Transfusion and Apheresis Science 50 (2014) 53–55
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Case Report
A rare but severe complication of filgrastim in a healthy donor: Splenic rupture Gulsah Akyol a,⇑, Cigdem Pala a, Afra Yildirim b, Muzaffer Keklika a, Koray Demir a, Sumeyra Dortdudak c, Serdar Sivgin a, Leylagul Kaynar a, Bulent Esera a, Ali Unal a, Mustafa Cetin a a
Erciyes Stem Cell Transplantation Center, Erciyes University, Kayseri, Turkey Radiology, Erciyes University, Kayseri, Turkey c Internal Medicine, Erciyes University, Kayseri, Turkey b
a r t i c l e
i n f o
Article history: Received 23 May 2013 Accepted 5 July 2013
Keywords: Splenic rupture Filgrastim Stem cell transplantation
a b s t r a c t Background: Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSCs) for individuals who undergo hematopoietic stem cell transplants. G-CSF administration is associated with a small but definite risks of serious adverse events like splenic rupture. Case Study: In this case, we report a 40 year old women, a healthy donor for her sister who has aplastic anemia, who had sharp left upper abdominal pain on the forth mobilization day. The diagnosis at CT scan was splenic rupture; irregular intrasplenic low-attenuation areas consistent with ruptured spleen and perisplenic high density fluid. Her bidimensional spleen size was 16 6 cm. Results: She was followed conservatively. One month later the CT scan signs of rupture disappeared. Conclusion: We must pay attention to this rare but serious adverse event during filgrastim use. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Since recombinant G-CSF was produced in the late 1980s, it has been widely used for mobilization of peripheral blood progenitor cells from healthy donors. Other clinical use areas include; acceleration of neutrophil recovery after chemotherapy in acute myeloid leukemia, bone marrow/peripheral stem cell transplantation in patients receiving myelo suppresive chemotherapy for solid as well as hematologic malignancies, and in the management of neutropenia due to other causes including AIDS and genetic disorders of granulocyte production [1]. The most common adverse events are bone pain (84%), ⇑ Corresponding author. Address: Erciyes Stem Cell Transplantation Center, Erciyes University, Kayseri 38039, Turkey. Tel.: +90 0(352) 2076666, mobile: +90 0(50) 56376776; fax: +90 0(352) 4379348. E-mail address: [email protected] (G. Akyol). 1473-0502/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.07.036
headache (80%) and fatigue [2]. Life-threatening complications such as stroke, myocardial infarction and splenic rupture, resulting from short-term or long-term use of these agents, however rare, can occur [3].
2. Case report The donor, healthy individual with a body weight of 66 kg and height of 149 cm, had no remarkable previous history except a 10 year history of smoking (10 cigarettes/day) and any physical examination abnormality. Her complete blood count, biochemistry and chest X-ray were normal. Serologic tests for hepatitis B, C and HIV were all negative.We started G-CSF (filgrastim) therapy at a dose of 11 lg kg/day (twice daily administration) for 5 days. On the forth day of mobilization, 2 h after administration of G-CSF at 06 PM, she suffered from pain in her chest bones.
54
G. Akyol et al. / Transfusion and Apheresis Science 50 (2014) 53–55
EKG findings were normal. At 10:30 PM her pain became severe and sharp and radiated to all abdominal regions. On physical assessment she had left upper tenderness and rigidity. Tachycardia (110/min) and tachypnea (30/ min) was present while significant hypotension was not seen. An abdominal computed tomography (CT) scan showed splenic rupture and perisplenic fluid (Fig. 1). There was no sudden decrease in hematocrit and haemoglobin (Hgb) levels according to the blood count, so that, at first, splenectomy was not planned and she was followed closely. We could not collect stem cells from our donor as expected due to the risk of extra bleeding with citrate usage during apheresis and she refused collection of stem cells from her bone marrow. When the Hgb decreased of 2 g/dl and the hematocrit decreased to a value of 28.5%, we replaced her with one unit of a red cell suspension (Table 1). One month later the CT scan showed that the signs of rupture had disappeared (Fig. 2).
