Bone Marrow Transplantation (2011) 46, 291–293 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11
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ORIGINAL ARTICLE
Low risk of symptomatic venous thromboembolic events during growth factor administration for PBSC mobilization HV Naina, RK Pruthi, DJ Inwards, D Dingli, MR Litzow, SM Ansell, HJ William, A Dispenzieri, FK Buadi, MA Elliott, DA Gastineau, MA Gertz, SR Hayman, PB Johnston, MQ Lacy, IN Micallef, LF Porrata and S Kumar Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA
The use of erythropoietic agents has been associated with an increased risk of venous thromboembolic events (VTEs), especially in patients with underlying malignancies. However, it is not known whether there is an increased risk of VTE associated with granulocyte growth factors. We reviewed 621 patients undergoing PBSC mobilization using granulocyte growth factors, alone or in combination with CY. Patients with a diagnosis of AL amyloidosis (AL: 114; 18%), multiple myeloma (MM: 278; 44%) Hodgkin lymphoma (HL: 20; 3%) or nonHodgkin lymphoma (NHL: 209; 33%) were included. Symptomatic VTE occurred in six (0.97%) patients: two AL, two MM and two NHL. Of the six patients, two had pulmonary embolism, one developed deep vein thrombosis and three developed symptomatic catheter related thrombosis. Two patients with AL had heparin-induced thrombocytopenia and thrombosis. We found a low incidence of VTE among patients undergoing PBSC mobilization. Bone Marrow Transplantation (2011) 46, 291–293; doi:10.1038/bmt.2010.106; published online 3 May 2010 Keywords: stem cell mobilization; G-CSF; venous thrombosis
Introduction Peripheral blood is currently the most common source of hematopoietic stem cells for Auto-SCT and G-CSF is the most commonly used cytokine for peripheral blood stem cell mobilization (PBSCM). Recent studies have shown that 3.7–4.6% of patients undergoing PBSCT developed symptomatic venous thromboembolic events (VTEs).1,2 Several clinical and biological observations raise concerns about the possibility that G-CSF might induce a hypercoagulable
Correspondence: Dr S Kumar, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55906, USA. E-mail:
[email protected] Received 10 July 2009; revised 9 March 2010; accepted 17 March 2010; published online 3 May 2010
state and consequently, increase the risk of thrombosis. There are reports of arterial thrombosis occurring in healthy donors during PBSCM.3 One showed a significant increase in thrombin/antithrombin complex, prothrombin fragment F 1 þ 2 (F1 þ 2), thrombomodulin, factor VIII, von Willebrand factor antigen and activity following G-CSF.4 Platelet aggregation studies have shown hypercoagulability after G-CSF administration in stem cell donors. The high doses of growth factors used for PBSCM could potentially lead to a hypercoagulable state with increased risk for VTE. No studies have been conducted to systematically assess the incidence of VTE occurring in patients with hematological malignancies during PBSCM. It should be noted that these patients have multiple other risk factors for VTE, including the presence of apheresis catheters, heparin administration leading to risk of heparin-induced thrombocytopenia (HIT), underlying malignancy and chemotherapy, either for mobilization or before mobilization.
Materials and methods Patients We reviewed the outcome among patients with hematologic malignancies undergoing PBSCM for Auto-SCT at Mayo Clinic between 2000 and 2008. Patients with a diagnosis of AL amyloidosis (AL), multiple myeloma (MM), Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) were included. Data from patients undergoing Auto-SCT are captured prospectively into a database that is continuously updated. Complete follow-up was available for all patients. Approval of Mayo Foundation Institutional Review Board was obtained in accordance with Federal regulations and the Declaration of Helsinki Principles. Stem cell mobilization Stem cells were collected using G-CSF alone in 448/621 patients (72%). G-CSF was administered once a day subcutaneously (10 mcg/kg) until the completion of collection with aphereses beginning on the fifth day after starting G-CSF. In 134/621 (22%) patients, stem cells were collected after administration of CY 1.5 g/m2 per day for 2 consecutive days, followed by GM-CSF or G-CSF at
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5 mcg/kg starting on day 3 and continuing through the period of neutropenia. The remaining patients were mobilized using a combination of G-CSF and GM-CSF (30; 4.8%) or using plerixafor along with G-CSF (9; 1.4%). Patients received a regime of either G-CSF 10 mcg/kg or GM-CSF 250 mcg/m2 subcutaneously once daily until apheresis was completed. Patients who did not achieve either a cell count nadir of 2 106 CD34 þ cells per kg after 4 days of apheresis or a peripheral blood CD34 count of 410 per mL after 5 days of G-CSF had their dose of G-CSF increased to 16 mcg/kg per dose twice daily. Those who failed to show an effect with the increased dose of G-CSF received GM-CSF 10 mcg/kg/day for 2 days followed by G-CSF 16 mcg/kg/day subcutaneously until stem cell collection was completed. A tunneled central venous catheter was placed before the PBCSM in the majority of patients. To maintain the patency of the central venous catheter, 5 mL of 0.9% preservative free normal saline is used routinely after the administration of medication and blood products. In the outpatient setting, patients use 5 mL of heparin (10 U/mL) every 24 h to maintain the patency. A diagnosis of growth factor-associated thrombosis was made if a patient developed VTE between day 0 and day 14 after the administration of the growth factors. Individual electronic medical records were searched for a diagnosis of pulmonary embolism (PE), catheter-associated thrombosis (CAT) or deep vein thrombosis (DVT). The diagnosis of VTE was confirmed by either ultrasound or CT using a PE protocol. A diagnosis of HIT was made, where applicable, based on clinical and laboratory testing with ELISA for platelet factor 4-heparin Abs.
