granulocytes in patients who have received a large number of CD 34+ cells, there are occasional patients in whom a mobilization defect of neutrophils may prevent early engraftment. These cases may be observed in either autologous or allogeneic stem cell transplantation. In these cases, just one or a few injections of G-CSF may help to accelerate the recovery of neutrophil counts. Hence more individualized use of G-CSF may be advisable, particularly for cases such as these.
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FOOTNOTES |
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+ For reprints and all correspondence: Shin Mineishi, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan E-mail: smineish@ncc.go.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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1 Klumpp TR, Mangan KF, Goldberg SL, Pearlman ES, Macdonald JS. Granulocyte colony-stimulating factor accelerates neutrophil engraftment following peripheral-blood stem-cell transplantation: a prospective, randomized trial. J Clin Oncol 1995;13:1323–7.[Abstract]
2 Tarella C, Castellino C, Locatelli F, Caracciolo D, Corradini P, Falda M, et al. G-CSF administration following peripheral blood progenitor cell (PBPC) autograft in lymphoid malignancies: evidence for clinical benefits and reduction of treatment costs. Bone Marrow Transplant 1998;21:401–7.[Web of Science][Medline]
3 Ketterer N, Salles G, Raba M, Espinouse D, Sonet A, Tremisi P, et al. High CD34 (+) cell counts decrease hematologic toxicity of autologous peripheral blood progenitor cell transplantation. Blood 1998;91:3148–55.
4 Van Hoef ME. Haematological recovery after high-dose consolidation chemotherapy with peripheral blood progenitor cell rescue: the effects of the mobilization regimen and post-transplant growth factors. Neth J Med 1998;52:30–9.[Web of Science][Medline]
5 Cetkovsky P, Koza V, Jindra P, Skopek P, Svojgrova M. Individual criteria could be optimal for starting G-CSF application after autologous stem cell transplantation. Bone Marrow Transplant 1997;20:639–41.[Web of Science][Medline]
6 Kawano Y, Takaue Y, Mimaya J, Horikoshi Y, Watanabe T, Abe T, et al. Marginal benefit/disadvantage of granulocyte colony-stimulating factor therapy after autologous blood stem cell transplantation in children: results of a prospective randomized trial. Blood 1998;92:4040–6.
Received August 2, 2000; accepted November 1, 2000.
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