Table 1 Daily complete blood count and follow up after rupture. Hgb (g/dl)
Hct
WBC (lL)
plt (lL)
12.7 11.8 11.2
38.0 35.2 31.3
7250 47,600 59,250
326.000 302.000 321.000
Day 1
9.2 9.1
28.5 27.2
61,510 59,400
320.000 263.000
Day 2
9.4 9.2
28.5 28.1
52,830 44,610
278.000 243.000
Day 3
8.9 8.9 9.6
28.0 27.6 28.9
36,600 28,680 28,440
204.000 188.000 193.000
Day 4
9.2
27.9
21,420
156.000
Day 5
9.4
27.4
16,350
155.000
Hospitalization day Splenic rupture day 0
Hgb: hemoglobin, WBC: white blood cell, plt: platelet, Hct: hemotocrit.
3. Discussion G-CCF administration is thought to be safe. The complications are mostly mild and moderate [4]. There are rare life-threatening adverse effects published in literature. Splenic rupture is the one sample of this complications and most of them were successfully treated by emergent splenectomy operation [5–8]. We have consulated our patient to general surgery department and they took care of patient closely one week. Splenectomy was not performed as not indicated. May be we diagnosed splenic rupture early and discontinued filgrastim apply. We believe bleeding and damage stopped. The size of spleen is not important as risk of rupture during stem cell mobilisation with G-CSF. Spleen size is observed to increase significant at day 4–6 [9]. And in a study of spleen size assessment after G-CSF mobilisation procedure in 304 voluntary donors, mean spleen enlargement volume was 1.47-fold (0.63–2.60). Spleen volume fold change was not correlated with filgrastim _ seven dosage, absolute neutrofil counts, CD34+ count. In days after apheresis, spleen size returned normal and no rupture case was reported [10]. But in our case when her clinical status worsened at forth day, maximum spleen length in computed tomography scan was 16 6 cm.
Fig. 2. Axial contrast CT scan obtained 1 month later, shows normal spleen size and appearance.
Her initial symptoms were not specific to spleen region. She described pain at chest bones. We first thought that it was bone pain related to G-CSF. We had counted white blood cells, CD34+ cells daily. We used 11 lg/kg/day of Filgrastim. At the time of first complaints, the white blood cell count was: 47,700/lL. That is advised that to stop or taper G-CSF administration while white blood cell count is over 50,000 per ml. Most rupture cases in literature occur during or after _ this case apheresis or after day of five [3,5,6,11–13]. In splenic rupture occured at forth day and before apheresis. May be this is the reason that we did not need splenectomy
Fig. 1. Contrast-enhanced CT scan of the upper abdomen reveals irregular intrasplenic low-attenuation areas (arrows) consistent with ruptured spleen and perisplenic high density fluid (50 HU) compatible with blood. HU: Hounsfield unit.
G. Akyol et al. / Transfusion and Apheresis Science 50 (2014) 53–55
as early detection. But we are unlucky we could not be able to collect stem cell. We should take care of splenic rupture in patients, previously administrated G-CSF and suffer from sharp and sudden abdominal pain. Monitoring of G-CSF recipients must include; close monitoring vital signs, abdominal physical examination, daily complete blood count, as needed computed tomography and abdominal ultrasonography. Donors should be informed about this rare but fatal complication and avoid difficult activities. References [1] Dale DC. The discovery, development and clinical applications of granulocyte colony-stimulating factor. Trans Am Clin Climatol Assoc 1998;109:27–36. [2] Morstyn G, Campbell L, Souza LM, et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988;1:667–72. [3] Nuamah NM, Goker H, Kilic YA, Dagmoura H, Cakmak A. Spontaneous splenic rupture in a healthy allogeneic donor of peripheral-blood stem cell following the administration of granulocyte colony-stimulating factor (G-CSF). A case report and review of the literature. Haematologica 2006;91:ECR08. [4] Borletts Jan CC, Bosschaert Mike, Vrehen Henk M, et al. Effect of escalating doses of recombinant human granulocyte colony stimulating factor (Filgrastim) on circulating neutrophils in healthy subjects. Clin Therap 1998;20(4):722–36.
