Int J Hematol (2009) 89:368–373 DOI 10.1007/s12185-009-0261-1
ORIGINAL ARTICLE
Hemophagocytic syndrome after hematopoietic stem cell transplantation: a prospective observational study Abderrahman Abdelkefi Æ Wassim Ben Jamil Æ Lamia Torjman Æ Saloua Ladeb Æ Habib Ksouri Æ Amel Lakhal Æ Assia Ben Hassen Æ Abdeladhim Ben Abdeladhim Æ Tarek Ben Othman
Received: 8 September 2008 / Revised: 11 January 2009 / Accepted: 22 January 2009 / Published online: 28 February 2009 The Japanese Society of Hematology 2009
Abstract The aim of this prospective observational study was to evaluate the incidence of hemophagocytic syndrome (HPS) after hematopoietic stem cell transplantation (HSCT). Between July 2006 and December 2007, all patients who received a HSCT in our institution were included in this study. All the following criteria were needed for the diagnosis of HPS: sustained fever over 7 days; cytopenia (neutropenia and/or thrombocytopenia); presence of more than 3% mature macrophages in bone marrow; hyperferritinaemia ([1,000 ng/mL). During this study, 171 patients received a HSCT (68 allogeneic and 103 autologous). The median age was 32 years (3–62). We observed six cases of HPS (6/68; 8.8%) after allogeneic stem cell transplantation (ASCT): one case of EBV-related HPS, two cases of CMV-related HPS, and three cases with no evidence of bacterial, fungal or viral infections. We observed only one case of CMV-related HPS (1/103; 0.9%) after autologous stem cell transplantation. Four patients died despite aggressive supportive care. To our knowledge, this is the first prospective observational study conducted with the aim to evaluate the incidence of HPS after HSCT. This study provides a relatively high incidence of HPS after ASCT. When sustained fever with progressive cytopenia and hyperferritinaemia are observed, HPS should be suspected, and bone marrow aspirate considered. The rapid diagnosis of
A. Abdelkefi (&) W. B. Jamil L. Torjman S. Ladeb H. Ksouri A. Lakhal A. B. Hassen A. B. Abdeladhim T. B. Othman Centre National de Greffe de Moelle Osseuse, Rue Jebel Lakhdar, 1006 Bab Saadoun, Tunis, Tunisia e-mail:
[email protected]
123
HPS and the early initiation of an appropriate treatment are essential for patient management. Keywords Hemophagocytic syndrome Stem cell transplantation
1 Introduction The hemophagocytic syndrome (HPS) is a clinicopathological entity characterized by macrophage or histiocyte activation and marked hemophagocytosis in bone marrow and other parts of the reticuloendothelial system, resulting in cytopenias [1, 2]. Primary or familial HPS is genetically mediated and usually occurs in childhood [3]. Secondary or reactive HPS is associated with infections, malignancies and autoimmune disorders [4]. After hematopoietic stem cell transplantation (HSCT), patients are at risk of HPS because of viral infections due to immunodeficiency, and administration of immunosuppressants for the treatment of graft versus host disease (GvHD). However, HPS is a rare complication after allogeneic stem cell transplantation (ASCT). To our knowledge, this is the first prospective observational study conducted with the aim to evaluate the incidence of HPS after HSCT.
2 Patients and methods Between July 2006 and December 2007, all patients who received a HSCT in our institution, were included in this prospective study. All the following criteria were needed for the diagnosis of HPS [5]:
Hemophagocytic syndrome after hematopoietic stem cell transplantation
– –
– –
sustained fever over 7 days; cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin \90 g/L; platelets \100 9 109/L; neutrophils\1 9 109/L); presence of more than 3% mature macrophages in bone marrow, and hyperferritinaemia ([1,000 ng/mL)
Hemophagocytic syndrome criteria (fever/4 h; complete blood count, rash, liver and spleen size/daily; ferritin, triglycerides, fibrinogen/twice a week) were prospectively measured at regular time points following transplant. When sustained fever with progressive cytopenia and hyperferritinaemia were observed, HPS was suspected and bone marrow aspirate performed. Patients were evaluated for the presence of HPS before transplantation. All patients were followed for 6 months after transplantation. Extensive investigations have been performed for potential infection [bacterial, fungal, parasitic or viral (EBV, CMV, HSV, HHV6, adenovirus, HIV)] or auto-immune etiology. 2.1 Supportive care Patients were treated in laminar air flow isolation rooms with gut decontamination. Acyclovir prophylaxis (500 mg/ m2/8 h) against herpesvirus infection and fluconazole prophylaxis (400 mg/day) against candidal infection was used in allogeneic transplant recipients [6]. All transfused blood products were irradiated (25 Gy) before infusion. Subcutaneous G-CSF (5 lg/kg/day) was given after transplantation, starting on day ?7 and continued until the neutrophil count reached 1 9 109/L on three consecutive days. 2.2 GvHD prophylaxis GvHD prophylaxis consisted of short-term methotrexate (15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6) and cyclosporin A (CsA) at a dosage of 3 mg/kg/day i.v. starting at day -1. CsA levels from whole blood were adjusted to maintain 150–300 ng/mL.
