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Originally published as JCO Early Release 10.1200/JCO.2006.06.4238 on September 25 2006 © 2006 American Society of Clinical Oncology. Case-Control Comparison of At-Home to Total Hospital Care for Autologous Stem-Cell Transplantation for Hematologic Malignancies
From the Department of Hematology, Institute of Hematology and Oncology, IDIBAPS, Postgraduate School of Hematology Farreras Valentí, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Spain Address reprint requests to Francesc Fernández-Avilés, MD, Institute of Haematology and Oncology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; e-mail: ffernand{at}clinic.ub.es
PURPOSE: One of the most significant limitations of at-home autologous stem-cell transplantation (ASCT) is the necessity for hospital readmission. We developed an at-home ASCT program in which prophylactic ceftriaxone and treatment of febrile neutropenia with piperacillin and tazobactam was introduced to minimize the readmission rate. PATIENTS AND METHODS: Between November 2000 and February 2005, 178 consecutive patients underwent ASCT for a hematologic malignancy. Of these, 50 patients fulfilled the requirements for at-home ASCT. Results were compared with those observed in a control group of 50 patients individually matched to the group of patients treated at home for age, sex, diagnosis, stage of disease, conditioning, and source of stem cells.
RESULTS: Febrile neutropenia occurred in fewer patients in the at-home group as compared with the hospitalized group (76% v 96%: P = .008), and duration of fever was also shorter in the at-home group (median, 2 and 6 days, respectively; range, 1 to 11 and 1 to 20 days, respectively; P = .00003). Hospital readmission in the at-home group was required in only four cases (8%). This resulted in a reduction of 18.6 days of hospitalization per patient. Likewise, total median charges were approximately half in the at-home group as compared with the in-hospital group (3,345 CONCLUSION: Results of at-home ASCT with prophylactic administration of ceftriaxone and domiciliary treatment of febrile neutropenia with piperacillin and tazobactam are highly satisfactory and significantly cheaper compared with those obtained with conventional in-hospital ASCT.
High-dose chemoradiotherapy followed by autologous stem-cell transplantation (ASCT) has become standard practice for many hematologic malignancies, solid tumors and other nonmalignant disorders.1 Toxicity and mortality associated with ASCT have been reduced thanks to several factors, principally the use of mobilized peripheral blood stem cells, administration of granulocyte colony-stimulating factor after progenitor cells infusion, and improvement of prophylactic antibiotic regimens.2-4 Aside from these factors, outpatient parenteral antimicrobial treatment has been proven feasible and safe thanks to modern intravenous catheters and infusion devices (ie, portable intermittent infusion pump).5,6 These advances have led to the development of ASCT programs on an at-home basis, and several studies have demonstrated the safety of such programs.7-20 The main advantages of at-home ASCT are the improvement in the quality of life of the patients and the reduction in the number of days during which patients have to be admitted to hospital, with a consequent reduction of costs, risk of nosocomial infections and pressure on available beds. These facts have prompted the extension of this procedure to the allogeneic setting.21-24 In this context, Svahn et al showed that at-home management of allogeneic transplants reduced the incidence of infections and improved survival with respect to a control group managed at the hospital.21,22 However, there are no studies making a similar comparison for autologous transplants, which represent more than 60% of the patients who undergo transplantation and, consequently, represent a significant workload for most transplant units.25 Nevertheless, one of the most significant limitations of at-home ASCT is the frequent need for hospital readmission because of fever and infections related to neutropenia.7-15 Against this background, we developed an at-home ASCT program in which ceftriaxone was administered from day +1 after transplantation, with the hypothesis that this approach would reduce the rate of bacterial infections and the need for rehospitalization. In this report, the results obtained in 50 patients receiving an ASCT at home are compared with those observed in 50 matched patients who underwent conventional ASCT in the hospital.
Patients and Requirements for At-Home ASCT Between November 2000 and February 2005, 178 consecutive patients underwent ASCT for a hematologic malignancy at the Hematology Department of the Hospital Clinic of Barcelona (Barcelona, Spain). Eligibility for at-home ASCT included Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; travel time from home to the hospital less than 60 minutes; a caregiver available 24 hours a day, 7 days a week; and patient acceptance. The hospital clinic ethical committee approved the study, and all patients signed a written informed consent.
