Jpn J Clin Oncol 2001;31(1)43–45
Delayed Recovery of Neutrophil Counts After Peripheral Stem Cell Transplantation Which Improved with Administration of a Minimal Dose of G-CSF: A Case Report Shin Mineishi, Takeshi Saito, Yoshinobu Kanda, Ryuji Tanosaki, Kensei Tobinai and Yoichi Takaue Hematopoietic Stem Cell Transplantation/Immunotherapy Unit, National Cancer Center Hospital, Tokyo, Japan Received August 2, 2000; accepted November 1, 2000
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. Key words: stem cell transplantation – engraftment – G-CSF
INTRODUCTION 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 (GCSF) 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.
CASE REPORTS 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 × 108/kg of mononuclear cells (MNC) containing 26.3 × 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 GCSF 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
For reprints and all correspondence: Shin Mineishi, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan E-mail:
[email protected]
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 recur© 2001 Foundation for Promotion of Cancer Research
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Delayed neutrophil recovery after transplantation
rence 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 × 108/kg of MNC containing 21.7 × 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, GCSF 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 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 GCSF. 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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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.
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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. 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.