369
•
•
•
For autologous SCT, conditioning consisted of • •
Results of the study were analyzed as of 1 April 2008. Univariate analyses were used to test associations between pretransplant variables (age, sex, underlying disease, source of stem cells) and probability of HPS. Pretransplant risk factors for HPS were examined in multivariate analysis using a Cox proportional hazards regression model. Statistical tests were performed with STATA statistical package.
3 Results During this 18-month study, 171 patients (96 males, 75 females) received a HSCT. Patient characteristics are shown in Table 1. In the ‘‘allogeneic group’’ (n = 68): • •
•
For allogeneic SCT, conditioning consisted of the following:
•
once-a-day fractionated-total body irradiation (F-TBI) on days -7, -6, -5 and etoposide (60 mg/kg on day -3) [for acute lymphoid leukemia (ALL)]. Busilvex 0.8 mg/kg/6 h, on days -8, -7, -6, -5 and cyclophosphamide (60 mg/kg/day on days -3 and -2) [for acute myeloid leukemia (AML)].
melphalan (200 mg/m2) on day -2 (for multiple myeloma). Beam (for lymphoma).
2.4 Statistical analysis
2.3 Conditioning regimen
•
Cyclophosphamide (50 mg/kg/day on days -6, -5, -4, -3) and antithymocyte globulin (30 mg/kg/day on days -6, -5, and -4) (for aplastic anemia). Busilvex 0.8 mg/kg/6 h on days -8, -7, -6, -5 and cyclophosphamide (50 mg/kg/day on days -4, -3 and -2) (for Gaucher disease). Busulfan per os (14 mg/kg, total dose) and cyclophosphamide (60 mg/kg/day on days -3 and -2) (for multiple myeloma).
•
31 patients presented sustained fever for over 7 days, 31 patients presented sustained fever for over 7 days with cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin \90 g/L; platelets \100 9 109/L; neutrophils \1 9 109/L) Thirteen patients presented sustained fever for over 7 days with cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin \90 g/L; platelets \100 9 109/L; neutrophils \1 9 109/L), and hyperferritinaemia ([1,000 ng/mL). A bone marrow aspirate was performed in these 13 patients. Presence of more than 3% mature macrophages in bone marrow was found in six patients (6/13; 46%). Six patients presented the following four criteria: • •
sustained fever over 7 days cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin \90 g/L; platelets \100 9 109/L; neutrophils \1 9 109/L)
123
370
A. Abdelkefi et al.
•
Table 1 Patient characteristics Allogeneic Autologous transplantation transplantation (n = 68) (n = 103) Median age (years) (range)
23 (3–49)
43 (15–62)
Sex (male/female)
38/30
58/45
Underlying disease Aplastic anemia
26
–
Acute leukemia
28
–
Multiple myeloma
7
62
Hodgkin lymphoma
4
20
Non-Hodgkin lymphoma
–
21
Gaucher disease
3
–
MTX ? CSA
57
NA
CSA alone
11
NA
GvHD prophylaxis
Source of graft Bone marrow
52
–
PBSC
16
103
Cyclophosphamide ? Atgam
26
–
Busilvex ? cyclophosphamide TBI ? etoposide
19 12
– –
Busulfan per os ? cyclophosphamide
7
–
Conditioning regimen
Fludarabine ? melphalan
4
–
BEAM
–
41
Melphalan
–
62
NA not applicable
• •
hyperferritinaemia ([1,000 ng/mL) presence of more than 3% mature macrophages in bone marrow.