55
[5] Falzetti F, Aversa F, Minelli O, Tabilio A. Spontaneous rupture of spleen during peripheral blood stem-cell mobilization in a healthy donor. Lancet 1999;353:555. [6] Balaguer H, Galmes A, Ventayol G, Bargay J, Besalduch J. Splenic rupture after granulocyte-colony-stimulating factor mobilization in a peripheral blood progenitor cell donor. Transfusion 2004;44:1260–1. [7] Kasper C, Jones L, Fujita Y, Morgenstern GR, Scarffe JH, Chang J. Splenic rupture in a patient with acute myeloid leukemia undergoing peripheral blood stem cell transplantation. Ann Hematol 1999;78:91–2. [8] Pitini V, Ciccolo A, Arrigo C, Aloi G, Micali C, La Torre F. Spontaneous rupture of spleen during peripheral stem-cell mobilization in a patient with breast cancer. Haematologica 2000;85:559–60. [9] Stroncek David, Shawker Thomas, Follmann Dean, Leitman SusanF. G-CSF-induced spleen size changes in peripheral blood progenitor cell donors. Transfusion 2003;43:609–13. [10] Stiff Patrick J, Bensinger William, Abidi Muneer H, et al. Clinical and ultrasonic evaluation of spleen size during peripheral blood progenitor cell mobilization by filgrastim: results of an open-label trial in normal donors. Biol Blood Marrow Transpl 2009;15:827–34. [11] Becker PS, Wagle M, Matous S, et al. Spontaneous splenic rupture following administration of granulocyte colony stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells. Biol Blood Marrow Transpl 1997;3:45–9. [12] Dincer AP, Gottschall J, Margolis DA. Splenic rupture in a parental donor undergoing peripheral blood progenitor cell mobilization. J Pediatr Hematol Oncol 2004;26:761–3. [13] Kröger N, Renges H, Sonnenberg S, et al. Stem cell mobilisation with 16 mg/kg vs 10 mg/kg of G-CSF for allogeneic transplantation in healthy donors. Bone Marrow Transpl 2002;29:727–30.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Case Report
A rare but severe complication of filgrastim in a healthy donor: Splenic rupture Gulsah Akyol a,⇑, Cigdem Pala a, Afra Yildirim b, Muzaffer Keklika a, Koray Demir a, Sumeyra Dortdudak c, Serdar Sivgin a, Leylagul Kaynar a, Bulent Esera a, Ali Unal a, Mustafa Cetin a a
Erciyes Stem Cell Transplantation Center, Erciyes University, Kayseri, Turkey Radiology, Erciyes University, Kayseri, Turkey c Internal Medicine, Erciyes University, Kayseri, Turkey b
a r t i c l e
i n f o
Article history: Received 23 May 2013 Accepted 5 July 2013
Keywords: Splenic rupture Filgrastim Stem cell transplantation
a b s t r a c t Background: Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSCs) for individuals who undergo hematopoietic stem cell transplants. G-CSF administration is associated with a small but definite risks of serious adverse events like splenic rupture. Case Study: In this case, we report a 40 year old women, a healthy donor for her sister who has aplastic anemia, who had sharp left upper abdominal pain on the forth mobilization day. The diagnosis at CT scan was splenic rupture; irregular intrasplenic low-attenuation areas consistent with ruptured spleen and perisplenic high density fluid. Her bidimensional spleen size was 16 6 cm. Results: She was followed conservatively. One month later the CT scan signs of rupture disappeared. Conclusion: We must pay attention to this rare but serious adverse event during filgrastim use. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Since recombinant G-CSF was produced in the late 1980s, it has been widely used for mobilization of peripheral blood progenitor cells from healthy donors. Other clinical use areas include; acceleration of neutrophil recovery after chemotherapy in acute myeloid leukemia, bone marrow/peripheral stem cell transplantation in patients receiving myelo suppresive chemotherapy for solid as well as hematologic malignancies, and in the management of neutropenia due to other causes including AIDS and genetic disorders of granulocyte production [1]. The most common adverse events are bone pain (84%), ⇑ Corresponding author. Address: Erciyes Stem Cell Transplantation Center, Erciyes University, Kayseri 38039, Turkey. Tel.: +90 0(352) 2076666, mobile: +90 0(50) 56376776; fax: +90 0(352) 4379348. E-mail address: [email protected] (G. Akyol). 1473-0502/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.07.036
headache (80%) and fatigue [2]. Life-threatening complications such as stroke, myocardial infarction and splenic rupture, resulting from short-term or long-term use of these agents, however rare, can occur [3].