At-Home Unit
Home Care
Infection Prophylaxis and Supportive Therapy
Empirical Antibiotic Regimen In the at-home group, patients were instructed to go to the hospital in the case of temperature of 38°C or higher. After a chest x-ray and appropriate cultures, piperacillin and tazobactam 4.5 g/8 hours IV was started. In the absence of hemodynamic instability, pneumonia, or cardiac or respiratory distress, patients were discharged the same day to continue the antibiotic IV treatment through a portable intermittent infusion pump (Table 1). Teicoplanin was added, 400 mg/12 hours IV two doses followed by 400 mg/d, if WHO mucositis grade 2 or higher, signs of infection at the catheter insertion, or positive blood cultures taken from the indwelling IV catheter for Coagulase-negative Staphylococci. If fever persisted more than 3 days, empirical amikacin 15 mg/kg/d IV was started. The same algorithm was used for the in-hospital group management of febrile neutropenia, but imipenem 500 mg/6 hours IV was administered as first-line antibiotic and vancomycin 15 mg/kg/12 hours IV was added under the same indications as with teicoplanin. Amphotericin B 0.7 to 1 mg/kg/d IV was started if fever persisted more than 5 days. Antibiotic treatment was maintained until the neutrophil count was superior to 1 x 109/L and patients were afebrile for at least 3 days with no infectious symptoms.
Criteria for Hospital Readmission in At-Home Group
Definitions Fever. Febrile neutropenia was defined as a temperature of 38°C or higher in a patient with an absolute neutrophil count of less than 0.5 x 109/L. A new febrile episode was defined as the reappearance of temperature of 38°C or higher after an afebrile period of 5 consecutive days or longer, not related to transfusion or reaction to drug administration. Bacteremia was defined as the isolation of bacteria from a blood culture in the presence of fever with or without other symptoms and/or signs of infection. Coagulase-negative Staphylococci was considered as significant pathogen when isolated from at least two separate consecutive blood cultures.
Analysis of Charges
Statistical Methods
Patient Cohorts One hundred seventy-eight patients received an ASCT during the study period, of which 128 (72%) were not included in the at-home program due to ECOG performance status more than 2 (n = 35; 27.3%), patient decision (n = 45; 35.2%), geographic distance (n = 32; 25%), no caregiver available (n = 12; 9.4%), and previous ASCT (n = 4; 3.1%). Fifty patients (28%) were eligible for at-home ASCT. The control-group patients were selected from the 89 patients with ECOG performance status 0 to 2 who were not allocated to the at-home program because of patient decision, geographic distance, or because there was no available caregiver. Control patients were individually matched to the at-home cases on a 1:1 ratio, taking into account all characteristics: age ± 5 years, sex, diagnosis, stage of disease, conditioning, and source of stem cells (Table 2).
Engraftment and Days to Transfer to the Outpatient Unit Among the 50 patients of the at-home group, 45 cases (90%) were discharged the day after the infusion of progenitor cells. In five cases, discharge was delayed to the second (n = 3) or third day (n = 2) after stem-cell infusion because of transient toxicity. Days CSF after transplantation, engraftment failure rate, time to neutrophil and platelet engraftment, number of RBC and platelet transfusions, and survival were similar in both groups (Table 3). The median time to discharge the patient to the outpatient unit was 14 days (range, 5 to 27 days) in the at-home group compared with 15 days (range, 13 to 31 days) in the in-hospital group (P = NS).
Fever, Days Receiving Antibiotics, and Infections Thirty-eight patients (76%) experienced body temperature of 38°C or higher in the at-home group compared with 48 patients (96%) in the in-hospital group (P = .008). Median day of appearance of fever was day +4 (range, day +2 to +13) in the at-home group and day +3.5 (range, +1 to +12) in the control group (P = NS; Table 3). Patients with fever received IV antibiotics for a median of 8 days (range, 5 to 16 days) in the at-home group and 9 days (range, 6 to 24 days) in the in-hospital group (P = NS). Moreover, glycopeptide and/or amikacin was added in 26 (68%) of the 38 febrile episodes in the at-home group compared with 31 (65%) of the 48 in the in-hospital group (P = NS). Empirical use of amphotericin B was 0% in the at-home group versus 10% in the in-hospital group (P = NS). Duration of the fever was significantly shorter in the at-home group, with a median of 2 days (range, 1 to 11 days) versus 5 days (range, 1 to 20 days), respectively (P = .00003). No single patient of both groups presented a new febrile episode after resolution of the first episode. No significant difference was observed in the incidence of bacteremia between the two groups (Table 3). Bacterial infection was documented in 10 (26%) of 38 febrile episodes in the at-home group compared with 14 (29%) of 48 in the hospital group. Coagulase-negative Staphylococci was the more frequent bacteria isolated in both groups (80% and 78%, respectively). The other infectious agents were Pseudomonas aeruginosa (n = 1) and Streptococcus viridans (n = 1) in the at-home group; and Candida inconspicua (n = 1), Streptococcus mitis (n = 1) and Enterococcus faecalis (n = 1) in the in-hospital group.