In the ‘‘autologous group’’ (n = 103) • •
•
•
Twenty-three patients presented sustained fever over 7 days. Twenty-three patients presented sustained fever over 7 days with cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin \90 g/L; platelets \100 9 109/L; neutrophils \1 9 109/L). Six patients presented sustained fever over 7 days with cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin\90 g/L; platelets\100 9 109/ L; neutrophils \1 9 109/L), and hyperferritinaemia ([1,000 ng/mL). A bone marrow aspirate was performed in these six patients. Presence of more than 3% mature macrophages in bone marrow was found in one patient (1/6; 17%). Only one patient presented the four criteria: •
sustained fever over 7 days,
123
• •
cytopenia affecting C2 of three lineages in the peripheral blood (hemoglobin \90 g/L; platelets \100 9 109/L; neutrophils \1 9 109/L), hyperferritinaemia ([1,000 ng/mL), presence of more than 3% mature macrophages in bone marrow.
3.1 Evolution of ferritin level In patients with aplastic anemia (n = 26), the median number of transfused red blood cell units was 3 (0–14). Evolution of ferritin in patients with aplastic anemia (n = 26): Before transplant: mean 300 ng/mL (230–1,300). After transplant: mean 500 ng/mL (300–29,150). In the allogeneic group, the pretransplant ferritin levels in patients with HPS (n = 6) were as follows: 250, 250, 252, 267, 280, and 850 ng/mL. Ferritin level in patients with aplastic anemia and HPS (n = 5): Before transplant: mean 379 ng/mL (250–850). After transplant: mean 13,400 ng/mL (3,500–29,150). The patients were evaluated for the presence of HPS before transplantation. In the allogeneic group, ten patients had sustained fever, and six patients had hyperferritinaemia ([1,000 ng/mL). Before transplantation, we have not observed significant mature macrophages ([3%) in bone marrow. A total of seven cases of HPS have been observed (7/171; 4%). In the allogeneic group, we observed six cases of HPS (6/68; 8.8%): one case of EBV-related HPS, two cases of CMV-related HPS, and three cases with no evidence of bacterial, fungal or viral infections. We observed only one case of CMV-related HPS (1/103; 0.97%) after autologous stem cell transplantation. In the allogeneic group (n = 68), the frequency of viral infections (especially EBV and CMV) in patients not diagnosed with HPS was 3.2% (2/62) and 17.7% (11/62), respectively. In the allogeneic group (n = 68), the frequency of acute GvHD or severe infections in patients not diagnosed with HPS was 22.6% (14/62) and 16% (10/62), respectively. At the time of HPS diagnosis, the six patients were on ciclosporin. Twenty-six patients received the ASCT for severe aplastic anemia (SAA). Five out of six HPS were observed in patients transplanted for SAA (5/26; 19.2%) and among the five patients two have rejected their graft. Characteristics of patients with HPS are shown in Table 2. Concerning the clinical parameters, we have observed a spleen enlargement in two patients, hypertriglyceridemia
SAA severe aplastic anemia, ALL acute lymphoid leukemia, Cy cyclophosphamide, TBI total body irradiation, MNC mononucleated cells, Ig intravenous immunoglobulins, TMA thrombotic microangiopathy
Dead (d ?42): severe multiorgan failure No CMV 56 Case 7
Myeloma
d ?12 6.5 3 106 CD34/kg Melphalan 200 mg/m2
d ?26
TMA Acute GvHD alive No CMV d ?15 Engraftment syndrome 4.9 3 108 MNC/kg 18 Case 6
SAA
Atgam ? Cy
d ?21
Dead (d ?65): severe multiorgan failure Corticosteroids No d ?42 d ?29 1.5 3 10 MNC/kg TBI ? Etoposide 22 Case 5
ALL
Pneumoniae alive No No d ?9 d ?16 3.1 3 108 MNC/kg Atgam ? Cy 24 Case 4
SAA
8
Graft failure, hemorrhagic cystitis, acute GvHD, dead (d ?82): severe multiorgan failure IV Ig CMV d ?18 30 Case 3
SAA
Atgam ? Cy
2.2 3 106 CD34/kg
d ?15
Graft failure, hemorrhagic cystitis, second allograft alive IV Ig No d ?29 36 Case 2
SAA
Atgam ? Cy
0.9 3 108 MNC/kg
d ?25
Acute GvHD, hemorrhagic cystitis, dead (d ?63): severe multiorgan failure IV Ig EBV d ?20 d ?28 2.1 3 108 MNC/kg 19 Case 1
SAA
Atgam ? Cy
Engraftment Cell dose Conditioning regimen Underlying disease Age Case
Table 2 Characteristics of patients with HPS
Diagnosis of HPS
Etiology
Treatment
Evolution
Hemophagocytic syndrome after hematopoietic stem cell transplantation
371 Table 3 Variables of prognosis significance for HPS in univariate analysis Patients with HPS/total of patients (%)
Univariate analysis P