2. Case report The donor, healthy individual with a body weight of 66 kg and height of 149 cm, had no remarkable previous history except a 10 year history of smoking (10 cigarettes/day) and any physical examination abnormality. Her complete blood count, biochemistry and chest X-ray were normal. Serologic tests for hepatitis B, C and HIV were all negative.We started G-CSF (filgrastim) therapy at a dose of 11 lg kg/day (twice daily administration) for 5 days. On the forth day of mobilization, 2 h after administration of G-CSF at 06 PM, she suffered from pain in her chest bones.
54
G. Akyol et al. / Transfusion and Apheresis Science 50 (2014) 53–55
EKG findings were normal. At 10:30 PM her pain became severe and sharp and radiated to all abdominal regions. On physical assessment she had left upper tenderness and rigidity. Tachycardia (110/min) and tachypnea (30/ min) was present while significant hypotension was not seen. An abdominal computed tomography (CT) scan showed splenic rupture and perisplenic fluid (Fig. 1). There was no sudden decrease in hematocrit and haemoglobin (Hgb) levels according to the blood count, so that, at first, splenectomy was not planned and she was followed closely. We could not collect stem cells from our donor as expected due to the risk of extra bleeding with citrate usage during apheresis and she refused collection of stem cells from her bone marrow. When the Hgb decreased of 2 g/dl and the hematocrit decreased to a value of 28.5%, we replaced her with one unit of a red cell suspension (Table 1). One month later the CT scan showed that the signs of rupture had disappeared (Fig. 2).
Table 1 Daily complete blood count and follow up after rupture. Hgb (g/dl)
Hct
WBC (lL)
plt (lL)
12.7 11.8 11.2
38.0 35.2 31.3
7250 47,600 59,250
326.000 302.000 321.000
Day 1
9.2 9.1
28.5 27.2
61,510 59,400
320.000 263.000
Day 2
9.4 9.2
28.5 28.1
52,830 44,610
278.000 243.000
Day 3
8.9 8.9 9.6
28.0 27.6 28.9
36,600 28,680 28,440
204.000 188.000 193.000
Day 4
9.2
27.9
21,420
156.000
Day 5
9.4
27.4
16,350
155.000
Hospitalization day Splenic rupture day 0
Hgb: hemoglobin, WBC: white blood cell, plt: platelet, Hct: hemotocrit.
3. Discussion G-CCF administration is thought to be safe. The complications are mostly mild and moderate [4]. There are rare life-threatening adverse effects published in literature. Splenic rupture is the one sample of this complications and most of them were successfully treated by emergent splenectomy operation [5–8]. We have consulated our patient to general surgery department and they took care of patient closely one week. Splenectomy was not performed as not indicated. May be we diagnosed splenic rupture early and discontinued filgrastim apply. We believe bleeding and damage stopped. The size of spleen is not important as risk of rupture during stem cell mobilisation with G-CSF. Spleen size is observed to increase significant at day 4–6 [9]. And in a study of spleen size assessment after G-CSF mobilisation procedure in 304 voluntary donors, mean spleen enlargement volume was 1.47-fold (0.63–2.60). Spleen volume fold change was not correlated with filgrastim _ seven dosage, absolute neutrofil counts, CD34+ count. In days after apheresis, spleen size returned normal and no rupture case was reported [10]. But in our case when her clinical status worsened at forth day, maximum spleen length in computed tomography scan was 16 6 cm.
Fig. 2. Axial contrast CT scan obtained 1 month later, shows normal spleen size and appearance.