Results A total of 621 consecutive patients underwent stem cell mobilization. The median age of the patients was 57 years (range 17–77); and 375 (59%) were men. Of the 621 patients, 278 (44%) had MM, 209 (33%) had NHL, 114
Table 1
(18%) had AL and 20 (3%) had HL. Of the 621 patients, 34 (5.5%) patients had a history of VTE requiring anticoagulation. We identified 6 (0.97%) patients with symptomatic VTE occurring between initiation of growth factors and stem cell transplant: two patients with amyloidosis, two with MM, and two with NHL. Of the six patients, two had PE, one developed DVT and three patients developed symptomatic CAT. Only one patient had a history of VTE. The median interval from the start of growth factor to VTE was 5 (range 2–11) days. Of the six patients, four received G-CSF alone, two received GM-CSF and CY. The median Hb, platelet count and WBC count on the day of VTE diagnosis were 10.7 g/100 mL (range 7.6–11.8), 154 (range 83–277 109 per L) and 31.5 109 per L (1–106), respectively. The two patients with amyloidosis and VTE had developed HIT. HIT presented as PE in one patient whereas the other patient developed CAT. Both patients with HIT were started on direct thrombin inhibitors. Of the three patients who developed CAT, the catheter was removed in two patients. One patient who developed femoral DVT had a history of thrombosis and was managed with long-term anticoagulation. The remaining five patients did not have a history of VTE (Table 1). There were no patient deaths as a result of the VTE episodes.
Discussion The incidence of symptomatic CAT during PBSCM has been reported to be 1.8–10.6%.5,6 In our cohort, only 0.5% of the patients developed symptomatic CAT during PBSCM. Stephens et al.7 compared normal saline and heparin flush for maintaining central venous catheter patency during PBSCM. They did not find a significant difference in study end points such as slow apheresis flow, urokinase use for thrombolysis and radiographic evidence of CAT between heparin and saline flush. One interesting observation by Stephens et al.7 was an increased incidence of CAT with GM-CSF as compared to G-CSF. Of our
Patient characteristics at diagnosis of VTE
Age Diagnosis Chemo in last 4 weeks Chemo agents before PBSCM History of VTE Mobilizing agent Interval between growth factor and VTE Anticoagulation at the time of VTE Site of VTE WBC 109 per L Platelet 109 per L HIT Immediate treatment
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
64 MM Yes Thalidomide/ dexamethasone Yes GM-CSF+CY 11 Yes Superficial femoral vein 1 203 No LMWH
47 AL No None
70 MM Yes Dexamethasone
46 AL No None
70 NHL Yes RICE
56 NHL No DHAP
No G-CSF 5 No PE
No G-CSF 2 No PE
No G-CSF 9 No IJV thrombus
No G-CSF 5 No IJV thrombus
No GM-CSF+CY 5 No IJV thrombus
16.1 83 Yes Argatroban
34.1 277 No LMWH
66.8 116 Yes Lepirudin
29 120 No LMWH
106 188 No LMWH
Abbreviations: AL ¼ AL amyloidosis; MM, ¼ multiple myeloma; NHL ¼ non-Hodgkin lymphoma; IJV ¼ internal jugular vein; LMWH ¼ low-molecularweight heparin; PE ¼ pulmonary embolism; RICE ¼ rituximab, ifosfamide, carboplatin, etoposide; VTE ¼ venous thromboembolic event. Bone Marrow Transplantation
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patients, 72% received G-CSF only and only two patients developed CAT. In this study, two patients who had PBSCM with G-CSF developed symptomatic HIT. HIT is caused by platelet-activating Abs of IgG class that recognize complexes of platelet factor 4 and heparin (or certain other polyanions). The risk of developing HIT during catheter flushes has been reported to be o0.1%.8 Both patients’ PBSCT was temporarily held due to HIT. They were treated with direct thrombin inhibitors and later switched to oral anticoagulation. One patient underwent PBSCT without heparin flushes, whereas the other patient is still receiving anticoagulation. Although thrombocytopenia is common after PBSCM, HIT is never reported.9 Though rare, HIT should be considered as a possible cause of thrombocytopenia in patients undergoing PBSCM. In a prospective study on the effects of G-CSF on hemostasis, LeBlanc et al. did not find a significant increase in platelet factor 4 activation. They also showed a decrease in final percentage of ADP induced platelet aggregation whereas Kuroiwa et al. showed an increase in platelet aggregation.4,10 Prophylactic anticoagulation to prevent CAT is not routinely used. Recent studies suggest that thromboprophylaxis with either low-molecular-weight heparin (LMWH) or low-dose warfarin does not prevent symptomatic CAT in patients with cancer.11,12 In view of the low incidence of CAT in this patient population, and the risk of bleeding during periods of thrombocytopenia, routine prophylactic anticoagulation or aspirin does not appear to be warranted. In a retrospective study, Hong et al.13 showed that central venous catheters contribute to the development of upper extremity DVT among patients with HIT. In our series, one patient developed HIT who presented with CAT. In conclusion, we found a low incidence of VTE among patients undergoing stem cell mobilization (0.97%). It is not clear whether growth factor administration precipitated the VTE. We hypothesize that growth factor may be one of the contributing factors for the symptomatic VTE; however, we cannot make a causal relationship between the growth factors and VTE due to the retrospective nature of the study. Other causes, such as HIT, should be taken into consideration and appropriate work up initiated when VTE occurs in the setting of PBSCM.
Conflict of interest The authors declare no conflict of interest.
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