C30
3/102 (2.9%)
0.17
\30
4/69 (5.8%)
Age (years)
Sex Female
2/75 (2.6%)
Male
5/96 (5.2%)
0.3
Transplantation Allogeneic
6/68 (8.8%)
Autologous
1/103 (0.9%)
0.016
Source of allogeneic graft PBSC
1/16 (6.2%)
Bone marrow
5/52 (9.6%)
0.56
Underlying disease (allogeneic transplant) Aplastic anemia Others
5/26 (19%) 1/42 (2.3%)
0.02
(3.9, 4.1, 4.4, and 4.6 mmol/L), and fibropenia (1.2, 1.4 g/L) in four and two patients, respectively. In the allogeneic group, three patients received intravenous immunoglobulin (Ig) and one patient received steroids. Only one patient (Ig) presented a clinical response. Two patients did not receive treatment and are alive. Four patients died (3 in the allogeneic group, 1 in the autologous group) despite aggressive supportive care. In univariate analysis (Table 3), pretransplant factors correlated with HPS were allogeneic transplant and aplastic anemia.
4 Discussion After ASCT, patients are at risk of HPS because of viral infections due to immunodeficiency, and administration of immunosuppressants for the treatment of GvHD. However, HPS is a rare complication after allogeneic SCT [7–11]. Reardon et al. [12], reported the first case of HPS following allogeneic SCT. In our study, the diagnosis of HPS was made according to the following criteria: (1) sustained fever for over 7 days, (2) progressive cytopenia, (3) presence of more than 3% mature macrophages in bone marrow, and hyperferritinaemia (74,000 ng/mL) [13]. Our study provides a relatively high incidence of HPS after ASCT [(6/68; 8.8%): 1 case of EBV-related HPS, 2 cases of CMV-related HPS, and three cases with no evidence of bacterial, fungal or viral infections]. To our
123
372
knowledge, there have been at least two case reports in which a causative viral infection was not documented [7, 8]. We report here three cases in which a causal viral infection was not documented. The definition of HPS used in our study was not consistent with the current clinical criteria as defined by the Histiocyte Society [14]. However, our results were not different when these criteria were retrospectively applied. The various clinical features observed in the early phase after allo-HSCT are largely driven by complex alloresponse mechanisms (either graft vs host or host vs graft) that involve the activation of donor T cells and host epithelial cells, and the abundant secretion of pro-inflammatory cytokines [15]. Theoretically, these allo-responses inappropriately activate macrophages and cause HPS. However, the origin of the macrophages that manifest the hemophagocytosis observed after allo-HSCT is unclear. Thus, further analysis is required to confirm whether hostderived macrophages are responsible for allo-HSCT-associated HPS in general, whether host-derived macrophages are involved in the development of the early onset-alloHSCT-associated HPS as a form of host versus graft response, and also whether this may induce graft rejection. Indeed, in our study 26 patients received the ASCT for SAA. Five out of six HPS were observed in patients transplanted for SAA (5/26; 19%) and among these five patients two have rejected their graft suggesting a possible role of HPS in host versus graft response [16]. A variety of systemic inflammatory syndromes with both distinct and overlapping features occur in association with HSCT, including disseminated intravascular coagulation, capillary leak syndrome, engraftment syndrome and infection-associated HPS [17]. The diagnosis of HPS and its differentiation from other systemic inflammatory conditions remain a challenging task for the clinician. Macrophage activation may lead to an excessive release of ferritin and a close correlation between serum ferritin levels and clinical disease activity has been reported in patients with HPS [18–20]. However, ferritin is a ubiquitously expressed protein and thus not specific for macrophages. Recently, Schaer et al. [21] suggested that sCD163 was an excellent clinical marker of HPS and other disorders associated with overwhelming macrophage activity. In conclusion, our study provides a relatively high incidence of HPS after ASCT. When sustained fever with progressive cytopenia and hyperferritinaemia are observed, HPS should be suspected, and bone marrow aspirate considered. The rapid diagnosis of HPS and the early initiation of an appropriate treatment are essential for patient management.