Her initial symptoms were not specific to spleen region. She described pain at chest bones. We first thought that it was bone pain related to G-CSF. We had counted white blood cells, CD34+ cells daily. We used 11 lg/kg/day of Filgrastim. At the time of first complaints, the white blood cell count was: 47,700/lL. That is advised that to stop or taper G-CSF administration while white blood cell count is over 50,000 per ml. Most rupture cases in literature occur during or after _ this case apheresis or after day of five [3,5,6,11–13]. In splenic rupture occured at forth day and before apheresis. May be this is the reason that we did not need splenectomy
Fig. 1. Contrast-enhanced CT scan of the upper abdomen reveals irregular intrasplenic low-attenuation areas (arrows) consistent with ruptured spleen and perisplenic high density fluid (50 HU) compatible with blood. HU: Hounsfield unit.
G. Akyol et al. / Transfusion and Apheresis Science 50 (2014) 53–55
as early detection. But we are unlucky we could not be able to collect stem cell. We should take care of splenic rupture in patients, previously administrated G-CSF and suffer from sharp and sudden abdominal pain. Monitoring of G-CSF recipients must include; close monitoring vital signs, abdominal physical examination, daily complete blood count, as needed computed tomography and abdominal ultrasonography. Donors should be informed about this rare but fatal complication and avoid difficult activities. References [1] Dale DC. The discovery, development and clinical applications of granulocyte colony-stimulating factor. Trans Am Clin Climatol Assoc 1998;109:27–36. [2] Morstyn G, Campbell L, Souza LM, et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988;1:667–72. [3] Nuamah NM, Goker H, Kilic YA, Dagmoura H, Cakmak A. Spontaneous splenic rupture in a healthy allogeneic donor of peripheral-blood stem cell following the administration of granulocyte colony-stimulating factor (G-CSF). A case report and review of the literature. Haematologica 2006;91:ECR08. [4] Borletts Jan CC, Bosschaert Mike, Vrehen Henk M, et al. Effect of escalating doses of recombinant human granulocyte colony stimulating factor (Filgrastim) on circulating neutrophils in healthy subjects. Clin Therap 1998;20(4):722–36.
55
[5] Falzetti F, Aversa F, Minelli O, Tabilio A. Spontaneous rupture of spleen during peripheral blood stem-cell mobilization in a healthy donor. Lancet 1999;353:555. [6] Balaguer H, Galmes A, Ventayol G, Bargay J, Besalduch J. Splenic rupture after granulocyte-colony-stimulating factor mobilization in a peripheral blood progenitor cell donor. Transfusion 2004;44:1260–1. [7] Kasper C, Jones L, Fujita Y, Morgenstern GR, Scarffe JH, Chang J. Splenic rupture in a patient with acute myeloid leukemia undergoing peripheral blood stem cell transplantation. Ann Hematol 1999;78:91–2. [8] Pitini V, Ciccolo A, Arrigo C, Aloi G, Micali C, La Torre F. Spontaneous rupture of spleen during peripheral stem-cell mobilization in a patient with breast cancer. Haematologica 2000;85:559–60. [9] Stroncek David, Shawker Thomas, Follmann Dean, Leitman SusanF. G-CSF-induced spleen size changes in peripheral blood progenitor cell donors. Transfusion 2003;43:609–13. [10] Stiff Patrick J, Bensinger William, Abidi Muneer H, et al. Clinical and ultrasonic evaluation of spleen size during peripheral blood progenitor cell mobilization by filgrastim: results of an open-label trial in normal donors. Biol Blood Marrow Transpl 2009;15:827–34. [11] Becker PS, Wagle M, Matous S, et al. Spontaneous splenic rupture following administration of granulocyte colony stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells. Biol Blood Marrow Transpl 1997;3:45–9. [12] Dincer AP, Gottschall J, Margolis DA. Splenic rupture in a parental donor undergoing peripheral blood progenitor cell mobilization. J Pediatr Hematol Oncol 2004;26:761–3. [13] Kröger N, Renges H, Sonnenberg S, et al. Stem cell mobilisation with 16 mg/kg vs 10 mg/kg of G-CSF for allogeneic transplantation in healthy donors. Bone Marrow Transpl 2002;29:727–30.