Other Complications
Day Care Unit Consultations and Readmissions In the at-home group, readmission to the aplasia period was necessary in four patients (8%), due to pneumonia (n = 1) and fever with hemodynamic instability (n = 3). Time to readmission was on days +3, +4, +6 and +10, respectively, and the total number of hospitalization days was 26. The median number of days in the inpatient area for the 50 patients in the at-home ASCT group was 8 days (range, 0 to 18 days), as compared with 25 days (range, 18 to 49 days) for patients in the in-hospital group (P < .00001). Thus, at-home management of the aplasia phase after ASCT was associated with a reduction of 18.6 hospitalization days per patient.
Quality of Life
Total Medical Charges
In this prospective series of patients receiving at-home ASCT we have observed a lower incidence of episodes of febrile neutropenia and shorter duration of fever than in a well-matched control group of patients who underwent ASCT at the hospital. Interestingly, the need for hospitalization was much lower than that reported in previous series of at-home ASCT.7-15 Three factors might explain these results: a highly experienced team, the prophylactic administration of ceftriaxone, and the treatment of febrile neutropenia with piperacillin and tazobactam using a portable intermittent infusion pump. Infection is one of the most common and severe complications after hematopoietic transplantation. Chemoprophylaxis with fluoroquinolones has reduced the incidence of Gram-negative bacteremia, including those caused by Pseudomonas aeruginosa, but has increased the incidence of quinolone-resistant aerobic Gram-negative bacilli infections and Gram-positive infections, in particular those caused by Staphylococcus spp and Streptococcus spp.26 Moreover, despite prophylaxis with oral antibiotics most of the patients who receive myeloablative hematopoietic transplantation will develop fever.27 This observation has led some investigators to study the effectiveness of the administration of prophylactic intravenous antibiotic after hematopoietic transplantation. Preliminary reports suggest that this approach could be effective in preventing early bacterial infections and related complications after hematopoietic transplantation and to be cost effective.28-30 Ceftriaxone is a third-generation cephalosporin with a long elimination half-life, effective against a broad range of Gram-positive and Gram-negative bacteria but having a limited activity against Pseudomonas aeruginosa.31,32 This antibiotic is suitable for once-daily intravenous administration and facilitates patient management on an outpatient basis. Of note, whereas data on the safety and efficacy of ceftriaxone in the treatment of febrile neutropenia in low-risk patients are available,31,32 no previous studies have addressed the role of prophylactic intravenous ceftriaxone in high-risk neutropenic patients. This study indicates that prophylaxis with ceftriaxone reduces the incidence of febrile neutropenia in at-home ASCT patients. Thus, patients in the at-home ASCT group, as compared with those in the in-hospital group receiving only quinolone prophylaxis, had a lower rate febrile neutropenia (76% v 96%; P = .008). Empirical first-line antibacterial treatment of febrile neutropenia of at-home ASCT has not been sufficiently studied. For this reason, the most appropriate antibiotic strategy has not been yet defined.33,34 We administered piperacillin and tazobactam IV using a portable intermittent infusion pump in the at-home group because this antibiotic has shown stability for at least 24 hours at 37°C.6 Use of carbapenem for empirical first-line antibacterial treatment is an alternative to piperacillin and tazobactam, but we discarded it because this antibiotic becomes unstable after more than 3 hours at 37°C. Piperacillin and tazobactam administration as an at-home treatment of febrile neutropenia proven to be effective and safe. Thus, it was associated with a significant reduction in the number of fever days in the at-home ASCT group with respect to the in-hospital ASCT group, which received imipenem. Moreover, management of the intermittent pump, which automatically delivers the required dose of antibiotic each 8 hours without nurse intervention, was not associated with a higher incidence of infection by Staphylococcus spp or to local complications. In our study, both the lower febrile neutropenia and the successful control of fever at-home resulted in an overall readmission rate significantly lower (8% v 20% to 72%, respectively) than that observed in previous at-home ASCT series (Table 5). 7-15 In all these studies, the conditioning was delivered at the hospital and the aplasia period was followed at home, and the criteria for rehospitalization were similar to those of our series. The hospitalization rate was significantly higher than in the present series in all of them but in the study by Jagannath et al10 that included only patients diagnosed with multiple myeloma conditioned with melphalan and, hence, of low-risk related complications. The rehospitalization rate resulted in a savings of 18.6 hospital bed days per patient with respect to the in-hospital control group. This fact significantly reduced the cost of ASCT (Table 4), which may be of particular interest for ASCT programs in developing countries.35
In a previous report, Summers et al18 compared the psychosocial impact of at-home versus in-hospital ASCT, finding that the first group had significantly higher scores for emotional well-being and global quality of life. In agreement with these findings, patients and caregivers in our study were largely very positive about the program. In conclusion, we report a strategy of at-home ASCT that, in comparison with in-hospital ASCT, is associated with fewer episodes of fever, lower duration of febrile neutropenia, low rate of rehospitalization, and a drastic reduction in the cost and of the need for hospital beds.