123
A. Abdelkefi et al.
References 1. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18:29–33. 2. Larroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun Rev. 2004;3:69–75. doi:10.1016/ S1568-9972(03)00091-0. 3. Stepp SE, Dufourcq-Lagelouse R, Le Deist R, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286:1957–9. doi:10.1126/science.286.5446.1957. 4. Janka G, Imashuku S, Elinder G, et al. Infection and malignancyassociated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12:435–44. doi:10.1016/S0889-8588(05)70521-9. 5. Imashuku S. Differential diagnosis of hemophagocytic syndrome, underlying disorders and selection of the most effective treatment. Int J Hematol. 1997;66:135–51. doi:10.1016/S0925-5710(97)00584-7. 6. Marr KA, Seidel K, Slavin MA, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up, of a randomized, placebo-controlled trial. Blood. 2000;96:2055–61. 7. Sato M, Matsushima T, Takada S, et al. Fulminant CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation. Bone Marrow Transplant. 1998;22: 1219–22. doi:10.1038/sj.bmt.1701501. 8. Ishikawa J, Maeda T, Miyazaki T, et al. Early onset of hemophagocytic syndrome following allogeneic bone marrow transplantation. Int J Hematol. 2000;72:243–6. 9. Abe Y, Choi I, Hara K, et al. Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29:799–801. doi:10.1038/sj.bmt.1703554. 10. Iyama S, Matsunaga T, Fujimi A, et al. Successful treatment with oral ribavirin of adenovirus-associated hemophagocytic syndrome in a stem cell transplantation recipient. Rinsho Ketsueki. 2005;46:363–7. 11. Abdelkefi A, Ben Othman T, Torjman L, et al. Plasmodium falciparum causing hemophagocytic syndrome after allogeneic blood stem cell transplantation. Hematol J. 2004;5:449–50. doi: 10.1038/sj.thj.6200531. 12. Reardon DA, Roskos R, Hanson Ca, et al. Virus-associated hemophagocytic syndrome following bone marrow transplantation. Am J Pediatr Hematol Oncol. 1991;13:305–9. doi:10.1097/ 00043426-199123000-00010. 13. Tsuda H. Hemophagocytic syndrome in children and adults. Int J Hematol. 1997;65:215–26. doi:10.1016/S0925-5710(96)00560-9. 14. Henter JI, Horne A, Arico´ M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31. doi:10.1002/pbc.21039. 15. Spitzer TS. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:893–8. doi:10.1038/sj.bmt.1703015. 16. Tanaka T, Matsubara H, Adachi S, Chang H, Fujino H, Higashi Y, et al. Second transplantation from HLA 2-locimismatched mother for graft failure due to hemophagocytic syndrome after cord blood transplantation. Int J Hematol. 2004;80:467–9. doi: 10.1532/IJH97.04063. 17. Sreedharan A, Bowyer S, Wallace CA, et al. Macrophage activation syndrome and other systemic inflammatory conditions after BMT. Bone Marrow Transplant. 2006;37:629–34. doi: 10.1038/sj.bmt.1705305.
Hemophagocytic syndrome after hematopoietic stem cell transplantation 18. Allen CE, Yu X, Kozinetz CA, MuClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50:1227–35. doi:10.1002/ pbc.21423. 19. Esumi N, Ikushima S, Hibi S, Todo S, Imashuku S. High serum ferritin level as a marker of malignant histiocytosis and virusassociated hemophagocytic syndrome. Cancer. 1988;61: 2071–6. doi:10.1002/1097-0142(19880515)61:10\2071::AIDCNCR2820611023[3.0.CO;2-6.
373 20. Emmenegger U, Reimers A, Frey U, et al. Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation. Swiss Med Wkly. 2002;132:230–6. 21. Schaer DJ, Schleiffenbaum B, Kurrer M, et al. Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineagespecific marker in the reactive hemophagocytic syndrome. Eur J Haematol. 2005;74:6–10. doi:10.1111/j.1600-0609.2004.00318.x .
123