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on September 25, 2006. Supported by Grant No. RTICCC03/10 from Instituto de Salud Carlos III (ISCIII), Grant No. 2005SGR00825 from Generalitat de Catalunya, and an unrestricted grant from Schering (Madrid, Spain) and Roche (Madrid, Spain). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ljungman P, Urbano-Ispizua A, Cavazzana-Calvo M, et al: Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: Definitions and current practice in Europe. Bone Marrow Transplant 37:439-449, 2006[CrossRef][Medline] 2. Peters WP, Rosner G, Ross M, et al: Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy. Blood 81:1709-1719, 1993 3. Klumpp TR, Mangan KF, Goldberg SL, et al: Granulocyte colony-stimulating factor accelerates neutrophil engraftment following peripheral-blood stem-cell transplantation: A prospective, randomized trial. J Clin Oncol 13:1323-1327, 1995[Abstract] 4. Gilbert C, Meisenberg B, Vredenburgh J, et al: Sequential prophylactic oral and empiric once-daily parenteral antibiotics for neutropenia and fever after high-dose chemotherapy and autologous bone marrow support. J Clin Oncol 12:1005-1011, 1994 5. Gilbert DN, Dworkin RJ, Raber SR, et al: Outpatient parenteral antimicrobial-drug therapy. N Engl J Med 337:829-838, 1997 6. Viaene E, Chanteux H, Servais H, et al: Comparative stability studies of antipseudomonal beta-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother 46:2327-2332, 2002 7. Peters WP, Ross M, Vredenburgh JJ, et al: The use of intensive clinic support to permit outpatient autologous bone marrow transplantation for breast cancer. Semin Oncol 21:25-31, 1994[Medline] 8. Meisenberg BR, Miller WE, McMillan R, et al: Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies. J Clin Oncol 15:11-17, 1997 9. Glück S, des Rochers C, Cano C, et al: High-dose chemotherapy followed by autologous blood cell transplantation: A safe and effective outpatient approach. Bone Marrow Transplant 20:431-434, 1997[CrossRef][Medline] 10. Jagannath S, Vesole DH, Zhang M, et al: Feasibility and cost-effectiveness of outpatient autotransplants in multiple myeloma. Bone Marrow Transplant 20:445-450, 1997[CrossRef][Medline] 11. Chandrasekar PH, Abraham OC, Klein J, et al: Low infectious morbidity after intensive chemotherapy and autologous peripheral blood progenitor cell transplantation in the outpatient setting for women with breast cancer. Clin Infect Dis 32:546-551, 2001[CrossRef][Medline] 12. Morabito F, Martino M, Stelitano C, et al: Feasibility of a mixed inpatient-outpatient model of peripheral blood stem cell transplantation for multiple myeloma. Haematologica 87:1192-1199, 2002 13. Westermann AM, Holtkamp MMJ, Linthorst GAM, et al: At-home management of aplastic phase following high-dose chemotherapy with stem-cell rescue for hematological and non-hematological malignancies. Ann Oncol 10:511-517, 1999 14. Ferrara F, Palmieri S, Viola A, et al: Outpatient-based peripheral blood stem cell transplantation for patients with multiple myeloma. Hematol J 5:222-226, 2004[CrossRef][Medline] 15. Herrmann RP, Trent M, Cooney J, et al: Infections in patients managed at-home during autologous stem cell transplantation for lymphoma and multiple myeloma. Bone Marrow Transplant 24:1213-1217, 1999[CrossRef][Medline] 16. Weaver CH, Schwartzberg L, Zhen B, et al: High-dose chemotherapy and peripheral blood stem cell infusion in patients with non-Hodgkin's lymphoma: Results of outpatient treatment in community cancer centers. Bone Marrow Transplant 20:753-760, 1997[CrossRef][Medline] 17. Dix SP, Geller RB: High-dose chemotherapy with autologous stem cell rescue in the outpatient setting. Oncology (Williston Park) 14:171-192, 2000[Medline] 18. Summers N, Dawe U, Stewart DA: A comparison of inpatient and outpatient ASCT. Bone Marrow Transplant 26:389-395, 2000[CrossRef][Medline] 19. van Tiel FH, Harbers MM, Kessels AG, et al: Home care versus hospital care of patients with hematological malignancies and chemotherapy-induced cytopenia. Ann Oncol 16:195-205, 2005 20. Meisenberg BR, Ferran K, Hollenbach K, et al: Reduced charges and costs associated with outpatient autologous stem cell transplantation. Bone Marrow Transplant 21:927-932, 1998[CrossRef][Medline] 21. Svahn BM, Remberger M, Myrbäck KE, et al: Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 100:4317-4324, 2002 22. Svahn BM, Ringden O, Remberger M: Long-term follow-up of patients treated at-home during the pancytopenic phase after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 36:511-516, 2005[CrossRef][Medline] 23. Fernández-Avilés F, Urbano-Ispizua A, Aymerich M, et al: Low-dose total-body irradiation and fludarabine followed by hematopoietic cell transplantation from HLA-identical sibling donors do not induce complete T-cell donor engraftment in most patients with progressive hematologic diseases. Exp Hematol 31:934-940, 2003[CrossRef][Medline] 24. Petersen SL, Madsen HO, Ryder LP, et al: Haematopoietic stem cell transplantation with non-myeloablative conditioning in the outpatient setting: Results, complications and admission requirements in a single institution. Br J Haematol 125:225-231, 2004[CrossRef][Medline] 25. Gratwohl A, Baldomero H, Horisberger B, et al: Current trends in hematopoetic stem cell transplantation in Europe. Blood 100:2374-2386, 2002 26. Eric AE, Joseph L, Michael B: Efficacy of quinolone prophylaxis in neutropenic cancer patients: A meta-analysis. J Clin Oncol 16:1179-1187, 1998[Abstract] 27. Meisenberg B, Gollard R, Brehm T, et al: Prophylactic antibiotics eliminate bacteremia and allow safe outpatient management following high-dose chemotherapy and autologous stem cell rescue. Support Care Cancer 4:364-369, 1996[CrossRef][Medline] 28. Kroschinsky F, Wichmann G, Bornhauser M, et al: Efficacy and tolerability of prophylactic treatment with intravenous piperacillin/tazobactam in patients undergoing hematopoietic stem cell transplantation. Transpl Infect Dis 4:132-136, 2002[CrossRef][Medline] 29. Pérez-Simón JA, García-Escobar I, Martínez J, et al: Antibiotic prophylaxis with meropenem after allogeneic stem cell transplantation. Bone Marrow Transplant 33:183-187, 2004[CrossRef][Medline] 30. Solano C, Gutierrez A, Martínez F, et al: Prophylaxis of early bacterial infections after autologous peripheral blood stem cell transplantation (PBSCT): a matched-pair study comparing oral fluoroquinolones and intravenous piperacillin-tazobactam. Bone Marrow Transplant 36:59-65, 2005[CrossRef][Medline] 31. Furno P, Dionisi MS, Bucaneve G, et al: Ceftriaxone versus beta-lactams with antipseudomonal activity for empirical combined antibiotic therapy in febrile neutropenia: A meta-analysis. Support Care Cancer 8:293-301, 2000[CrossRef][Medline] 32. Karthaus M, Cornely OA: Ceftriaxone in febrile neutropenia. J Chemother 15:211-219, 2003[Medline] 33. Bertz H, Auner HW, Weissinger F, et al: Antimicrobial therapy of febrile complications after high-dose chemo-/radiotherapy and autologous hematopoetic stem cell transplantation. Ann Hematol 82:S167-S174, 2003 (suppl 2)[Medline] 34. Reich G, Cornely OA, Sandherr M, et al: Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: A randomized, multicentre trial. Br J Haematol 130:265-270, 2005[CrossRef][Medline] 35. Gratwohl A, Passweg J, Baldomero H, et al: Economics, health care systems and utilisation of haematopoietic stem cell transplants in Europe. Br J Haematol 117:451-468, 2002[CrossRef][Medline] Submitted March 8, 2006; accepted August 17, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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2 test or Fisher's exact test (two tailed) for categoric variables and t test or the Mann-Whitney U nonparametric test for continuous variables. The level of significance was set at P < .05. All analyses were carried out using SPSS version 12 statistical software (SPSS Inc, Chicago, IL). 
